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Diagnosis of Rubella, Congenital
Diagnosis of Rubella, Congenital.
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Rubella, Congenital
nord_1085_6
Therapies of Rubella, Congenital
There is no treatment for maternal rubella or congenital rubella syndrome. Therefore, prevention assumes paramount importance. It is most important to immunize all children, in an attempt to prevent epidemics. Children should receive rubella immunization at 15 months of age, along with mumps and measles in a combined vaccine. Many authorities now recommend that a repeat rubella immunization be given to 10-year-olds, because vaccine-induced immunity may not persist as long as naturally acquired immunity.Women of childbearing age who are susceptible to rubella (a serum test can establish the presence of the rubella-antibody in their blood) should also be vaccinated. Until recently, the Centers for Disease Control and Prevention (CDC) recommended that a woman should wait for three months after vaccination against rubella before getting pregnant. The CDC has now (2004) reduced that period to 28 days.
Therapies of Rubella, Congenital. There is no treatment for maternal rubella or congenital rubella syndrome. Therefore, prevention assumes paramount importance. It is most important to immunize all children, in an attempt to prevent epidemics. Children should receive rubella immunization at 15 months of age, along with mumps and measles in a combined vaccine. Many authorities now recommend that a repeat rubella immunization be given to 10-year-olds, because vaccine-induced immunity may not persist as long as naturally acquired immunity.Women of childbearing age who are susceptible to rubella (a serum test can establish the presence of the rubella-antibody in their blood) should also be vaccinated. Until recently, the Centers for Disease Control and Prevention (CDC) recommended that a woman should wait for three months after vaccination against rubella before getting pregnant. The CDC has now (2004) reduced that period to 28 days.
1,085
Rubella, Congenital
nord_1086_0
Overview of Rubinstein Taybi Syndrome
Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder that affects many organ systems. RSTS is characterized by growth delays, distinctive facial features, intellectual disability (with an average IQ of 25-79), broad and often angulated thumbs and great toes (halluces) and feeding difficulties (dysphagia). Craniofacial features of RSTS include downward slanted eyes (down slanted palpebral fissures), long eyelashes, high-arched eyebrows, low-hanging nasal septum (columella), high palate and an extra cusp on the lingual side of a front tooth (talon cusps). In most affected children, RSTS occurs as the result of a new (de novo) gene variant (mutation), although rarely, the syndrome has been inherited from an affected parent in an autosomal dominant pattern. Management generally involves monitoring of growth and feeding, yearly eye and hearing evaluations, and evaluation for cardiac, dental, and renal abnormalities. Behavioral therapy and special education are also indicated.
Overview of Rubinstein Taybi Syndrome. Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder that affects many organ systems. RSTS is characterized by growth delays, distinctive facial features, intellectual disability (with an average IQ of 25-79), broad and often angulated thumbs and great toes (halluces) and feeding difficulties (dysphagia). Craniofacial features of RSTS include downward slanted eyes (down slanted palpebral fissures), long eyelashes, high-arched eyebrows, low-hanging nasal septum (columella), high palate and an extra cusp on the lingual side of a front tooth (talon cusps). In most affected children, RSTS occurs as the result of a new (de novo) gene variant (mutation), although rarely, the syndrome has been inherited from an affected parent in an autosomal dominant pattern. Management generally involves monitoring of growth and feeding, yearly eye and hearing evaluations, and evaluation for cardiac, dental, and renal abnormalities. Behavioral therapy and special education are also indicated.
1,086
Rubinstein Taybi Syndrome
nord_1086_1
Symptoms of Rubinstein Taybi Syndrome
GeneralRSTS is a rare genetic disorder which may affect many organ systems of the body. Features include distinctively broad and/or angled fingers and toes, developmental delays, short stature, speech delays, intellectual disability, characteristic appearance of the head and face (craniofacial dysmorphism), breathing and feeding difficulties (dysphagia) and urogenital abnormalities. In some people, the skin, heart and/or respiratory system may also be affected. Symptoms associated with RSTS vary greatly from person to person. Most infants with RSTS have thumbs and/or great toes that are broad because of unusual broadness of the bones in the tips of the thumbs and great toes (terminal phalanges). In addition, the distal bones of the thumbs and great toes may be angled improperly (misaligned) on a proximal bone that is abnormally shaped (delta phalanx). The fifth fingers may be curved inward (clinodactyly). Individuals with RSTS with EP300 gene variants (mutations) have fewer characteristic facial and extremity findings and milder developmental impairment than people with CREBBP gene variants.Growth and DevelopmentWhile prenatal growth is often normal, in most infants with RSTS, parameters for height, weight and head circumference fall below the fifth percentile during infancy. Affected infants fail to grow and gain weight at the expected rate (failure to thrive). Although weight gain can be very slow in infancy, children with RSTS may later show a relative obesity for their height. Feeding difficulties (dysphagia) may occur and many affected individuals are prone to repeated respiratory infections. As children age, they may continue to experience poor growth and exhibit short stature (most below the third percentile).Most infants and children with RSTS have varying degrees of intellectual disability (average IQ between 25-79), delays in the acquisition of skills requiring coordination of muscular and mental activities (psychomotor delays) and delayed socialization. Most affected infants and children do not reach certain developmental milestones (e.g., sitting, crawling, standing, walking, etc.) at a time when they would otherwise be expected. Most children with RSTS experience a significant delay in expressive speech. In addition, there may be diminished muscle tone (hypotonia), abnormally exaggerated reflexes (hyperreflexia) and a stiff, unsteady gait.Physical FeaturesInfants with RSTS have several distinctive head and facial (craniofacial) features. Most affected infants have a “beak-shaped” or straight nose with a broad nasal bridge. Typically, there are down slanting eyelid openings (palpebral fissures) and the wall (septum) dividing the nostrils may extend below the nostrils (low hanging columella). Children with RSTS typically have a small head (microcephaly), below the 5th percentile.Characteristic features of the mouth and jaw may be present including a small mouth, short, thin upper lip, highly arched roof of the mouth (palate), underdeveloped upper jawbone (maxilla) and a small lower jaw (micrognathia) that is displaced farther back than otherwise expected (retrognathia). Many affected infants have irregularly shaped, crowded teeth, resulting in upper and lower jaws that do not meet properly (malocclusion). Affected individuals may have a boney protuberance on the lingual aspect of the upper front teeth (talon cusps). The soft tissue structure that hangs in the back of the throat may also be divided (bifid uvula). In addition, some affected individuals may appear to be frowning or upset when they smile.In addition to broad thumbs and toes, some children with RSTS may have toes that overlap or unusually shaped bones of the feet (metatarsals).Affected individuals may have overgrowth of scar tissue at the site of a cut, injury, or surgical incision (keloid formation) or this may occur spontaneously.EyesAffected infants have specific characteristics of the eyes including eyes that appear widely spaced (apparent hypertelorism); crossed eyes (strabismus); upper eyelids that droop (ptosis) and/or extra folds of skin on either side of the nose that may cover the eyes’ inner corners (epicanthal folds).Skeletal AbnormalitiesThere may be additional skeletal characteristics including side-to-side (scoliosis) or front-to-back (kyphosis) curvature of the spine, depression of the bone forming the center of the chest (sternum), known as “funnel chest” or pectus excavatum, abnormalities of vertebrae and the pelvis, malformations of ribs, and recurrent dislocation of the kneecaps. The lower end of the spinal cord may be abnormally tied down (tethering).Genitourinary TractMale infants with RSTS have abnormalities of the genitourinary tract including failure of one or both testes to descend into the scrotum (cryptorchidism), a fold of skin extending around the base of the penis (shawl scrotum) and/or misplacement of the urinary opening, such as on the underside of the penis (hypospadias). In addition, infants with RSTS may have underdeveloped (hypoplastic) or absent kidney(s), repeated infections of the urinary tract, kidney stones, unusual accumulation of urine in the kidney (hydronephrosis) and/or backflow (reflux) of urine into the tubes (ureters) that normally bring urine to the bladder. In some cases, duplication of the kidneys and/or ureters may also be present.CardiacApproximately one third of infants with RSTS have an associated heart defect that is present at birth (congenital heart defect). According to the medical literature, patent ductus arteriosus may be the most common congenital heart defect present in infants with RSTS. Infants with RSTS may also have extra heart sounds (heart murmurs), narrowing of the opening between the pulmonary artery and the right ventricle of the heart (pulmonary stenosis), narrowing of the aorta (aortic coarctation) and/or ventricular septal defects (VSDs) and/or atrial septal defects (ASDs). The symptoms associated with a ventricular septal defect or atrial septal defect vary from person to person, depending upon the size and location of the defect. RespiratoryAffected individuals may also have abnormalities of the respiratory system. The lungs may be abnormally divided into small extra sections (lung lobulation) and/or the walls of the voice box (larynx) may be weak and easily collapsible, potentially resulting in swallowing and breathing difficulties (e.g., temporary cessation of normal breathing rhythm during sleep [sleep apnea]).Individuals with RSTS can be difficult to intubate because of the easy collapsibility of the laryngeal wall. An anesthesiologist comfortable with managing complex pediatric airway problems should administer general anesthesia when needed.BehaviorIndividuals with RSTS often exhibit a short attention span, decreased tolerance for noise and crowds, impulsivity, aggressive behavior, repetitive behaviors and moodiness. Autistic behaviors are common.Susceptibility to MalignancyThere are reports of persons with RSTS with various benign and malignant tumors including meningioma, pilomatixoma, rhabdomysarcoma, pheochromocytoma, neuroblastoma, medulloblastona, oligodendroglioma, leioyosarcoma, seminoma, odontoma, choristoma and leukemia. However, one recent study found only an increased risk for meningiomas and pilomatrixomas, but not for malignancies in general.
Symptoms of Rubinstein Taybi Syndrome. GeneralRSTS is a rare genetic disorder which may affect many organ systems of the body. Features include distinctively broad and/or angled fingers and toes, developmental delays, short stature, speech delays, intellectual disability, characteristic appearance of the head and face (craniofacial dysmorphism), breathing and feeding difficulties (dysphagia) and urogenital abnormalities. In some people, the skin, heart and/or respiratory system may also be affected. Symptoms associated with RSTS vary greatly from person to person. Most infants with RSTS have thumbs and/or great toes that are broad because of unusual broadness of the bones in the tips of the thumbs and great toes (terminal phalanges). In addition, the distal bones of the thumbs and great toes may be angled improperly (misaligned) on a proximal bone that is abnormally shaped (delta phalanx). The fifth fingers may be curved inward (clinodactyly). Individuals with RSTS with EP300 gene variants (mutations) have fewer characteristic facial and extremity findings and milder developmental impairment than people with CREBBP gene variants.Growth and DevelopmentWhile prenatal growth is often normal, in most infants with RSTS, parameters for height, weight and head circumference fall below the fifth percentile during infancy. Affected infants fail to grow and gain weight at the expected rate (failure to thrive). Although weight gain can be very slow in infancy, children with RSTS may later show a relative obesity for their height. Feeding difficulties (dysphagia) may occur and many affected individuals are prone to repeated respiratory infections. As children age, they may continue to experience poor growth and exhibit short stature (most below the third percentile).Most infants and children with RSTS have varying degrees of intellectual disability (average IQ between 25-79), delays in the acquisition of skills requiring coordination of muscular and mental activities (psychomotor delays) and delayed socialization. Most affected infants and children do not reach certain developmental milestones (e.g., sitting, crawling, standing, walking, etc.) at a time when they would otherwise be expected. Most children with RSTS experience a significant delay in expressive speech. In addition, there may be diminished muscle tone (hypotonia), abnormally exaggerated reflexes (hyperreflexia) and a stiff, unsteady gait.Physical FeaturesInfants with RSTS have several distinctive head and facial (craniofacial) features. Most affected infants have a “beak-shaped” or straight nose with a broad nasal bridge. Typically, there are down slanting eyelid openings (palpebral fissures) and the wall (septum) dividing the nostrils may extend below the nostrils (low hanging columella). Children with RSTS typically have a small head (microcephaly), below the 5th percentile.Characteristic features of the mouth and jaw may be present including a small mouth, short, thin upper lip, highly arched roof of the mouth (palate), underdeveloped upper jawbone (maxilla) and a small lower jaw (micrognathia) that is displaced farther back than otherwise expected (retrognathia). Many affected infants have irregularly shaped, crowded teeth, resulting in upper and lower jaws that do not meet properly (malocclusion). Affected individuals may have a boney protuberance on the lingual aspect of the upper front teeth (talon cusps). The soft tissue structure that hangs in the back of the throat may also be divided (bifid uvula). In addition, some affected individuals may appear to be frowning or upset when they smile.In addition to broad thumbs and toes, some children with RSTS may have toes that overlap or unusually shaped bones of the feet (metatarsals).Affected individuals may have overgrowth of scar tissue at the site of a cut, injury, or surgical incision (keloid formation) or this may occur spontaneously.EyesAffected infants have specific characteristics of the eyes including eyes that appear widely spaced (apparent hypertelorism); crossed eyes (strabismus); upper eyelids that droop (ptosis) and/or extra folds of skin on either side of the nose that may cover the eyes’ inner corners (epicanthal folds).Skeletal AbnormalitiesThere may be additional skeletal characteristics including side-to-side (scoliosis) or front-to-back (kyphosis) curvature of the spine, depression of the bone forming the center of the chest (sternum), known as “funnel chest” or pectus excavatum, abnormalities of vertebrae and the pelvis, malformations of ribs, and recurrent dislocation of the kneecaps. The lower end of the spinal cord may be abnormally tied down (tethering).Genitourinary TractMale infants with RSTS have abnormalities of the genitourinary tract including failure of one or both testes to descend into the scrotum (cryptorchidism), a fold of skin extending around the base of the penis (shawl scrotum) and/or misplacement of the urinary opening, such as on the underside of the penis (hypospadias). In addition, infants with RSTS may have underdeveloped (hypoplastic) or absent kidney(s), repeated infections of the urinary tract, kidney stones, unusual accumulation of urine in the kidney (hydronephrosis) and/or backflow (reflux) of urine into the tubes (ureters) that normally bring urine to the bladder. In some cases, duplication of the kidneys and/or ureters may also be present.CardiacApproximately one third of infants with RSTS have an associated heart defect that is present at birth (congenital heart defect). According to the medical literature, patent ductus arteriosus may be the most common congenital heart defect present in infants with RSTS. Infants with RSTS may also have extra heart sounds (heart murmurs), narrowing of the opening between the pulmonary artery and the right ventricle of the heart (pulmonary stenosis), narrowing of the aorta (aortic coarctation) and/or ventricular septal defects (VSDs) and/or atrial septal defects (ASDs). The symptoms associated with a ventricular septal defect or atrial septal defect vary from person to person, depending upon the size and location of the defect. RespiratoryAffected individuals may also have abnormalities of the respiratory system. The lungs may be abnormally divided into small extra sections (lung lobulation) and/or the walls of the voice box (larynx) may be weak and easily collapsible, potentially resulting in swallowing and breathing difficulties (e.g., temporary cessation of normal breathing rhythm during sleep [sleep apnea]).Individuals with RSTS can be difficult to intubate because of the easy collapsibility of the laryngeal wall. An anesthesiologist comfortable with managing complex pediatric airway problems should administer general anesthesia when needed.BehaviorIndividuals with RSTS often exhibit a short attention span, decreased tolerance for noise and crowds, impulsivity, aggressive behavior, repetitive behaviors and moodiness. Autistic behaviors are common.Susceptibility to MalignancyThere are reports of persons with RSTS with various benign and malignant tumors including meningioma, pilomatixoma, rhabdomysarcoma, pheochromocytoma, neuroblastoma, medulloblastona, oligodendroglioma, leioyosarcoma, seminoma, odontoma, choristoma and leukemia. However, one recent study found only an increased risk for meningiomas and pilomatrixomas, but not for malignancies in general.
1,086
Rubinstein Taybi Syndrome
nord_1086_2
Causes of Rubinstein Taybi Syndrome
In most affected children, RSTS occurs as the result of a new (de novo) genetic mutation that is not present in or carried by the parents. In these cases, the risk of having a second affected child is less than 1%.RSTS may also be inherited in an autosomal dominant pattern, meaning that if a person has RSTS, each of his/her children has a 50% chance of having RSTS.The most common gene responsible for RSTS is the CREBBP gene. Pathogenic variants in the CREBBP gene have been identified in 50-60% of individuals with RSTS. Mutations in the EP300 gene have been identified in 8-10% of individuals with RSTS.
Causes of Rubinstein Taybi Syndrome. In most affected children, RSTS occurs as the result of a new (de novo) genetic mutation that is not present in or carried by the parents. In these cases, the risk of having a second affected child is less than 1%.RSTS may also be inherited in an autosomal dominant pattern, meaning that if a person has RSTS, each of his/her children has a 50% chance of having RSTS.The most common gene responsible for RSTS is the CREBBP gene. Pathogenic variants in the CREBBP gene have been identified in 50-60% of individuals with RSTS. Mutations in the EP300 gene have been identified in 8-10% of individuals with RSTS.
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Rubinstein Taybi Syndrome
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Affects of Rubinstein Taybi Syndrome
RSTS is a rare disorder that affects males and females in equal numbers. The exact incidence of RSTS is unknown, although a study in the Netherlands estimates the incidence to be between 1/100,000 to 1/125,000 individuals.
Affects of Rubinstein Taybi Syndrome. RSTS is a rare disorder that affects males and females in equal numbers. The exact incidence of RSTS is unknown, although a study in the Netherlands estimates the incidence to be between 1/100,000 to 1/125,000 individuals.
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Rubinstein Taybi Syndrome
nord_1086_4
Related disorders of Rubinstein Taybi Syndrome
Symptoms of the following disorders can be similar to those of Rubinstein-Taybi syndrome. Comparisons may be useful for a differential diagnosis:Saethre-Chotzen syndrome: For more information on this disorder, choose “Saethre Chotzen” as your search term in the Rare Disease Database.Greig cephalopolysyndactyly syndrome (GCPS): For more information on this disorder, choose “Greig cephalopolysyndactyly syndrome” as your search term in the Rare Disease Database.The facial features of Floating-Harbor syndrome can appear similar to RSTS in some individuals. This syndrome is characterized by unique facial features, low birth weight, normal head circumference, short stature and bone age delay that normalizes between ages 6-12 years old. There may also be severe language impairments. Hand and foot findings are distinct from those of RSTS. (For more information on this disorder, choose “Floating Harbor” as your search term in the Rare Disease Database.)
Related disorders of Rubinstein Taybi Syndrome. Symptoms of the following disorders can be similar to those of Rubinstein-Taybi syndrome. Comparisons may be useful for a differential diagnosis:Saethre-Chotzen syndrome: For more information on this disorder, choose “Saethre Chotzen” as your search term in the Rare Disease Database.Greig cephalopolysyndactyly syndrome (GCPS): For more information on this disorder, choose “Greig cephalopolysyndactyly syndrome” as your search term in the Rare Disease Database.The facial features of Floating-Harbor syndrome can appear similar to RSTS in some individuals. This syndrome is characterized by unique facial features, low birth weight, normal head circumference, short stature and bone age delay that normalizes between ages 6-12 years old. There may also be severe language impairments. Hand and foot findings are distinct from those of RSTS. (For more information on this disorder, choose “Floating Harbor” as your search term in the Rare Disease Database.)
1,086
Rubinstein Taybi Syndrome
nord_1086_5
Diagnosis of Rubinstein Taybi Syndrome
The diagnosis of RSTS is primarily based on physical (clinical) features, including short stature, a downward slant to the eyes (down slanted palpebral fissures), a low-hanging nasal septum (columella), a high palate, cusp-like structures (talon cusps) on the front teeth and/or broad and angulated thumbs and great toes. The diagnosis may be further supported by x-ray studies revealing malformations of the bones of the hands and feet characteristic to RSTS. Genetic testing by sequencing of the CREBBP and EP300 genes or the use of large gene panels may confirm RSTS. Pathogenic variants may be detected in the CREBBP gene (identified in 50%-60% of affected individuals) or in the EP300 gene (identified in 8-10% of RSTS individuals).
Diagnosis of Rubinstein Taybi Syndrome. The diagnosis of RSTS is primarily based on physical (clinical) features, including short stature, a downward slant to the eyes (down slanted palpebral fissures), a low-hanging nasal septum (columella), a high palate, cusp-like structures (talon cusps) on the front teeth and/or broad and angulated thumbs and great toes. The diagnosis may be further supported by x-ray studies revealing malformations of the bones of the hands and feet characteristic to RSTS. Genetic testing by sequencing of the CREBBP and EP300 genes or the use of large gene panels may confirm RSTS. Pathogenic variants may be detected in the CREBBP gene (identified in 50%-60% of affected individuals) or in the EP300 gene (identified in 8-10% of RSTS individuals).
1,086
Rubinstein Taybi Syndrome
nord_1086_6
Therapies of Rubinstein Taybi Syndrome
Treatment The management of RSTS is directed toward the specific symptoms of each individual. Management may require the coordinated efforts of a team of specialists, including pediatricians, physicians who diagnose and treat heart abnormalities (cardiologists), skeletal abnormalities (orthopedists), hearing problems (audiologists), urinary tract abnormalities (urologists), kidney dysfunction(nephrologists), as well as dental specialists, physical therapists, speech pathologists, dietitians and/or other health care professionals. Growth parameters should be regularly plotted on an RSTS-specific growth chart. There should be yearly eye and hearing evaluations and routine monitoring for cardiac, dental, and renal abnormalities.Orthopedic surgery, physical therapy, and/or other supportive techniques may help treat certain skeletal differences associated with RSTS, such as scoliosis. In some cases, surgery may be performed on the hands and/or feet, particularly when the thumbs are angulated or the broad first toes make it difficult to wear shoes.Affected individuals may require early intervention to prevent and/or monitor respiratory and feeding difficulties. Special education programs, vocational training, speech, and/or behavioral therapy may also be recommended.Genetic counseling is recommended for affected individuals and their family members.
Therapies of Rubinstein Taybi Syndrome. Treatment The management of RSTS is directed toward the specific symptoms of each individual. Management may require the coordinated efforts of a team of specialists, including pediatricians, physicians who diagnose and treat heart abnormalities (cardiologists), skeletal abnormalities (orthopedists), hearing problems (audiologists), urinary tract abnormalities (urologists), kidney dysfunction(nephrologists), as well as dental specialists, physical therapists, speech pathologists, dietitians and/or other health care professionals. Growth parameters should be regularly plotted on an RSTS-specific growth chart. There should be yearly eye and hearing evaluations and routine monitoring for cardiac, dental, and renal abnormalities.Orthopedic surgery, physical therapy, and/or other supportive techniques may help treat certain skeletal differences associated with RSTS, such as scoliosis. In some cases, surgery may be performed on the hands and/or feet, particularly when the thumbs are angulated or the broad first toes make it difficult to wear shoes.Affected individuals may require early intervention to prevent and/or monitor respiratory and feeding difficulties. Special education programs, vocational training, speech, and/or behavioral therapy may also be recommended.Genetic counseling is recommended for affected individuals and their family members.
1,086
Rubinstein Taybi Syndrome
nord_1087_0
Overview of Russell-Silver Syndrome
SummaryRussell-Silver syndrome (RSS) is a rare disorder characterized by intrauterine growth restriction (IUGR), poor growth after birth, a relatively large head size, a triangular facial appearance, a prominent forehead (looking from the side of the face), body asymmetry and significant feeding difficulties. The wide spectrum of findings varies both in frequency and severity from one affected individual to another. The majority of individuals with RSS are of normal intelligence, but motor and/or speech delay is common.RSS is genetically heterogeneous, meaning that different genetic abnormalities are known to cause the disorder. Abnormalities involving chromosomes 7 or 11 have been found in up to 60% of RSS patients. However, in approximately 40% of patients with a clinical diagnosis of RSS, the underlying cause is still not known.Consensus guidelines have been published which give recommendations regarding the investigation, diagnosis and management of individuals with RSS. The management of children with RSS should start as early as possible and often requires the involvement of many different health professionals.IntroductionRussell-Silver syndrome was first described by Silver in 1953 and Russell in 1954. At first it was thought that they were describing two separate conditions; it took nearly 20 years for doctors to realize that they had seen different aspects of the same condition. The disorder is usually called Russell-Silver syndrome in the United States and Silver-Russell syndrome in Europe.
Overview of Russell-Silver Syndrome. SummaryRussell-Silver syndrome (RSS) is a rare disorder characterized by intrauterine growth restriction (IUGR), poor growth after birth, a relatively large head size, a triangular facial appearance, a prominent forehead (looking from the side of the face), body asymmetry and significant feeding difficulties. The wide spectrum of findings varies both in frequency and severity from one affected individual to another. The majority of individuals with RSS are of normal intelligence, but motor and/or speech delay is common.RSS is genetically heterogeneous, meaning that different genetic abnormalities are known to cause the disorder. Abnormalities involving chromosomes 7 or 11 have been found in up to 60% of RSS patients. However, in approximately 40% of patients with a clinical diagnosis of RSS, the underlying cause is still not known.Consensus guidelines have been published which give recommendations regarding the investigation, diagnosis and management of individuals with RSS. The management of children with RSS should start as early as possible and often requires the involvement of many different health professionals.IntroductionRussell-Silver syndrome was first described by Silver in 1953 and Russell in 1954. At first it was thought that they were describing two separate conditions; it took nearly 20 years for doctors to realize that they had seen different aspects of the same condition. The disorder is usually called Russell-Silver syndrome in the United States and Silver-Russell syndrome in Europe.
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Russell-Silver Syndrome
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Symptoms of Russell-Silver Syndrome
The symptoms of RSS vary greatly from one individual to another. Some are mildly affected; others may have serious complications. The wide range of potential features can affect many different parts of the body. It is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals/ parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. With appropriate medical care, most individuals with RSS will live full, productive lives. Growth and puberty: Almost all infants with RSS have a birth weight well below the 3rd percentile (Asymmetry: In many children with RSS, all or part of one side of the body is smaller than the other (asymmetry). This results from the underdevelopment of one side of the body (hemihypotrophy). The extent and severity of asymmetry is extremely variable. In most cases, asymmetry is found in just leg length or arm length but, in some children, one entire side of the body is affected. Individuals may experience difficulties with balance and walking as a result. Any child with significant asymmetry should be followed regularly by an orthopedist. Although, in the majority of children, asymmetry is apparent at birth, it may not become evident until later during childhood. Asymmetry may also improve with age. Treatment with GH does not appear to increase the severity of asymmetry.Craniofacial features: Characteristic craniofacial features are commonly seen in affected children, particularly in infancy and early childhood. The most common finding is a “large-head-for-body”. The head circumference is almost always far higher on the growth curve than either weight or length (called head sparing/ relative macrocephaly). This, along with the tendency for the jaw to be small (micrognathia), gives rise to the typical triangular facial shape seen in children with RSS. The relatively large head size may cause a child with RSS to be mistakenly diagnosed with hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain. In addition, affected children may have delayed closure of the ‘soft spot’ (anterior fontanelle) on the top of the head where two of the fibrous joints (sutures) of the skull meet. Another common facial feature is an abnormally prominent forehead, where the forehead protrudes out when the face is viewed from the side. Other craniofacial features associated with RSS are less common, but can include bluish discoloration of the whites of the eyes (blue sclera) during infancy; a small mouth; downturned corners of the mouth; and a high, narrow roof of the mouth (palate). These characteristic facial features typically become less noticeable with age. A variety of dental abnormalities have been reported including absence of teeth, abnormally small teeth (microdontia), and crowding of the teeth. Feeding difficulties: Gastrointestinal problems are common in children with RSS. These can include inflammation of the tube that carries food from the mouth to the stomach (esophagitis), backflow of the contents of the stomach or small intestines into the esophagus (gastroesophageal reflux), delayed gastric emptying (where ingested food takes longer than normal to digest causing the child to feel full) and failure to gain weight or grow at the expected rate for age and sex (failure to thrive). Some children with RSS simply never have a sensation of hunger during early childhood, while others may develop an aversion to food. Paradoxically, some children will overeat later on. Due to a low muscle mass, it is important to be cautious that children with RSS do not put on too much fat mass. There is also evidence that rapid weight gain in early childhood can lead to problems with the body’s metabolism and increased risk of high blood pressure and heart disease later on in life. RSS children should be well nourished but stay thin. Hypoglycemia: Infants and children with RSS are at increased risk of hypoglycemia (recurrent episodes of unusually low blood sugar levels). This is likely to be due to their lack of subcutaneous fat and poor appetite. Hypoglycaemia is usually triggered when an affected infant does not eat for an extended period of time (fasting). Symptoms associated with hypoglycemia include weakness, hunger, dizziness, sweating and/or headaches. However, it is important to note that studies have found that infants with RSS have been found to have had night-time hypoglycemic episodes with little to no physical symptoms. Excessive sweating also occurs in some children with RSS without associated hypoglycemia. Neurodevelopment: Motor development skills may be delayed due to low muscle tone (hypotonia) and relatively large head size, especially in infancy and toddlerhood. Delay in speech development is also common, particularly in those patients with maternal uniparental disomy of chromosome 7 (see ‘Causes’, below). Early intervention (physical, occupational and/or speech therapy) is important and parents should ask their pediatrician for more information. The majority of children with RSS have normal intelligence. However, there is evidence for differences in frequency of learning and/or behavioral problems, including autistic spectrum, between the different genetic subtypes of RSS, with greater risk for children with maternal uniparental disomy of chromosome 7. Additional features: Other features have been described in the medical literature with varying frequency. Orthopedic problems associated with RSS, in addition to body asymmetry, include curvature of the spine (scoliosis) and occasionally hip dislocation. Minor hand and/or foot anomalies are also common, including short and in-curving 5th fingers (clinodactyly), fingers that are fixed in a bent position and cannot be fully straightened (camptodactyly) and webbing of the second and third toes (syndactyly). A variety of abnormalities affecting the organs of the reproduction and urinary systems (genitourinary abnormalities) have been reported, including failure of one or both testes to descend into the scrotum (cryptorchidism) and abnormal placement of the urinary opening on the underside of the penis (hypospadias) or under-development of the uterus and upper part of the vagina (Rokitansky syndrome). Structural kidney (renal) abnormalities may also occur. Genitourinary abnormalities are also found at increased frequency in children who are born small-for-gestational-age and who do not have RSS. Other congenital abnormalities reported less commonly in RSS include structural heart defects and cleft palate (an opening in the roof of the mouth). Congenital anomalies are more common in children with loss of methylation on chromosome 11p15 (see ‘Causes’ below)
Symptoms of Russell-Silver Syndrome. The symptoms of RSS vary greatly from one individual to another. Some are mildly affected; others may have serious complications. The wide range of potential features can affect many different parts of the body. It is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals/ parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. With appropriate medical care, most individuals with RSS will live full, productive lives. Growth and puberty: Almost all infants with RSS have a birth weight well below the 3rd percentile (Asymmetry: In many children with RSS, all or part of one side of the body is smaller than the other (asymmetry). This results from the underdevelopment of one side of the body (hemihypotrophy). The extent and severity of asymmetry is extremely variable. In most cases, asymmetry is found in just leg length or arm length but, in some children, one entire side of the body is affected. Individuals may experience difficulties with balance and walking as a result. Any child with significant asymmetry should be followed regularly by an orthopedist. Although, in the majority of children, asymmetry is apparent at birth, it may not become evident until later during childhood. Asymmetry may also improve with age. Treatment with GH does not appear to increase the severity of asymmetry.Craniofacial features: Characteristic craniofacial features are commonly seen in affected children, particularly in infancy and early childhood. The most common finding is a “large-head-for-body”. The head circumference is almost always far higher on the growth curve than either weight or length (called head sparing/ relative macrocephaly). This, along with the tendency for the jaw to be small (micrognathia), gives rise to the typical triangular facial shape seen in children with RSS. The relatively large head size may cause a child with RSS to be mistakenly diagnosed with hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain. In addition, affected children may have delayed closure of the ‘soft spot’ (anterior fontanelle) on the top of the head where two of the fibrous joints (sutures) of the skull meet. Another common facial feature is an abnormally prominent forehead, where the forehead protrudes out when the face is viewed from the side. Other craniofacial features associated with RSS are less common, but can include bluish discoloration of the whites of the eyes (blue sclera) during infancy; a small mouth; downturned corners of the mouth; and a high, narrow roof of the mouth (palate). These characteristic facial features typically become less noticeable with age. A variety of dental abnormalities have been reported including absence of teeth, abnormally small teeth (microdontia), and crowding of the teeth. Feeding difficulties: Gastrointestinal problems are common in children with RSS. These can include inflammation of the tube that carries food from the mouth to the stomach (esophagitis), backflow of the contents of the stomach or small intestines into the esophagus (gastroesophageal reflux), delayed gastric emptying (where ingested food takes longer than normal to digest causing the child to feel full) and failure to gain weight or grow at the expected rate for age and sex (failure to thrive). Some children with RSS simply never have a sensation of hunger during early childhood, while others may develop an aversion to food. Paradoxically, some children will overeat later on. Due to a low muscle mass, it is important to be cautious that children with RSS do not put on too much fat mass. There is also evidence that rapid weight gain in early childhood can lead to problems with the body’s metabolism and increased risk of high blood pressure and heart disease later on in life. RSS children should be well nourished but stay thin. Hypoglycemia: Infants and children with RSS are at increased risk of hypoglycemia (recurrent episodes of unusually low blood sugar levels). This is likely to be due to their lack of subcutaneous fat and poor appetite. Hypoglycaemia is usually triggered when an affected infant does not eat for an extended period of time (fasting). Symptoms associated with hypoglycemia include weakness, hunger, dizziness, sweating and/or headaches. However, it is important to note that studies have found that infants with RSS have been found to have had night-time hypoglycemic episodes with little to no physical symptoms. Excessive sweating also occurs in some children with RSS without associated hypoglycemia. Neurodevelopment: Motor development skills may be delayed due to low muscle tone (hypotonia) and relatively large head size, especially in infancy and toddlerhood. Delay in speech development is also common, particularly in those patients with maternal uniparental disomy of chromosome 7 (see ‘Causes’, below). Early intervention (physical, occupational and/or speech therapy) is important and parents should ask their pediatrician for more information. The majority of children with RSS have normal intelligence. However, there is evidence for differences in frequency of learning and/or behavioral problems, including autistic spectrum, between the different genetic subtypes of RSS, with greater risk for children with maternal uniparental disomy of chromosome 7. Additional features: Other features have been described in the medical literature with varying frequency. Orthopedic problems associated with RSS, in addition to body asymmetry, include curvature of the spine (scoliosis) and occasionally hip dislocation. Minor hand and/or foot anomalies are also common, including short and in-curving 5th fingers (clinodactyly), fingers that are fixed in a bent position and cannot be fully straightened (camptodactyly) and webbing of the second and third toes (syndactyly). A variety of abnormalities affecting the organs of the reproduction and urinary systems (genitourinary abnormalities) have been reported, including failure of one or both testes to descend into the scrotum (cryptorchidism) and abnormal placement of the urinary opening on the underside of the penis (hypospadias) or under-development of the uterus and upper part of the vagina (Rokitansky syndrome). Structural kidney (renal) abnormalities may also occur. Genitourinary abnormalities are also found at increased frequency in children who are born small-for-gestational-age and who do not have RSS. Other congenital abnormalities reported less commonly in RSS include structural heart defects and cleft palate (an opening in the roof of the mouth). Congenital anomalies are more common in children with loss of methylation on chromosome 11p15 (see ‘Causes’ below)
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Russell-Silver Syndrome
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Causes of Russell-Silver Syndrome
In the last few years it has become possible to confirm the clinical diagnosis by genetic testing in approximately 60% of individuals with RSS. Two main genetic changes (involving chromosome 7 and chromosome 11) are currently known to cause RSS. These are specific to the condition and not seen in most children with IUGR and poor postnatal growth. Chromosomes, which are present in the nucleus of human cells, carry the genetic information (genes) for each individual. We 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 11p15.5” refers to band 15.5 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Everyone has two copies of each gene – one inherited from the father and one inherited from the mother. In most cases, both genes are “turned on” or active. However, some genes are preferentially silenced or “turned off” based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical switches through a process called methylation. Proper genetic imprinting is necessary for normal development. Problems with imprinting have been associated with several disorders, including RSS. Chromosome 11: Imprinted genes tend to be found clustered or grouped together. Several imprinted genes are found in a cluster on chromosome 11p15.5. The cluster is divided into two functional regions known as imprinting center regions (ICR1 and ICR2). Researchers have identified several imprinted genes regulated by these imprinting centers. These genes play a critical role in the regulation of fetal growth. Abnormalities in this region have also been shown to cause Beckwith-Wiedemann syndrome, an imprinting disorder which results in overgrowth. About 30-60% of children with RSS have changes (loss of methylation (LOM)/ hypomethylation) affecting the ICR1 region on chromosome 11 (11p15 LOM). This, in turn, affects the activity of two genes (maternally expressed H19 and paternally expressed IGF2) which are believed to play a role in the development of RSS. Further research is necessary to learn more about the role of these genes and the complex genetic mechanisms responsible for RSS. Approximately 1% of individuals with RSS have been shown to have variants (mutations) in genes in the IGF2 pathway (IGF2, HMGA2, PLAG1) or CDKN1C. Single gene variants are most often seen in rare familial cases of RSS. Chromosome 7: About 5-10% of individuals with RSS have been found to have both copies of chromosome 7 from their mother, rather than one from each parent. This is called maternal uniparental disomy of chromosome 7 (upd(7)mat). The exact way in which this affects growth and development is not fully understood, though this is likely to be due to increased activity of maternally-expressed gene(s) and/or under-activity of paternally-expressed gene(s) on chromosome 7. Clinical RSS: The genetics underlying RSS are complex and the specific reasons for the development of the symptoms of this disorder are not fully understood. Currently, genetic test results are normal in about 40% of children who have a clinical diagnosis of RSS. More work is needed to try to identify the underlying cause in this group of children. Other imprinting disorders: Rarely, other disorders of genomic imprinting can result in clinical features of RSS. Additional testing for these conditions may be considered in children with overlapping features. For example, changes affecting an imprinted region on chromosome 14q32 result in a condition known as Temple syndrome. Children with this condition commonly have IUGR, poor postnatal growth, low muscle tone, delay in development of motor skills and early puberty- all features which can be seen in RSS. Asymmetry is rarely a feature in Temple syndrome. Around 25-30% of children with RSS due to 11p15 LOM also have LOM at other imprinting regions on ICR2 and/or other chromosomes. This is known as multi-locus imprinting disturbance (MLID). The clinical significance of this finding is not yet well understood.
Causes of Russell-Silver Syndrome. In the last few years it has become possible to confirm the clinical diagnosis by genetic testing in approximately 60% of individuals with RSS. Two main genetic changes (involving chromosome 7 and chromosome 11) are currently known to cause RSS. These are specific to the condition and not seen in most children with IUGR and poor postnatal growth. Chromosomes, which are present in the nucleus of human cells, carry the genetic information (genes) for each individual. We 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 11p15.5” refers to band 15.5 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Everyone has two copies of each gene – one inherited from the father and one inherited from the mother. In most cases, both genes are “turned on” or active. However, some genes are preferentially silenced or “turned off” based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical switches through a process called methylation. Proper genetic imprinting is necessary for normal development. Problems with imprinting have been associated with several disorders, including RSS. Chromosome 11: Imprinted genes tend to be found clustered or grouped together. Several imprinted genes are found in a cluster on chromosome 11p15.5. The cluster is divided into two functional regions known as imprinting center regions (ICR1 and ICR2). Researchers have identified several imprinted genes regulated by these imprinting centers. These genes play a critical role in the regulation of fetal growth. Abnormalities in this region have also been shown to cause Beckwith-Wiedemann syndrome, an imprinting disorder which results in overgrowth. About 30-60% of children with RSS have changes (loss of methylation (LOM)/ hypomethylation) affecting the ICR1 region on chromosome 11 (11p15 LOM). This, in turn, affects the activity of two genes (maternally expressed H19 and paternally expressed IGF2) which are believed to play a role in the development of RSS. Further research is necessary to learn more about the role of these genes and the complex genetic mechanisms responsible for RSS. Approximately 1% of individuals with RSS have been shown to have variants (mutations) in genes in the IGF2 pathway (IGF2, HMGA2, PLAG1) or CDKN1C. Single gene variants are most often seen in rare familial cases of RSS. Chromosome 7: About 5-10% of individuals with RSS have been found to have both copies of chromosome 7 from their mother, rather than one from each parent. This is called maternal uniparental disomy of chromosome 7 (upd(7)mat). The exact way in which this affects growth and development is not fully understood, though this is likely to be due to increased activity of maternally-expressed gene(s) and/or under-activity of paternally-expressed gene(s) on chromosome 7. Clinical RSS: The genetics underlying RSS are complex and the specific reasons for the development of the symptoms of this disorder are not fully understood. Currently, genetic test results are normal in about 40% of children who have a clinical diagnosis of RSS. More work is needed to try to identify the underlying cause in this group of children. Other imprinting disorders: Rarely, other disorders of genomic imprinting can result in clinical features of RSS. Additional testing for these conditions may be considered in children with overlapping features. For example, changes affecting an imprinted region on chromosome 14q32 result in a condition known as Temple syndrome. Children with this condition commonly have IUGR, poor postnatal growth, low muscle tone, delay in development of motor skills and early puberty- all features which can be seen in RSS. Asymmetry is rarely a feature in Temple syndrome. Around 25-30% of children with RSS due to 11p15 LOM also have LOM at other imprinting regions on ICR2 and/or other chromosomes. This is known as multi-locus imprinting disturbance (MLID). The clinical significance of this finding is not yet well understood.
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Russell-Silver Syndrome
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Affects of Russell-Silver Syndrome
RSS occurs in all populations and affects males and females in equal numbers. In the past, many infants with IUGR and relatively large head circumference were incorrectly diagnosed with RSS. Because of the difficulty in diagnosis, other cases may go unrecognized and undiagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population. Recent data suggests that around 1 in 15,000 children will have RSS.
Affects of Russell-Silver Syndrome. RSS occurs in all populations and affects males and females in equal numbers. In the past, many infants with IUGR and relatively large head circumference were incorrectly diagnosed with RSS. Because of the difficulty in diagnosis, other cases may go unrecognized and undiagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population. Recent data suggests that around 1 in 15,000 children will have RSS.
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Russell-Silver Syndrome
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Related disorders of Russell-Silver Syndrome
Poor growth prior to birth (IUGR) is a feature of many different congenital disorders. Although some of these disorders may have signs and symptoms that are similar to RSS, they usually have other physical features that help differentiate them. For example, relative microcephaly (head size smaller than expected for height and weight) is almost never seen in RSS. Alternative diagnoses should also be considered if there is global developmental delay or significant intellectual disability, no history of feeding difficulties, distinctive facial features (different from those described in RSS), additional congenital anomalies or other features atypical for RSS. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) 3M syndrome is an extremely rare genetic disorder characterized by low birth weight, short stature, distinctive facial features, and subtle skeletal changes. The name “3M” refers to the last initials of three researchers (Miller, McKusick, Malvaux) who were among the first to identify the disorder. Characteristic facial features include a long, narrow head (dolichocephaly), an unusually prominent forehead (frontal bossing), and a triangular-shaped face with an up-turned nose and full lips. Subtle skeletal changes associated with the disorder include unusually thin bones, particularly the long bones of the arms and legs; abnormally tall bones of the spinal column (vertebrae); congenital dislocation of the hip; and/or distinctive malformations of the breast bone (pectus deformity) and shoulder blades (scapulae). Affected individuals may also have additional features including prominent heels and/or increased flexibility (hypermobility) of the joints. Intelligence appears to be normal. 3M syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “three M” as your search term in the Rare Disease Database.) Chromosomal instability disorders such as Fanconi anemia, Bloom syndrome, and Nijmegen breakage syndrome may have similar features to RSS. In individuals with these disorders, the chromosomes within their cells are unstable and break and rearrange easily (chromosome instability), damaging deoxyribonucleic acid (DNA) found within cells. In most people, damage to DNA is repaired. However, in affected individuals, breaks and rearrangements occur more often and their bodies are slow or fail to repair the damage, which in turn affects the genetic code. These disorders are commonly associated with IUGR and short stature as well as additional features, including small head size (microcephaly), limb abnormalities, frequent infections and an abnormal sensitivity of the skin to ultraviolet (UV) light (photosensitivity). It is important to recognize these diagnoses as growth hormone treatment is contraindicated in this group of disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.
Related disorders of Russell-Silver Syndrome. Poor growth prior to birth (IUGR) is a feature of many different congenital disorders. Although some of these disorders may have signs and symptoms that are similar to RSS, they usually have other physical features that help differentiate them. For example, relative microcephaly (head size smaller than expected for height and weight) is almost never seen in RSS. Alternative diagnoses should also be considered if there is global developmental delay or significant intellectual disability, no history of feeding difficulties, distinctive facial features (different from those described in RSS), additional congenital anomalies or other features atypical for RSS. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) 3M syndrome is an extremely rare genetic disorder characterized by low birth weight, short stature, distinctive facial features, and subtle skeletal changes. The name “3M” refers to the last initials of three researchers (Miller, McKusick, Malvaux) who were among the first to identify the disorder. Characteristic facial features include a long, narrow head (dolichocephaly), an unusually prominent forehead (frontal bossing), and a triangular-shaped face with an up-turned nose and full lips. Subtle skeletal changes associated with the disorder include unusually thin bones, particularly the long bones of the arms and legs; abnormally tall bones of the spinal column (vertebrae); congenital dislocation of the hip; and/or distinctive malformations of the breast bone (pectus deformity) and shoulder blades (scapulae). Affected individuals may also have additional features including prominent heels and/or increased flexibility (hypermobility) of the joints. Intelligence appears to be normal. 3M syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “three M” as your search term in the Rare Disease Database.) Chromosomal instability disorders such as Fanconi anemia, Bloom syndrome, and Nijmegen breakage syndrome may have similar features to RSS. In individuals with these disorders, the chromosomes within their cells are unstable and break and rearrange easily (chromosome instability), damaging deoxyribonucleic acid (DNA) found within cells. In most people, damage to DNA is repaired. However, in affected individuals, breaks and rearrangements occur more often and their bodies are slow or fail to repair the damage, which in turn affects the genetic code. These disorders are commonly associated with IUGR and short stature as well as additional features, including small head size (microcephaly), limb abnormalities, frequent infections and an abnormal sensitivity of the skin to ultraviolet (UV) light (photosensitivity). It is important to recognize these diagnoses as growth hormone treatment is contraindicated in this group of disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.
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Russell-Silver Syndrome
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Diagnosis of Russell-Silver Syndrome
The diagnosis of RSS is based on clinical findings. Because many of the symptoms are nonspecific, making a diagnosis of RSS remains difficult. Consensus guidelines for investigation and diagnosis of RSS have recently been published, based on the Netchine-Harbison clinical scoring system for RSS: http://www.nature.com/nrendo/journal/v13/n2/full/nrendo.2016.138.html Testing for known genetic causes of RSS (chromosome 7 and 11) can confirm the clinical diagnosis in up to 60% of individuals. Knowing the underlying genetic cause can also help guide treatment as some problems are more common in association with abnormalities of chromosome 7 or 11.
Diagnosis of Russell-Silver Syndrome. The diagnosis of RSS is based on clinical findings. Because many of the symptoms are nonspecific, making a diagnosis of RSS remains difficult. Consensus guidelines for investigation and diagnosis of RSS have recently been published, based on the Netchine-Harbison clinical scoring system for RSS: http://www.nature.com/nrendo/journal/v13/n2/full/nrendo.2016.138.html Testing for known genetic causes of RSS (chromosome 7 and 11) can confirm the clinical diagnosis in up to 60% of individuals. Knowing the underlying genetic cause can also help guide treatment as some problems are more common in association with abnormalities of chromosome 7 or 11.
1,087
Russell-Silver Syndrome
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Therapies of Russell-Silver Syndrome
Treatment Treatment in RSS is directed toward the specific symptoms that are apparent in each individual. Recommendations for management are described in detail in the published consensus guidelines: http://www.nature.com/nrendo/journal/v13/n2/full/nrendo.2016.138.html Early diagnosis and intervention can help improve growth and ensure that affected children reach their highest potential. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, doctors who specialize in treating disorders of the skeleton (orthopedic surgeons), physicians who specialize in disorders of the glands and hormones (endocrinologists), dental specialists, physicians who specialize in the gastrointestinal tract (gastroenterologists), psychologists, and other healthcare professionals may need to be involved developing a comprehensive treatment plan. Parents may also wish to be referred for genetic counselling if they are planning to have further children. Growth and puberty: Failure to thrive is very common in children with RSS, due to a combination of feeding difficulties and gastrointestinal problems, such as reflux. In the first 2 years of life the main goal is to ensure adequate intake of calories. This in turn will allow growth, avoid malnutrition and help maintain blood sugar levels. In some cases, feeding tubes may be necessary to assist feeding. Initially a nasogastric tube (a thin tube that runs from the nose to the stomach through the esophagus) may be used. If feeding difficulties are severe and persistent, a gastrostomy tube (inserted directly into the stomach through a small incision in the abdomen wall) may be needed. It is, however, important not to overfeed an RSS infant (which can occur quickly, especially with feeding tubes). Babies born small-for-gestational-age should remain lean (but not underweight) due to high risk of medical problems related to insulin resistance and metabolic syndrome. It is important to monitor weight-for-height. Increasing the calories of a child with RSS can result in a brief spurt of length/height growth which often then levels off. The child then simply becomes more overweight rather than gaining any further height. Growth hormone (GH) therapy is recommended for children with RSS for a number of reasons: to improve body composition (especially lean body mass), motor development and appetite, to reduce the risk of hypoglycemia and to optimize growth. GH therapy was approved by the Food and Drug Administration (FDA) in 2001 for children who were born small-for-gestational-age (SGA) and who have not displayed adequate catch up growth by the age of 2. Due to the small numbers of children with RSS, the FDA studies of SGA combined children with RSS into the overall pool of subjects. If a child with RSS is not born SGA, the child may qualify for GH therapy coverage under the FDA approval for idiopathic short stature. Many studies have now shown that GH therapy significantly improves childhood growth and final adult height. Furthermore, these studies indicate that RSS children who are not growth deficient respond in similar ways to the few RSS children who are GH deficient. As a result, GH stimulation testing is no longer recommended for an RSS child unless GH deficiency is suspected. A low starting dose of GH is recommended and has to be adapted to growth velocity. IGF-1 levels (which are routinely measured during GH therapy) are high in children with RSS, especially in those with 11p15 LOM. Prior to puberty, children typically enter an early stage of sexual maturation known as adrenarche. In children with RSS, bone age starts to advance at around 7 or 8 years, when they enter adrenarche. This may happen even earlier, especially if there is a period of rapid weight gain. Children may then enter puberty, which accelerates bone age even further. If not diagnosed and treated, this can lead to a reduced final height, even if treated with GH. From mid-childhood, children with RSS need to be monitored closely by a pediatric endocrinologist to look for early signs of adrenarche and puberty. If necessary, puberty can be delayed by using a medicine known as gonadotropin-releasing hormone analogue (GnRHa). Feeding difficulties: It is important to consider the possibility of underlying gastrointestinal problems and to treat these effectively as early as possible. Gastroesophageal reflux can result in arching of the back and/or a tendency to bring feeds back up; it can also be “silent”, with almost no physical symptoms. Acid reflux can be helped by providing smaller, more frequent meals and upright positioning of babies so gravity can help prevent food from flowing back up into the esophagus. Medications such as H2 blockers or proton pump inhibitors may also be prescribed. In rare cases of severe gastroesophageal reflux, (especially when a gastrostomy tube is being placed), a surgical procedure known as fundoplication may be necessary. During this surgical procedure the upper curve of the stomach (fundus) is wrapped around the lower portion of the esophagus. This procedure strengthens the valve (sphincter) between the esophagus and stomach and helps prevent acid reflux. Decreasing the quantity of foods high in fat and providing smaller, more frequent meals can help improve delayed gastric emptying. Constipation is also common in RSS and can cause a child to feel full so they do not want to eat. Hypoglycaemia: Hypoglycemia is treated by standard guidelines, including frequent feeding, dietary supplementation and the use of complex carbohydrates such as corn starch. To avoid low blood sugar levels, children with RSS should never go without food for long periods (even for medical procedures) and should go to the emergency room for glucose infusion when they are ill and unable to eat food by mouth. It is helpful for parents to be taught to measure ketones in the urine as an early warning sign, particularly when a child is unwell. Neurodevelopment: Some children with RSS may need additional support with development and learning. Early intervention is important to ensure that they reach their potential. Special services that may be beneficial include physical therapy, occupational therapy, and other medical, social, and/or vocational services. An individual education plan (IEP) may be developed to support children in school if special services are required; a 504 plan can ensure that the child receives access to an equal education by adapting their learning environment. Speech problems are common (especially in children with upd(7)mat) and speech and language therapy may be recommended. An audiological examination should also be performed to rule out hearing loss as the cause of speech problems. Additional problems: Braces and oral surgery may be needed to correct dental problems, such as crowding of the teeth. Difficulties can sometimes arise with walking due to limb asymmetry. Special braces and shoes may help improve balance and gait. In a small number of cases, surgical intervention may eventually be required; this is usually performed when growth has ceased. Cryptorchidism can sometimes resolve spontaneously, although some boys require surgical treatment. Hypospadias requires surgery, ideally by an experienced pediatric surgeon. Kidney (renal) abnormalities are treated along standard guidelines. Psychological support: Short stature and other medical issues can lead to problems with self-image in some children, adolescents and adults. Referral for psychosocial support may be beneficial in those experiencing issues with self-image, peer relationships and other social interactions. RSS in adulthood: Research about the long-term health of adults with RSS is limited and most adults with RSS are not routinely followed up. It is well recognized that being SGA at birth with accelerated gain in weight for length, particularly in early life, increases the risk of metabolic problems in adulthood. A recent study of individuals with RSS aged ≥18 years recorded impaired glucose tolerance (predisposing to diabetes) in 25%, high blood pressure in 33% and high cholesterol levels in 52%. In adults with RSS, other health problems (such as muscle and joint pains) have been highlighted but there remains uncertainty as to whether such problems are seen more frequently when compared to adults without RSS. Overall, however, most adults with RSS will have a normal quality of life, educational attainment and normal fertility. Genetic counseling: Genetic counseling is recommended for affected individuals and their families. In most families, only one child is affected and the chance of parents having another baby with RSS is likely to be very low. Similarly, the chance of an individual with RSS having an affected child themselves is also likely to be very low. However, in rare families, familial occurrence of RSS has been noted and the risk of recurrence can be as high as 50%. Genetic investigation is therefore important before parents are advised about recurrence risk.
Therapies of Russell-Silver Syndrome. Treatment Treatment in RSS is directed toward the specific symptoms that are apparent in each individual. Recommendations for management are described in detail in the published consensus guidelines: http://www.nature.com/nrendo/journal/v13/n2/full/nrendo.2016.138.html Early diagnosis and intervention can help improve growth and ensure that affected children reach their highest potential. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, doctors who specialize in treating disorders of the skeleton (orthopedic surgeons), physicians who specialize in disorders of the glands and hormones (endocrinologists), dental specialists, physicians who specialize in the gastrointestinal tract (gastroenterologists), psychologists, and other healthcare professionals may need to be involved developing a comprehensive treatment plan. Parents may also wish to be referred for genetic counselling if they are planning to have further children. Growth and puberty: Failure to thrive is very common in children with RSS, due to a combination of feeding difficulties and gastrointestinal problems, such as reflux. In the first 2 years of life the main goal is to ensure adequate intake of calories. This in turn will allow growth, avoid malnutrition and help maintain blood sugar levels. In some cases, feeding tubes may be necessary to assist feeding. Initially a nasogastric tube (a thin tube that runs from the nose to the stomach through the esophagus) may be used. If feeding difficulties are severe and persistent, a gastrostomy tube (inserted directly into the stomach through a small incision in the abdomen wall) may be needed. It is, however, important not to overfeed an RSS infant (which can occur quickly, especially with feeding tubes). Babies born small-for-gestational-age should remain lean (but not underweight) due to high risk of medical problems related to insulin resistance and metabolic syndrome. It is important to monitor weight-for-height. Increasing the calories of a child with RSS can result in a brief spurt of length/height growth which often then levels off. The child then simply becomes more overweight rather than gaining any further height. Growth hormone (GH) therapy is recommended for children with RSS for a number of reasons: to improve body composition (especially lean body mass), motor development and appetite, to reduce the risk of hypoglycemia and to optimize growth. GH therapy was approved by the Food and Drug Administration (FDA) in 2001 for children who were born small-for-gestational-age (SGA) and who have not displayed adequate catch up growth by the age of 2. Due to the small numbers of children with RSS, the FDA studies of SGA combined children with RSS into the overall pool of subjects. If a child with RSS is not born SGA, the child may qualify for GH therapy coverage under the FDA approval for idiopathic short stature. Many studies have now shown that GH therapy significantly improves childhood growth and final adult height. Furthermore, these studies indicate that RSS children who are not growth deficient respond in similar ways to the few RSS children who are GH deficient. As a result, GH stimulation testing is no longer recommended for an RSS child unless GH deficiency is suspected. A low starting dose of GH is recommended and has to be adapted to growth velocity. IGF-1 levels (which are routinely measured during GH therapy) are high in children with RSS, especially in those with 11p15 LOM. Prior to puberty, children typically enter an early stage of sexual maturation known as adrenarche. In children with RSS, bone age starts to advance at around 7 or 8 years, when they enter adrenarche. This may happen even earlier, especially if there is a period of rapid weight gain. Children may then enter puberty, which accelerates bone age even further. If not diagnosed and treated, this can lead to a reduced final height, even if treated with GH. From mid-childhood, children with RSS need to be monitored closely by a pediatric endocrinologist to look for early signs of adrenarche and puberty. If necessary, puberty can be delayed by using a medicine known as gonadotropin-releasing hormone analogue (GnRHa). Feeding difficulties: It is important to consider the possibility of underlying gastrointestinal problems and to treat these effectively as early as possible. Gastroesophageal reflux can result in arching of the back and/or a tendency to bring feeds back up; it can also be “silent”, with almost no physical symptoms. Acid reflux can be helped by providing smaller, more frequent meals and upright positioning of babies so gravity can help prevent food from flowing back up into the esophagus. Medications such as H2 blockers or proton pump inhibitors may also be prescribed. In rare cases of severe gastroesophageal reflux, (especially when a gastrostomy tube is being placed), a surgical procedure known as fundoplication may be necessary. During this surgical procedure the upper curve of the stomach (fundus) is wrapped around the lower portion of the esophagus. This procedure strengthens the valve (sphincter) between the esophagus and stomach and helps prevent acid reflux. Decreasing the quantity of foods high in fat and providing smaller, more frequent meals can help improve delayed gastric emptying. Constipation is also common in RSS and can cause a child to feel full so they do not want to eat. Hypoglycaemia: Hypoglycemia is treated by standard guidelines, including frequent feeding, dietary supplementation and the use of complex carbohydrates such as corn starch. To avoid low blood sugar levels, children with RSS should never go without food for long periods (even for medical procedures) and should go to the emergency room for glucose infusion when they are ill and unable to eat food by mouth. It is helpful for parents to be taught to measure ketones in the urine as an early warning sign, particularly when a child is unwell. Neurodevelopment: Some children with RSS may need additional support with development and learning. Early intervention is important to ensure that they reach their potential. Special services that may be beneficial include physical therapy, occupational therapy, and other medical, social, and/or vocational services. An individual education plan (IEP) may be developed to support children in school if special services are required; a 504 plan can ensure that the child receives access to an equal education by adapting their learning environment. Speech problems are common (especially in children with upd(7)mat) and speech and language therapy may be recommended. An audiological examination should also be performed to rule out hearing loss as the cause of speech problems. Additional problems: Braces and oral surgery may be needed to correct dental problems, such as crowding of the teeth. Difficulties can sometimes arise with walking due to limb asymmetry. Special braces and shoes may help improve balance and gait. In a small number of cases, surgical intervention may eventually be required; this is usually performed when growth has ceased. Cryptorchidism can sometimes resolve spontaneously, although some boys require surgical treatment. Hypospadias requires surgery, ideally by an experienced pediatric surgeon. Kidney (renal) abnormalities are treated along standard guidelines. Psychological support: Short stature and other medical issues can lead to problems with self-image in some children, adolescents and adults. Referral for psychosocial support may be beneficial in those experiencing issues with self-image, peer relationships and other social interactions. RSS in adulthood: Research about the long-term health of adults with RSS is limited and most adults with RSS are not routinely followed up. It is well recognized that being SGA at birth with accelerated gain in weight for length, particularly in early life, increases the risk of metabolic problems in adulthood. A recent study of individuals with RSS aged ≥18 years recorded impaired glucose tolerance (predisposing to diabetes) in 25%, high blood pressure in 33% and high cholesterol levels in 52%. In adults with RSS, other health problems (such as muscle and joint pains) have been highlighted but there remains uncertainty as to whether such problems are seen more frequently when compared to adults without RSS. Overall, however, most adults with RSS will have a normal quality of life, educational attainment and normal fertility. Genetic counseling: Genetic counseling is recommended for affected individuals and their families. In most families, only one child is affected and the chance of parents having another baby with RSS is likely to be very low. Similarly, the chance of an individual with RSS having an affected child themselves is also likely to be very low. However, in rare families, familial occurrence of RSS has been noted and the risk of recurrence can be as high as 50%. Genetic investigation is therefore important before parents are advised about recurrence risk.
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Overview of RYR1-Related Diseases
SummaryRYR1-related diseases affect skeletal muscle and are caused by changes in the RYR1 gene. These changes are referred to as genetic variants (mutations) [1]. RYR1 variants are the most common cause of muscle weakness present from birth (congenital myopathy). The RYR1 gene contains instructions for the body’s cells to produce a protein called the ryanodine receptor (RyR1) which is important for muscle function [2].IntroductionRyR1 proteins are located in skeletal muscles, more specifically on the outer edge (membrane) of a calcium-containing structure (sarcoplasmic reticulum) within muscle cells. For skeletal muscles to contract and produce force, calcium must be released from the sarcoplasmic reticulum in a highly controlled manner into the space outside the cell (cytoplasm). Here the calcium binds to other proteins to initiate muscle contraction and produce force. This process is referred to as “excitation-contraction coupling.” RyR1 acts as a gate for muscle cell calcium stores. RYR1 variants can prevent RyR1 proteins from being fully closed when they are supposed to be (causing calcium leak) or not opening fully when they are supposed to (causing decreased calcium release). Dysfunctional RyR1 can therefore impair excitation-contraction coupling resulting in muscle weakness. A visual representation of this process is available from the RYR-1 Foundation in the Clinical Care Guidelines (Chapter 3). Dysfunctional flow of calcium within muscle cells can also increase production of unstable molecules (free radicals) resulting in oxidative stress (an imbalance between free radicals and antioxidants). RyR1 proteins are susceptible to modification from oxidative stress. This modification can make the existing dysfunction in muscle cell calcium flow worse (increased RyR1 leakiness). Certain RYR1 variants can also result in less RyR1 protein being produced. Collectively these mechanisms, all stemming from defects in the RYR1 gene, are responsible for RYR1-related diseases [3].“RYR1-related diseases” is an umbrella term which covers a range of RYR1-related subtypes that affect the neuromuscular system in humans. RYR1-related diseases can be inherited in a dominant or recessive manner or result from de novo (spontaneous) variants [5]. For more information on inheritance of RYR1-related diseases, refer to the RYR-1 Clinical Care Guidelines (Chapter 1). Subtypes of RYR1-related disease have been named based on the following.Muscle biopsy findings (histopathology). Examples include:Symptoms (clinical phenotype). Examples include:Drug-gene interactions (pharmacogenetics). Examples include:Symptoms of RYR1-related diseases are often present from birth (congenital) or appear in early infancy and can be static, dynamic or a combination of both. Static symptoms (present at all times) include muscle weakness, motor delay, difficulties walking and climbing stairs, scoliosis, facial muscle weakness and eye muscle weakness (ophthalmoparesis) [13, 14]. Dynamic symptoms (come and go based on certain triggers) include heat illness, exercise-induced muscle breakdown (rhabdomyolysis), muscle pain (myalgia), muscle cramps and fatigue [8].RYR1 variants are also the leading cause of malignant hyperthermia (MH) susceptibility (MHS) accounting for >60% of cases. MH is a potentially fatal reaction which occurs in susceptible individuals following exposure to volatile anesthetics or depolarizing muscle relaxants which trigger a rapid increase in body temperature (hyperthermia) and muscle breakdown (rhabdomyolysis) [11]. MH reactions are treated with the drug Dantrolene. For more information on MHS, refer to the RYR-1 Clinical Care Guidelines (Chapter 4).Symptoms experienced by individuals with RYR1-related diseases can be highly variable; however, disease course is often non-progressive or very slowly progressive. Lifespan is generally normal in affected individuals and cognitive development is unaffected. Although there is no cure or approved treatment for RYR1-related diseases, supportive strategies including physical therapy can help manage functional impairments and promote a high quality of life.
Overview of RYR1-Related Diseases. SummaryRYR1-related diseases affect skeletal muscle and are caused by changes in the RYR1 gene. These changes are referred to as genetic variants (mutations) [1]. RYR1 variants are the most common cause of muscle weakness present from birth (congenital myopathy). The RYR1 gene contains instructions for the body’s cells to produce a protein called the ryanodine receptor (RyR1) which is important for muscle function [2].IntroductionRyR1 proteins are located in skeletal muscles, more specifically on the outer edge (membrane) of a calcium-containing structure (sarcoplasmic reticulum) within muscle cells. For skeletal muscles to contract and produce force, calcium must be released from the sarcoplasmic reticulum in a highly controlled manner into the space outside the cell (cytoplasm). Here the calcium binds to other proteins to initiate muscle contraction and produce force. This process is referred to as “excitation-contraction coupling.” RyR1 acts as a gate for muscle cell calcium stores. RYR1 variants can prevent RyR1 proteins from being fully closed when they are supposed to be (causing calcium leak) or not opening fully when they are supposed to (causing decreased calcium release). Dysfunctional RyR1 can therefore impair excitation-contraction coupling resulting in muscle weakness. A visual representation of this process is available from the RYR-1 Foundation in the Clinical Care Guidelines (Chapter 3). Dysfunctional flow of calcium within muscle cells can also increase production of unstable molecules (free radicals) resulting in oxidative stress (an imbalance between free radicals and antioxidants). RyR1 proteins are susceptible to modification from oxidative stress. This modification can make the existing dysfunction in muscle cell calcium flow worse (increased RyR1 leakiness). Certain RYR1 variants can also result in less RyR1 protein being produced. Collectively these mechanisms, all stemming from defects in the RYR1 gene, are responsible for RYR1-related diseases [3].“RYR1-related diseases” is an umbrella term which covers a range of RYR1-related subtypes that affect the neuromuscular system in humans. RYR1-related diseases can be inherited in a dominant or recessive manner or result from de novo (spontaneous) variants [5]. For more information on inheritance of RYR1-related diseases, refer to the RYR-1 Clinical Care Guidelines (Chapter 1). Subtypes of RYR1-related disease have been named based on the following.Muscle biopsy findings (histopathology). Examples include:Symptoms (clinical phenotype). Examples include:Drug-gene interactions (pharmacogenetics). Examples include:Symptoms of RYR1-related diseases are often present from birth (congenital) or appear in early infancy and can be static, dynamic or a combination of both. Static symptoms (present at all times) include muscle weakness, motor delay, difficulties walking and climbing stairs, scoliosis, facial muscle weakness and eye muscle weakness (ophthalmoparesis) [13, 14]. Dynamic symptoms (come and go based on certain triggers) include heat illness, exercise-induced muscle breakdown (rhabdomyolysis), muscle pain (myalgia), muscle cramps and fatigue [8].RYR1 variants are also the leading cause of malignant hyperthermia (MH) susceptibility (MHS) accounting for >60% of cases. MH is a potentially fatal reaction which occurs in susceptible individuals following exposure to volatile anesthetics or depolarizing muscle relaxants which trigger a rapid increase in body temperature (hyperthermia) and muscle breakdown (rhabdomyolysis) [11]. MH reactions are treated with the drug Dantrolene. For more information on MHS, refer to the RYR-1 Clinical Care Guidelines (Chapter 4).Symptoms experienced by individuals with RYR1-related diseases can be highly variable; however, disease course is often non-progressive or very slowly progressive. Lifespan is generally normal in affected individuals and cognitive development is unaffected. Although there is no cure or approved treatment for RYR1-related diseases, supportive strategies including physical therapy can help manage functional impairments and promote a high quality of life.
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Symptoms of RYR1-Related Diseases
The signs and symptoms of RYR1-related diseases are highly variable, sometimes even among affected individuals within the same family. In general, greater disease severity is associated with a recessive inheritance pattern, however, there are exceptions.Common symptoms related to skeletal muscles include:Breathing problems: It is very important to be aware of breathing problems associated with RYR1-related diseases since this can be severe to life-threatening in some patients. Weakness of breathing (respiratory) muscles can occur in affected individuals because the muscles that support breathing (diaphragm and accessory abdominal muscles) are skeletal muscles. Breathing problems can range from mild impairment of respiratory function, to sleep apnea requiring breathing support during sleep (CPAP/BiPAP), to severe breathing problems require continuous support via mechanical ventilation [13]. For more information on breathing problems associated with RYR1-related diseases, refer to the RYR-1 Clinical Care Guidelines (Chapter 5).Malignant hyperthermia: Some RYR1 variants are associated with susceptibility to malignant hyperthermia (MH), a severe and potentially fatal reaction to certain inhaled anesthetics (sedating or paralyzing drugs given by a doctor for medical/surgical procedures) or depolarizing muscle relaxants (succinylcholine) [11]. Anyone with a potentially disease-causing (pathogenic) RYR1 variant should take malignant hyperthermia precautions if anesthesia or succinylcholine is required for a medical/surgical procedure. Although rare, there are also case reports of episodic RYR1-related crises [15] (also referred to as “MH-like events,” or “awake MH”) in which individuals develop life-threatening reactions to non-anesthetic stimuli such as environmental heat stress or viral illness [16, 17]. For more information on MH, refer to the RYR-1 Clinical Care Guidelines (Chapter 4).Exertional rhabdomyolysis: Certain RYR1 variants may also lower the threshold for onset of muscle fiber breakdown upon physical exertion (exertional rhabdomyolysis), accounting for up to 30% of reported cases [8]. Symptoms include muscle pain, exercise intolerance, and cold-induced muscle stiffness. Affected individuals are often asymptomatic prior to being exposed to one or more triggers which include exercise in the heat, viral illness and use of statin medications. A subset of individuals with RYR1-related exertional rhabdomyolysis also test positive for malignant hyperthermia susceptibility. Preventative measures for exertional rhabdomyolysis include limiting exercise in hot and humid environments and consulting a sports medicine specialist or physical therapist to help develop a structured incremental exercise program at lower intensities. For more information on exertional rhabdomyolysis, refer to the RYR-1 Clinical Care Guidelines (Chapter 4).
Symptoms of RYR1-Related Diseases. The signs and symptoms of RYR1-related diseases are highly variable, sometimes even among affected individuals within the same family. In general, greater disease severity is associated with a recessive inheritance pattern, however, there are exceptions.Common symptoms related to skeletal muscles include:Breathing problems: It is very important to be aware of breathing problems associated with RYR1-related diseases since this can be severe to life-threatening in some patients. Weakness of breathing (respiratory) muscles can occur in affected individuals because the muscles that support breathing (diaphragm and accessory abdominal muscles) are skeletal muscles. Breathing problems can range from mild impairment of respiratory function, to sleep apnea requiring breathing support during sleep (CPAP/BiPAP), to severe breathing problems require continuous support via mechanical ventilation [13]. For more information on breathing problems associated with RYR1-related diseases, refer to the RYR-1 Clinical Care Guidelines (Chapter 5).Malignant hyperthermia: Some RYR1 variants are associated with susceptibility to malignant hyperthermia (MH), a severe and potentially fatal reaction to certain inhaled anesthetics (sedating or paralyzing drugs given by a doctor for medical/surgical procedures) or depolarizing muscle relaxants (succinylcholine) [11]. Anyone with a potentially disease-causing (pathogenic) RYR1 variant should take malignant hyperthermia precautions if anesthesia or succinylcholine is required for a medical/surgical procedure. Although rare, there are also case reports of episodic RYR1-related crises [15] (also referred to as “MH-like events,” or “awake MH”) in which individuals develop life-threatening reactions to non-anesthetic stimuli such as environmental heat stress or viral illness [16, 17]. For more information on MH, refer to the RYR-1 Clinical Care Guidelines (Chapter 4).Exertional rhabdomyolysis: Certain RYR1 variants may also lower the threshold for onset of muscle fiber breakdown upon physical exertion (exertional rhabdomyolysis), accounting for up to 30% of reported cases [8]. Symptoms include muscle pain, exercise intolerance, and cold-induced muscle stiffness. Affected individuals are often asymptomatic prior to being exposed to one or more triggers which include exercise in the heat, viral illness and use of statin medications. A subset of individuals with RYR1-related exertional rhabdomyolysis also test positive for malignant hyperthermia susceptibility. Preventative measures for exertional rhabdomyolysis include limiting exercise in hot and humid environments and consulting a sports medicine specialist or physical therapist to help develop a structured incremental exercise program at lower intensities. For more information on exertional rhabdomyolysis, refer to the RYR-1 Clinical Care Guidelines (Chapter 4).
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Causes of RYR1-Related Diseases
Humans have two copies (alleles) of each gene, one inherited from the mother and one from the father. RYR1-related diseases can be inherited in a dominant or recessive manner and can also occur due to de novo (spontaneous) RYR1 variants.Dominant inheritance: only one copy of the gene must possess a disease-causing (pathogenic) variation for the individual to be clinically affected.Recessive inheritance: both copies of the gene must have pathogenic variations for the individual to be clinically affected. If only one copy has a pathogenic variation, the individual will be a carrier and most likely asymptomatic.De novo variants: variants which occur “spontaneously” i.e., are not present in either parent.To date more than 700 RYR1 variants have been identified, however, the majority are categorized as “variants of uncertain significance” (variants for which the association with disease has not been firmly established) [1]. The RYR1 gene contains instructions for the body’s cells to produce a large molecule (protein) called the ryanodine receptor (RyR1). RyR1 is the gatekeeper of calcium within the muscle cell. RyR1 is located on the edge (membrane) of the muscle cell calcium store (sarcoplasmic reticulum). Controlled release of calcium from the sarcoplasmic reticulum is required for skeletal muscle contraction. RYR1 variants can alter the number, structure and/or function of RyR1 channels, which can lead to the wide range of symptoms described in the previous section [18].
Causes of RYR1-Related Diseases. Humans have two copies (alleles) of each gene, one inherited from the mother and one from the father. RYR1-related diseases can be inherited in a dominant or recessive manner and can also occur due to de novo (spontaneous) RYR1 variants.Dominant inheritance: only one copy of the gene must possess a disease-causing (pathogenic) variation for the individual to be clinically affected.Recessive inheritance: both copies of the gene must have pathogenic variations for the individual to be clinically affected. If only one copy has a pathogenic variation, the individual will be a carrier and most likely asymptomatic.De novo variants: variants which occur “spontaneously” i.e., are not present in either parent.To date more than 700 RYR1 variants have been identified, however, the majority are categorized as “variants of uncertain significance” (variants for which the association with disease has not been firmly established) [1]. The RYR1 gene contains instructions for the body’s cells to produce a large molecule (protein) called the ryanodine receptor (RyR1). RyR1 is the gatekeeper of calcium within the muscle cell. RyR1 is located on the edge (membrane) of the muscle cell calcium store (sarcoplasmic reticulum). Controlled release of calcium from the sarcoplasmic reticulum is required for skeletal muscle contraction. RYR1 variants can alter the number, structure and/or function of RyR1 channels, which can lead to the wide range of symptoms described in the previous section [18].
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RYR1-Related Diseases
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Affects of RYR1-Related Diseases
RYR1-related diseases are rare and classified as an orphan disease with an estimated prevalence of least 1:90,000 in the United States [19]. This estimate was based on a pediatric population study. Based on this, the overall frequency in the general population is likely to be higher. True disease prevalence is difficult to calculate since many cases go misdiagnosed or undiagnosed. There are also reports of slightly increased prevalence in certain ethnic and geographic populations.
Affects of RYR1-Related Diseases. RYR1-related diseases are rare and classified as an orphan disease with an estimated prevalence of least 1:90,000 in the United States [19]. This estimate was based on a pediatric population study. Based on this, the overall frequency in the general population is likely to be higher. True disease prevalence is difficult to calculate since many cases go misdiagnosed or undiagnosed. There are also reports of slightly increased prevalence in certain ethnic and geographic populations.
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Related disorders of RYR1-Related Diseases
RYR-1-related disease subtypes have historically been defined by muscle biopsy findings (histopathology) and/or symptoms (clinical phenotype) [20].Subtypes based on muscle biopsy findingsRYR1 variants lead to changes within the muscle cell that can be visualized on muscle biopsy tissue under the microscope. This is done using staining techniques in the laboratory (histopathology). Although histopathology remains an important step in diagnosing neuromuscular disorders, genetic testing is required to link the muscle biopsy findings to a specific gene, such as RYR1. This is because similar muscle biopsy findings can be observed across different neuromuscular disorders. These findings may also change over time (e.g., may not be present when biopsied at a young age).The earliest reports of these muscle biopsy findings predate genetic testing. As such, many early cases cannot be definitively linked to RYR1. However, following the advent of genetic testing, the link between RYR1 and certain muscle biopsy findings became clearer. Several subtypes are described below.Central core disease (CCD): First described by Magee and Shy in 1956 [21]. CCD is usually inherited in a dominant manner. When looked at under the microscope, CCD muscle fibers are stained dark but also have light areas in the middle of fibers which have no stain. These light areas represent an absence of mitochondrial activity [22]. Mitochondria are the structures responsible for generating energy for the cell.CCD causes mild to very severe muscle weakness, however, most affected individuals experience persistent, mild muscle weakness that may worsen over time. This weakness affects the muscles near the trunk of the body (proximal muscles), particularly in the upper legs and hips. Muscle weakness can also cause affected infants to appear “floppy” and result in a delay of motor milestones such as sitting, standing, and walking. Severely affected infants experience profoundly weak muscle tone (hypotonia), resulting in feeding difficulties and serious or life-threatening breathing problems. CCD is also associated with abnormalities of the skeleton such as excessive curvature of the spine (scoliosis), hip dislocation and joint deformities called contractures that restrict the movement of certain joints. Individuals with CCD are usually able to walk throughout their lifetime [4]. More information about CCD can be found here.Multiminicore disease (MmD): MmD was first described as multicore disease by Engel and colleagues in 1971 [23]. MmD is inherited in a recessive manner and causes muscle weakness and related health problems ranging from mild to life-threatening. When looked at under the microscope, MmD muscle fibers are stained dark but also have several light areas within each muscle fiber that have no stain resulting in a “moth-eaten” appearance. As in CCD, these areas without staining represent an absence of mitochondrial activity.In general, MmD causes more severe symptoms than CCD [24]. Researchers have identified four distinct forms of MmD:Muscle weakness causes affected infants to appear “floppy” with poor muscle tone (hypotonia) and results in delay of motor milestones such as sitting, standing, and walking. Stiffness of the chest wall and the spine has been associated with MmD. When combined with weakness of the muscles needed for breathing, severe or life-threatening respiratory problems can occur. Almost all children with MmD develop an abnormal curvature of the spine (scoliosis), which appears during childhood and steadily worsens over time. Although MmD is most frequently associated with RYR1 variants, MmD has also been reported in individuals with variants in other genes such as SEPN1 [4]. More information about MmD can be found here.Congenital fiber type disproportion (CFTD): First described by Brooke and colleagues in 1969 [25], CFTD is inherited in a recessive manner [6]. When looked at under the microscope, CFTD muscle tissue has type 1 (slow-twitch) muscle fibers that are consistently smaller than type 2 (fast-twitch) muscle fibers.CFTD causes muscle weakness, particularly in the muscles of the shoulders, upper arms, hips and thighs. Weakness can also affect facial muscles, extraocular muscles that control eye movement (ophthalmoplegia) and muscles of the upper eyelid (ptosis). Individuals with CFTD generally have a long face, a high arch in the roof of the mouth (high-arched palate) and crowded teeth. Affected individuals may have joint deformities (contractures) and an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Approximately 30% of people with CFTD experience mild to severe breathing problems related to weakness of muscles needed for breathing. Some people who experience these breathing problems require use of a machine to help regulate their breathing at night, and occasionally during the day as well. About 30% of affected individuals have difficulty swallowing due to muscle weakness in the throat. Rarely, people with this condition have a weakened and enlarged heart muscle (dilated cardiomyopathy) [26]. More information on CFTD can be found here.Centronuclear myopathy (CNM): First described by Spiro and colleagues in 1966 [27], CNM is inherited in a recessive manner. When looked at under the microscope, CNM muscle fibers show nuclei (structures containing chromosomes) that are localized to the center of muscle fibers, rather than to the periphery. This muscle biopsy finding has also been identified in several other genetic neuromuscular disorders including MTM1, BIN1 and DNM2-related myopathies.CNM can cause muscle weakness at any time from birth to early adulthood. Muscle weakness due to CNM can lead to delayed motor milestones (crawling or walking) and can be slowly progressive. Some affected individuals may require wheelchair assistance. Other symptoms include mild to severe breathing problems, upper eyelid drooping(ptosis), weakness in facial muscles, foot abnormalities, high arch in the roof of the mouth (high-arched palate) and abnormal curvature of the spine (scoliosis) [5]. More information on CNM can be found here.Other RYR1-related disease subtypes based on histopathology include dusty core disease (DuCD) [28], congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) [29], and core-rod myopathy [30].Subtypes based on clinical phenotypeMany RYR1-related diseases have been characterized by their associated symptoms (clinical phenotype). Several of these subtypes are described below.Malignant hyperthermia susceptibility (MHS): MHS was first described in humans by Denborough and Lovell in 1960 [31]. MHS individuals may experience normal everyday functioning without any muscle weakness. However, when exposed to certain anesthetic agents or depolarizing muscle relaxants, patients can experience an episode of malignant hyperthermia (MH). MH episodes are characterized by an abnormal increase in body heat and metabolism with associated muscle rigidity and increased heart rate. Body temperature may exceed 110 degrees Fahrenheit and muscle breakdown can co-occur. Severe complications of MH include brain damage, internal bleeding, cardiac arrest, and/or multisystem organ failure. Associated cardiovascular complications can be fatal. Patients who develop an MH episode are treated with the drug dantrolene [11]. Guidelines for interpreting whether RYR1 variants are disease-causing (pathogenic) for MH are currently being developed [32]. Anyone with a potentially pathogenic RYR1 variant is advised to take MH precautions. This includes wearing a MH alert bracelet and speaking with your physician about your RYR1 variant before undergoing anesthetic procedures or using muscle relaxants. More information on MH precautions and questions to ask your physician are provided here and in the RYR-1 Clinical Care Guidelines (Chapter 4).Two organizations exist that are dedicated to malignant hyperthermia:Rhabdomyolysis-myalgia syndrome and heat-related illness: Individuals who are MH susceptible due to one or more RYR1 variants are also at risk for muscle breakdown (rhabdomyolysis) as well as other heat and exertion-related muscle pain (myalgia) and cramping symptoms [8]. Rhabdomyolysis is associated with a range of external triggers, including strenuous exercise beyond the limit of fatigue, heat stress, illicit drug or alcohol abuse, use of supplements or certain medications, recent viral illness or muscle trauma. Signs and symptoms of rhabdomyolysis include severe muscle pain, sudden elevation and subsequent fall of serum creatine phosphokinase (CPK) levels and products of muscle breakdown in the urine (myoglobinuria). The course of rhabdomyolysis is mostly characterized by myalgia with mild to moderate CPK increases. In these mild cases, many patients will not seek medical attention. However, in some patients the clinical course is severe, resulting in profound elevations in CPK levels (hyperCKaemia), acute renal failure, increased pressure within muscles (compartment syndrome), formation of blood clots (disseminated intravascular coagulation), cardiac arrhythmias secondary to electrolyte imbalances and possibly cardiac arrest if left untreated [33]. Therefore, individuals with one or more RYR1 variants associated with MH should be aware of the rhabdomyolysis triggers and may want to consult with a sports medicine physician prior to the initiation of an exercise regimen and/or sporting activities.Other syndromes and conditions associated with RYR1 variations include King-Denborough syndrome [7], fetal akinesia deformation syndrome (FADS) [34, 35], lethal multiple pterygium syndrome (LMPS) [34], exertional heat illness (EHI) [36], late-onset axial myopathy [9], distal myopathy [37], samaritan myopathy [38] and atypical periodic paralysis [39].
Related disorders of RYR1-Related Diseases. RYR-1-related disease subtypes have historically been defined by muscle biopsy findings (histopathology) and/or symptoms (clinical phenotype) [20].Subtypes based on muscle biopsy findingsRYR1 variants lead to changes within the muscle cell that can be visualized on muscle biopsy tissue under the microscope. This is done using staining techniques in the laboratory (histopathology). Although histopathology remains an important step in diagnosing neuromuscular disorders, genetic testing is required to link the muscle biopsy findings to a specific gene, such as RYR1. This is because similar muscle biopsy findings can be observed across different neuromuscular disorders. These findings may also change over time (e.g., may not be present when biopsied at a young age).The earliest reports of these muscle biopsy findings predate genetic testing. As such, many early cases cannot be definitively linked to RYR1. However, following the advent of genetic testing, the link between RYR1 and certain muscle biopsy findings became clearer. Several subtypes are described below.Central core disease (CCD): First described by Magee and Shy in 1956 [21]. CCD is usually inherited in a dominant manner. When looked at under the microscope, CCD muscle fibers are stained dark but also have light areas in the middle of fibers which have no stain. These light areas represent an absence of mitochondrial activity [22]. Mitochondria are the structures responsible for generating energy for the cell.CCD causes mild to very severe muscle weakness, however, most affected individuals experience persistent, mild muscle weakness that may worsen over time. This weakness affects the muscles near the trunk of the body (proximal muscles), particularly in the upper legs and hips. Muscle weakness can also cause affected infants to appear “floppy” and result in a delay of motor milestones such as sitting, standing, and walking. Severely affected infants experience profoundly weak muscle tone (hypotonia), resulting in feeding difficulties and serious or life-threatening breathing problems. CCD is also associated with abnormalities of the skeleton such as excessive curvature of the spine (scoliosis), hip dislocation and joint deformities called contractures that restrict the movement of certain joints. Individuals with CCD are usually able to walk throughout their lifetime [4]. More information about CCD can be found here.Multiminicore disease (MmD): MmD was first described as multicore disease by Engel and colleagues in 1971 [23]. MmD is inherited in a recessive manner and causes muscle weakness and related health problems ranging from mild to life-threatening. When looked at under the microscope, MmD muscle fibers are stained dark but also have several light areas within each muscle fiber that have no stain resulting in a “moth-eaten” appearance. As in CCD, these areas without staining represent an absence of mitochondrial activity.In general, MmD causes more severe symptoms than CCD [24]. Researchers have identified four distinct forms of MmD:Muscle weakness causes affected infants to appear “floppy” with poor muscle tone (hypotonia) and results in delay of motor milestones such as sitting, standing, and walking. Stiffness of the chest wall and the spine has been associated with MmD. When combined with weakness of the muscles needed for breathing, severe or life-threatening respiratory problems can occur. Almost all children with MmD develop an abnormal curvature of the spine (scoliosis), which appears during childhood and steadily worsens over time. Although MmD is most frequently associated with RYR1 variants, MmD has also been reported in individuals with variants in other genes such as SEPN1 [4]. More information about MmD can be found here.Congenital fiber type disproportion (CFTD): First described by Brooke and colleagues in 1969 [25], CFTD is inherited in a recessive manner [6]. When looked at under the microscope, CFTD muscle tissue has type 1 (slow-twitch) muscle fibers that are consistently smaller than type 2 (fast-twitch) muscle fibers.CFTD causes muscle weakness, particularly in the muscles of the shoulders, upper arms, hips and thighs. Weakness can also affect facial muscles, extraocular muscles that control eye movement (ophthalmoplegia) and muscles of the upper eyelid (ptosis). Individuals with CFTD generally have a long face, a high arch in the roof of the mouth (high-arched palate) and crowded teeth. Affected individuals may have joint deformities (contractures) and an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Approximately 30% of people with CFTD experience mild to severe breathing problems related to weakness of muscles needed for breathing. Some people who experience these breathing problems require use of a machine to help regulate their breathing at night, and occasionally during the day as well. About 30% of affected individuals have difficulty swallowing due to muscle weakness in the throat. Rarely, people with this condition have a weakened and enlarged heart muscle (dilated cardiomyopathy) [26]. More information on CFTD can be found here.Centronuclear myopathy (CNM): First described by Spiro and colleagues in 1966 [27], CNM is inherited in a recessive manner. When looked at under the microscope, CNM muscle fibers show nuclei (structures containing chromosomes) that are localized to the center of muscle fibers, rather than to the periphery. This muscle biopsy finding has also been identified in several other genetic neuromuscular disorders including MTM1, BIN1 and DNM2-related myopathies.CNM can cause muscle weakness at any time from birth to early adulthood. Muscle weakness due to CNM can lead to delayed motor milestones (crawling or walking) and can be slowly progressive. Some affected individuals may require wheelchair assistance. Other symptoms include mild to severe breathing problems, upper eyelid drooping(ptosis), weakness in facial muscles, foot abnormalities, high arch in the roof of the mouth (high-arched palate) and abnormal curvature of the spine (scoliosis) [5]. More information on CNM can be found here.Other RYR1-related disease subtypes based on histopathology include dusty core disease (DuCD) [28], congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) [29], and core-rod myopathy [30].Subtypes based on clinical phenotypeMany RYR1-related diseases have been characterized by their associated symptoms (clinical phenotype). Several of these subtypes are described below.Malignant hyperthermia susceptibility (MHS): MHS was first described in humans by Denborough and Lovell in 1960 [31]. MHS individuals may experience normal everyday functioning without any muscle weakness. However, when exposed to certain anesthetic agents or depolarizing muscle relaxants, patients can experience an episode of malignant hyperthermia (MH). MH episodes are characterized by an abnormal increase in body heat and metabolism with associated muscle rigidity and increased heart rate. Body temperature may exceed 110 degrees Fahrenheit and muscle breakdown can co-occur. Severe complications of MH include brain damage, internal bleeding, cardiac arrest, and/or multisystem organ failure. Associated cardiovascular complications can be fatal. Patients who develop an MH episode are treated with the drug dantrolene [11]. Guidelines for interpreting whether RYR1 variants are disease-causing (pathogenic) for MH are currently being developed [32]. Anyone with a potentially pathogenic RYR1 variant is advised to take MH precautions. This includes wearing a MH alert bracelet and speaking with your physician about your RYR1 variant before undergoing anesthetic procedures or using muscle relaxants. More information on MH precautions and questions to ask your physician are provided here and in the RYR-1 Clinical Care Guidelines (Chapter 4).Two organizations exist that are dedicated to malignant hyperthermia:Rhabdomyolysis-myalgia syndrome and heat-related illness: Individuals who are MH susceptible due to one or more RYR1 variants are also at risk for muscle breakdown (rhabdomyolysis) as well as other heat and exertion-related muscle pain (myalgia) and cramping symptoms [8]. Rhabdomyolysis is associated with a range of external triggers, including strenuous exercise beyond the limit of fatigue, heat stress, illicit drug or alcohol abuse, use of supplements or certain medications, recent viral illness or muscle trauma. Signs and symptoms of rhabdomyolysis include severe muscle pain, sudden elevation and subsequent fall of serum creatine phosphokinase (CPK) levels and products of muscle breakdown in the urine (myoglobinuria). The course of rhabdomyolysis is mostly characterized by myalgia with mild to moderate CPK increases. In these mild cases, many patients will not seek medical attention. However, in some patients the clinical course is severe, resulting in profound elevations in CPK levels (hyperCKaemia), acute renal failure, increased pressure within muscles (compartment syndrome), formation of blood clots (disseminated intravascular coagulation), cardiac arrhythmias secondary to electrolyte imbalances and possibly cardiac arrest if left untreated [33]. Therefore, individuals with one or more RYR1 variants associated with MH should be aware of the rhabdomyolysis triggers and may want to consult with a sports medicine physician prior to the initiation of an exercise regimen and/or sporting activities.Other syndromes and conditions associated with RYR1 variations include King-Denborough syndrome [7], fetal akinesia deformation syndrome (FADS) [34, 35], lethal multiple pterygium syndrome (LMPS) [34], exertional heat illness (EHI) [36], late-onset axial myopathy [9], distal myopathy [37], samaritan myopathy [38] and atypical periodic paralysis [39].
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Diagnosis of RYR1-Related Diseases
The most definitive diagnostic test for RYR1-related diseases is genetic testing. A genetic test is often ordered due to clinical suspicion related to clinical signs and symptoms, family history, muscle biopsy, and muscle MRI. Muscle biopsy evaluates for changes in muscle fibers that may be associated with RYR1-related disease (e.g., CCD, MmD, CNM, CFTD). Muscle MRI allows the physician to evaluate for muscle damage throughout the body, with varying patterns being associated with forms of muscular dystrophies and myopathies, including subtypes of RYR1-related diseases.
Diagnosis of RYR1-Related Diseases. The most definitive diagnostic test for RYR1-related diseases is genetic testing. A genetic test is often ordered due to clinical suspicion related to clinical signs and symptoms, family history, muscle biopsy, and muscle MRI. Muscle biopsy evaluates for changes in muscle fibers that may be associated with RYR1-related disease (e.g., CCD, MmD, CNM, CFTD). Muscle MRI allows the physician to evaluate for muscle damage throughout the body, with varying patterns being associated with forms of muscular dystrophies and myopathies, including subtypes of RYR1-related diseases.
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Therapies of RYR1-Related Diseases
Treatment At this time, there is no cure or approved treatment for RYR1-related diseases.For acute episodes of MH, dantrolene is administered emergently. In addition, for affected individuals with a history of rhabdomyolysis and/or exertional or heat-related muscle symptoms, dantrolene has been reported as a prophylactic agent. Please consult with your physician.The RYR-1 Foundation has developed a comprehensive set of Clinical Care Guidelines for RYR1-related diseases.Supportive Therapies and Genetic CounselingPhysical therapy can be helpful in managing musculoskeletal symptoms associated with RYR1-related diseases. This includes helping to prevent tight joints (contractures), increasing mobility and developing an exercise regimen to improve endurance. Physical activity is an important component of maintaining a healthy lifestyle and preventing deterioration in muscle function. In individuals with RYR1-related diseases, regular low to moderate intensity, low-impact exercise may be of benefit. Since there are no specific guidelines on physical therapy or physical activity for RYR1-related diseases, it is best practice to speak with a physical therapist or sports medicine physician.Some individuals with RYR1-related diseases have weakness of their breathing muscles. Ventilatory support provided by a machine can therefore be an important tool for individuals with RYR1-related diseases, especially during sleep. These machines can help prevent potentially life-threatening situations (e.g., nocturnal oxygen desaturation) from occurring. These machines provide either bilevel positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP). It is therefore best practice for individuals with RYR1-related diseases to speak with a pulmonologist experienced in neuromuscular diseases to see what ventilatory support may be needed.Genetic counselling is an important component of care for individuals with genetic diseases, such as RYR1-related diseases. Certified Genetic Counselors are professionals with specialized education and training and can help to answer patient questions related to genetics and health. This ranges from helping to understand the results of genetic testing, how diseases are inherited, which genetic tests may be most appropriate and risk assessment and education related to specific diseases.
Therapies of RYR1-Related Diseases. Treatment At this time, there is no cure or approved treatment for RYR1-related diseases.For acute episodes of MH, dantrolene is administered emergently. In addition, for affected individuals with a history of rhabdomyolysis and/or exertional or heat-related muscle symptoms, dantrolene has been reported as a prophylactic agent. Please consult with your physician.The RYR-1 Foundation has developed a comprehensive set of Clinical Care Guidelines for RYR1-related diseases.Supportive Therapies and Genetic CounselingPhysical therapy can be helpful in managing musculoskeletal symptoms associated with RYR1-related diseases. This includes helping to prevent tight joints (contractures), increasing mobility and developing an exercise regimen to improve endurance. Physical activity is an important component of maintaining a healthy lifestyle and preventing deterioration in muscle function. In individuals with RYR1-related diseases, regular low to moderate intensity, low-impact exercise may be of benefit. Since there are no specific guidelines on physical therapy or physical activity for RYR1-related diseases, it is best practice to speak with a physical therapist or sports medicine physician.Some individuals with RYR1-related diseases have weakness of their breathing muscles. Ventilatory support provided by a machine can therefore be an important tool for individuals with RYR1-related diseases, especially during sleep. These machines can help prevent potentially life-threatening situations (e.g., nocturnal oxygen desaturation) from occurring. These machines provide either bilevel positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP). It is therefore best practice for individuals with RYR1-related diseases to speak with a pulmonologist experienced in neuromuscular diseases to see what ventilatory support may be needed.Genetic counselling is an important component of care for individuals with genetic diseases, such as RYR1-related diseases. Certified Genetic Counselors are professionals with specialized education and training and can help to answer patient questions related to genetics and health. This ranges from helping to understand the results of genetic testing, how diseases are inherited, which genetic tests may be most appropriate and risk assessment and education related to specific diseases.
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Overview of Sacrococcygeal Teratoma
Sacrococcygeal teratomas are rare tumors that develop at the base of the spine by the tailbone (coccyx) known as the sacrococcygeal region. Although most of these tumors are non-cancerous (benign), they may grow quite large and once diagnosed, always require surgical removal. It is likely that all sacrococcygeal teratomas are present at birth (congenital) and most are discovered before birth by a routine prenatal ultrasound examination or an exam indicated for a uterus too large for dates. In rare cases, sacrococcygeal teratomas may be cancerous (malignant) at birth and many will become malignant if surgical resection is not performed. In extremely rare cases, sacrococcygeal tumors may be seen in adults. Most of these represent slow growing tumors that originated prenatally. In the majority of these cases, the tumor is benign, but may cause lower back pain and genitourinary and gastrointestinal symptoms. The cause of sacrococcygeal teratomas is unknown.
Overview of Sacrococcygeal Teratoma. Sacrococcygeal teratomas are rare tumors that develop at the base of the spine by the tailbone (coccyx) known as the sacrococcygeal region. Although most of these tumors are non-cancerous (benign), they may grow quite large and once diagnosed, always require surgical removal. It is likely that all sacrococcygeal teratomas are present at birth (congenital) and most are discovered before birth by a routine prenatal ultrasound examination or an exam indicated for a uterus too large for dates. In rare cases, sacrococcygeal teratomas may be cancerous (malignant) at birth and many will become malignant if surgical resection is not performed. In extremely rare cases, sacrococcygeal tumors may be seen in adults. Most of these represent slow growing tumors that originated prenatally. In the majority of these cases, the tumor is benign, but may cause lower back pain and genitourinary and gastrointestinal symptoms. The cause of sacrococcygeal teratomas is unknown.
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Symptoms of Sacrococcygeal Teratoma
The symptoms that occur with sacrococcygeal teratomas vary widely depending upon the size and specific location of the tumor. Small tumors often do not cause any symptoms (asymptomatic) and can usually be removed surgically after birth without difficulty.However, larger sacrococcygeal tumors can cause a variety of complications before and after birth. Sacrococcygeal teratomas can grow rapidly in the fetus and require very high blood flow resulting in fetal heart failure, a condition known as hydrops. This is manifest as dilation of the heart, and the collection of fluid in tissues of the body, including the skin and body cavities such as around the lungs (pleural effusion), around the heart (pericardial effusion), and/or in the abdominal cavity (ascites). If neglected, hydrops can also be dangerous for the mother resulting in similar symptoms of swelling, hypertension, and fluid on the lungs with shortness of breath. In addition to hydrops, which can occur in approximately 15% of very large fetal sacrococcygeal teratomas, these tumors can cause polyhydramnios (too much amniotic fluid), fetal urinary obstruction (hydronephrosis), bleeding into the tumor or rupture of the tumor with bleeding into the amniotic space, or dystocia (a condition where the fetus cannot be delivered due to the size of the tumor. It is very important to have very close monitoring during pregnancy to recognize these symptoms as early as possible.In adults, sacrococcygeal teratomas may not cause symptoms (asymptomatic). In some cases, they may cause progressive lower back pain, weakness, and abnormalities due to obstruction of the genitourinary and gastrointestinal tracts. Such symptoms include constipation and increased frequency of stools or urinary tract infections. In rare cases, sacrococcygeal tumors cause partial paralysis (paresis) of the legs and tingling or numbness (paresthesia).
Symptoms of Sacrococcygeal Teratoma. The symptoms that occur with sacrococcygeal teratomas vary widely depending upon the size and specific location of the tumor. Small tumors often do not cause any symptoms (asymptomatic) and can usually be removed surgically after birth without difficulty.However, larger sacrococcygeal tumors can cause a variety of complications before and after birth. Sacrococcygeal teratomas can grow rapidly in the fetus and require very high blood flow resulting in fetal heart failure, a condition known as hydrops. This is manifest as dilation of the heart, and the collection of fluid in tissues of the body, including the skin and body cavities such as around the lungs (pleural effusion), around the heart (pericardial effusion), and/or in the abdominal cavity (ascites). If neglected, hydrops can also be dangerous for the mother resulting in similar symptoms of swelling, hypertension, and fluid on the lungs with shortness of breath. In addition to hydrops, which can occur in approximately 15% of very large fetal sacrococcygeal teratomas, these tumors can cause polyhydramnios (too much amniotic fluid), fetal urinary obstruction (hydronephrosis), bleeding into the tumor or rupture of the tumor with bleeding into the amniotic space, or dystocia (a condition where the fetus cannot be delivered due to the size of the tumor. It is very important to have very close monitoring during pregnancy to recognize these symptoms as early as possible.In adults, sacrococcygeal teratomas may not cause symptoms (asymptomatic). In some cases, they may cause progressive lower back pain, weakness, and abnormalities due to obstruction of the genitourinary and gastrointestinal tracts. Such symptoms include constipation and increased frequency of stools or urinary tract infections. In rare cases, sacrococcygeal tumors cause partial paralysis (paresis) of the legs and tingling or numbness (paresthesia).
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Causes of Sacrococcygeal Teratoma
The cause of sacrococcygeal teratomas is unknown. Sacrococcygeal teratomas are germ cell tumors. Germ cells are the cells that develop into the embryo and later on become the cells that make up the reproductive system of men and women. Most germ cell tumors occur in the testes or ovaries (gonads) or the lower back. When these tumors occur outside of the gonads, they are known as extragonadal tumors. Researchers do not know how extragonadal germ cell tumors form. One theory suggests that germ cells accidentally migrate during to unusual locations early during the development of the embryo (embryogenesis). Normally, such misplaced germ cells degenerate and die, but in cases of extragonadal teratomas researchers speculate that these cells continue to undergo mitosis, the process where cells divide and multiply, eventually forming a teratoma.Sacrococcygeal teratomas are thought to arise from an area under the coccyx called “Henson's Node”. This is an area where primitive cells persist (germ cells) that can give rise to cells of the three major tissue layers of an embryo: ectoderm, endoderm, and mesoderm. These embryonic layers eventually give rise to the various cells and structures of the body. Sacrococcygeal teratomas can contain mature tissue that looks like any tissue in the body, or immature tissue resembling embryonic tissues.
Causes of Sacrococcygeal Teratoma. The cause of sacrococcygeal teratomas is unknown. Sacrococcygeal teratomas are germ cell tumors. Germ cells are the cells that develop into the embryo and later on become the cells that make up the reproductive system of men and women. Most germ cell tumors occur in the testes or ovaries (gonads) or the lower back. When these tumors occur outside of the gonads, they are known as extragonadal tumors. Researchers do not know how extragonadal germ cell tumors form. One theory suggests that germ cells accidentally migrate during to unusual locations early during the development of the embryo (embryogenesis). Normally, such misplaced germ cells degenerate and die, but in cases of extragonadal teratomas researchers speculate that these cells continue to undergo mitosis, the process where cells divide and multiply, eventually forming a teratoma.Sacrococcygeal teratomas are thought to arise from an area under the coccyx called “Henson's Node”. This is an area where primitive cells persist (germ cells) that can give rise to cells of the three major tissue layers of an embryo: ectoderm, endoderm, and mesoderm. These embryonic layers eventually give rise to the various cells and structures of the body. Sacrococcygeal teratomas can contain mature tissue that looks like any tissue in the body, or immature tissue resembling embryonic tissues.
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Affects of Sacrococcygeal Teratoma
Sacrococcygeal teratomas occur in females more often than males by a 4:1 ratio. Malignancy is more common in males. The prevalence of these tumors is estimated to be between 1 in 30,000-70,000 live births. Sacrococcygeal teratomas are the most common solid tumor found in newborn babies (neonates). The sacrococcygeal region is the most common site for a teratoma in infants. Sacrococcygeal teratomas affecting adults is extremely rare. Adults cases often represent tumors that were present at birth (congenital), but not detected until adulthood.
Affects of Sacrococcygeal Teratoma. Sacrococcygeal teratomas occur in females more often than males by a 4:1 ratio. Malignancy is more common in males. The prevalence of these tumors is estimated to be between 1 in 30,000-70,000 live births. Sacrococcygeal teratomas are the most common solid tumor found in newborn babies (neonates). The sacrococcygeal region is the most common site for a teratoma in infants. Sacrococcygeal teratomas affecting adults is extremely rare. Adults cases often represent tumors that were present at birth (congenital), but not detected until adulthood.
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Related disorders of Sacrococcygeal Teratoma
Symptoms of the following disorders can be similar to those of sacrococcygeal teratomas. Comparisons may be useful for a differential diagnosis.Myelomeningocele is a congenital birth defect in which the spinal canal and backbone do not close properly, often causing the spinal cord and the membranes that cover the spinal cord (meninges) to protrude from the back. Myelomeningocele is the most common form of spina bifida, a general term for any congenital defect in which closure of the spine is incomplete. Symptoms are related to the specific location of the defect and may include paralysis of the legs, loss of bladder or bowel control, and lack of sensation in the affected area. The exact cause of myelomeningocele is unknown. (For more information on this disorder, choose “spina bifida” as your search term in the Rare Disease Database.)Chordomas are rare primary bone tumors that can arise at almost any point along the axis of the spine from the base of the skull to the sacrum and coccyx (tailbone). The incidence of chordoma in the general U.S. population is about 8 per 10,000,000 people. They occur somewhat more often in males than females. Under the microscope, chordoma cells appear to be benign, but because of their location, invasive nature, and recurrence rate, the tumors are considered to be malignant. They arise from cellular remnants of the primitive notochord, which is present in the early embryo. In normal mammalian development, the notochord and substances produced by it are involved in forming the tissues that give rise to vertebrae. Normally, the tissues derived from the notochord disappear after the vertebral bodies have begun forming. However, in a small percentage of people, some tissues from the notochord do not disappear. Rarely, these leftover tissues give rise to chordomas. About one-third of chordomas are found in the region around the clivus. The clivus is a bone in the base of the skull. It is located in front of the brainstem and behind the back of the throat (nasopharynx). Chordomas occur with equal frequency in the skull base, the vertebrae and the sacrococcygeal area towards the bottom of the spine. Symptoms of the presence of chordomas vary with their location and size. Most chordomas occur randomly among the population (sporadic). (For more information on this disorder, choose “chordoma” as your search term in the Rare Disease Database.)A variety of additional tumors must be differentiated from individuals with sacrococcygeal teratomas including tumors consisting of fat (lipomas), extrarenal Wilms' tumor, hamartomas, neuroblastomas, and pacinomas.
Related disorders of Sacrococcygeal Teratoma. Symptoms of the following disorders can be similar to those of sacrococcygeal teratomas. Comparisons may be useful for a differential diagnosis.Myelomeningocele is a congenital birth defect in which the spinal canal and backbone do not close properly, often causing the spinal cord and the membranes that cover the spinal cord (meninges) to protrude from the back. Myelomeningocele is the most common form of spina bifida, a general term for any congenital defect in which closure of the spine is incomplete. Symptoms are related to the specific location of the defect and may include paralysis of the legs, loss of bladder or bowel control, and lack of sensation in the affected area. The exact cause of myelomeningocele is unknown. (For more information on this disorder, choose “spina bifida” as your search term in the Rare Disease Database.)Chordomas are rare primary bone tumors that can arise at almost any point along the axis of the spine from the base of the skull to the sacrum and coccyx (tailbone). The incidence of chordoma in the general U.S. population is about 8 per 10,000,000 people. They occur somewhat more often in males than females. Under the microscope, chordoma cells appear to be benign, but because of their location, invasive nature, and recurrence rate, the tumors are considered to be malignant. They arise from cellular remnants of the primitive notochord, which is present in the early embryo. In normal mammalian development, the notochord and substances produced by it are involved in forming the tissues that give rise to vertebrae. Normally, the tissues derived from the notochord disappear after the vertebral bodies have begun forming. However, in a small percentage of people, some tissues from the notochord do not disappear. Rarely, these leftover tissues give rise to chordomas. About one-third of chordomas are found in the region around the clivus. The clivus is a bone in the base of the skull. It is located in front of the brainstem and behind the back of the throat (nasopharynx). Chordomas occur with equal frequency in the skull base, the vertebrae and the sacrococcygeal area towards the bottom of the spine. Symptoms of the presence of chordomas vary with their location and size. Most chordomas occur randomly among the population (sporadic). (For more information on this disorder, choose “chordoma” as your search term in the Rare Disease Database.)A variety of additional tumors must be differentiated from individuals with sacrococcygeal teratomas including tumors consisting of fat (lipomas), extrarenal Wilms' tumor, hamartomas, neuroblastomas, and pacinomas.
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Diagnosis of Sacrococcygeal Teratoma
In most cases, sacrococcygeal teratomas are diagnosed at birth when a large tumor is detected protruding from the sacral region. Many sacrococcygeal teratomas are found incidentally on routine prenatal ultrasounds or they may be detected on an ultrasound that is obtained because the uterus is too large for the stage of pregnancy due to the bulk of the tumor, or accumulation of amniotic fluid. During an ultrasound, reflected sound waves create an image of the developing fetus. Even small sacrococcygeal teratomas may be visible on an ultrasound picture.In some cases, a sample of the amniotic fluid or maternal serum may be taken and studied to determine the levels of alpha-fetoprotein (AFP). AFP is a normal fetal plasma protein that when elevated may indicate the presence of certain conditions such as a sacrococcygeal teratoma.If a sacrococcygeal teratoma is diagnosed prenatally a careful examination is usually done to rule out other anomalies. In some institutions a fetal MRI scan is also performed to better delineate the anatomy of the tumor and displaced structures. For large sacrococcygeal teratomas, very frequent ultrasounds and echocardiograms (to measure the size of the cardiac chambers and blood flows) are required to monitor for signs of evolving hydrops. During an echocardiogram, reflected sound waves are used to take pictures of the heart. It is extremely important that a medical team experienced with large fetal sacrococcygeal teratoma follows the pregnancy. All fetuses with large sacrococcygeal teratomas need delivery by a “classical” cesarean section (large incision in the uterus) to avoid tumor rupture and hemorrhage at the time of delivery. Most fetuses with large tumors are born premature and need expert perinatal care from a multidisciplinary team.In adults, a diagnosis of sacrococcygeal teratoma may be suspected during a routine pelvic or rectal examination that detects the presence of a mass or tumor. A diagnosis of sacrococcygeal teratoma may be confirmed by surgical removal and microscopic examination of affected tissue (biopsy). One procedure is known as fine needle aspiration, in which a thin, hollow needle is passed though the skin and inserted into the nodule or mass to withdraw small samples of tissue for study.In addition to an ultrasound, other specialized imaging techniques may be used to diagnose a tumor as well as evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures. After birth, such imaging techniques may 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. In cases of malignant sacrococcygeal teratomas, laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases.StagingWhen an individual is diagnosed with a sacrococcygeal teratoma, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. Certain of the same diagnostic tests described above may be used in staging.Sacrococcygeal teratomas are classified according to the American Academy of Pediatrics Surgical Section:Type I – the tumor is predominantly external with a very minimal internal component. Type I is rarely associated with malignancy.Type II – the tumor is predominantly external but has some internal extension into the presacral space.Type III – the tumor is visible externally, but is predominantly located in the pelvic area with some extension into the abdomen.Type IV – the tumor is not visible externally and is located in the presacral space. Type IV has the highest rate of malignancy.
Diagnosis of Sacrococcygeal Teratoma. In most cases, sacrococcygeal teratomas are diagnosed at birth when a large tumor is detected protruding from the sacral region. Many sacrococcygeal teratomas are found incidentally on routine prenatal ultrasounds or they may be detected on an ultrasound that is obtained because the uterus is too large for the stage of pregnancy due to the bulk of the tumor, or accumulation of amniotic fluid. During an ultrasound, reflected sound waves create an image of the developing fetus. Even small sacrococcygeal teratomas may be visible on an ultrasound picture.In some cases, a sample of the amniotic fluid or maternal serum may be taken and studied to determine the levels of alpha-fetoprotein (AFP). AFP is a normal fetal plasma protein that when elevated may indicate the presence of certain conditions such as a sacrococcygeal teratoma.If a sacrococcygeal teratoma is diagnosed prenatally a careful examination is usually done to rule out other anomalies. In some institutions a fetal MRI scan is also performed to better delineate the anatomy of the tumor and displaced structures. For large sacrococcygeal teratomas, very frequent ultrasounds and echocardiograms (to measure the size of the cardiac chambers and blood flows) are required to monitor for signs of evolving hydrops. During an echocardiogram, reflected sound waves are used to take pictures of the heart. It is extremely important that a medical team experienced with large fetal sacrococcygeal teratoma follows the pregnancy. All fetuses with large sacrococcygeal teratomas need delivery by a “classical” cesarean section (large incision in the uterus) to avoid tumor rupture and hemorrhage at the time of delivery. Most fetuses with large tumors are born premature and need expert perinatal care from a multidisciplinary team.In adults, a diagnosis of sacrococcygeal teratoma may be suspected during a routine pelvic or rectal examination that detects the presence of a mass or tumor. A diagnosis of sacrococcygeal teratoma may be confirmed by surgical removal and microscopic examination of affected tissue (biopsy). One procedure is known as fine needle aspiration, in which a thin, hollow needle is passed though the skin and inserted into the nodule or mass to withdraw small samples of tissue for study.In addition to an ultrasound, other specialized imaging techniques may be used to diagnose a tumor as well as evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures. After birth, such imaging techniques may 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. In cases of malignant sacrococcygeal teratomas, laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases.StagingWhen an individual is diagnosed with a sacrococcygeal teratoma, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. Certain of the same diagnostic tests described above may be used in staging.Sacrococcygeal teratomas are classified according to the American Academy of Pediatrics Surgical Section:Type I – the tumor is predominantly external with a very minimal internal component. Type I is rarely associated with malignancy.Type II – the tumor is predominantly external but has some internal extension into the presacral space.Type III – the tumor is visible externally, but is predominantly located in the pelvic area with some extension into the abdomen.Type IV – the tumor is not visible externally and is located in the presacral space. Type IV has the highest rate of malignancy.
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Therapies of Sacrococcygeal Teratoma
TreatmentThe initial management of a fetus with a sacrococcygeal teratoma requires the coordinated efforts of a perinatal team of medical professionals such as maternal fetal medicine physicians to deliver the infant, and pediatric surgeons and neonatologists to resect the tumor and manage the medical issues of the infant who can sometimes be critically ill. All prenatally diagnosed sacrococcygeal teratomas require resection during the neonatalperiod and if the tumor is large, as quickly as possible to avoid rupture of the tumor. Resection always involves resection of the tumor along with the coccyx. Failure to resect the coccyx is associated with a 30% local recurrence rate of the tumor. This can usually be done from the back of the neonate but for some tumors with extensive extension into the pelvis and abdomen, an abdominal incision must also be performed. Most children that undergo early resection of sacrococcygeal teratomas ultimately do well with a very low incidence of malignant or benign tumor recurrance, and normal urogenital, bowel, and lower extremity neurologic function. These children are usually followed by the pediatric surgeon by rectal examinations and interval serum AFP levels to monitor for recurrence for 3 years before they are considered cured with no possibility of tumor recurrence.In rare instances where malignancy is diagnosed by the pathologist after resection a team of medical professionals who specialize in the diagnosis and treatment of cancer (medical oncologists) will need to be consulted. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location and corresponding complications; extent of the primary tumor (stage); whether it has spread to lymph nodes or distant sites; an individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient or parents, based upon the specifics of the case; a thorough discussion of the potential benefits and risks; and other appropriate factors.In rare cases, complications resulting from a sacrococcygeal teratoma may necessitate intervention before birth (prenatally). Interventions such as tapping the amniotic fluid (amniocentesis) to reduce the volume and delay the onset of preterm labor may be required. If the tumor has hemorrhaged and the fetus is anemic, a fetal blood transfusion may be helpful. Occasionally, an obstructed fetal urinary tract will need to be treated by a vesicoamniotic shunt (a catheter between the bladder and amniotic fluid) to relieve the obstruction and prevent damage to the kidneys. In rare cases when the fetus is documented to be in the early stages of hydrops, open fetal surgery may be required (surgery on the fetus in the womb) to “debulk” the tumor and reduce the demand for blood flow. After removal of the bulk of the tumor, the fetus is returned to the womb so that the hydrops can improve prior to birth. Although this has been successful about 50% of the time, it is a major undertaking and extensive consideration of the risks to the mother is appropriate. Although radio frequency ablation (a technique where a needle is inserted into the tumor and radiofrequency energy is applied to the tumor to destroy blood flow) has been reported, all survivors have had complications of damage to the genitourinary system so this approach is considered highly experimental.In adults, surgical removal of the entire tumor and the tailbone (coccyx) is the main treatment option. Removal of the coccyx lowers the chance of recurrence. For benign tumors surgical removal of the tumor is usually sufficient. However, for malignant tumors, affected individuals should receive additional treatment with chemotherapy and radiation therapy.Because malignant sacrococcygeal teratomas are extremely rare, especially in adults, no standard chemotherapeutic regimen or radiation therapy has been established.
Therapies of Sacrococcygeal Teratoma. TreatmentThe initial management of a fetus with a sacrococcygeal teratoma requires the coordinated efforts of a perinatal team of medical professionals such as maternal fetal medicine physicians to deliver the infant, and pediatric surgeons and neonatologists to resect the tumor and manage the medical issues of the infant who can sometimes be critically ill. All prenatally diagnosed sacrococcygeal teratomas require resection during the neonatalperiod and if the tumor is large, as quickly as possible to avoid rupture of the tumor. Resection always involves resection of the tumor along with the coccyx. Failure to resect the coccyx is associated with a 30% local recurrence rate of the tumor. This can usually be done from the back of the neonate but for some tumors with extensive extension into the pelvis and abdomen, an abdominal incision must also be performed. Most children that undergo early resection of sacrococcygeal teratomas ultimately do well with a very low incidence of malignant or benign tumor recurrance, and normal urogenital, bowel, and lower extremity neurologic function. These children are usually followed by the pediatric surgeon by rectal examinations and interval serum AFP levels to monitor for recurrence for 3 years before they are considered cured with no possibility of tumor recurrence.In rare instances where malignancy is diagnosed by the pathologist after resection a team of medical professionals who specialize in the diagnosis and treatment of cancer (medical oncologists) will need to be consulted. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location and corresponding complications; extent of the primary tumor (stage); whether it has spread to lymph nodes or distant sites; an individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient or parents, based upon the specifics of the case; a thorough discussion of the potential benefits and risks; and other appropriate factors.In rare cases, complications resulting from a sacrococcygeal teratoma may necessitate intervention before birth (prenatally). Interventions such as tapping the amniotic fluid (amniocentesis) to reduce the volume and delay the onset of preterm labor may be required. If the tumor has hemorrhaged and the fetus is anemic, a fetal blood transfusion may be helpful. Occasionally, an obstructed fetal urinary tract will need to be treated by a vesicoamniotic shunt (a catheter between the bladder and amniotic fluid) to relieve the obstruction and prevent damage to the kidneys. In rare cases when the fetus is documented to be in the early stages of hydrops, open fetal surgery may be required (surgery on the fetus in the womb) to “debulk” the tumor and reduce the demand for blood flow. After removal of the bulk of the tumor, the fetus is returned to the womb so that the hydrops can improve prior to birth. Although this has been successful about 50% of the time, it is a major undertaking and extensive consideration of the risks to the mother is appropriate. Although radio frequency ablation (a technique where a needle is inserted into the tumor and radiofrequency energy is applied to the tumor to destroy blood flow) has been reported, all survivors have had complications of damage to the genitourinary system so this approach is considered highly experimental.In adults, surgical removal of the entire tumor and the tailbone (coccyx) is the main treatment option. Removal of the coccyx lowers the chance of recurrence. For benign tumors surgical removal of the tumor is usually sufficient. However, for malignant tumors, affected individuals should receive additional treatment with chemotherapy and radiation therapy.Because malignant sacrococcygeal teratomas are extremely rare, especially in adults, no standard chemotherapeutic regimen or radiation therapy has been established.
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Sacrococcygeal Teratoma
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Overview of Saethre Chotzen Syndrome
Saethre Chotzen syndrome (SCS) belongs to a group of rare genetic disorders known as “acrocephalosyndactyly” disorders. All of these are characterized by premature closure of the fibrous joints (cranial sutures) between certain bones of the skull (craniosynostosis), and/or webbing or fusion (syndactyly) of certain fingers or toes (digits). In many infants with SCS, cranial sutures may fuse unevenly and this may contribute to the head and face appearing to be dissimilar from one side to the other (craniofacial asymmetry). Additional variations of the skull and facial (craniofacial) region may also be present, such as widely spaced eyes (ocular hypertelorism) with unusually shallow eye cavities (orbits); drooping of the upper eyelids (ptosis); and a state where the eyes do not point in the same direction (strabismus). Some affected individuals may also have a “beaked” nose; deviation of the partition that separates the nostrils (deviated nasal septum); small, low-set ears; and an underdeveloped upper jaw (hypoplastic maxilla). The disorder is also associated with variations of the hands and feet, such as partial fusion of soft tissues (cutaneous syndactyly) of certain fingers and toes (digits); unusually short digits (brachydactyly); and broad great toes. Intelligence is usually normal. SCS is inherited in an autosomal dominant manner.
Overview of Saethre Chotzen Syndrome. Saethre Chotzen syndrome (SCS) belongs to a group of rare genetic disorders known as “acrocephalosyndactyly” disorders. All of these are characterized by premature closure of the fibrous joints (cranial sutures) between certain bones of the skull (craniosynostosis), and/or webbing or fusion (syndactyly) of certain fingers or toes (digits). In many infants with SCS, cranial sutures may fuse unevenly and this may contribute to the head and face appearing to be dissimilar from one side to the other (craniofacial asymmetry). Additional variations of the skull and facial (craniofacial) region may also be present, such as widely spaced eyes (ocular hypertelorism) with unusually shallow eye cavities (orbits); drooping of the upper eyelids (ptosis); and a state where the eyes do not point in the same direction (strabismus). Some affected individuals may also have a “beaked” nose; deviation of the partition that separates the nostrils (deviated nasal septum); small, low-set ears; and an underdeveloped upper jaw (hypoplastic maxilla). The disorder is also associated with variations of the hands and feet, such as partial fusion of soft tissues (cutaneous syndactyly) of certain fingers and toes (digits); unusually short digits (brachydactyly); and broad great toes. Intelligence is usually normal. SCS is inherited in an autosomal dominant manner.
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Saethre Chotzen Syndrome
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Symptoms of Saethre Chotzen Syndrome
SCS is primarily characterized by premature closure of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis), distinctive facial variations, and/or variations of the fingers and toes (digits). However, associated symptoms and findings may be extremely variable, including among affected members of the same family. For example, there have been reports in which some family members have had characteristic digital abnormalities alone, whereas others have been primarily affected by craniosynostosis. When craniosynostosis is present, the degree of skull (cranial) malformation may be variable, depending on the specific cranial sutures involved and the order and rate of progression. In many affected infants and children, early closure of the coronal suture which is found between bones forming the forehead (frontal bone) and the upper sides of the skull causes the top of the head to appear pointed (acrocephaly) or the head to seem unusually short or broad (brachycephaly). In addition, the cranial sutures often fuse unevenly, causing the head and face to appear somewhat dissimilar from one side to the other (plagiocephaly and facial asymmetry). Cases have also been reported in which the head appears triangular in shape (trigonocephaly) or the forehead is unusually prominent due to premature closure of the suture of the frontal bone (i.e. frontal or metopic suture). In some instances, early closure of certain cranial sutures may lead to abnormally increased pressure within the skull (intracranial pressure). Many individuals with SCS have additional craniofacial variations, resulting in a subtle, but distinctive, facial appearance. Such abnormalities may include a broad forehead with a low hairline; drooping of the upper eyelids (ptosis); a “beaked” nose, depressed nasal bridge, and deviated nasal septum; unusually broad, flat mid-facial regions (midface hypoplasia); and a small upper jaw (hypoplastic maxilla), with protrusion of the lower jaw (relative mandibular prognathism). Additional eye (ocular) abnormalities are also often present, such as widely spaced eyes (ocular hypertelorism); shallow eye cavities (orbits); strabismus; and/or abnormal narrowing of the tear ducts (lacrimal duct stenosis), potentially causing decreased tearing and an increased susceptibility to eye infections. Other craniofacial variations may also be associated with the disorder. Many affected individuals have small, low-set, or differences in parts of the ear (e.g. prominent ear crura). In addition, mild hearing impairment is frequent. Abnormalities of the mouth (oral) region often include a highly arched roof of the mouth (palate) and dental defects, such as absence or malformation of certain teeth, the presence of extra (supernumerary) teeth, and/or improper contact of the teeth of the upper jaw with those of the lower jaw (malocclusion) may occur. In rare cases, there may be incomplete closure of the roof of the mouth (cleft palate). SCS may also be characterized by variations of the fingers and toes (digits). Some affected individuals have partial webbing or fusion of the soft tissues (cutaneous syndactyly) of certain digits, particularly between the second and third fingers and second and third toes. However, less commonly, syndactyly extends from the second to the fourth fingers or involves other toes. Additional digital malformations may include unusually short fingers and toes (brachydactyly); abnormal bending or deviation (clinodactyly) of the fifth fingers (“pinkies”); “finger-like” thumbs; and/or broad, deviating great toes. Additional physical abnormalities may also be associated with SCS. Some affected individuals have short stature. Less commonly, musculoskeletal abnormalities may also be present, such as union or fusion of certain bones of the spinal column within the neck (cervical vertebrae), abnormal fusion of the forearm bones (radioulnar synostosis), limited extension of the elbows or knees, short collarbones (clavicles), and/or hip deformities (coxa valga). Occasional additional findings may include failure of the testes to descend into the scrotum (cryptorchidism) in affected males; kidney (renal) abnormalities; and/or heart (cardiac) defects. Most individuals with SCS have normal intelligence. However, mild to moderate intellectual disability is sometimes present. For further information, please see the “Causes” section of this report below regarding the “TWIST1” gene.
Symptoms of Saethre Chotzen Syndrome. SCS is primarily characterized by premature closure of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis), distinctive facial variations, and/or variations of the fingers and toes (digits). However, associated symptoms and findings may be extremely variable, including among affected members of the same family. For example, there have been reports in which some family members have had characteristic digital abnormalities alone, whereas others have been primarily affected by craniosynostosis. When craniosynostosis is present, the degree of skull (cranial) malformation may be variable, depending on the specific cranial sutures involved and the order and rate of progression. In many affected infants and children, early closure of the coronal suture which is found between bones forming the forehead (frontal bone) and the upper sides of the skull causes the top of the head to appear pointed (acrocephaly) or the head to seem unusually short or broad (brachycephaly). In addition, the cranial sutures often fuse unevenly, causing the head and face to appear somewhat dissimilar from one side to the other (plagiocephaly and facial asymmetry). Cases have also been reported in which the head appears triangular in shape (trigonocephaly) or the forehead is unusually prominent due to premature closure of the suture of the frontal bone (i.e. frontal or metopic suture). In some instances, early closure of certain cranial sutures may lead to abnormally increased pressure within the skull (intracranial pressure). Many individuals with SCS have additional craniofacial variations, resulting in a subtle, but distinctive, facial appearance. Such abnormalities may include a broad forehead with a low hairline; drooping of the upper eyelids (ptosis); a “beaked” nose, depressed nasal bridge, and deviated nasal septum; unusually broad, flat mid-facial regions (midface hypoplasia); and a small upper jaw (hypoplastic maxilla), with protrusion of the lower jaw (relative mandibular prognathism). Additional eye (ocular) abnormalities are also often present, such as widely spaced eyes (ocular hypertelorism); shallow eye cavities (orbits); strabismus; and/or abnormal narrowing of the tear ducts (lacrimal duct stenosis), potentially causing decreased tearing and an increased susceptibility to eye infections. Other craniofacial variations may also be associated with the disorder. Many affected individuals have small, low-set, or differences in parts of the ear (e.g. prominent ear crura). In addition, mild hearing impairment is frequent. Abnormalities of the mouth (oral) region often include a highly arched roof of the mouth (palate) and dental defects, such as absence or malformation of certain teeth, the presence of extra (supernumerary) teeth, and/or improper contact of the teeth of the upper jaw with those of the lower jaw (malocclusion) may occur. In rare cases, there may be incomplete closure of the roof of the mouth (cleft palate). SCS may also be characterized by variations of the fingers and toes (digits). Some affected individuals have partial webbing or fusion of the soft tissues (cutaneous syndactyly) of certain digits, particularly between the second and third fingers and second and third toes. However, less commonly, syndactyly extends from the second to the fourth fingers or involves other toes. Additional digital malformations may include unusually short fingers and toes (brachydactyly); abnormal bending or deviation (clinodactyly) of the fifth fingers (“pinkies”); “finger-like” thumbs; and/or broad, deviating great toes. Additional physical abnormalities may also be associated with SCS. Some affected individuals have short stature. Less commonly, musculoskeletal abnormalities may also be present, such as union or fusion of certain bones of the spinal column within the neck (cervical vertebrae), abnormal fusion of the forearm bones (radioulnar synostosis), limited extension of the elbows or knees, short collarbones (clavicles), and/or hip deformities (coxa valga). Occasional additional findings may include failure of the testes to descend into the scrotum (cryptorchidism) in affected males; kidney (renal) abnormalities; and/or heart (cardiac) defects. Most individuals with SCS have normal intelligence. However, mild to moderate intellectual disability is sometimes present. For further information, please see the “Causes” section of this report below regarding the “TWIST1” gene.
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Saethre Chotzen Syndrome
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Causes of Saethre Chotzen Syndrome
In most individuals, SCS is caused by mutations in the TWIST1 gene. The TWIST1 gene has been mapped to the short arm (p) of chromosome 7 (7p21). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “7p21” refers to band 21 on the short arm of chromosome 7. Although learning differences may be noted in individuals with mutations in TWIST1, severe delay or intellectual disability is not typical. In contrast, individuals with a deletion (missing piece) of chromosome 7p21, that includes TWIST1 and other adjacent genes, usually show significant intellectual disability. In most cases, individuals with a SCS associated mutation will manifest some features of this condition (high penetrance). However, they type and severity of manifestations may vary greatly between individuals (variable expressivity). The majority of individuals with an identified mutation have a fault in the TWIST gene, however at least one individual has been identified with a mutation in the FGFR2 gene.SCS is an autosomal dominant condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is sufficient to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% (1 in2) for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
Causes of Saethre Chotzen Syndrome. In most individuals, SCS is caused by mutations in the TWIST1 gene. The TWIST1 gene has been mapped to the short arm (p) of chromosome 7 (7p21). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “7p21” refers to band 21 on the short arm of chromosome 7. Although learning differences may be noted in individuals with mutations in TWIST1, severe delay or intellectual disability is not typical. In contrast, individuals with a deletion (missing piece) of chromosome 7p21, that includes TWIST1 and other adjacent genes, usually show significant intellectual disability. In most cases, individuals with a SCS associated mutation will manifest some features of this condition (high penetrance). However, they type and severity of manifestations may vary greatly between individuals (variable expressivity). The majority of individuals with an identified mutation have a fault in the TWIST gene, however at least one individual has been identified with a mutation in the FGFR2 gene.SCS is an autosomal dominant condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is sufficient to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% (1 in2) for each pregnancy. The risk is the same for males and females.In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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Saethre Chotzen Syndrome
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Affects of Saethre Chotzen Syndrome
SCS affects males and females in equal numbers. Due to its variability including that manifestations can be mild, SCS may often go unrecognized. Therefore, it is difficult to determine the true frequency of the disorder in the general population.
Affects of Saethre Chotzen Syndrome. SCS affects males and females in equal numbers. Due to its variability including that manifestations can be mild, SCS may often go unrecognized. Therefore, it is difficult to determine the true frequency of the disorder in the general population.
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Related disorders of Saethre Chotzen Syndrome
The findings in the following disorders may be similar to those of Saethre-Chotzen syndrome. Comparisons may be useful for a differential diagnosis: Muenke syndrome may cause premature fusion of one or both coronal sutures. It is an autosomal dominant condition associated with a specific mutation (p.Pro250Arg) in the FGFR3 gene. Features that are typically absent in this condition and that may be present in SCS include: ptosis, ear abnormalities, webbed digits, down-slanting palpebral fissures (outside corners of the eyes that point downwards) and a low frontal hairline (a hair line that extends down on to the forehead). Affected individuals are more likely to have developmental delay and nerve based hearing loss than individuals with SCS. Isolated unilateral coronal synostosis is coronal suture fusion without other abnormalities. This condition is far more common than SCS and, if left untreated, facial asymmetry, similar to SCS, may be found. Baller-Gerold syndrome is a rare genetic disorder characterized by craniosynostosis, a prominent forehead, downslanting palpebral fissures, small, malformed (dysplastic), low-set ears, and/or other craniofacial abnormalities. This condition is also characterized by underdevelopment (hypoplasia) or absence (aplasia) of the bones on the thumb side of the forearms (radii). Baller-Gerold syndrome is an autosomal recessive condition associated with mutations in the RECQL4 gene. (For more information about this condition, choose “Baller-Gerold syndrome” as your search term in the Rare Disease Database.) Other congenital (present at birth) disorders may be characterized by various forms of craniosynostosis, additional craniofacial malformations, syndactyly, broad great toes, and/or other symptoms and findings similar to those potentially associated with SCS. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
Related disorders of Saethre Chotzen Syndrome. The findings in the following disorders may be similar to those of Saethre-Chotzen syndrome. Comparisons may be useful for a differential diagnosis: Muenke syndrome may cause premature fusion of one or both coronal sutures. It is an autosomal dominant condition associated with a specific mutation (p.Pro250Arg) in the FGFR3 gene. Features that are typically absent in this condition and that may be present in SCS include: ptosis, ear abnormalities, webbed digits, down-slanting palpebral fissures (outside corners of the eyes that point downwards) and a low frontal hairline (a hair line that extends down on to the forehead). Affected individuals are more likely to have developmental delay and nerve based hearing loss than individuals with SCS. Isolated unilateral coronal synostosis is coronal suture fusion without other abnormalities. This condition is far more common than SCS and, if left untreated, facial asymmetry, similar to SCS, may be found. Baller-Gerold syndrome is a rare genetic disorder characterized by craniosynostosis, a prominent forehead, downslanting palpebral fissures, small, malformed (dysplastic), low-set ears, and/or other craniofacial abnormalities. This condition is also characterized by underdevelopment (hypoplasia) or absence (aplasia) of the bones on the thumb side of the forearms (radii). Baller-Gerold syndrome is an autosomal recessive condition associated with mutations in the RECQL4 gene. (For more information about this condition, choose “Baller-Gerold syndrome” as your search term in the Rare Disease Database.) Other congenital (present at birth) disorders may be characterized by various forms of craniosynostosis, additional craniofacial malformations, syndactyly, broad great toes, and/or other symptoms and findings similar to those potentially associated with SCS. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Saethre Chotzen Syndrome
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Diagnosis of Saethre Chotzen Syndrome
The diagnosis of SCS is primarily based on physical signs and symptoms. Molecular genetic testing for mutations in the TWIST1 gene can be identified in some, but not all, individuals.
Diagnosis of Saethre Chotzen Syndrome. The diagnosis of SCS is primarily based on physical signs and symptoms. Molecular genetic testing for mutations in the TWIST1 gene can be identified in some, but not all, individuals.
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Saethre Chotzen Syndrome
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Therapies of Saethre Chotzen Syndrome
Treatment The management of SCS is directed toward identifying potentially medically important manifestations in an individual and treating those manifestations. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in disorders of the ears, nose, and throat (otolaryngologists); physicians who diagnose and treat neurological disorders (neurologists); and/or other health care professionals. Surgery may be advised in the first year of life to help prevent or correct early closure of cranial sutures, to prevent increased intracranial pressure, and to prevent progressive facial asymmetry. Corrective and reconstructive surgery may also be performed to help correct certain craniofacial malformations and associated findings, syndactyly, other skeletal defects, or other physical abnormalities potentially associated with the disorder. The surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors. Evaluation by an ophthalmologist for eye and vision abnormalities and audiologic evaluation for hearing loss is recommended. X-ray of the neck bones should be considered at around age 2 years. Other tests may be considered depending on an individual’s findings. If intellectual disability is identified, early intervention may be important to ensure that children with SCS reach their potential. Special services that may be beneficial include special education and/or other medical, social, or vocational services.Genetic counseling will be of benefit for affected individuals and their families. If mutation is not identified, an evaluation to assess for features of SCS should be considered for the relevant family members.
Therapies of Saethre Chotzen Syndrome. Treatment The management of SCS is directed toward identifying potentially medically important manifestations in an individual and treating those manifestations. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in disorders of the ears, nose, and throat (otolaryngologists); physicians who diagnose and treat neurological disorders (neurologists); and/or other health care professionals. Surgery may be advised in the first year of life to help prevent or correct early closure of cranial sutures, to prevent increased intracranial pressure, and to prevent progressive facial asymmetry. Corrective and reconstructive surgery may also be performed to help correct certain craniofacial malformations and associated findings, syndactyly, other skeletal defects, or other physical abnormalities potentially associated with the disorder. The surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors. Evaluation by an ophthalmologist for eye and vision abnormalities and audiologic evaluation for hearing loss is recommended. X-ray of the neck bones should be considered at around age 2 years. Other tests may be considered depending on an individual’s findings. If intellectual disability is identified, early intervention may be important to ensure that children with SCS reach their potential. Special services that may be beneficial include special education and/or other medical, social, or vocational services.Genetic counseling will be of benefit for affected individuals and their families. If mutation is not identified, an evaluation to assess for features of SCS should be considered for the relevant family members.
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Saethre Chotzen Syndrome
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Overview of Sakati Syndrome
Sakati syndrome is an extremely rare disorder that belongs to a group of rare genetic disorders known as “Acrocephalopolysyndactyly” (ACPS). All forms of ACPS are characterized by premature closure of the fibrous joints (cranial sutures) between certain bones of the skull (craniosynostosis), causing the top of the head to appear pointed (acrocephaly); webbing or fusion (syndactyly) of certain fingers or toes (digits); and/or more than the normal number of digits (polydactyly). In addition, Sakati syndrome, which is also known as ACPS type III, is associated with abnormalities of bones of the legs, structural heart malformations that are present at birth (congenital heart defects), and/or other findings. Sakati syndrome is thought to be caused by a new genetic change (mutation) that occurs randomly for unknown reasons (sporadically). This mutation is inherited as an autosomal dominant trait.
Overview of Sakati Syndrome. Sakati syndrome is an extremely rare disorder that belongs to a group of rare genetic disorders known as “Acrocephalopolysyndactyly” (ACPS). All forms of ACPS are characterized by premature closure of the fibrous joints (cranial sutures) between certain bones of the skull (craniosynostosis), causing the top of the head to appear pointed (acrocephaly); webbing or fusion (syndactyly) of certain fingers or toes (digits); and/or more than the normal number of digits (polydactyly). In addition, Sakati syndrome, which is also known as ACPS type III, is associated with abnormalities of bones of the legs, structural heart malformations that are present at birth (congenital heart defects), and/or other findings. Sakati syndrome is thought to be caused by a new genetic change (mutation) that occurs randomly for unknown reasons (sporadically). This mutation is inherited as an autosomal dominant trait.
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Sakati Syndrome
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Symptoms of Sakati Syndrome
In Sakati syndrome, the fibrous joints between the bones in the skull (cranial sutures) close prematurely (craniosynostosis), causing an affected infant's head to grow upward at an accelerated rate. As a result, the head appears long, narrow, and pointed at the top (acrocephaly). Affected individuals also have several unusual facial characteristics including a flat, abnormally small face; protruding eyes; an abnormally wide space between the eyes (ocular hypertelorism); an elongated nose; large, malformed (dysplastic) and low-set ears; and a prominent forehead.Sakati syndrome is also characterized by several deformities of the hands and feet, including abnormally short fingers (brachydactyly), unusually broad thumbs and big toes, webbed toes (syndactyly), and more than the normal number of fingers and/or toes (polydactyly). Abnormalities of the legs are also present, including bowed thigh bones (femurs); abnormally shaped, displaced calf bones (fibulas); and underdeveloped shin bones (hypoplastic tibias). In addition, both the legs and arms are shorter than normal.Additional symptoms associated with this disorder may include teeth that are crowded together, an underdeveloped upper jaw bone (maxillary hypoplasia), jaws that project forward (prognathism), a short neck, a low hairline, absence of hair (alopecia), and congenital heart disease. Intelligence is usually within normal limits.
Symptoms of Sakati Syndrome. In Sakati syndrome, the fibrous joints between the bones in the skull (cranial sutures) close prematurely (craniosynostosis), causing an affected infant's head to grow upward at an accelerated rate. As a result, the head appears long, narrow, and pointed at the top (acrocephaly). Affected individuals also have several unusual facial characteristics including a flat, abnormally small face; protruding eyes; an abnormally wide space between the eyes (ocular hypertelorism); an elongated nose; large, malformed (dysplastic) and low-set ears; and a prominent forehead.Sakati syndrome is also characterized by several deformities of the hands and feet, including abnormally short fingers (brachydactyly), unusually broad thumbs and big toes, webbed toes (syndactyly), and more than the normal number of fingers and/or toes (polydactyly). Abnormalities of the legs are also present, including bowed thigh bones (femurs); abnormally shaped, displaced calf bones (fibulas); and underdeveloped shin bones (hypoplastic tibias). In addition, both the legs and arms are shorter than normal.Additional symptoms associated with this disorder may include teeth that are crowded together, an underdeveloped upper jaw bone (maxillary hypoplasia), jaws that project forward (prognathism), a short neck, a low hairline, absence of hair (alopecia), and congenital heart disease. Intelligence is usually within normal limits.
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Sakati Syndrome
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Causes of Sakati Syndrome
The exact cause of Sakati syndrome is not fully understood. It is believed that the syndrome may be caused by a new or sporadic, dominant genetic change (mutation). Although the exact reason for such a mutation remains unclear, some researchers suggest that advanced parental age may be a contributing factor.If a person with Sakati syndrome were to have children, the altered gene for the disorder may be transmitted as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Causes of Sakati Syndrome. The exact cause of Sakati syndrome is not fully understood. It is believed that the syndrome may be caused by a new or sporadic, dominant genetic change (mutation). Although the exact reason for such a mutation remains unclear, some researchers suggest that advanced parental age may be a contributing factor.If a person with Sakati syndrome were to have children, the altered gene for the disorder may be transmitted as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Sakati Syndrome
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Affects of Sakati Syndrome
Sakati syndrome is named after the researcher (N. Sakati) who, along with colleagues, originally described the condition in 1971. They reported the disease entity in a single male child of a couple who were of advanced parental age. This apparently remains the only case reported in the medical literature to date.
Affects of Sakati Syndrome. Sakati syndrome is named after the researcher (N. Sakati) who, along with colleagues, originally described the condition in 1971. They reported the disease entity in a single male child of a couple who were of advanced parental age. This apparently remains the only case reported in the medical literature to date.
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Sakati Syndrome
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Related disorders of Sakati Syndrome
Symptoms of the following disorders can be similar to those of Sakati syndrome. Comparisons may be useful for a differential diagnosis:Acrocephalopolysyndactyly (ACPS) is a group of very rare genetic disorders including Noack syndrome (Type I), Carpenter syndrome (Type II), Sakati syndrome (Type III), and Goodman syndrome (Type IV). All of these disorders are characterized by a long, narrow head that appears pointed at the top (acrocephaly), more than the usual number of fingers and/or toes (polydactyly), and webbing of fingers and/or toes (syndactyly).Carpenter syndrome (Acrocephalopolysyndactyly Type II) is a very rare inherited disorder characterized by a long, narrow head (acrocephaly); abnormally short, webbed fingers (brachysyndactyly); and feet with more than five toes that may also be webbed (polysyndactyly). Affected individuals have characteristic downslanted eyes, a flattened nasal bridge, broad cheeks, low-set ears, and underdeveloped jaw bones (hypoplastic mandible). Other features may include mild obesity, mental retardation, protrusion of portions of the intestines through the abdominal wall (abdominal hernias), underdeveloped sex organs (hypogenitalism), and congenital heart disease. Carpenter syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Carpenter” as your search term in the Rare Disease Database.)Goodman syndrome (Acrocephalopolysyndactyly Type IV) is an extremely rare genetic disorder characterized by a long, narrow head (acrocephaly); several facial defects; webbed fingers and/or toes (syndactyly); extra fingers (postaxial polydactyly); and fifth fingers that are abnormally bent (clinodactyly) and permanently flexed (camptodactyly). Other features include a deviation of one of the forearm bones (ulna), abnormally close together knees and abnormally far apart ankles (genu valgum), and congenital heart disease. Intelligence is within normal limits. Some researchers feel that Goodman syndrome is a variant of Carpenter syndrome (Acrocephalopolysyndactyly Type II), which is described above. Goodman syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Goodman” as your search term in the Rare Disease Database.)Apert syndrome (Acrocephalosyndactyly Type I) is a rare genetic disorder characterized by a wedge-shaped or pointed head; a prominent forehead; a face that may appear flat in the middle; and eyes that may protrude, appear to squint, and/or be set widely apart (ocular hypertelorism). Abnormalities of the hands and feet may include fingers and toes that are webbed and/or fused (syndactyly) and a single nail that is common to the second to fourth fingers. Other features may include crowded upper teeth, a prominent jaw (mandible), an unusually high and pointed palate (gothic palata), low-set ears, hearing loss, and mental retardation. It is believed that Apert syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Apert” as your search term in the Rare Disease Database.)
Related disorders of Sakati Syndrome. Symptoms of the following disorders can be similar to those of Sakati syndrome. Comparisons may be useful for a differential diagnosis:Acrocephalopolysyndactyly (ACPS) is a group of very rare genetic disorders including Noack syndrome (Type I), Carpenter syndrome (Type II), Sakati syndrome (Type III), and Goodman syndrome (Type IV). All of these disorders are characterized by a long, narrow head that appears pointed at the top (acrocephaly), more than the usual number of fingers and/or toes (polydactyly), and webbing of fingers and/or toes (syndactyly).Carpenter syndrome (Acrocephalopolysyndactyly Type II) is a very rare inherited disorder characterized by a long, narrow head (acrocephaly); abnormally short, webbed fingers (brachysyndactyly); and feet with more than five toes that may also be webbed (polysyndactyly). Affected individuals have characteristic downslanted eyes, a flattened nasal bridge, broad cheeks, low-set ears, and underdeveloped jaw bones (hypoplastic mandible). Other features may include mild obesity, mental retardation, protrusion of portions of the intestines through the abdominal wall (abdominal hernias), underdeveloped sex organs (hypogenitalism), and congenital heart disease. Carpenter syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Carpenter” as your search term in the Rare Disease Database.)Goodman syndrome (Acrocephalopolysyndactyly Type IV) is an extremely rare genetic disorder characterized by a long, narrow head (acrocephaly); several facial defects; webbed fingers and/or toes (syndactyly); extra fingers (postaxial polydactyly); and fifth fingers that are abnormally bent (clinodactyly) and permanently flexed (camptodactyly). Other features include a deviation of one of the forearm bones (ulna), abnormally close together knees and abnormally far apart ankles (genu valgum), and congenital heart disease. Intelligence is within normal limits. Some researchers feel that Goodman syndrome is a variant of Carpenter syndrome (Acrocephalopolysyndactyly Type II), which is described above. Goodman syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Goodman” as your search term in the Rare Disease Database.)Apert syndrome (Acrocephalosyndactyly Type I) is a rare genetic disorder characterized by a wedge-shaped or pointed head; a prominent forehead; a face that may appear flat in the middle; and eyes that may protrude, appear to squint, and/or be set widely apart (ocular hypertelorism). Abnormalities of the hands and feet may include fingers and toes that are webbed and/or fused (syndactyly) and a single nail that is common to the second to fourth fingers. Other features may include crowded upper teeth, a prominent jaw (mandible), an unusually high and pointed palate (gothic palata), low-set ears, hearing loss, and mental retardation. It is believed that Apert syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Apert” as your search term in the Rare Disease Database.)
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Sakati Syndrome
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Diagnosis of Sakati Syndrome
Sakati syndrome can be detected at birth, based upon a clinical evaluation and identification of characteristic physical findings.
Diagnosis of Sakati Syndrome. Sakati syndrome can be detected at birth, based upon a clinical evaluation and identification of characteristic physical findings.
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Therapies of Sakati Syndrome
TreatmentTreatment primarily consists of surgical correction of malformations. Early craniofacial surgery may be performed to correct the premature closure of the bones in the skull (craniosynostosis) and. Additional craniofacial surgery may be done later in life as well as surgery to correct deformities of the hands and feet. In addition, surgical repair of the bone abnormalities of the legs may also be performed to improve the affected individuals' ability to walk.Infants with Sakati syndrome who have congenital heart defects may also be treated surgically. The surgical procedure performed will depend upon the severity and location of the heart defects and their associated symptoms.Other treatment is symptomatic and supportive. Genetic counseling will be of benefit for affected individuals and their families.
Therapies of Sakati Syndrome. TreatmentTreatment primarily consists of surgical correction of malformations. Early craniofacial surgery may be performed to correct the premature closure of the bones in the skull (craniosynostosis) and. Additional craniofacial surgery may be done later in life as well as surgery to correct deformities of the hands and feet. In addition, surgical repair of the bone abnormalities of the legs may also be performed to improve the affected individuals' ability to walk.Infants with Sakati syndrome who have congenital heart defects may also be treated surgically. The surgical procedure performed will depend upon the severity and location of the heart defects and their associated symptoms.Other treatment is symptomatic and supportive. Genetic counseling will be of benefit for affected individuals and their families.
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Sakati Syndrome
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Overview of Sandhoff Disease
Summary Sandhoff disease is a rare lysosomal storage disease. It causes the destruction of nerve cells (neurodegeneration). This leads to problems with thinking and moving. Sandhoff disease is caused by harmful changes in the HEXB gene. Harmful changes in this gene cause decreased amounts of two enzymes in the recycling centers (lysosomes) of the cell. Without these enzymes, certain fats (lipids) build up in large amounts in the nerve cells. This damages the brain and spinal cord (central nervous system). Sandhoff disease is very similar to Tay Sachs disease.IntroductionLysosomal storage diseases affect the enzymes in the recycling centers (lysosomes) of the cell. Lysosomes use enzymes to break down or “digest” molecules in our cells. When these enzymes are not working properly, the molecules accumulate in harmful amounts. This causes damage to different organs in the body.
Overview of Sandhoff Disease. Summary Sandhoff disease is a rare lysosomal storage disease. It causes the destruction of nerve cells (neurodegeneration). This leads to problems with thinking and moving. Sandhoff disease is caused by harmful changes in the HEXB gene. Harmful changes in this gene cause decreased amounts of two enzymes in the recycling centers (lysosomes) of the cell. Without these enzymes, certain fats (lipids) build up in large amounts in the nerve cells. This damages the brain and spinal cord (central nervous system). Sandhoff disease is very similar to Tay Sachs disease.IntroductionLysosomal storage diseases affect the enzymes in the recycling centers (lysosomes) of the cell. Lysosomes use enzymes to break down or “digest” molecules in our cells. When these enzymes are not working properly, the molecules accumulate in harmful amounts. This causes damage to different organs in the body.
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Sandhoff Disease
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Symptoms of Sandhoff Disease
Infantile Sandhoff Disease The most common type of Sandhoff disease causes rapidly progressing mental and motor decline in infancy. Within the first six months of life, infants with Sandhoff disease will experience weakness. They lose skills like turning over, sitting, and crawling. They can also have trouble with feeding, overreaction to loud sudden noises, delayed speech, early blindness, seizures, heart murmur, and continuously tight muscles (spasticity). A doctor may notice red spots in the back of the eye (cherry-red spots of the macula) and an abnormal reflex of the foot that indicates damage to the nervous system (the Babinski reflex). Other signs of Sandhoff disease can include a large head (macrocephaly) and unique facial features. Infants with this form of Sandhoff disease usually do not live past 2-5 years. Juvenile and Adult Sandhoff Disease Sandhoff disease can also happen in older children and adults. These individuals will experience a slower mental and motor decline than in infantile Sandhoff disease. The onset and severity of symptoms can vary. A specific symptom of later-onset Sandhoff disease is muscle weakness affecting the muscles of the arms, legs, and hips. Other symptoms include muscle loss (muscle atrophy), balance problems, uncontrollable muscle contraction (dystonia), damage to nerves controlling involuntary bodily functions (autonomic neuropathy), a loss of intellectual function (cognitive dysfunction), psychiatric illness and dementia.
Symptoms of Sandhoff Disease. Infantile Sandhoff Disease The most common type of Sandhoff disease causes rapidly progressing mental and motor decline in infancy. Within the first six months of life, infants with Sandhoff disease will experience weakness. They lose skills like turning over, sitting, and crawling. They can also have trouble with feeding, overreaction to loud sudden noises, delayed speech, early blindness, seizures, heart murmur, and continuously tight muscles (spasticity). A doctor may notice red spots in the back of the eye (cherry-red spots of the macula) and an abnormal reflex of the foot that indicates damage to the nervous system (the Babinski reflex). Other signs of Sandhoff disease can include a large head (macrocephaly) and unique facial features. Infants with this form of Sandhoff disease usually do not live past 2-5 years. Juvenile and Adult Sandhoff Disease Sandhoff disease can also happen in older children and adults. These individuals will experience a slower mental and motor decline than in infantile Sandhoff disease. The onset and severity of symptoms can vary. A specific symptom of later-onset Sandhoff disease is muscle weakness affecting the muscles of the arms, legs, and hips. Other symptoms include muscle loss (muscle atrophy), balance problems, uncontrollable muscle contraction (dystonia), damage to nerves controlling involuntary bodily functions (autonomic neuropathy), a loss of intellectual function (cognitive dysfunction), psychiatric illness and dementia.
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Sandhoff Disease
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Causes of Sandhoff Disease
Sandhoff disease is caused by harmful mutations in a gene called HEXB. These gene mutations cause decreased amounts of two important enzymes: beta-hexosaminidase A and beta-hexosaminidase B. These enzymes are found in the recycling centers (lysosomes) of the cell and their job is to break down fatty substances called GM2 gangliosides and globosides. The symptoms of Sandhoff disease happen because these fats (lipids) accumulate in harmful amounts in the brain and nerve cells. This damages the brain and spinal cord (central nervous system). Sandhoff disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Causes of Sandhoff Disease. Sandhoff disease is caused by harmful mutations in a gene called HEXB. These gene mutations cause decreased amounts of two important enzymes: beta-hexosaminidase A and beta-hexosaminidase B. These enzymes are found in the recycling centers (lysosomes) of the cell and their job is to break down fatty substances called GM2 gangliosides and globosides. The symptoms of Sandhoff disease happen because these fats (lipids) accumulate in harmful amounts in the brain and nerve cells. This damages the brain and spinal cord (central nervous system). Sandhoff disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Sandhoff Disease
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Affects of Sandhoff Disease
Sandhoff disease is a rare disorder that is estimated to affect 1 in 1,000,000 individuals. It affects males and females in equal numbers. Sandhoff disease occurs in multiple populations but may be most common in the Creole population of Argentina, Metis citizens of Saskatchewan, Canada and people with Lebanese ancestry.
Affects of Sandhoff Disease. Sandhoff disease is a rare disorder that is estimated to affect 1 in 1,000,000 individuals. It affects males and females in equal numbers. Sandhoff disease occurs in multiple populations but may be most common in the Creole population of Argentina, Metis citizens of Saskatchewan, Canada and people with Lebanese ancestry.
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Sandhoff Disease
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Related disorders of Sandhoff Disease
Symptoms of the following disorders can be similar to those of Sandhoff disease. Comparisons may be useful for a differential diagnosis. Tay-Sachs disease is a rare, inherited lysosomal storage disease. It causes the destruction of nerve cells (neurodegeneration), leading to problems with thinking and moving. Tay-Sachs disease happens because of a lack of an enzyme called beta-hexosaminidase A. This causes a buildup of certain fats (lipids) called GM2 gangliosides in the brain and nerve cells which damages the brain and spinal cord (central nervous system). Common symptoms include an overreaction to sudden noises, listlessness, loss of previously acquired skills, severely diminished muscle tone (hypotonia), cherry-red spots within the middle layer of the eyes, gradual loss of vision, hearing loss, increasing muscle stiffness, restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). Most commonly, Tay-Sachs happens in infancy, but there are juvenile and adult forms of the disease. (For more information on this disorder, choose “Tay-Sachs” as your search term in the Rare Disease Database.) Gaucher disease is a rare, inherited lysosomal storage disease. It is caused by a lack of an enzyme called glucocerebrosidase. This causes a buildup of a certain sugar-containing fat (glycolipid) called glucocerebroside. Buildup of glucocerebroside can lead to a variety of symptoms including an abnormally enlarged liver and/or spleen (hepatosplenomegaly), low levels of red blood cells (anemia) and platelets (thrombocytopenia), skeletal abnormalities, neurological complications. There are different forms of Gaucher disease that affect which symptoms occur and when. The severity of symptoms can differ between affected people. (For more information on this disorder, choose “Gaucher” as your search term in the Rare Disease Database.) Niemann-Pick disease refers to a group of rare disorders that affect how fats (lipids) are broken down. There is a harmful buildup of these fats (lipids) in the spleen, liver, lungs, bone marrow, and brain. Symptoms may include lack of muscle coordination, brain decline, learning problems, loss of muscle tone (hypotonia), increased sensitivity to touch, spasticity, feeding and swallowing difficulties, slurred speech, and an enlarged liver and spleen (hepatosplenomegaly). The different types of disorders include Niemann-Pick type A, type B, type C1, and type C2. Symptoms and onset of disease differ depending on the type of Niemann-Pick disorder. (For more information on this disorder, choose “Niemann-Pick” as your search term in the Rare Disease Database.) Juvenile CLN3 disease (formerly called Batten disease) is a rare lysosomal storage disease that belongs to a group of disorders known as neuronal ceroid lipofuscinoses. These disorders are caused by the harmful buildup of fatty, granular molecules in nerve cells and other parts of the body. Symptoms of Juvenile CLN3 disease begin between 5 and 15 years of age and include loss of vision, seizures, and neurological degeneration causing clumsiness, balance problems, and changes in behavior and personality. (For more information on this disorder, choose “Juvenile CLN3” as your search term in the Rare Disease Database.) Adult neuronal ceroid lipofuscinosis (ANCL) (also known as Kufs disease) refers to several rare disorders known as neuronal ceroid lipofuscinoses. These disorders are caused by the harmful buildup of fatty, granular molecules in nerve cells and other parts of the body. Symptoms of ANCL typically begin around age 30, but it is possible for symptoms to occur in the teen years and in people over the age of 50. There are two forms of ANCL. In ANCL type A, symptoms include muscle contraction (myoclonus), seizures, difficulty coordinating voluntary movements (ataxia), and difficulty speaking (dysarthria). Symptoms of ANCL type B include difficulty coordinating voluntary movements (ataxia), tics or tremors, dementia, and behavioral or psychiatric changes. (For more information on this disorder, choose “Adult Neuronal Ceroid Lipofuscinosis” as your search term in the Rare Disease Database.) Leigh syndrome is a rare disorder causing decline of the central nervous system. Leigh syndrome is caused by an error in enzymes that help produce energy in the mitochondria of the cells. Symptoms usually begin between two months and two years of age. They include loss of motor skills, loss of appetite, vomiting, seizures, irritability, weakness, poor muscle tone (hypotonia), and high levels of lactic acid in the blood (lactic acidosis). (For more information on this disorder, choose “Leigh” as your search term in the Rare Disease Database.)
Related disorders of Sandhoff Disease. Symptoms of the following disorders can be similar to those of Sandhoff disease. Comparisons may be useful for a differential diagnosis. Tay-Sachs disease is a rare, inherited lysosomal storage disease. It causes the destruction of nerve cells (neurodegeneration), leading to problems with thinking and moving. Tay-Sachs disease happens because of a lack of an enzyme called beta-hexosaminidase A. This causes a buildup of certain fats (lipids) called GM2 gangliosides in the brain and nerve cells which damages the brain and spinal cord (central nervous system). Common symptoms include an overreaction to sudden noises, listlessness, loss of previously acquired skills, severely diminished muscle tone (hypotonia), cherry-red spots within the middle layer of the eyes, gradual loss of vision, hearing loss, increasing muscle stiffness, restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). Most commonly, Tay-Sachs happens in infancy, but there are juvenile and adult forms of the disease. (For more information on this disorder, choose “Tay-Sachs” as your search term in the Rare Disease Database.) Gaucher disease is a rare, inherited lysosomal storage disease. It is caused by a lack of an enzyme called glucocerebrosidase. This causes a buildup of a certain sugar-containing fat (glycolipid) called glucocerebroside. Buildup of glucocerebroside can lead to a variety of symptoms including an abnormally enlarged liver and/or spleen (hepatosplenomegaly), low levels of red blood cells (anemia) and platelets (thrombocytopenia), skeletal abnormalities, neurological complications. There are different forms of Gaucher disease that affect which symptoms occur and when. The severity of symptoms can differ between affected people. (For more information on this disorder, choose “Gaucher” as your search term in the Rare Disease Database.) Niemann-Pick disease refers to a group of rare disorders that affect how fats (lipids) are broken down. There is a harmful buildup of these fats (lipids) in the spleen, liver, lungs, bone marrow, and brain. Symptoms may include lack of muscle coordination, brain decline, learning problems, loss of muscle tone (hypotonia), increased sensitivity to touch, spasticity, feeding and swallowing difficulties, slurred speech, and an enlarged liver and spleen (hepatosplenomegaly). The different types of disorders include Niemann-Pick type A, type B, type C1, and type C2. Symptoms and onset of disease differ depending on the type of Niemann-Pick disorder. (For more information on this disorder, choose “Niemann-Pick” as your search term in the Rare Disease Database.) Juvenile CLN3 disease (formerly called Batten disease) is a rare lysosomal storage disease that belongs to a group of disorders known as neuronal ceroid lipofuscinoses. These disorders are caused by the harmful buildup of fatty, granular molecules in nerve cells and other parts of the body. Symptoms of Juvenile CLN3 disease begin between 5 and 15 years of age and include loss of vision, seizures, and neurological degeneration causing clumsiness, balance problems, and changes in behavior and personality. (For more information on this disorder, choose “Juvenile CLN3” as your search term in the Rare Disease Database.) Adult neuronal ceroid lipofuscinosis (ANCL) (also known as Kufs disease) refers to several rare disorders known as neuronal ceroid lipofuscinoses. These disorders are caused by the harmful buildup of fatty, granular molecules in nerve cells and other parts of the body. Symptoms of ANCL typically begin around age 30, but it is possible for symptoms to occur in the teen years and in people over the age of 50. There are two forms of ANCL. In ANCL type A, symptoms include muscle contraction (myoclonus), seizures, difficulty coordinating voluntary movements (ataxia), and difficulty speaking (dysarthria). Symptoms of ANCL type B include difficulty coordinating voluntary movements (ataxia), tics or tremors, dementia, and behavioral or psychiatric changes. (For more information on this disorder, choose “Adult Neuronal Ceroid Lipofuscinosis” as your search term in the Rare Disease Database.) Leigh syndrome is a rare disorder causing decline of the central nervous system. Leigh syndrome is caused by an error in enzymes that help produce energy in the mitochondria of the cells. Symptoms usually begin between two months and two years of age. They include loss of motor skills, loss of appetite, vomiting, seizures, irritability, weakness, poor muscle tone (hypotonia), and high levels of lactic acid in the blood (lactic acidosis). (For more information on this disorder, choose “Leigh” as your search term in the Rare Disease Database.)
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Sandhoff Disease
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Diagnosis of Sandhoff Disease
Sandhoff disease is commonly diagnosed by testing the activity of the beta-hexosaminidase A and beta-hexosaminidase B enzymes (enzyme assays). People with Sandoff disease have reduced or absent activity of both enzymes. Genetic testing is used to confirm the diagnosis.
Diagnosis of Sandhoff Disease. Sandhoff disease is commonly diagnosed by testing the activity of the beta-hexosaminidase A and beta-hexosaminidase B enzymes (enzyme assays). People with Sandoff disease have reduced or absent activity of both enzymes. Genetic testing is used to confirm the diagnosis.
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Sandhoff Disease
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Therapies of Sandhoff Disease
There is currently no cure for Sandhoff disease. Management is based on the symptoms and is mostly supportive. Supportive treatment includes ensuring proper nutrition and hydration, keeping the airway open, and seizure control with anticonvulsants. Genetic counseling is recommended for affected individuals and their families.
Therapies of Sandhoff Disease. There is currently no cure for Sandhoff disease. Management is based on the symptoms and is mostly supportive. Supportive treatment includes ensuring proper nutrition and hydration, keeping the airway open, and seizure control with anticonvulsants. Genetic counseling is recommended for affected individuals and their families.
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Sandhoff Disease
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Overview of Schimke Immuno-Osseous Dysplasia
Schimke immuno-osseous dysplasia (SIOD) is a multisystem disorder that is inherited in an autosomal recessive pattern. It usually manifests first with growth failure. Other features of the disease are generally noted in the ensuing evaluation of the growth failure or develop in the following years. According to the severity of the clinical features and the age of onset, SIOD has been divided into an infantile or severe early-onset form and a juvenile or milder late-onset form. Affected individuals with early-onset manifest severe symptoms and have a mean age of death at 9.2 years. These individuals have died from strokes, severe opportunistic infections, bone marrow failure, complications of kidney failure, congestive heart failure, and unspecified lung disease. On the other hand, those with milder disease have survived into the fifth decade if symptomatically treated. However, severity and age of onset of symptoms do not invariably predict survival as a few of those with early-onset disease have survived into the third and fourth decade.
Overview of Schimke Immuno-Osseous Dysplasia. Schimke immuno-osseous dysplasia (SIOD) is a multisystem disorder that is inherited in an autosomal recessive pattern. It usually manifests first with growth failure. Other features of the disease are generally noted in the ensuing evaluation of the growth failure or develop in the following years. According to the severity of the clinical features and the age of onset, SIOD has been divided into an infantile or severe early-onset form and a juvenile or milder late-onset form. Affected individuals with early-onset manifest severe symptoms and have a mean age of death at 9.2 years. These individuals have died from strokes, severe opportunistic infections, bone marrow failure, complications of kidney failure, congestive heart failure, and unspecified lung disease. On the other hand, those with milder disease have survived into the fifth decade if symptomatically treated. However, severity and age of onset of symptoms do not invariably predict survival as a few of those with early-onset disease have survived into the third and fourth decade.
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Schimke Immuno-Osseous Dysplasia
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Symptoms of Schimke Immuno-Osseous Dysplasia
The multiple symptoms of SIOD and the relative frequency of them are listed in the table. The symptoms are subsequently discussed according to the organ system affected.Physical Traits Most affected individuals have distinctive physical features. These include fine hair (60%), a thin upper lip, a broad, low nasal bridge (68%), a bulbous nasal tip (83%), and disproportionately short stature (98%). Additional features include excessive inward curvature of the lumbar spine (lumbar lordosis, 84%), a protruding abdomen, and hyperpigmented macules (85%) on the trunk and occasionally on the neck, face, arms and legs. Less common physical features include absent or small teeth and corneal opacities (19%).Growth and Skeletal System Growth failure, which is often the first obvious sign of SIOD, occurs despite normal growth hormone production and is not corrected with growth hormone supplementation. In most affected individuals, the growth failure begins prior to and continues after birth; however, some affected children do have normal birth lengths and weights and their growth failure is not noted until after birth (range: 0 to 13 years, mean: 2 years). The heights of those who survived to adulthood were 136-157 cm for men and 98.5-143 cm for women.The short stature arises generally because of spondyloepiphyseal dysplasia (86%), a disorder of skeletal growth; it does not arise as a complication of their renal failure. The anthropometric characteristics of patients with SIOD differ markedly from those of patients with other forms of chronic kidney disease, especially with respect to median leg length and sitting height. The spinal column and hip joint are most severely affected. The radiological abnormalities include ovoid or mildly flattened vertebral bodies, small and laterally displaced femurs (thigh bone), and shallow abnormal acetabular fossae (hip sockets). Less frequent skeletal problems include lordosis, kyphosis and scoliosis (abnormal curvatures of the spine) as well as osteopenia (decreased bone mineral density) and degenerative hip disease. Many patients have required hip replacements.Endocrine System Approximately 42% of individuals with SIOD have reduced thyroid function. However, to date, the poor thyroid function has not caused clinical symptoms (subclinical hypothyroidism). Among those who have received thyroid hormone supplementation, the correction of thyroid hormone levels does not mitigate other symptoms of SIOD.Renal System All reported affected individuals have eventually developed renal dysfunction. The kidney disease is characterized by progressively worsening loss of protein in the urine and ultimately concludes with renal failure. The progressive renal disease is not responsive to immunosuppressant therapy. The diagnosis of renal dysfunction is usually made concurrent with or within the five years following the diagnosis of the growth failure. Renal failure requiring dialysis or kidney transplantation usually develops within the subsequent 11 years, although the rate of progression varies greatly. Because renal disease causes high blood pressure and high levels of blood cholesterol and lipids, the theory is that it accentuates the vascular disease of SIOD; however, renal transplantation does not prevent progression of the atherosclerosis. The incidence of a single kidney may be higher than in the unaffected population and this is associated with a more rapid onset of renal failure. Cardiovascular system Half of SIOD individuals develop clinical signs of atherosclerosis. The onset is often in early childhood and relentlessly progressive. The disease is not abrogated by renal or bone marrow transplantation nor by cholesterol lowering agents, although the cholesterol lowering agents and renal transplantation can slow the progression by mitigating factors such as high blood pressure and high blood lipid and cholesterol levels. Consistent with the atherosclerosis resulting from an intrinsic defect of SIOD tissue, the vascular disease does not recur in the transplanted kidneys. Besides atherosclerosis, splitting and fraying of the arterial internal elastic layer and thickening of the muscular layer of the arterial walls have been found on autopsy. The latter finding may be a complication of high blood pressure or an intrinsic defect in the blood vessels. A few patients have also developed subaortic stenosis, one patient showed severe bicuspid aortic stenosis and one patient had extensive fatty infiltration resembling that of arrhythmogenic right ventricular cardiomyopathy.Central nervous system (CNS) The central nervous system shows both multiple developmental and ischemic changes. The developmental defects include brain malformations suggestive of aberrant neuronal migration including heterotopia, irregular cortical thickness, incomplete gyral formation, poor definition of cortical layers, and hamartia. Additionally, adolescent and adult patients have very few neural progenitors (stem cells). Despite these malformations, most SIOD patients have normal social, language, motor, and cognitive development until the onset of symptoms from reduced brain blood supply (cerebral ischemia).The cerebral ischemia can either temporarily or permanently disturb the blood supply of a given area of the brain and thereby cause temporary (47%, transient ischemic attacks) or permanent (44%, strokes) dysfunction. The cerebral ischemic attacks and strokes are often precipitated by acute changes in blood pressure, such as following the administration of high doses of steroids. Ischemic changes include loss of neurons and myelin, gliosis (scarring), brain atrophy, and degeneration of infarcted regions including atrophy of the cerebellum. Likely as a complication of the cerebral ischemia and atherosclerosis, a few of the patients have also manifest Moyamoya disease.Another common neurological feature in SIOD patients is severe migraine-like headaches (60%). The cause of the headaches is still unknown but they tend to be more severe and refractory to anti-migraine medications that migraine-like headaches in the general population. In one patient a reversible cerebral vasoconstriction syndrome was suspected.Pulmonary system Several patients have died from pulmonary complications including pulmonary emboli, pulmonary hypertension, and lung disease. Lung abnormalities identified by autopsy include diffuse thickening (hyperplasia) of the airway (bronchial) smooth muscles, enlargement (emphysematous changes) of the gas exchange regions (alveoli), and diffuse hyperplasia of the pulmonary artery smooth muscles. The last finding could account for the pulmonary hypertension observed in some patients.Hematopoietic and Immune Systems Nearly all affected individuals have some blood cell deficiency. Deficiency of T lymphocytes, a subgroup of white blood cells that plays an important role in immunity, is most common (97%) and is usually present at birth. Reductions in both CD4 T cells, which regulate multiple aspects of the immune system and CD8 T lymphocytes, which are important in the control of viruses are typical. However, in addition to a deficit of T lymphocytes, the hematopoietic disturbance can include any or all other blood cell lineages. These hematopoietic cell deficiencies reflect reduced production of these cells by the bone marrow, and affected individuals are more prone than unaffected ones to developing decreased hematopoietic cell levels in the blood as a side effect of drug therapy. Affected individuals are also less responsive to the effects of G-CSF therapy to increase bone marrow production of neutrophils and erythropoietin therapy to increase the bone marrow production or red blood cell precursors. Because of their immunodeficiency, affected individuals have an increased risk for opportunistic fungal, viral and bacterial infections. They also have an increased risk of more severe infections. The immunodeficiency is also associated with immune dysregulation disorders, such as autoimmune blood diseases. Reproductive system Few SIOD patients have reached sexual maturity and of the ones who have, no children were subsequently born. However, the patients who have survived to adulthood did develop with secondary sexual characteristics and the women have menstrual cycles. The autopsy of two affected males revealed that sperm production was affected in a varying degree. In one patient, the testes showed interstitial fibrosis and absence of sperm (azoospermia), whereas the other had less interstitial fibrosis individual and produced some sperm.
Symptoms of Schimke Immuno-Osseous Dysplasia. The multiple symptoms of SIOD and the relative frequency of them are listed in the table. The symptoms are subsequently discussed according to the organ system affected.Physical Traits Most affected individuals have distinctive physical features. These include fine hair (60%), a thin upper lip, a broad, low nasal bridge (68%), a bulbous nasal tip (83%), and disproportionately short stature (98%). Additional features include excessive inward curvature of the lumbar spine (lumbar lordosis, 84%), a protruding abdomen, and hyperpigmented macules (85%) on the trunk and occasionally on the neck, face, arms and legs. Less common physical features include absent or small teeth and corneal opacities (19%).Growth and Skeletal System Growth failure, which is often the first obvious sign of SIOD, occurs despite normal growth hormone production and is not corrected with growth hormone supplementation. In most affected individuals, the growth failure begins prior to and continues after birth; however, some affected children do have normal birth lengths and weights and their growth failure is not noted until after birth (range: 0 to 13 years, mean: 2 years). The heights of those who survived to adulthood were 136-157 cm for men and 98.5-143 cm for women.The short stature arises generally because of spondyloepiphyseal dysplasia (86%), a disorder of skeletal growth; it does not arise as a complication of their renal failure. The anthropometric characteristics of patients with SIOD differ markedly from those of patients with other forms of chronic kidney disease, especially with respect to median leg length and sitting height. The spinal column and hip joint are most severely affected. The radiological abnormalities include ovoid or mildly flattened vertebral bodies, small and laterally displaced femurs (thigh bone), and shallow abnormal acetabular fossae (hip sockets). Less frequent skeletal problems include lordosis, kyphosis and scoliosis (abnormal curvatures of the spine) as well as osteopenia (decreased bone mineral density) and degenerative hip disease. Many patients have required hip replacements.Endocrine System Approximately 42% of individuals with SIOD have reduced thyroid function. However, to date, the poor thyroid function has not caused clinical symptoms (subclinical hypothyroidism). Among those who have received thyroid hormone supplementation, the correction of thyroid hormone levels does not mitigate other symptoms of SIOD.Renal System All reported affected individuals have eventually developed renal dysfunction. The kidney disease is characterized by progressively worsening loss of protein in the urine and ultimately concludes with renal failure. The progressive renal disease is not responsive to immunosuppressant therapy. The diagnosis of renal dysfunction is usually made concurrent with or within the five years following the diagnosis of the growth failure. Renal failure requiring dialysis or kidney transplantation usually develops within the subsequent 11 years, although the rate of progression varies greatly. Because renal disease causes high blood pressure and high levels of blood cholesterol and lipids, the theory is that it accentuates the vascular disease of SIOD; however, renal transplantation does not prevent progression of the atherosclerosis. The incidence of a single kidney may be higher than in the unaffected population and this is associated with a more rapid onset of renal failure. Cardiovascular system Half of SIOD individuals develop clinical signs of atherosclerosis. The onset is often in early childhood and relentlessly progressive. The disease is not abrogated by renal or bone marrow transplantation nor by cholesterol lowering agents, although the cholesterol lowering agents and renal transplantation can slow the progression by mitigating factors such as high blood pressure and high blood lipid and cholesterol levels. Consistent with the atherosclerosis resulting from an intrinsic defect of SIOD tissue, the vascular disease does not recur in the transplanted kidneys. Besides atherosclerosis, splitting and fraying of the arterial internal elastic layer and thickening of the muscular layer of the arterial walls have been found on autopsy. The latter finding may be a complication of high blood pressure or an intrinsic defect in the blood vessels. A few patients have also developed subaortic stenosis, one patient showed severe bicuspid aortic stenosis and one patient had extensive fatty infiltration resembling that of arrhythmogenic right ventricular cardiomyopathy.Central nervous system (CNS) The central nervous system shows both multiple developmental and ischemic changes. The developmental defects include brain malformations suggestive of aberrant neuronal migration including heterotopia, irregular cortical thickness, incomplete gyral formation, poor definition of cortical layers, and hamartia. Additionally, adolescent and adult patients have very few neural progenitors (stem cells). Despite these malformations, most SIOD patients have normal social, language, motor, and cognitive development until the onset of symptoms from reduced brain blood supply (cerebral ischemia).The cerebral ischemia can either temporarily or permanently disturb the blood supply of a given area of the brain and thereby cause temporary (47%, transient ischemic attacks) or permanent (44%, strokes) dysfunction. The cerebral ischemic attacks and strokes are often precipitated by acute changes in blood pressure, such as following the administration of high doses of steroids. Ischemic changes include loss of neurons and myelin, gliosis (scarring), brain atrophy, and degeneration of infarcted regions including atrophy of the cerebellum. Likely as a complication of the cerebral ischemia and atherosclerosis, a few of the patients have also manifest Moyamoya disease.Another common neurological feature in SIOD patients is severe migraine-like headaches (60%). The cause of the headaches is still unknown but they tend to be more severe and refractory to anti-migraine medications that migraine-like headaches in the general population. In one patient a reversible cerebral vasoconstriction syndrome was suspected.Pulmonary system Several patients have died from pulmonary complications including pulmonary emboli, pulmonary hypertension, and lung disease. Lung abnormalities identified by autopsy include diffuse thickening (hyperplasia) of the airway (bronchial) smooth muscles, enlargement (emphysematous changes) of the gas exchange regions (alveoli), and diffuse hyperplasia of the pulmonary artery smooth muscles. The last finding could account for the pulmonary hypertension observed in some patients.Hematopoietic and Immune Systems Nearly all affected individuals have some blood cell deficiency. Deficiency of T lymphocytes, a subgroup of white blood cells that plays an important role in immunity, is most common (97%) and is usually present at birth. Reductions in both CD4 T cells, which regulate multiple aspects of the immune system and CD8 T lymphocytes, which are important in the control of viruses are typical. However, in addition to a deficit of T lymphocytes, the hematopoietic disturbance can include any or all other blood cell lineages. These hematopoietic cell deficiencies reflect reduced production of these cells by the bone marrow, and affected individuals are more prone than unaffected ones to developing decreased hematopoietic cell levels in the blood as a side effect of drug therapy. Affected individuals are also less responsive to the effects of G-CSF therapy to increase bone marrow production of neutrophils and erythropoietin therapy to increase the bone marrow production or red blood cell precursors. Because of their immunodeficiency, affected individuals have an increased risk for opportunistic fungal, viral and bacterial infections. They also have an increased risk of more severe infections. The immunodeficiency is also associated with immune dysregulation disorders, such as autoimmune blood diseases. Reproductive system Few SIOD patients have reached sexual maturity and of the ones who have, no children were subsequently born. However, the patients who have survived to adulthood did develop with secondary sexual characteristics and the women have menstrual cycles. The autopsy of two affected males revealed that sperm production was affected in a varying degree. In one patient, the testes showed interstitial fibrosis and absence of sperm (azoospermia), whereas the other had less interstitial fibrosis individual and produced some sperm.
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Causes of Schimke Immuno-Osseous Dysplasia
SIOD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal 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 abnormal 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 is 25%. The risk is the same for males and females. Two mutations in the swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAl1) gene are found in 50 to 60% of individuals clinically diagnosed with SIOD. The individuals without detectable mutations in SMARCAL1 have a lower frequency of hyperpigmented macules and lymphopenia and higher frequency of cognitive impairment. This suggests that they have might have a subtly different disorder or SIOD secondary to another genetic cause.The mutations identified in SMARCAL1 suggest that SIOD arises from loss of function in the encoded protein. These mutations include gene deletions as well as nonsense, frame shift, splicing and missense mutations. Mutations in SMARCAL1 have not been found to cause any other disease.With the exception of the sibling of an affected patient, all identified patients with two mutations in SMARCAL1 have had SIOD and none of the tested unaffected siblings have had two mutations. The asymptomatic boy with two mutations was 2 years when first described and may develop symptoms later.Despite extensive analysis, there are no predictable relationships between particular SMARCAL1 mutations and the severity of the symptoms or the outcome. This has led to the idea that SIOD is the result of the interaction between the SMARCAL1 mutations and environmental, genetic, and epigenetic factors.The SMARCAL1 gene encodes the SMARCAL1 enzyme which has a role in DNA repair and the DNA stress response, participates in activating stalled DNA replication forks and reannealing single stranded DNA to double stranded DNA. SMARCAL1 deficiency in tissue culture cells also impairs normal replication of telomere DNA at the ends of the chromosomes. Recent studies of some SIOD patients with SMARCAL1 deficiency caused by two SMARCAL1 mutations has found significantly shortened telomeres in white blood cells, including T cells. The deficiency of SMARCAL1 causes non-random, global changes in gene expression and changes in gene expression cause the arteriosclerosis, renal disease and immunodeficiency. The arteriosclerosis appears to be a consequence of reduced expression of elastin. The renal disease appears to arise from overexpression and activity of the WNT and NOTCH pathways. The T-cell deficiency arises from lack of expression of IL7 receptor alpha chain expression and is associated with hypermethylation of the IL7R promotor as well as the shortened telomere length. These changes in gene expression might well develop from the changes in epigenetic marks associated with replication fork stalling and collapse.
Causes of Schimke Immuno-Osseous Dysplasia. SIOD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal 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 abnormal 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 is 25%. The risk is the same for males and females. Two mutations in the swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAl1) gene are found in 50 to 60% of individuals clinically diagnosed with SIOD. The individuals without detectable mutations in SMARCAL1 have a lower frequency of hyperpigmented macules and lymphopenia and higher frequency of cognitive impairment. This suggests that they have might have a subtly different disorder or SIOD secondary to another genetic cause.The mutations identified in SMARCAL1 suggest that SIOD arises from loss of function in the encoded protein. These mutations include gene deletions as well as nonsense, frame shift, splicing and missense mutations. Mutations in SMARCAL1 have not been found to cause any other disease.With the exception of the sibling of an affected patient, all identified patients with two mutations in SMARCAL1 have had SIOD and none of the tested unaffected siblings have had two mutations. The asymptomatic boy with two mutations was 2 years when first described and may develop symptoms later.Despite extensive analysis, there are no predictable relationships between particular SMARCAL1 mutations and the severity of the symptoms or the outcome. This has led to the idea that SIOD is the result of the interaction between the SMARCAL1 mutations and environmental, genetic, and epigenetic factors.The SMARCAL1 gene encodes the SMARCAL1 enzyme which has a role in DNA repair and the DNA stress response, participates in activating stalled DNA replication forks and reannealing single stranded DNA to double stranded DNA. SMARCAL1 deficiency in tissue culture cells also impairs normal replication of telomere DNA at the ends of the chromosomes. Recent studies of some SIOD patients with SMARCAL1 deficiency caused by two SMARCAL1 mutations has found significantly shortened telomeres in white blood cells, including T cells. The deficiency of SMARCAL1 causes non-random, global changes in gene expression and changes in gene expression cause the arteriosclerosis, renal disease and immunodeficiency. The arteriosclerosis appears to be a consequence of reduced expression of elastin. The renal disease appears to arise from overexpression and activity of the WNT and NOTCH pathways. The T-cell deficiency arises from lack of expression of IL7 receptor alpha chain expression and is associated with hypermethylation of the IL7R promotor as well as the shortened telomere length. These changes in gene expression might well develop from the changes in epigenetic marks associated with replication fork stalling and collapse.
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Affects of Schimke Immuno-Osseous Dysplasia
SIOD is panethnic with an unknown prevalence. As deduced from referrals and published birth rates, the incidence is approximately 1 per million live births in North America.
Affects of Schimke Immuno-Osseous Dysplasia. SIOD is panethnic with an unknown prevalence. As deduced from referrals and published birth rates, the incidence is approximately 1 per million live births in North America.
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Related disorders of Schimke Immuno-Osseous Dysplasia
Related disorders of Schimke Immuno-Osseous Dysplasia.
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Diagnosis of Schimke Immuno-Osseous Dysplasia
The diagnosis of SIOD is made on clinical findings. The most definitive diagnostic findings are skeletal dysplasia (spondyloepiphyseal dysplasia), renal dysfunction (urinary protein loss), T lymphocyte deficiency (particularly for naïve CD4 and CD8 T cells), dysmorphic facial features, and hyperpigmented macules. Anthropometry can help to distinguish SIOD from other forms of chronic kidney disease: a sitting height: leg length ratio of 1.01 is indicative of non-SIOD chronic kidney disease. DNA testing for mutations in the SMARCAL1 gene is available to confirm the diagnosis.
Diagnosis of Schimke Immuno-Osseous Dysplasia. The diagnosis of SIOD is made on clinical findings. The most definitive diagnostic findings are skeletal dysplasia (spondyloepiphyseal dysplasia), renal dysfunction (urinary protein loss), T lymphocyte deficiency (particularly for naïve CD4 and CD8 T cells), dysmorphic facial features, and hyperpigmented macules. Anthropometry can help to distinguish SIOD from other forms of chronic kidney disease: a sitting height: leg length ratio of 1.01 is indicative of non-SIOD chronic kidney disease. DNA testing for mutations in the SMARCAL1 gene is available to confirm the diagnosis.
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Therapies of Schimke Immuno-Osseous Dysplasia
Treatment Treatments are selected to address individual symptoms as they develop. Renal transplantation effectively treats the renal disease, and bone marrow transplantation effectively treats the immunodeficiency and other hematological abnormalities. Blood thinning medications such as pentoxifylline, acetylsalicylic acid, dipyridamole, warfarin and heparin can transiently improve blood flow through the atherosclerotic arteries but do not provide enduring relief from cerebral ischemia. Treatment with acyclovir and some antibacterial agents has been beneficial for preventing or reducing the frequency of opportunistic infections. Hip replacement effectively treats the degenerative hip disease.
Therapies of Schimke Immuno-Osseous Dysplasia. Treatment Treatments are selected to address individual symptoms as they develop. Renal transplantation effectively treats the renal disease, and bone marrow transplantation effectively treats the immunodeficiency and other hematological abnormalities. Blood thinning medications such as pentoxifylline, acetylsalicylic acid, dipyridamole, warfarin and heparin can transiently improve blood flow through the atherosclerotic arteries but do not provide enduring relief from cerebral ischemia. Treatment with acyclovir and some antibacterial agents has been beneficial for preventing or reducing the frequency of opportunistic infections. Hip replacement effectively treats the degenerative hip disease.
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Overview of Schindler disease
Schindler disease is a rare inherited metabolic disorder characterized by the deficient activity of the lysosomal enzyme alpha-N-acetylgalactosaminidase (alpha-NAGA or alpha-galactosidase B). The enzyme defect leads to the abnormal accumulation of certain complex compounds (glycosphingolipids, glycoproteins, and oligosaccharides), which have terminal or preterminal N-acetylgalactosaminyl residues in many tissues of the body and in urine. Two major forms of Schindler disease exist – a severe form with onset in infancy (type I) and a milder form with onset in adulthood (type II). Some researchers have proposed a type III form of Schindler disease that is less severe than type I, but more severe than type II. The specific symptoms and severity of Schindler disease can vary from one person to another. Schindler disease is caused by mutations of the NAGA gene and is inherited as an autosomal recessive trait.Schindler disease belongs to a group of diseases known as lysosomal storage disorders. Within cells, lysosomes are small compartments or organelles which are bound by membranes. They function as the primary digestive units of cells. Enzymes within lysosomes break down or digest particular nutrients and cellular debris. Low levels or inactivity of these enzymes leads to the abnormal accumulation of the substances that they normally breakdown, resulting in the enlargement and increased numbers of lysosomes within cells of the body, as well as leakage of their stored contents. These disturbances may interfere with normal cellular function and cause the disease manifestations.
Overview of Schindler disease. Schindler disease is a rare inherited metabolic disorder characterized by the deficient activity of the lysosomal enzyme alpha-N-acetylgalactosaminidase (alpha-NAGA or alpha-galactosidase B). The enzyme defect leads to the abnormal accumulation of certain complex compounds (glycosphingolipids, glycoproteins, and oligosaccharides), which have terminal or preterminal N-acetylgalactosaminyl residues in many tissues of the body and in urine. Two major forms of Schindler disease exist – a severe form with onset in infancy (type I) and a milder form with onset in adulthood (type II). Some researchers have proposed a type III form of Schindler disease that is less severe than type I, but more severe than type II. The specific symptoms and severity of Schindler disease can vary from one person to another. Schindler disease is caused by mutations of the NAGA gene and is inherited as an autosomal recessive trait.Schindler disease belongs to a group of diseases known as lysosomal storage disorders. Within cells, lysosomes are small compartments or organelles which are bound by membranes. They function as the primary digestive units of cells. Enzymes within lysosomes break down or digest particular nutrients and cellular debris. Low levels or inactivity of these enzymes leads to the abnormal accumulation of the substances that they normally breakdown, resulting in the enlargement and increased numbers of lysosomes within cells of the body, as well as leakage of their stored contents. These disturbances may interfere with normal cellular function and cause the disease manifestations.
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Symptoms of Schindler disease
Some researchers have broken Schindler disease into three distinct types. Type I is a severe form that occurs during infancy and is associated with neurological symptoms. Type II is a milder form of the disorder with onset usually in adulthood and mild, if any associated neurological symptoms. Type III is an intermediate form whose onset and severity fall in between the other two. Consequently, the severity and specific symptoms of Schindler disease can vary greatly from patients in one family to those in another. 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.SCHINDLER DISEASE TYPE ISchindler disease type I, the classic form of the disease, begins in infancy. Affected children develop normally until approximately 9 months to 1 year of age. They may then begin to exhibit a delay in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation). After a period of such developmental delays, affected children may begin to lose previously acquired physical and mental abilities (developmental retrogression); such regression may begin at approximately 2 years of age. Affected children may then start to exhibit a variety of neurological symptoms, such as muscular weakness and diminished muscle tone (hypotonia); involuntary muscle spasms that result in slow, stiff movements (spasticity), misalignment of the eyes (strabismus); involuntary, rapid eye movements (nystagmus); and/or visual impairment due to the gradual deterioration of the nerves of the eyes (optic atrophy). They may also experience brief, shock-like muscle spasms of the arms, legs, or entire body (myoclonic movements and grand-mal seizures).SCHINDLER DISEASE TYPE IIIn the adult-onset form of Schindler disease (also known as Schindler disease type II or Kanzaki disease), symptoms may not appear until the second or third decade of life. A distinctive symptom of Schindler disease type II is involvement of small blood vessels (telangiectasia) in the skin that cause reddish small skin lesions, and an increase of its horny layer (stratum corneum; hyperkeratosis) referred to as angiokeratomas. The dilation of small lymph vessels may lead to swelling (lymphedema) particularly of the lower extremities.Angiokeratomas may first be restricted to a single area (localized), such as the lower torso, and then appear later in additional locations (e.g., from the lower torso to the chest area). These reddish lesions may be flat or raised and vary in color, and may occur in clusters. Affected individuals may also have these lesions in other areas of the body such as the mucous membranes including the mouth and eyes. Individuals with Schindler disease type II have also mild intellectual impairment, but do not show the serious neurological complications associated with Schindler disease type I. Individuals with Schindler disease type II may also develop distinctive facial features including mildly coarse features, thick lips, a depressed nasal bridge and an enlarged tip of the nose. Additional symptoms have been reported in the medical literature including vertigo, hearing loss, ringing in the ears (tinnitus), and muscle weakness. Patients may also experience pain crises. Many of the latter manifestations are thought to be due to lysosomal storage.SCHINDLER DISEASE TYPE IIISchindler disease type III, is an intermediate form the disorder. Symptoms can range from more serious intellectual impairment, neurological dysfunction and seizures to milder neurological and psychiatric issues such as speech and language delays and mild autism-like symptoms.
Symptoms of Schindler disease. Some researchers have broken Schindler disease into three distinct types. Type I is a severe form that occurs during infancy and is associated with neurological symptoms. Type II is a milder form of the disorder with onset usually in adulthood and mild, if any associated neurological symptoms. Type III is an intermediate form whose onset and severity fall in between the other two. Consequently, the severity and specific symptoms of Schindler disease can vary greatly from patients in one family to those in another. 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.SCHINDLER DISEASE TYPE ISchindler disease type I, the classic form of the disease, begins in infancy. Affected children develop normally until approximately 9 months to 1 year of age. They may then begin to exhibit a delay in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation). After a period of such developmental delays, affected children may begin to lose previously acquired physical and mental abilities (developmental retrogression); such regression may begin at approximately 2 years of age. Affected children may then start to exhibit a variety of neurological symptoms, such as muscular weakness and diminished muscle tone (hypotonia); involuntary muscle spasms that result in slow, stiff movements (spasticity), misalignment of the eyes (strabismus); involuntary, rapid eye movements (nystagmus); and/or visual impairment due to the gradual deterioration of the nerves of the eyes (optic atrophy). They may also experience brief, shock-like muscle spasms of the arms, legs, or entire body (myoclonic movements and grand-mal seizures).SCHINDLER DISEASE TYPE IIIn the adult-onset form of Schindler disease (also known as Schindler disease type II or Kanzaki disease), symptoms may not appear until the second or third decade of life. A distinctive symptom of Schindler disease type II is involvement of small blood vessels (telangiectasia) in the skin that cause reddish small skin lesions, and an increase of its horny layer (stratum corneum; hyperkeratosis) referred to as angiokeratomas. The dilation of small lymph vessels may lead to swelling (lymphedema) particularly of the lower extremities.Angiokeratomas may first be restricted to a single area (localized), such as the lower torso, and then appear later in additional locations (e.g., from the lower torso to the chest area). These reddish lesions may be flat or raised and vary in color, and may occur in clusters. Affected individuals may also have these lesions in other areas of the body such as the mucous membranes including the mouth and eyes. Individuals with Schindler disease type II have also mild intellectual impairment, but do not show the serious neurological complications associated with Schindler disease type I. Individuals with Schindler disease type II may also develop distinctive facial features including mildly coarse features, thick lips, a depressed nasal bridge and an enlarged tip of the nose. Additional symptoms have been reported in the medical literature including vertigo, hearing loss, ringing in the ears (tinnitus), and muscle weakness. Patients may also experience pain crises. Many of the latter manifestations are thought to be due to lysosomal storage.SCHINDLER DISEASE TYPE IIISchindler disease type III, is an intermediate form the disorder. Symptoms can range from more serious intellectual impairment, neurological dysfunction and seizures to milder neurological and psychiatric issues such as speech and language delays and mild autism-like symptoms.
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Causes of Schindler disease
Schindler disease is caused by mutations in the NAGA gene. These mutations are inherited as autosomal recessive traits. Genetic diseases are determined by the combination of mutations for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an 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. Investigators have determined that the NAGA (alpha-N-acetylgalactosaminidase) gene is located on the long arm (q) of chromosome 22 (22q13.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 22q13.2” refers to band 13 sub-band 2 on the long arm of chromosome 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Investigators have determined that the NAGA gene contains instructions for generating (encoding) an enzyme known as alpha-N-acetylgalactosaminidase (alpha-NAGA). All three forms of Schindler disease are characterized by very low levels or deficient activity of this enzyme. Low levels or absent activity of the enzyme leads to the abnormal accumulation of certain complex compounds (glycosphingolipids, glycoproteins, and oligosaccharides) in certain tissues of the body and in urine.Although mutations in the NAGA gene are clearly linked to the accumulation of the complex compounds containing alpha-N-acetylgalactosaminyl residues in the body, some researchers have questioned whether mutations in the NAGA gene cause the neurological symptoms associated with Schindler disease. Although all individuals with Schindler disease have mutations in the NAGA gene, not all develop neurological symptoms. The severe neurological symptoms of type I Schindler disease are associated with characteristic swellings at the end of nerve fibers (axons). These swellings may be referred to as dystrophic axonal swellings or “spheroids”. The spheroids are characteristic of a neuroaxonal dystrophy – a severe alteration of nerve cells. These swellings appear to disrupt proper nerve function by blocking the transmission of impulses between nerve cells. Some researchers suspect that other factors in addition to or instead of mutations of the NAGA gene may cause the development of the neurological symptoms of Schindler disease. For example, some researchers have speculated that individuals with Schindler disease who have neurological symptoms may have additional mutations in an unrelated gene. However, no conclusive evidence exists to confirm this theory. More research is necessary to determine the exact complex mechanisms that ultimately cause the neuroaxonal dystrophy of Schindler disease.
Causes of Schindler disease. Schindler disease is caused by mutations in the NAGA gene. These mutations are inherited as autosomal recessive traits. Genetic diseases are determined by the combination of mutations for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an 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. Investigators have determined that the NAGA (alpha-N-acetylgalactosaminidase) gene is located on the long arm (q) of chromosome 22 (22q13.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 22q13.2” refers to band 13 sub-band 2 on the long arm of chromosome 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Investigators have determined that the NAGA gene contains instructions for generating (encoding) an enzyme known as alpha-N-acetylgalactosaminidase (alpha-NAGA). All three forms of Schindler disease are characterized by very low levels or deficient activity of this enzyme. Low levels or absent activity of the enzyme leads to the abnormal accumulation of certain complex compounds (glycosphingolipids, glycoproteins, and oligosaccharides) in certain tissues of the body and in urine.Although mutations in the NAGA gene are clearly linked to the accumulation of the complex compounds containing alpha-N-acetylgalactosaminyl residues in the body, some researchers have questioned whether mutations in the NAGA gene cause the neurological symptoms associated with Schindler disease. Although all individuals with Schindler disease have mutations in the NAGA gene, not all develop neurological symptoms. The severe neurological symptoms of type I Schindler disease are associated with characteristic swellings at the end of nerve fibers (axons). These swellings may be referred to as dystrophic axonal swellings or “spheroids”. The spheroids are characteristic of a neuroaxonal dystrophy – a severe alteration of nerve cells. These swellings appear to disrupt proper nerve function by blocking the transmission of impulses between nerve cells. Some researchers suspect that other factors in addition to or instead of mutations of the NAGA gene may cause the development of the neurological symptoms of Schindler disease. For example, some researchers have speculated that individuals with Schindler disease who have neurological symptoms may have additional mutations in an unrelated gene. However, no conclusive evidence exists to confirm this theory. More research is necessary to determine the exact complex mechanisms that ultimately cause the neuroaxonal dystrophy of Schindler disease.
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Affects of Schindler disease
Schindler disease affects males and females in equal numbers. The exact incidence of Schindler disease in the general population is unknown. Because cases of Schindler disease may go unrecognized or misdiagnosed, determining the disorder's true frequency in the general population is difficult. As a group, lysosomal storage diseases are infrequent, although certain disorders may occur in specific ethnic or demographic groups at higher frequencies, about one in every 1,000-2,000 live births for Gaucher and Fabry diseases, or very infrequently (1 in 100,000 to 200,000 live births) for most of these disorders, which may be the case for alpha-N-acetylgalactosaminidase deficiency. Schindler disease was first reported in the medical literature in the late 1980s.
Affects of Schindler disease. Schindler disease affects males and females in equal numbers. The exact incidence of Schindler disease in the general population is unknown. Because cases of Schindler disease may go unrecognized or misdiagnosed, determining the disorder's true frequency in the general population is difficult. As a group, lysosomal storage diseases are infrequent, although certain disorders may occur in specific ethnic or demographic groups at higher frequencies, about one in every 1,000-2,000 live births for Gaucher and Fabry diseases, or very infrequently (1 in 100,000 to 200,000 live births) for most of these disorders, which may be the case for alpha-N-acetylgalactosaminidase deficiency. Schindler disease was first reported in the medical literature in the late 1980s.
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Related disorders of Schindler disease
Symptoms of the following disorders can be similar to those of Schindler disease. Comparisons may be useful for a differential diagnosis.Infantile neuroaxonal dystrophy (INAD), also known as Seitelberger disease, is an extremely rare, inherited degenerative disorder of the nervous system characterized by abnormalities of nerve endings (axon terminals) within the brain and spinal cord (central nervous system) and outside the central nervous system (peripheral nerves). In most cases, infants and children with INAD appear to develop normally until approximately 14 to 18 months of age, when they may begin to experience progressively increased difficulties in walking. In other cases, symptoms may begin at approximately six to eight months of age, at which time infants may experience delays or an arrest in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development). Patients experience a rapid and severe course of neurodegeneration with loss of all previously acquired mental and motor skills. The symptoms and physical characteristics associated with INAD are the result of swelling and degeneration of nerve endings (dystrophic axonal swellings or “spheroids”, virtually identical to those in Schindler disease type I) within and without areas of the brain and spinal cord (central nervous system). INAD is inherited as an autosomal recessive genetic trait. About 60% of patients with INAD have been associated with mutations in the PLA2G6 gene encoding a cytosolic, calcium-independent phospholipase A2 (group IV). Intriguingly, mutations in that gene have also been detected in patients with other neurodegenerative disorders such as early-onset Parkinsonism and Dystonia, and there remain INAD patients without PLA2G6 mutations. Besides the relatively uniform manifestations of classic INAD, some researchers have suggested an atypical form of INAD with later-onset, milder, and divergent symptoms that overlap with those of neurodegeneration with brain iron accumulation (NBIA; Hallervorden-Spatz syndrome), see below. (For more information on this disorder, choose “infantile neuroaxonal dystrophy” as your search term in the Rare Disease Database.)NBIA is a clinically and genetically heterogeneous group of rare, inherited, neurological movement disorders of childhood, characterized by the progressive degeneration of the nervous system (neurodegenerative disorder). Two genes for the major forms of NBIA have been identified, but there remain patients without mutations in either gene. The disease that is associated with mutations in the pantothenate kinase 2 gene, PANK2, is termed pantothenate kinase-associated neurodegeneration (PKAN). Approximately 50% of individuals with a clinical diagnosis of NBIA have gene mutations in PANK2. Its product normally helps to metabolize vitamin B5 (pantothenic acid) to synthesize coenzyme A. Classical PKAN begins with clumsiness and gait (walking) problems around age 3 years. Common features include dystonia, (an abnormality in muscle tone), muscular rigidity, and sudden involuntary muscle spasms (spasticity). These features can result in difficulty controlling movement and in speech problems. Another common feature is degeneration of the retina, resulting in progressive night blindness and loss of peripheral (side) vision. In general, symptoms are progressive and become worse over time. There is also an atypical form of PKAN that is recognized with later-onset and more slowly progressive neuropsychiatric features in addition to a movement disorder. Individuals can plateau for long periods of time and then undergo intervals of rapid deterioration. There are different mutations within PANK2 that could lead to a more or less severe presentation. Other factors that influence disease severity and the rate of progression are still unknown. Many of non-PKAN NBIA patients reveal mutations in the PLA2G6 gene. Clinically, these patients may have a static encephalopathy during childhood and then present in adulthood with a degenerative course, or they may have a hyperkinetic movement disorder from early childhood, or they constitute a subset of INAD patients with high globus pallidus iron. Finally, there are non-PKAN patients without mutations in PLA2G6. Other genes that have been associated with non-PKAN NBIA include FA2H, ATP13A2, C2orf37, CP, and FTL. (For more information on this disorder, choose “neurodegeneration with brain iron accumulation” as your search term in the Rare Disease Database.)Fabry disease is a rare genetic disorder of lipid metabolism characterized by a deficiency of the enzyme alpha-galactosidase A. The disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain fats and carbohydrates. Absence or less than 1 percent of the alpha-galactosidase A enzyme results in the “classic” subtype of Fabry disease due to the abnormal accumulation of a substance consisting of fatty material and carbohydrates (i.e., glycolipids such as glycosphingolipid) in various cells and organs of the body, particularly in the cells of blood vessels. Symptoms of “classic” Fabry disease may include the appearance of clusters of wart-like discolorations on the skin (angiokeratomas), excruciating pain in the fingers and toes, and abdominal pain. Later in the course of the disease, kidney failure, heart disease, and/or strokes cause serious complications. Fabry disease, which is inherited as an X-linked trait, affects males and females. Males are more uniformly affected whereas females may be asymptomatic or as severely affected as males due to “skewing of X-inactivation.” Patients with alpha-galactosidase A levels greater than 1 percent of normal have a somewhat milder “later-onset” subtype of the disease. (For more information on this disorder, choose “Fabry” as your search term in the Rare Disease Database.)
Related disorders of Schindler disease. Symptoms of the following disorders can be similar to those of Schindler disease. Comparisons may be useful for a differential diagnosis.Infantile neuroaxonal dystrophy (INAD), also known as Seitelberger disease, is an extremely rare, inherited degenerative disorder of the nervous system characterized by abnormalities of nerve endings (axon terminals) within the brain and spinal cord (central nervous system) and outside the central nervous system (peripheral nerves). In most cases, infants and children with INAD appear to develop normally until approximately 14 to 18 months of age, when they may begin to experience progressively increased difficulties in walking. In other cases, symptoms may begin at approximately six to eight months of age, at which time infants may experience delays or an arrest in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development). Patients experience a rapid and severe course of neurodegeneration with loss of all previously acquired mental and motor skills. The symptoms and physical characteristics associated with INAD are the result of swelling and degeneration of nerve endings (dystrophic axonal swellings or “spheroids”, virtually identical to those in Schindler disease type I) within and without areas of the brain and spinal cord (central nervous system). INAD is inherited as an autosomal recessive genetic trait. About 60% of patients with INAD have been associated with mutations in the PLA2G6 gene encoding a cytosolic, calcium-independent phospholipase A2 (group IV). Intriguingly, mutations in that gene have also been detected in patients with other neurodegenerative disorders such as early-onset Parkinsonism and Dystonia, and there remain INAD patients without PLA2G6 mutations. Besides the relatively uniform manifestations of classic INAD, some researchers have suggested an atypical form of INAD with later-onset, milder, and divergent symptoms that overlap with those of neurodegeneration with brain iron accumulation (NBIA; Hallervorden-Spatz syndrome), see below. (For more information on this disorder, choose “infantile neuroaxonal dystrophy” as your search term in the Rare Disease Database.)NBIA is a clinically and genetically heterogeneous group of rare, inherited, neurological movement disorders of childhood, characterized by the progressive degeneration of the nervous system (neurodegenerative disorder). Two genes for the major forms of NBIA have been identified, but there remain patients without mutations in either gene. The disease that is associated with mutations in the pantothenate kinase 2 gene, PANK2, is termed pantothenate kinase-associated neurodegeneration (PKAN). Approximately 50% of individuals with a clinical diagnosis of NBIA have gene mutations in PANK2. Its product normally helps to metabolize vitamin B5 (pantothenic acid) to synthesize coenzyme A. Classical PKAN begins with clumsiness and gait (walking) problems around age 3 years. Common features include dystonia, (an abnormality in muscle tone), muscular rigidity, and sudden involuntary muscle spasms (spasticity). These features can result in difficulty controlling movement and in speech problems. Another common feature is degeneration of the retina, resulting in progressive night blindness and loss of peripheral (side) vision. In general, symptoms are progressive and become worse over time. There is also an atypical form of PKAN that is recognized with later-onset and more slowly progressive neuropsychiatric features in addition to a movement disorder. Individuals can plateau for long periods of time and then undergo intervals of rapid deterioration. There are different mutations within PANK2 that could lead to a more or less severe presentation. Other factors that influence disease severity and the rate of progression are still unknown. Many of non-PKAN NBIA patients reveal mutations in the PLA2G6 gene. Clinically, these patients may have a static encephalopathy during childhood and then present in adulthood with a degenerative course, or they may have a hyperkinetic movement disorder from early childhood, or they constitute a subset of INAD patients with high globus pallidus iron. Finally, there are non-PKAN patients without mutations in PLA2G6. Other genes that have been associated with non-PKAN NBIA include FA2H, ATP13A2, C2orf37, CP, and FTL. (For more information on this disorder, choose “neurodegeneration with brain iron accumulation” as your search term in the Rare Disease Database.)Fabry disease is a rare genetic disorder of lipid metabolism characterized by a deficiency of the enzyme alpha-galactosidase A. The disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain fats and carbohydrates. Absence or less than 1 percent of the alpha-galactosidase A enzyme results in the “classic” subtype of Fabry disease due to the abnormal accumulation of a substance consisting of fatty material and carbohydrates (i.e., glycolipids such as glycosphingolipid) in various cells and organs of the body, particularly in the cells of blood vessels. Symptoms of “classic” Fabry disease may include the appearance of clusters of wart-like discolorations on the skin (angiokeratomas), excruciating pain in the fingers and toes, and abdominal pain. Later in the course of the disease, kidney failure, heart disease, and/or strokes cause serious complications. Fabry disease, which is inherited as an X-linked trait, affects males and females. Males are more uniformly affected whereas females may be asymptomatic or as severely affected as males due to “skewing of X-inactivation.” Patients with alpha-galactosidase A levels greater than 1 percent of normal have a somewhat milder “later-onset” subtype of the disease. (For more information on this disorder, choose “Fabry” as your search term in the Rare Disease Database.)
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Diagnosis of Schindler disease
Schindler disease may be diagnosed after birth (postnatally) by a thorough clinical evaluation, detailed patient history, and a variety of specialized tests. Urinary analysis (e.g., oligosaccharide and glycopeptide profiles) may reveal increased levels of certain complex compounds in the urine (e.g., oligosacchariduria and glycopeptiduria). Reduced activity of the alpha-NAGA enzyme may be confirmed by conducting enzyme tests (assays) on cultured white blood cells (leukocytes), blood plasma, and/or certain skin cells (fibroblasts) from affected individuals.In children with Schindler disease type I, examination of samples of tissue (biopsy) from the rectum’s mucosal and muscular layers (submucosal and myenteric plexus) may reveal lysosomal accumulation in extensions of nerve cells (axons) of the vegetative (autonomous) nervous system. Advanced imaging techniques, such as magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) of the brain may reveal degeneration of the outer layer of the brain (cortex), the cerebellum, and the brain stem.For families with a previous history of Schindler disease, the disorder may be diagnosed before birth (prenatally) by specialized tests such as amniocentesis and/or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, tissue samples are removed from a portion of the placenta. Studies performed on these fluid or tissue samples can reveal that there is reduced activity of the alpha-NAGA enzyme.
Diagnosis of Schindler disease. Schindler disease may be diagnosed after birth (postnatally) by a thorough clinical evaluation, detailed patient history, and a variety of specialized tests. Urinary analysis (e.g., oligosaccharide and glycopeptide profiles) may reveal increased levels of certain complex compounds in the urine (e.g., oligosacchariduria and glycopeptiduria). Reduced activity of the alpha-NAGA enzyme may be confirmed by conducting enzyme tests (assays) on cultured white blood cells (leukocytes), blood plasma, and/or certain skin cells (fibroblasts) from affected individuals.In children with Schindler disease type I, examination of samples of tissue (biopsy) from the rectum’s mucosal and muscular layers (submucosal and myenteric plexus) may reveal lysosomal accumulation in extensions of nerve cells (axons) of the vegetative (autonomous) nervous system. Advanced imaging techniques, such as magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) of the brain may reveal degeneration of the outer layer of the brain (cortex), the cerebellum, and the brain stem.For families with a previous history of Schindler disease, the disorder may be diagnosed before birth (prenatally) by specialized tests such as amniocentesis and/or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, tissue samples are removed from a portion of the placenta. Studies performed on these fluid or tissue samples can reveal that there is reduced activity of the alpha-NAGA enzyme.
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Therapies of Schindler disease
TreatmentThere is no specific therapy for individuals with Schindler disease. The treatment of Schindler disease is directed toward the specific symptoms that are apparent in each individual.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Therapies of Schindler disease. TreatmentThere is no specific therapy for individuals with Schindler disease. The treatment of Schindler disease is directed toward the specific symptoms that are apparent in each individual.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of Schinzel Giedion Syndrome
Schinzel Giedion syndrome (SGS) is a very rare genetic disorder with characteristic facial features, skeletal abnormalities, and obstruction of the tube that carries urine from the kidney to the bladder (ureter). This obstruction may lead to enlarged and damaged kidneys (hydronephrosis). Symptoms characteristic of SGS also include excessive hair-growth (hypertrichosis), a flat midface (midface retraction), seizures, clubfeet, broad ribs, profound intellectual disability and short arms and legs. SGS is caused by a new mutation in the SETBP1 gene that is not inherited from the parents. SGS is a severe progressive syndrome and most affected individuals do not survive infancy.
Overview of Schinzel Giedion Syndrome. Schinzel Giedion syndrome (SGS) is a very rare genetic disorder with characteristic facial features, skeletal abnormalities, and obstruction of the tube that carries urine from the kidney to the bladder (ureter). This obstruction may lead to enlarged and damaged kidneys (hydronephrosis). Symptoms characteristic of SGS also include excessive hair-growth (hypertrichosis), a flat midface (midface retraction), seizures, clubfeet, broad ribs, profound intellectual disability and short arms and legs. SGS is caused by a new mutation in the SETBP1 gene that is not inherited from the parents. SGS is a severe progressive syndrome and most affected individuals do not survive infancy.
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Symptoms of Schinzel Giedion Syndrome
Schinzel Giedion syndrome is characterized by an unusual facial appearance as well as abnormalities of the skeleton, kidney, hair and brain. Individuals with this disorder have an obstruction of the tube that carries urine from the kidney into the bladder (ureter). This causes the kidney to become swollen as urine accumulates (hydronephrosis).Failure to grow and develop normally becomes apparent at an early age. Excessive growth of hair as well as widely spaced eyes, a flat midface, low-set ears, a short low-set nose, and a short and wide neck with an excess of skin are typical features of individuals with Schinzel Giedion syndrome.Abnormalities of the skeleton include widely spaced openings between the bones of the skull (patent fontanelles), and short lower arms and legs. Other skeletal signs may include clubfoot and broad ribs. Typical and specific findings on X-ray are a dense pyramid bone and gap between the two segments of the occipital bone.Sudden, aimless, uncontrollable discharge of electrical energy in the brain causing convulsions and/or loss of consciousness (epileptic seizures) has been found in most patients with this disorder.Visual and hearing problems as well as intellectual disability are also found in patients with Schinzel Giedion syndrome. A sleep disorder in which there is cessation of breathing during sleep (sleep apnea) may also be present.Other symptoms found in some patients with Schinzel Giedion syndrome may include a high forehead that protrudes outward, a large tongue (macroglossia), delayed eruption of teeth, a narrow passage between the nose and throat (choanal stenosis), underdeveloped nipples, abnormal nails of the fingers and toes, extra fingers and/or toes, a clubfoot, a short penis, failure of the testicles to descent into the scrotum (cryptorchidism), and/or a deep depression in the fold of skin at the opening of the vagina (interlabial sulcus).A common form of heart disease characterized by an abnormal opening between the two atria chambers of the heart (atrial septal defect) has also been found in the majority of reported cases of Schinzel Giedion syndrome.The main complications of Schinzel Giedion syndrome are feeding difficulties, respiratory failure, recurrent infections (e.g. pneumonia) and refractory seizures.
Symptoms of Schinzel Giedion Syndrome. Schinzel Giedion syndrome is characterized by an unusual facial appearance as well as abnormalities of the skeleton, kidney, hair and brain. Individuals with this disorder have an obstruction of the tube that carries urine from the kidney into the bladder (ureter). This causes the kidney to become swollen as urine accumulates (hydronephrosis).Failure to grow and develop normally becomes apparent at an early age. Excessive growth of hair as well as widely spaced eyes, a flat midface, low-set ears, a short low-set nose, and a short and wide neck with an excess of skin are typical features of individuals with Schinzel Giedion syndrome.Abnormalities of the skeleton include widely spaced openings between the bones of the skull (patent fontanelles), and short lower arms and legs. Other skeletal signs may include clubfoot and broad ribs. Typical and specific findings on X-ray are a dense pyramid bone and gap between the two segments of the occipital bone.Sudden, aimless, uncontrollable discharge of electrical energy in the brain causing convulsions and/or loss of consciousness (epileptic seizures) has been found in most patients with this disorder.Visual and hearing problems as well as intellectual disability are also found in patients with Schinzel Giedion syndrome. A sleep disorder in which there is cessation of breathing during sleep (sleep apnea) may also be present.Other symptoms found in some patients with Schinzel Giedion syndrome may include a high forehead that protrudes outward, a large tongue (macroglossia), delayed eruption of teeth, a narrow passage between the nose and throat (choanal stenosis), underdeveloped nipples, abnormal nails of the fingers and toes, extra fingers and/or toes, a clubfoot, a short penis, failure of the testicles to descent into the scrotum (cryptorchidism), and/or a deep depression in the fold of skin at the opening of the vagina (interlabial sulcus).A common form of heart disease characterized by an abnormal opening between the two atria chambers of the heart (atrial septal defect) has also been found in the majority of reported cases of Schinzel Giedion syndrome.The main complications of Schinzel Giedion syndrome are feeding difficulties, respiratory failure, recurrent infections (e.g. pneumonia) and refractory seizures.
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Causes of Schinzel Giedion Syndrome
Schinzel Giedion syndrome is caused by a new spontaneous mutation of the SETBP1 gene. The disorder is not inherited from the parents. The SETBP1 gene is a cancer promoting gene, and affected children who survive past three years of age are at risk for different types of cancer.
Causes of Schinzel Giedion Syndrome. Schinzel Giedion syndrome is caused by a new spontaneous mutation of the SETBP1 gene. The disorder is not inherited from the parents. The SETBP1 gene is a cancer promoting gene, and affected children who survive past three years of age are at risk for different types of cancer.
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Affects of Schinzel Giedion Syndrome
Schinzel Giedion syndrome is a very rare disorder that affects males and females in equal numbers. The birth prevalence is unknown. There have been 50 cases reported worldwide.
Affects of Schinzel Giedion Syndrome. Schinzel Giedion syndrome is a very rare disorder that affects males and females in equal numbers. The birth prevalence is unknown. There have been 50 cases reported worldwide.
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Related disorders of Schinzel Giedion Syndrome
Symptoms of the following disorders can be similar to those of Schinzel- Giedion syndrome. Comparisons may be useful for a differential diagnosis:Mucopolysaccharidosis (MPS) is a group of hereditary disorders of lysosomal storage. These diseases are characterized by an abnormal accumulation of mucopolysaccharides, especially in the cartilage and bone tissue. Symptoms of this disorder may include: abnormally slow growth and intellectual disability; vision and hearing problems; stiff joints; an excess of hair; dwarfism; and/or heart and breathing problems. (For more information on this disorder, choose “Mucopolysaccharidosis” as your search term in the Rare Disease Database.)The following disorders may be associated with Schinzel Giedion syndrome as secondary characteristics. They are not necessary for a differential diagnosis:Infantile apnea is characterized by the temporary, but recurrent cessation of breathing during sleep. Cyanosis (bluish discoloration of the skin and mucous membranes around the mouth and nose) as well as bradycardia (a pulse rate of less than 60 per minute) are also present. The cause of this disorder is not known. (For more information on this disorder choose “Infantile Apnea” as your search term in the Rare Disease Database.)Atrial septal defects are a relatively common form of congenital heart disease. The septum separating the two atria is incompletely formed before birth and the opening persists. This can result in inefficient distribution of oxygen to the various tissues of the body, heart failure characterized by edema, difficulty breathing, fatigue, and other cardiovascular disturbances. Symptoms tend to be mild at first, so that the defect is sometimes not recognized until later in life. (For more information on this disorder choose “Atrial Septal Defects” as your search term in the Rare Disease Database.)Epilepsy is a central nervous system disorder that is characterized by a sudden, aimless, uncontrollable discharge of electrical energy in the brain. This discharge is sometimes preceded by a strange feeling (aura) and is characterized by a convulsion and/or loss of consciousness.
Related disorders of Schinzel Giedion Syndrome. Symptoms of the following disorders can be similar to those of Schinzel- Giedion syndrome. Comparisons may be useful for a differential diagnosis:Mucopolysaccharidosis (MPS) is a group of hereditary disorders of lysosomal storage. These diseases are characterized by an abnormal accumulation of mucopolysaccharides, especially in the cartilage and bone tissue. Symptoms of this disorder may include: abnormally slow growth and intellectual disability; vision and hearing problems; stiff joints; an excess of hair; dwarfism; and/or heart and breathing problems. (For more information on this disorder, choose “Mucopolysaccharidosis” as your search term in the Rare Disease Database.)The following disorders may be associated with Schinzel Giedion syndrome as secondary characteristics. They are not necessary for a differential diagnosis:Infantile apnea is characterized by the temporary, but recurrent cessation of breathing during sleep. Cyanosis (bluish discoloration of the skin and mucous membranes around the mouth and nose) as well as bradycardia (a pulse rate of less than 60 per minute) are also present. The cause of this disorder is not known. (For more information on this disorder choose “Infantile Apnea” as your search term in the Rare Disease Database.)Atrial septal defects are a relatively common form of congenital heart disease. The septum separating the two atria is incompletely formed before birth and the opening persists. This can result in inefficient distribution of oxygen to the various tissues of the body, heart failure characterized by edema, difficulty breathing, fatigue, and other cardiovascular disturbances. Symptoms tend to be mild at first, so that the defect is sometimes not recognized until later in life. (For more information on this disorder choose “Atrial Septal Defects” as your search term in the Rare Disease Database.)Epilepsy is a central nervous system disorder that is characterized by a sudden, aimless, uncontrollable discharge of electrical energy in the brain. This discharge is sometimes preceded by a strange feeling (aura) and is characterized by a convulsion and/or loss of consciousness.
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Schinzel Giedion Syndrome
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Diagnosis of Schinzel Giedion Syndrome
A diagnosis is based on clinical findings, such as facial dysmorphism, the presence of hydronephrosis on the ultrasound and radiographic findings of skeletal malformation. Hydronephrosis is detectable on prenatal ultrasound from week 18 to week 37. Genetic testing for mutations in the SETBP1 gene is available to confirm the diagnosis. If a SETBP1 gene mutation is identified, it is important to confirm that the mutation is not present in in the parents.
Diagnosis of Schinzel Giedion Syndrome. A diagnosis is based on clinical findings, such as facial dysmorphism, the presence of hydronephrosis on the ultrasound and radiographic findings of skeletal malformation. Hydronephrosis is detectable on prenatal ultrasound from week 18 to week 37. Genetic testing for mutations in the SETBP1 gene is available to confirm the diagnosis. If a SETBP1 gene mutation is identified, it is important to confirm that the mutation is not present in in the parents.
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Therapies of Schinzel Giedion Syndrome
SGS is a severe progressive syndrome and most affected individuals do not survive infancy. However, one child has been reported to live until 6 years of age and another to still be living at 15 years of age.Treatment is based on symptoms and is more palliative or pain relieving care. When hydronephrosis is present in patients with Schinzel Giedion syndrome, temporary drainage of the urine may be necessary. Surgery may be indicated when kidney function is compromised, pain and/or infection occur.The definitive treatment for atrial septal defects is surgical. The hole in the septum is either sutured shut, or patched with a graft. The success rate is quite high. In ostim primum (endocardial cushion) defects, the atrioventricular valves may have to be repaired or replaced; the success rate is substantially lower in these more complex operations.Anti-convulsant drugs such as carbamazepine, valproic acid, phenobarbital, clonazepam, ethusuximide, primidone, phenytoin, corticotropin, and corticosteroid drugs are being used to help prevent and control seizures associated with Epilepsy.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
Therapies of Schinzel Giedion Syndrome. SGS is a severe progressive syndrome and most affected individuals do not survive infancy. However, one child has been reported to live until 6 years of age and another to still be living at 15 years of age.Treatment is based on symptoms and is more palliative or pain relieving care. When hydronephrosis is present in patients with Schinzel Giedion syndrome, temporary drainage of the urine may be necessary. Surgery may be indicated when kidney function is compromised, pain and/or infection occur.The definitive treatment for atrial septal defects is surgical. The hole in the septum is either sutured shut, or patched with a graft. The success rate is quite high. In ostim primum (endocardial cushion) defects, the atrioventricular valves may have to be repaired or replaced; the success rate is substantially lower in these more complex operations.Anti-convulsant drugs such as carbamazepine, valproic acid, phenobarbital, clonazepam, ethusuximide, primidone, phenytoin, corticotropin, and corticosteroid drugs are being used to help prevent and control seizures associated with Epilepsy.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
1,095
Schinzel Giedion Syndrome
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Overview of Schinzel Syndrome
Schinzel syndrome, also known as ulnar-mammary syndrome, is a rare inherited disorder characterized by abnormalities of the bones of the hands and forearms in association with underdevelopment (hypoplasia) and dysfunction of certain sweat (apocrine) glands and/or the breasts (mammary glands). Abnormalities affecting the hands and/or forearms range from underdevelopment of the bone in the tip of the fifth finger (hypoplastic terminal phalanx) to underdevelopment or complete absence of the bone on the outer aspect of the forearm (ulna).In addition, certain sweat glands such as those located under the arms may be underdeveloped or absent, resulting in diminished ability or inability to sweat (perspire). In some cases, the breasts (mammary glands) may also be underdeveloped or absent; as a result, affected females exhibit a diminished ability or an inability to produce milk (lactate).The range and severity of physical abnormalities associated with Schinzel syndrome varies greatly among affected individuals; some cases may be very mild, while others may be more severe.
Overview of Schinzel Syndrome. Schinzel syndrome, also known as ulnar-mammary syndrome, is a rare inherited disorder characterized by abnormalities of the bones of the hands and forearms in association with underdevelopment (hypoplasia) and dysfunction of certain sweat (apocrine) glands and/or the breasts (mammary glands). Abnormalities affecting the hands and/or forearms range from underdevelopment of the bone in the tip of the fifth finger (hypoplastic terminal phalanx) to underdevelopment or complete absence of the bone on the outer aspect of the forearm (ulna).In addition, certain sweat glands such as those located under the arms may be underdeveloped or absent, resulting in diminished ability or inability to sweat (perspire). In some cases, the breasts (mammary glands) may also be underdeveloped or absent; as a result, affected females exhibit a diminished ability or an inability to produce milk (lactate).The range and severity of physical abnormalities associated with Schinzel syndrome varies greatly among affected individuals; some cases may be very mild, while others may be more severe.
1,096
Schinzel Syndrome
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Symptoms of Schinzel Syndrome
Schinzel syndrome, also known as ulnar-mammary syndrome (UMS), is an extremely rare inherited disorder characterized by abnormalities affecting the bones of the hands and forearms and/or underdevelopment (hypoplasia) and dysfunction of certain sweat glands (apocrine) and/or the breasts (mammary glands). The physical features and symptoms associated with Schinzel syndrome vary greatly from case to case. Abnormalities affecting the hands and/or forearms may range from underdevelopment (hypoplasia) of the bone in the tip of the fifth finger (hypoplastic terminal phalanx) to underdevelopment or complete absence of the bone on the outer aspect of the forearm (ulna); underdevelopment (hypoplasia), abnormal bending (bowing), or absence of the forearm bone on the thumb side of the arm (radius); and/or hypoplasia or absence of certain fingers, such as the third, fourth, and/or fifth fingers (oligodactyly). In some cases, certain bones of the fingers (e.g., phalanges of the fourth and fifth digits), within the body of the hand (metacarpals), and/or within the wrist (carpal bones) may be underdeveloped or absent. In addition, in some infants with digital hypoplasia, certain fingers may be permanently fixed in a flexed position (camptodactyly) and/or the fifth fingers may be abnormally bent (clinodactyly). Affected infants may have additional finger (digital) abnormalities with or without ulnar, radial, and/or digital malformations on the other side of the body (contralateral limb deficiencies), such as extra digits on the “pinky” side of the hand (postaxial polydactyly). In rare cases, infants with Schinzel syndrome may also exhibit underdevelopment of the long bone of the upper arm (humerus). In affected individuals, digital and/or upper limb abnormalities tend to vary in severity from side to side (asymmetry). Malformations affecting the fingers, hands, and arms may lead to complications, such as limitations in range of movement. In rare cases, individuals with the disorder may also exhibit underdeveloped, abnormally short, or absent toes. In some cases, individuals with Schinzel syndrome may also have abnormalities of certain sweat glands such as those under the arms (axillary apocrine glands). Such abnormalities may include underdevelopment (hypoplasia) or absence of the sweat glands, resulting in a reduced ability or complete inability to sweat (perspire). Affected individuals may also have little or no hair under the arms and lack body odor. In addition, in some cases, affected individuals may exhibit underdevelopment or complete absence of the nipples and/or breasts (mammary glands) and, in affected females, the breasts may be unable to produce milk (lactate). However, in other cases, affected individuals may have normal breast development with, in affected females, the ability to produce milk. In some cases, affected individuals may experience delayed growth that, in some cases, may result in short stature. However, in other cases, affected individuals may experience late “catch-up” growth. In addition, individuals with Schinzel syndrome may also have genital abnormalities. In some cases, affected males may have abnormally low levels of testicular function (hypogenitalism), resulting in delayed development of secondary sexual characteristics (puberty) (e.g., deepening of the voice, characteristic hair growth patterns, sudden increase in growth and development of the testes and scrotum, etc.). In addition, affected males may have an abnormally small penis and one or both of the testes may fail to descend into the scrotum (cryptorchidism). In affected females, the thin membrane that normally partially covers the vaginal opening (hymen) may completely cover the vaginal opening (imperforate hymen), potentially causing menstrual blood to collect in the vagina. In addition, in some cases, the uterus may be abnormally shaped (bicornate uterus). In some cases, individuals with Schinzel syndrome may have additional abnormalities such as excessive body mass (obesity), absence or improper positioning of certain teeth (ectopic upper canines), and/or malformations of bones of the spine (vertebrae) such as abnormal side-to-side curvature of the spine (scoliosis). In addition, the soft-tissue structure that hangs at the back of the throat (uvula) may be abnormally divided (bifid). In some cases, the voice box (larynx) may be covered with an abnormal fibrous membrane (congenital laryngeal web) that involves the vocal cords, the two fibrous bands of tissue that are essential for voice production. In such cases, affected individuals may experience some difficulties with swallowing, breathing (aspiration), and/or speech. In addition, some affected infants may exhibit abnormal narrowing (stenosis) of the band of muscle fibers (pyloric sphincter) at the junction between the stomach and the small intestine (pyloric stenosis), potentially resulting in obstruction of the normal flow of stomach contents into the small intestine. In a few cases, affected individuals may have protrusion of portions of the large intestine through an abnormal opening in layers of muscle lining the abdominal cavity (inguinal hernia). In addition, the anus may be abnormally narrowed or closed off (anal stenosis or atresia).In addition, according to the medical literature, three of four affected individuals within one family (kindred) had a ventricular septal defect (VSD), a heart abnormality that is present at birth (congenital). In individuals with VSDs, there is an abnormal opening in the fibrous partition (septum) that separates the two lower chambers (ventricles) of the heart. The size and location of the defect determine the range and severity of the symptoms. Because it is not clear whether this is an incidental finding, its implications are not fully understood. (For more information on this disorder, choose “Ventricular Septal Defect” as your search term in the Rare Disease Database.)
Symptoms of Schinzel Syndrome. Schinzel syndrome, also known as ulnar-mammary syndrome (UMS), is an extremely rare inherited disorder characterized by abnormalities affecting the bones of the hands and forearms and/or underdevelopment (hypoplasia) and dysfunction of certain sweat glands (apocrine) and/or the breasts (mammary glands). The physical features and symptoms associated with Schinzel syndrome vary greatly from case to case. Abnormalities affecting the hands and/or forearms may range from underdevelopment (hypoplasia) of the bone in the tip of the fifth finger (hypoplastic terminal phalanx) to underdevelopment or complete absence of the bone on the outer aspect of the forearm (ulna); underdevelopment (hypoplasia), abnormal bending (bowing), or absence of the forearm bone on the thumb side of the arm (radius); and/or hypoplasia or absence of certain fingers, such as the third, fourth, and/or fifth fingers (oligodactyly). In some cases, certain bones of the fingers (e.g., phalanges of the fourth and fifth digits), within the body of the hand (metacarpals), and/or within the wrist (carpal bones) may be underdeveloped or absent. In addition, in some infants with digital hypoplasia, certain fingers may be permanently fixed in a flexed position (camptodactyly) and/or the fifth fingers may be abnormally bent (clinodactyly). Affected infants may have additional finger (digital) abnormalities with or without ulnar, radial, and/or digital malformations on the other side of the body (contralateral limb deficiencies), such as extra digits on the “pinky” side of the hand (postaxial polydactyly). In rare cases, infants with Schinzel syndrome may also exhibit underdevelopment of the long bone of the upper arm (humerus). In affected individuals, digital and/or upper limb abnormalities tend to vary in severity from side to side (asymmetry). Malformations affecting the fingers, hands, and arms may lead to complications, such as limitations in range of movement. In rare cases, individuals with the disorder may also exhibit underdeveloped, abnormally short, or absent toes. In some cases, individuals with Schinzel syndrome may also have abnormalities of certain sweat glands such as those under the arms (axillary apocrine glands). Such abnormalities may include underdevelopment (hypoplasia) or absence of the sweat glands, resulting in a reduced ability or complete inability to sweat (perspire). Affected individuals may also have little or no hair under the arms and lack body odor. In addition, in some cases, affected individuals may exhibit underdevelopment or complete absence of the nipples and/or breasts (mammary glands) and, in affected females, the breasts may be unable to produce milk (lactate). However, in other cases, affected individuals may have normal breast development with, in affected females, the ability to produce milk. In some cases, affected individuals may experience delayed growth that, in some cases, may result in short stature. However, in other cases, affected individuals may experience late “catch-up” growth. In addition, individuals with Schinzel syndrome may also have genital abnormalities. In some cases, affected males may have abnormally low levels of testicular function (hypogenitalism), resulting in delayed development of secondary sexual characteristics (puberty) (e.g., deepening of the voice, characteristic hair growth patterns, sudden increase in growth and development of the testes and scrotum, etc.). In addition, affected males may have an abnormally small penis and one or both of the testes may fail to descend into the scrotum (cryptorchidism). In affected females, the thin membrane that normally partially covers the vaginal opening (hymen) may completely cover the vaginal opening (imperforate hymen), potentially causing menstrual blood to collect in the vagina. In addition, in some cases, the uterus may be abnormally shaped (bicornate uterus). In some cases, individuals with Schinzel syndrome may have additional abnormalities such as excessive body mass (obesity), absence or improper positioning of certain teeth (ectopic upper canines), and/or malformations of bones of the spine (vertebrae) such as abnormal side-to-side curvature of the spine (scoliosis). In addition, the soft-tissue structure that hangs at the back of the throat (uvula) may be abnormally divided (bifid). In some cases, the voice box (larynx) may be covered with an abnormal fibrous membrane (congenital laryngeal web) that involves the vocal cords, the two fibrous bands of tissue that are essential for voice production. In such cases, affected individuals may experience some difficulties with swallowing, breathing (aspiration), and/or speech. In addition, some affected infants may exhibit abnormal narrowing (stenosis) of the band of muscle fibers (pyloric sphincter) at the junction between the stomach and the small intestine (pyloric stenosis), potentially resulting in obstruction of the normal flow of stomach contents into the small intestine. In a few cases, affected individuals may have protrusion of portions of the large intestine through an abnormal opening in layers of muscle lining the abdominal cavity (inguinal hernia). In addition, the anus may be abnormally narrowed or closed off (anal stenosis or atresia).In addition, according to the medical literature, three of four affected individuals within one family (kindred) had a ventricular septal defect (VSD), a heart abnormality that is present at birth (congenital). In individuals with VSDs, there is an abnormal opening in the fibrous partition (septum) that separates the two lower chambers (ventricles) of the heart. The size and location of the defect determine the range and severity of the symptoms. Because it is not clear whether this is an incidental finding, its implications are not fully understood. (For more information on this disorder, choose “Ventricular Septal Defect” as your search term in the Rare Disease Database.)
1,096
Schinzel Syndrome
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Causes of Schinzel Syndrome
Schinzel syndrome is inherited as an autosomal dominant genetic trait. It occurs as a result of an abnormality in a gene on the long arm of chromosome 12 (12q24.1). 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 12q24.1” refers to band 24.1 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.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. 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.The gene responsible for Schinzel syndrome is called “TBX3.” The gene (which is a member of the “T-box” transcription factor family) plays a role in the development of the outer aspect of the upper limbs (ulnar or postaxial limb anomalies) during embryonic growth.
Causes of Schinzel Syndrome. Schinzel syndrome is inherited as an autosomal dominant genetic trait. It occurs as a result of an abnormality in a gene on the long arm of chromosome 12 (12q24.1). 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 12q24.1” refers to band 24.1 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.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. 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.The gene responsible for Schinzel syndrome is called “TBX3.” The gene (which is a member of the “T-box” transcription factor family) plays a role in the development of the outer aspect of the upper limbs (ulnar or postaxial limb anomalies) during embryonic growth.
1,096
Schinzel Syndrome
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Affects of Schinzel Syndrome
Schinzel syndrome is a very rare disorder that affects males and females in equal numbers. Between 50 and 75 cases have been reported in the medical literature. Of these, about 33 cases involve individuals within one family (kindred) from Utah. The syndrome has been described in Asians, Africans, and Europeans. Individuals with this syndrome who have few symptoms may never be diagnosed with the disorder; therefore, it may be difficult to determine the true frequency of the syndrome in the general population. The syndrome was first identified by A. Schinzel in 1973. At that time, it was labeled Schinzel syndrome. All of Schinzel's reported cases involved males. P.D. Pallister identified a strikingly similar syndrome in 1976, which became known as Pallister syndrome or ulnar-mammary syndrome of Pallister, in which most cases involved females. Today, although some researchers consider these two distinct disorders, most consider them the same disease entity.
Affects of Schinzel Syndrome. Schinzel syndrome is a very rare disorder that affects males and females in equal numbers. Between 50 and 75 cases have been reported in the medical literature. Of these, about 33 cases involve individuals within one family (kindred) from Utah. The syndrome has been described in Asians, Africans, and Europeans. Individuals with this syndrome who have few symptoms may never be diagnosed with the disorder; therefore, it may be difficult to determine the true frequency of the syndrome in the general population. The syndrome was first identified by A. Schinzel in 1973. At that time, it was labeled Schinzel syndrome. All of Schinzel's reported cases involved males. P.D. Pallister identified a strikingly similar syndrome in 1976, which became known as Pallister syndrome or ulnar-mammary syndrome of Pallister, in which most cases involved females. Today, although some researchers consider these two distinct disorders, most consider them the same disease entity.
1,096
Schinzel Syndrome
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Related disorders of Schinzel Syndrome
Symptoms of the following disorder may be similar to those of Schinzel syndrome. A comparison may be useful for differential diagnosis: Holt-Oram syndrome is a rare inherited disorder characterized by malformations of the hands, particularly the thumbs, and abnormalities affecting the heart (cardiac). The thumbs may be absent or underdeveloped (hypoplastic) or have an extra bone (triphalangy). There may also be extra bones in the wrists (carpal bones) and malformations of the bones within the body of the hands (metacarpals). In addition, the forearm bones (ulna and radius), the bone of the upper arm (humerus), and the shoulder girdle may also be underdeveloped. In most cases, affected infants may also have heart abnormalities that are present at birth (congenital heart defects). The most common heart defects in such cases are Ventricular and atrial septal defects, which are characterized by an abnormal opening in the fibrous partition (septum) that separates the two lower chambers (ventricles) of the heart and the septum that divides the two upper chambers (atria) of the heart. The size and location of the atrial and/or ventricular septal defect determine the severity of associated symptoms. Symptoms may include excessive fatigue, difficulty breathing (dyspnea), bluish discoloration of the skin and mucous membranes due to insufficient oxygen supply (cyanosis), abnormally rapid heart beat (tachycardia), inability of the heart to pump blood effectively (congestive heart failure), and/or other abnormalities. Holt-Oram syndrome is inherited as an autosomal dominant genetic trait. The disorder is due to mutations in TBX5, a gene related to TBX3 that is located in the same region of chromosome 12 (12q24.1). TBX5 plays a role in the development of the upper limbs (particularly the inner aspect or “thumb side” of the upper limbs [preaxial limb anomalies]) and the heart during embryonic growth. (For more information on this disorder, choose “Holt Oram” as your search term in the Rare Disease Database.)
Related disorders of Schinzel Syndrome. Symptoms of the following disorder may be similar to those of Schinzel syndrome. A comparison may be useful for differential diagnosis: Holt-Oram syndrome is a rare inherited disorder characterized by malformations of the hands, particularly the thumbs, and abnormalities affecting the heart (cardiac). The thumbs may be absent or underdeveloped (hypoplastic) or have an extra bone (triphalangy). There may also be extra bones in the wrists (carpal bones) and malformations of the bones within the body of the hands (metacarpals). In addition, the forearm bones (ulna and radius), the bone of the upper arm (humerus), and the shoulder girdle may also be underdeveloped. In most cases, affected infants may also have heart abnormalities that are present at birth (congenital heart defects). The most common heart defects in such cases are Ventricular and atrial septal defects, which are characterized by an abnormal opening in the fibrous partition (septum) that separates the two lower chambers (ventricles) of the heart and the septum that divides the two upper chambers (atria) of the heart. The size and location of the atrial and/or ventricular septal defect determine the severity of associated symptoms. Symptoms may include excessive fatigue, difficulty breathing (dyspnea), bluish discoloration of the skin and mucous membranes due to insufficient oxygen supply (cyanosis), abnormally rapid heart beat (tachycardia), inability of the heart to pump blood effectively (congestive heart failure), and/or other abnormalities. Holt-Oram syndrome is inherited as an autosomal dominant genetic trait. The disorder is due to mutations in TBX5, a gene related to TBX3 that is located in the same region of chromosome 12 (12q24.1). TBX5 plays a role in the development of the upper limbs (particularly the inner aspect or “thumb side” of the upper limbs [preaxial limb anomalies]) and the heart during embryonic growth. (For more information on this disorder, choose “Holt Oram” as your search term in the Rare Disease Database.)
1,096
Schinzel Syndrome
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Diagnosis of Schinzel Syndrome
In some cases, a diagnosis of Schinzel syndrome may be made at birth based upon a thorough clinical evaluation, the identification of characteristic physical findings, and specialized imaging techniques. Such imaging studies may be conducted to confirm and/or characterize bone abnormalities affecting the fingers, hands, wrists, and/or arms; certain genital abnormalities (e.g., bicornate uterus in females, cryptorchidism in males); and/or other malformations (e.g., pyloric stenosis, inguinal hernia). Specialized tests may also be conducted to detect and verify dysfunction of certain sweat (apocrine) glands and/or the mammary glands in affected females. In addition, in some cases, additional testing may be conducted (e.g., echocardiograms, electrocardiograms, cardiac catheterization, specialized x-ray studies, etc.) to detect the presence of and/or characterize ventricular septal defects, which have been reported in one family with the disorder.
Diagnosis of Schinzel Syndrome. In some cases, a diagnosis of Schinzel syndrome may be made at birth based upon a thorough clinical evaluation, the identification of characteristic physical findings, and specialized imaging techniques. Such imaging studies may be conducted to confirm and/or characterize bone abnormalities affecting the fingers, hands, wrists, and/or arms; certain genital abnormalities (e.g., bicornate uterus in females, cryptorchidism in males); and/or other malformations (e.g., pyloric stenosis, inguinal hernia). Specialized tests may also be conducted to detect and verify dysfunction of certain sweat (apocrine) glands and/or the mammary glands in affected females. In addition, in some cases, additional testing may be conducted (e.g., echocardiograms, electrocardiograms, cardiac catheterization, specialized x-ray studies, etc.) to detect the presence of and/or characterize ventricular septal defects, which have been reported in one family with the disorder.
1,096
Schinzel Syndrome
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Therapies of Schinzel Syndrome
TreatmentThe treatment of Schinzel 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; physicians who specialize in diagnosing and treating disorders of the skeleton (orthopedists), the urogenital tract in males (urologists), the genital tract in females (gynecologists), and/or the endocrine glands (endocrinologists); dental specialists; physical therapists; and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Depending upon the severity of any limb and digital abnormalities, children with ulnar-mammary syndrome may experience difficulty performing certain tasks that require coordination of voluntary movements (motor skills). Treatment may consist of corrective or reconstructive surgery; the use of artificial replacements for portions of the forearms and hands that may be underdeveloped or absent (limb prosthetics); and/or physical therapy to help individuals enhance their motor skills.In some cases, reconstructive surgery may also be beneficial for affected individuals with nipple and breast abnormalities. In addition, in some affected females, surgery may be recommended to open (perforate) the hymen (hymenotomy). In affected males, surgery may be performed to move undescended testes into the scrotum (orchiopexy) and attach them in a fixed position to prevent retraction. In some cases, surgery may also be performed to correct pyloric stenosis (pyloromyotomy), inguinal hernias, and/or anal stenosis or atresia.Individuals with this syndrome may also benefit from special social support and vocational and occupational services. Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Therapies of Schinzel Syndrome. TreatmentThe treatment of Schinzel 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; physicians who specialize in diagnosing and treating disorders of the skeleton (orthopedists), the urogenital tract in males (urologists), the genital tract in females (gynecologists), and/or the endocrine glands (endocrinologists); dental specialists; physical therapists; and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Depending upon the severity of any limb and digital abnormalities, children with ulnar-mammary syndrome may experience difficulty performing certain tasks that require coordination of voluntary movements (motor skills). Treatment may consist of corrective or reconstructive surgery; the use of artificial replacements for portions of the forearms and hands that may be underdeveloped or absent (limb prosthetics); and/or physical therapy to help individuals enhance their motor skills.In some cases, reconstructive surgery may also be beneficial for affected individuals with nipple and breast abnormalities. In addition, in some affected females, surgery may be recommended to open (perforate) the hymen (hymenotomy). In affected males, surgery may be performed to move undescended testes into the scrotum (orchiopexy) and attach them in a fixed position to prevent retraction. In some cases, surgery may also be performed to correct pyloric stenosis (pyloromyotomy), inguinal hernias, and/or anal stenosis or atresia.Individuals with this syndrome may also benefit from special social support and vocational and occupational services. Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
1,096
Schinzel Syndrome
nord_1097_0
Overview of Schnitzler Syndrome
Schnitzler syndrome is a rare disorder characterized by a chronic reddish rash that resembles hives (urticaria) and elevated levels of a specific protein in the blood (monoclonal IgM gammopathy). Symptoms associated with Schnitzler syndrome may include repeated bouts of fever, joint inflammation (arthritis), joint pain (arthralgia), bone pain, and other findings such as enlarged lymph nodes (lymphadenopathy). A monoclonal IgM gammopathy refers to the uncontrolled growth of a single clone (monoclonal) of plasma cells, which results in the abnormal accumulation of M-proteins (also known as immunoglobulin M or IgM) in the blood. However, the specific role these proteins play and the exact cause of Schnitzler syndrome is unknown. Schnitzler syndrome is difficult to classify and some researchers have suggested that it is an acquired autoinflammatory syndrome. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. They are not the same as autoimmune disorders, in which the adaptive immune system malfunctions and mistakenly attacks healthy tissue.
Overview of Schnitzler Syndrome. Schnitzler syndrome is a rare disorder characterized by a chronic reddish rash that resembles hives (urticaria) and elevated levels of a specific protein in the blood (monoclonal IgM gammopathy). Symptoms associated with Schnitzler syndrome may include repeated bouts of fever, joint inflammation (arthritis), joint pain (arthralgia), bone pain, and other findings such as enlarged lymph nodes (lymphadenopathy). A monoclonal IgM gammopathy refers to the uncontrolled growth of a single clone (monoclonal) of plasma cells, which results in the abnormal accumulation of M-proteins (also known as immunoglobulin M or IgM) in the blood. However, the specific role these proteins play and the exact cause of Schnitzler syndrome is unknown. Schnitzler syndrome is difficult to classify and some researchers have suggested that it is an acquired autoinflammatory syndrome. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. They are not the same as autoimmune disorders, in which the adaptive immune system malfunctions and mistakenly attacks healthy tissue.
1,097
Schnitzler Syndrome
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Symptoms of Schnitzler Syndrome
The symptoms associated with Schnitzler syndrome can vary from one person to another. The symptoms can occur all at once or, because they often come and go, the symptoms can occur at different times. The symptoms tend to persist for many years (chronic disease).A reddish, rash that resembles hives (urticaria) is the hallmark finding associated with Schnitzler syndrome. The distinctive rash usually consists of raised, reddish bumps (papules) and flatter, wider lesions (plaques). In most cases, a rash is the first symptom to appear in individuals with Schnitzler syndrome. The rash usually lasts for a day to two and then disappears without scarring. However, a new rash often develops each day so that a rash is a constant occurrence but the frequency of the rash can vary greatly from one person to another and some people only develop a rash a few times during the year.When the rash first develops, it usually is not itchy (not pruritic). However, in approximately 45 percent of cases, the rash will become itchy within a few years. The trunk, arms and legs are most often affected. The head, neck, palms and soles are usually spared. Some affected individuals have reported that alcohol, spicy foods and stress have aggravated the rash.Fevers that come and go over a period of time (chronic, intermittent fevers) are the second most common symptom in individuals with Schnitzler syndrome. The frequency of fevers varies greatly, ranging from being a daily occurrence to only a couple times per year. Fevers are usually unrelated to the skin rash, are well-tolerated and are rarely accompanied by chills.Additional symptoms associated with Schnitzler syndrome include bone pain, most often affecting the lower legs and hips, and joint pain, most often affecting the large joints such as the hips, knees, wrists and ankles. In some cases, inflammation of the joints (arthritis) may develop with accompanying swelling, redness and a feeling of heat or warmth in the joint. Despite joint involvement, joint degeneration or destruction has not been reported in individuals with Schnitzler syndrome.Abnormal enlargement of the lymph nodes (lymphadenopathy), the liver (hepatomegaly) and the spleen (splenomegaly) may also occur in some cases. Additional nonspecific symptoms that have been reported in individuals with Schnitzler syndrome include unintended weight loss, fatigue and a general feeling of poor health (malaise). Rapid swelling due to fluid accumulation just beneath the surface skin (angioedema) is very rare.Most cases of Schnitzler syndrome have a chronic, benign course. However, over a period of 10 years, approximately 15 percent of affected individuals developed cancer, most often cancer caused by the overproduction of white blood cells (lymphoproliferative disorders) such as Waldenström macroglobulinemia.Some individuals with Schnitzler syndrome have elevated levels of a different protein (see Causes section below) than individuals with classic Schnitzler syndrome. These individuals are classified as having variant Schnitzler syndrome and have very similar symptoms to classic Schnitzler syndrome.
Symptoms of Schnitzler Syndrome. The symptoms associated with Schnitzler syndrome can vary from one person to another. The symptoms can occur all at once or, because they often come and go, the symptoms can occur at different times. The symptoms tend to persist for many years (chronic disease).A reddish, rash that resembles hives (urticaria) is the hallmark finding associated with Schnitzler syndrome. The distinctive rash usually consists of raised, reddish bumps (papules) and flatter, wider lesions (plaques). In most cases, a rash is the first symptom to appear in individuals with Schnitzler syndrome. The rash usually lasts for a day to two and then disappears without scarring. However, a new rash often develops each day so that a rash is a constant occurrence but the frequency of the rash can vary greatly from one person to another and some people only develop a rash a few times during the year.When the rash first develops, it usually is not itchy (not pruritic). However, in approximately 45 percent of cases, the rash will become itchy within a few years. The trunk, arms and legs are most often affected. The head, neck, palms and soles are usually spared. Some affected individuals have reported that alcohol, spicy foods and stress have aggravated the rash.Fevers that come and go over a period of time (chronic, intermittent fevers) are the second most common symptom in individuals with Schnitzler syndrome. The frequency of fevers varies greatly, ranging from being a daily occurrence to only a couple times per year. Fevers are usually unrelated to the skin rash, are well-tolerated and are rarely accompanied by chills.Additional symptoms associated with Schnitzler syndrome include bone pain, most often affecting the lower legs and hips, and joint pain, most often affecting the large joints such as the hips, knees, wrists and ankles. In some cases, inflammation of the joints (arthritis) may develop with accompanying swelling, redness and a feeling of heat or warmth in the joint. Despite joint involvement, joint degeneration or destruction has not been reported in individuals with Schnitzler syndrome.Abnormal enlargement of the lymph nodes (lymphadenopathy), the liver (hepatomegaly) and the spleen (splenomegaly) may also occur in some cases. Additional nonspecific symptoms that have been reported in individuals with Schnitzler syndrome include unintended weight loss, fatigue and a general feeling of poor health (malaise). Rapid swelling due to fluid accumulation just beneath the surface skin (angioedema) is very rare.Most cases of Schnitzler syndrome have a chronic, benign course. However, over a period of 10 years, approximately 15 percent of affected individuals developed cancer, most often cancer caused by the overproduction of white blood cells (lymphoproliferative disorders) such as Waldenström macroglobulinemia.Some individuals with Schnitzler syndrome have elevated levels of a different protein (see Causes section below) than individuals with classic Schnitzler syndrome. These individuals are classified as having variant Schnitzler syndrome and have very similar symptoms to classic Schnitzler syndrome.
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Causes of Schnitzler Syndrome
The exact cause of Schnitzler syndrome is unknown. Researchers believe that specific parts of the immune system may not function properly, eventually causing Schnitzler syndrome.Individuals with Schnitzler syndrome also have a clinical finding called monoclonal IgM gammopathy, in which abnormalities affecting the production of immunoglobulins result in elevated levels of a specific immunoglobulin M (IgM) in the body. Immunoglobulins are proteins produced by certain white blood cells. There are five classes of immunoglobulins known as IgA, IgD, IgE, IgG, and IgM. Immunoglobulins play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells.At the time of diagnosis, IgM levels may only be slightly elevated and may remain stable for years.A variant form of Schnitzler syndrome has been reported in which individuals have a monoclonal gammopathy of IgG instead of IgM.Certain cytokines (specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells) play a role in the development of Schnitzler syndrome. The cytokine interleukin-1 (IL-1), is an important mediator of the inflammation in Schnitzler syndrome. Abnormal clinical findings involving interleukin-1 have been found in some individuals with Schnitzler syndrome and therapy with drugs that block the activity of interleukin-1 have brought about complete remission (see Investigational Therapies below).
Causes of Schnitzler Syndrome. The exact cause of Schnitzler syndrome is unknown. Researchers believe that specific parts of the immune system may not function properly, eventually causing Schnitzler syndrome.Individuals with Schnitzler syndrome also have a clinical finding called monoclonal IgM gammopathy, in which abnormalities affecting the production of immunoglobulins result in elevated levels of a specific immunoglobulin M (IgM) in the body. Immunoglobulins are proteins produced by certain white blood cells. There are five classes of immunoglobulins known as IgA, IgD, IgE, IgG, and IgM. Immunoglobulins play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells.At the time of diagnosis, IgM levels may only be slightly elevated and may remain stable for years.A variant form of Schnitzler syndrome has been reported in which individuals have a monoclonal gammopathy of IgG instead of IgM.Certain cytokines (specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells) play a role in the development of Schnitzler syndrome. The cytokine interleukin-1 (IL-1), is an important mediator of the inflammation in Schnitzler syndrome. Abnormal clinical findings involving interleukin-1 have been found in some individuals with Schnitzler syndrome and therapy with drugs that block the activity of interleukin-1 have brought about complete remission (see Investigational Therapies below).
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Affects of Schnitzler Syndrome
Schnitzler syndrome affects males slightly more often than females. However, only approximately 160 cases of this rare disorder have been reported in the medical literature so no definitive conclusions can be made about ethnic or gender predispositions. Because of the varied symptoms and rarity of Schnitzler syndrome, a diagnosis is usually delayed by several years and researchers believe that the disorder is underdiagnosed, making it difficult to determine its true frequency in the general population. Most individuals with Schnitzler syndrome are in their 50s when the characteristic symptoms develop.Less often, symptoms have been noted in individuals in their 30s. In one reported case, symptoms were identified in an individual 12 years old. It is to be questioned whether these cases were classical Schnitzler syndrome (see Related Disorders below).Schnitzler syndrome was first described in the medical literature in 1972, by a French dermatologist named Liliane Schnitzler. Most of the reported cases of Schnitzler syndrome have been from Europe, particularly France, but cases from Australia, Japan and the United States have been reported too.
Affects of Schnitzler Syndrome. Schnitzler syndrome affects males slightly more often than females. However, only approximately 160 cases of this rare disorder have been reported in the medical literature so no definitive conclusions can be made about ethnic or gender predispositions. Because of the varied symptoms and rarity of Schnitzler syndrome, a diagnosis is usually delayed by several years and researchers believe that the disorder is underdiagnosed, making it difficult to determine its true frequency in the general population. Most individuals with Schnitzler syndrome are in their 50s when the characteristic symptoms develop.Less often, symptoms have been noted in individuals in their 30s. In one reported case, symptoms were identified in an individual 12 years old. It is to be questioned whether these cases were classical Schnitzler syndrome (see Related Disorders below).Schnitzler syndrome was first described in the medical literature in 1972, by a French dermatologist named Liliane Schnitzler. Most of the reported cases of Schnitzler syndrome have been from Europe, particularly France, but cases from Australia, Japan and the United States have been reported too.
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Related disorders of Schnitzler Syndrome
Symptoms of the following disorders can be similar to those of Schnitzler syndrome. Comparisons may be useful for a differential diagnosis.Autoinflammatory syndromes are a group of disorder characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. Symptoms of the syndromes often include periodic fevers, rash, abdominal pain, joint pain, bone pain and other characteristic findings associated with chronic inflammation. These disorders include the cryoprin-associated periodic syndromes (familial cold autoinflammatory syndrome, CINCA, and Muckle-Wells syndrome), mevalonate kinase deficiency (also known as hyperimmunoglobulin D syndrome (HIDS)), familial Mediterranean fever (FMF), TRAPS. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) Autoimmune disorders are a group of disorders in which the abnormalities affecting the adaptive immune system, which consists of cells and proteins (antibodies) that are suppose to protect the body from infection. These antibodies mistakenly attack healthy tissue and may be referred to as autoantibodies. Symptoms common to many autoimmune disorders include repeated episodes of fever, rash, abdominal pain, joint pain and other symptoms associated with chronic inflammation. Autoimmune disorders that may resemble Schnitzler syndrome include adult-onset Still’s disease, systemic lupus erythematosus, urticarial vasculitis, idiopathic chronic (or spontaneous) urticaria (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) POEMS syndrome is an extremely rare multisystem disorder. POEMS is an acronym that stands for (P)olyneuropathy, disease affecting many nerves; (O)rganomegaly, abnormal enlargement of an organ; (E)ndocrinoapthy, disease affecting certain hormone-producing glands that help to regulate the rate of growth, sexual development, and certain metabolic functions (endocrine system); (M)onoclonal gammopathy or M proteins; and (S)kin defects. Common symptoms include progressive weakness of the nerves in the arms and legs, an abnormally enlarged liver and/or spleen (hepatosplenomegaly), abnormally darkening of the skin (hyperpigmentation) and excessive hair growth (hypertrichosis). Endocrine abnormalities such as failure of the ovaries and testes (gonads) to function properly (primary gonadal failure) and diabetes mellitus type I may be present. Specific endocrine abnormalities associated with POEMS syndrome vary from case to case. Other important features of the disease include swelling around the optic nerve (papilledema), abnormal fluid retention, which may occur in the ankles (edema), the abdominal cavity (ascites), or around the lungs (pleural effusions), painless scars on bone x-ray (osteosclerosis), and an elevated platelet count (a blood cell responsible for clotting). POEMS syndrome is associated with a group of disorders known as monoclonal gammopathies or plasma cell dyscrasias. These disorders are characterized the uncontrolled growth of a single clone (monoclonal) of plasma cells, which results in the abnormal accumulation of M-proteins (IgM) in the blood. (For more information on this disorder, choose “POEMS” as your search term in the Rare Disease Database.) Waldenström macroglobulinemia (WMG) is a slow-growing (indolent) malignant (cancerous) disorder of the blood, closely related to lymphoma and characterized by the presence of abnormally large numbers of a particular kind of white blood cell known as B lymphocytes. As these cells accumulate in the body, excessive quantities of an antibody known as a monoclonal immunoglobulin M (IgM) are produced. This causes the blood to become thick (hyperviscosity) and affects the flow of blood through the smaller blood vessels, leading to some of symptoms of the disorder. Accumulation of B lymphocytes in the bone marrow can inhibit bone marrow production of new blood cells (pancytopenia). Affected individuals may have low levels of red blood cells (anemia), white blood cells (leukopenia) and platelets (thrombocytopenia). Consequently, affected individuals may experience fatigue, pallor, nose bleeds, and susceptibility to infection. Some individuals with Schnitzler syndrome have developed Waldenström macroglobulinemia later in life. The exact relationship between these two disorders is not fully understood. The exact cause of Waldenström macroglobulinemia is not known. (For more information on this disorder, choose “Waldenstrom macroglobulinemia” as your search term in the Rare Disease Database.)
Related disorders of Schnitzler Syndrome. Symptoms of the following disorders can be similar to those of Schnitzler syndrome. Comparisons may be useful for a differential diagnosis.Autoinflammatory syndromes are a group of disorder characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. Symptoms of the syndromes often include periodic fevers, rash, abdominal pain, joint pain, bone pain and other characteristic findings associated with chronic inflammation. These disorders include the cryoprin-associated periodic syndromes (familial cold autoinflammatory syndrome, CINCA, and Muckle-Wells syndrome), mevalonate kinase deficiency (also known as hyperimmunoglobulin D syndrome (HIDS)), familial Mediterranean fever (FMF), TRAPS. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) Autoimmune disorders are a group of disorders in which the abnormalities affecting the adaptive immune system, which consists of cells and proteins (antibodies) that are suppose to protect the body from infection. These antibodies mistakenly attack healthy tissue and may be referred to as autoantibodies. Symptoms common to many autoimmune disorders include repeated episodes of fever, rash, abdominal pain, joint pain and other symptoms associated with chronic inflammation. Autoimmune disorders that may resemble Schnitzler syndrome include adult-onset Still’s disease, systemic lupus erythematosus, urticarial vasculitis, idiopathic chronic (or spontaneous) urticaria (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) POEMS syndrome is an extremely rare multisystem disorder. POEMS is an acronym that stands for (P)olyneuropathy, disease affecting many nerves; (O)rganomegaly, abnormal enlargement of an organ; (E)ndocrinoapthy, disease affecting certain hormone-producing glands that help to regulate the rate of growth, sexual development, and certain metabolic functions (endocrine system); (M)onoclonal gammopathy or M proteins; and (S)kin defects. Common symptoms include progressive weakness of the nerves in the arms and legs, an abnormally enlarged liver and/or spleen (hepatosplenomegaly), abnormally darkening of the skin (hyperpigmentation) and excessive hair growth (hypertrichosis). Endocrine abnormalities such as failure of the ovaries and testes (gonads) to function properly (primary gonadal failure) and diabetes mellitus type I may be present. Specific endocrine abnormalities associated with POEMS syndrome vary from case to case. Other important features of the disease include swelling around the optic nerve (papilledema), abnormal fluid retention, which may occur in the ankles (edema), the abdominal cavity (ascites), or around the lungs (pleural effusions), painless scars on bone x-ray (osteosclerosis), and an elevated platelet count (a blood cell responsible for clotting). POEMS syndrome is associated with a group of disorders known as monoclonal gammopathies or plasma cell dyscrasias. These disorders are characterized the uncontrolled growth of a single clone (monoclonal) of plasma cells, which results in the abnormal accumulation of M-proteins (IgM) in the blood. (For more information on this disorder, choose “POEMS” as your search term in the Rare Disease Database.) Waldenström macroglobulinemia (WMG) is a slow-growing (indolent) malignant (cancerous) disorder of the blood, closely related to lymphoma and characterized by the presence of abnormally large numbers of a particular kind of white blood cell known as B lymphocytes. As these cells accumulate in the body, excessive quantities of an antibody known as a monoclonal immunoglobulin M (IgM) are produced. This causes the blood to become thick (hyperviscosity) and affects the flow of blood through the smaller blood vessels, leading to some of symptoms of the disorder. Accumulation of B lymphocytes in the bone marrow can inhibit bone marrow production of new blood cells (pancytopenia). Affected individuals may have low levels of red blood cells (anemia), white blood cells (leukopenia) and platelets (thrombocytopenia). Consequently, affected individuals may experience fatigue, pallor, nose bleeds, and susceptibility to infection. Some individuals with Schnitzler syndrome have developed Waldenström macroglobulinemia later in life. The exact relationship between these two disorders is not fully understood. The exact cause of Waldenström macroglobulinemia is not known. (For more information on this disorder, choose “Waldenstrom macroglobulinemia” as your search term in the Rare Disease Database.)
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Diagnosis of Schnitzler Syndrome
A diagnosis of Schnitzler syndrome is based upon a thorough clinical evaluation, a detailed patient history, exclusion of other disorders, and identification of characteristic findings, specifically a urticarial rash, an M protein and at least two of the following findings – fever, joint pain or inflammation, bone pain, palpable lymph nodes, enlargement of the liver or spleen, elevated numbers of white blood cells (leukocytosis), elevated red blood cell (erythrocyte) sedimentation rate or abnormalities on bone morphological study, which can reveal increased bone density (osteosclerosis).Sedimentation rate measures how long it takes red blood cells to settle in a test tube over a given period. Many individuals with Schnitzler syndrome have an elevated sedimentation rate, which is an indication of inflammation.In younger patients, careful attention should be paid because alternative diagnosis is much more likely and often overlooked – such as urticarial vasculitis, hematological disease or chronic idiopathic urticaria – which needs a different approach to treatment – so a diagnosis of Schnitzler’s syndrome in younger patients should only be made after extensive work on exclusion of other diagnoses.
Diagnosis of Schnitzler Syndrome. A diagnosis of Schnitzler syndrome is based upon a thorough clinical evaluation, a detailed patient history, exclusion of other disorders, and identification of characteristic findings, specifically a urticarial rash, an M protein and at least two of the following findings – fever, joint pain or inflammation, bone pain, palpable lymph nodes, enlargement of the liver or spleen, elevated numbers of white blood cells (leukocytosis), elevated red blood cell (erythrocyte) sedimentation rate or abnormalities on bone morphological study, which can reveal increased bone density (osteosclerosis).Sedimentation rate measures how long it takes red blood cells to settle in a test tube over a given period. Many individuals with Schnitzler syndrome have an elevated sedimentation rate, which is an indication of inflammation.In younger patients, careful attention should be paid because alternative diagnosis is much more likely and often overlooked – such as urticarial vasculitis, hematological disease or chronic idiopathic urticaria – which needs a different approach to treatment – so a diagnosis of Schnitzler’s syndrome in younger patients should only be made after extensive work on exclusion of other diagnoses.
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Therapies of Schnitzler Syndrome
TreatmentFirst-line treatment in mild cases is with nonsteroidal anti-inflammatory drugs (NSAIDs). But this is often not sufficient.In more severe cases, the standard treatment is with therapy to inhibit the cytokine IL-1. Patients with Schnitzler syndrome are successfully treated with anakinra, an interleukin-1 receptor antagonist. Anakinra is a drug that blocks the activity of interleukin-1, which some researchers believe plays a key role in the development of Schnitzler syndrome. There have also been at least 2 studies showing the efficacy of the interleukin-1 beta antibody canakinumab.High-dose regimens of corticosteroids have temporarily improved symptoms in some cases, but usually must be stopped due to side effects. In a small percentage of cases, colchicine (a medication used to suppress inflammation in acute gout) and dapsone were effective in treating some individuals with Schnitzler syndrome. Interleukin-6 is a cytokine that can be induced by interleukin-1; , anti-interleukin-6 therapy was also recently tried in three patients with Schnitzler syndrome, in which it was effective.At least three individuals with Schnitzler syndrome have been successfully treated with thalidomide, a drug that affects how the immune system works (immunomodulatory drugs). Thalidomide induced a complete resolution of the rash and dramatic improvement of other symptoms in three individuals who received the drug as a therapy for Schnitzler syndrome. However, thalidomide is often associated with significant side effects including pain, numbness and a tingling sensation in the hands and feet (peripheral neuropathy). Two of the three patients had to stop thalidomide therapy because of side effects. In addition, two additional individuals with Schnitzler syndrome did not improve after treatment with thalidomide. More research is necessary to determine the long-term safety, effectiveness and role, if any, of thalidomide in treating individuals with Schnitzler syndrome.A small study investigated the effectiveness of the antibiotic drug, pefloxacine, for the treatment of Schnitzler syndrome. Eleven affected individuals received pefloxacine, which caused rapid and dramatic improvement of both the rash and systemic symptoms associated with the disorder. More research is necessary to determine the long-term safety and effectiveness of pefloxacine in the treatment of individuals with Schnitzler syndrome.Schnitzler syndrome does not affect lifespan in most cases, but requires periodic follow up because of the increased risk of developing cancer.
Therapies of Schnitzler Syndrome. TreatmentFirst-line treatment in mild cases is with nonsteroidal anti-inflammatory drugs (NSAIDs). But this is often not sufficient.In more severe cases, the standard treatment is with therapy to inhibit the cytokine IL-1. Patients with Schnitzler syndrome are successfully treated with anakinra, an interleukin-1 receptor antagonist. Anakinra is a drug that blocks the activity of interleukin-1, which some researchers believe plays a key role in the development of Schnitzler syndrome. There have also been at least 2 studies showing the efficacy of the interleukin-1 beta antibody canakinumab.High-dose regimens of corticosteroids have temporarily improved symptoms in some cases, but usually must be stopped due to side effects. In a small percentage of cases, colchicine (a medication used to suppress inflammation in acute gout) and dapsone were effective in treating some individuals with Schnitzler syndrome. Interleukin-6 is a cytokine that can be induced by interleukin-1; , anti-interleukin-6 therapy was also recently tried in three patients with Schnitzler syndrome, in which it was effective.At least three individuals with Schnitzler syndrome have been successfully treated with thalidomide, a drug that affects how the immune system works (immunomodulatory drugs). Thalidomide induced a complete resolution of the rash and dramatic improvement of other symptoms in three individuals who received the drug as a therapy for Schnitzler syndrome. However, thalidomide is often associated with significant side effects including pain, numbness and a tingling sensation in the hands and feet (peripheral neuropathy). Two of the three patients had to stop thalidomide therapy because of side effects. In addition, two additional individuals with Schnitzler syndrome did not improve after treatment with thalidomide. More research is necessary to determine the long-term safety, effectiveness and role, if any, of thalidomide in treating individuals with Schnitzler syndrome.A small study investigated the effectiveness of the antibiotic drug, pefloxacine, for the treatment of Schnitzler syndrome. Eleven affected individuals received pefloxacine, which caused rapid and dramatic improvement of both the rash and systemic symptoms associated with the disorder. More research is necessary to determine the long-term safety and effectiveness of pefloxacine in the treatment of individuals with Schnitzler syndrome.Schnitzler syndrome does not affect lifespan in most cases, but requires periodic follow up because of the increased risk of developing cancer.
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Overview of Schwartz Jampel Syndrome
Schwartz-Jampel syndrome (SJS) is a rare genetic disorder characterized by abnormalities of the skeletal muscles, including muscle weakness and stiffness (myotonic myopathy); abnormal bone development (bone dysplasia); permanent bending or extension of certain joints in a fixed position (joint contractures); and/or growth delays resulting in abnormally short stature (dwarfism). Affected individuals may also have small, fixed facial features and various abnormalities of the eyes, some of which may cause impaired vision. The range and severity of symptoms may vary from person to person. Two types of the disorder have been identified that may be differentiated by age of onset and other factors. SJS type 1, which is considered the classical form of the disorder, may become apparent during early to late infancy or childhood. SJS type 2, a more rare form of the disorder, is typically recognized at birth (congenital). Most researchers now believe that SJS type 2 is actually the same disorder as Stuve-Wiedemann syndrome and not a form of SJS. (For more information on Stuve-Wiedemann syndrome see the Related Disorders section of this report.)SJS is thought to be inherited as an autosomal recessive trait. However, some cases reported in the medical literature suggest an autosomal dominant inheritance pattern.
Overview of Schwartz Jampel Syndrome. Schwartz-Jampel syndrome (SJS) is a rare genetic disorder characterized by abnormalities of the skeletal muscles, including muscle weakness and stiffness (myotonic myopathy); abnormal bone development (bone dysplasia); permanent bending or extension of certain joints in a fixed position (joint contractures); and/or growth delays resulting in abnormally short stature (dwarfism). Affected individuals may also have small, fixed facial features and various abnormalities of the eyes, some of which may cause impaired vision. The range and severity of symptoms may vary from person to person. Two types of the disorder have been identified that may be differentiated by age of onset and other factors. SJS type 1, which is considered the classical form of the disorder, may become apparent during early to late infancy or childhood. SJS type 2, a more rare form of the disorder, is typically recognized at birth (congenital). Most researchers now believe that SJS type 2 is actually the same disorder as Stuve-Wiedemann syndrome and not a form of SJS. (For more information on Stuve-Wiedemann syndrome see the Related Disorders section of this report.)SJS is thought to be inherited as an autosomal recessive trait. However, some cases reported in the medical literature suggest an autosomal dominant inheritance pattern.
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Symptoms of Schwartz Jampel Syndrome
SJS is primarily characterized by abnormalities of skeletal muscle, bone, and cartilage; malformations of the eyes and the face; and growth delays. In some cases, additional abnormalities may also be present. The range and severity of associated symptoms and physical findings varies from person to person, depending upon the form of the disorder present and other factors. Two forms of the disorder have been recognized, which are known as SJS types 1 and 2. SJS type 1, which is considered the classical form of the disorder, may be recognized during early to late infancy or childhood, whereas SJS type 2 is apparent at birth (congenital).Infants with classical or type 1 SJS may have a normal or low birth weight. From the first or second year of life through childhood, an affected child’s growth rate may be below the normal range. Although the growth rate may increase during puberty, adult height may still be below the normal range; as a result, such affected individuals may have abnormally short stature (dwarfism). In addition to possible growth delays, most infants with SJS are delayed in reaching developmental milestones, such as crawling, sitting, walking, etc. (delayed motor development). However, after the age of about two years, their motor abilities may improve. Mental development is generally normal.The skeletal muscle abnormalities associated with SJS may be recognized at birth or infancy or may become apparent within the second year of life. Affected children may have muscle stiffness and weakness, an inability to relax certain muscles after they have contracted (myotonic myopathy), and abnormally small skeletal muscles. In addition, several joints may become fixed in a permanently bent or extended position (joint contractures) due to shortening of muscle fibers. In some cases, the symptoms of myotonic myopathy associated with SJS may gradually diminish.Most individuals with classical SJS also have abnormalities of bone and cartilage growth (chondrodystrophy). The layers of cartilage that separate the shaft of a long bone (diaphysis) from its growing end (epiphyseal plate or growth plate) may develop abnormally (epiphyseal dysplasia). (Long bone refers to bones in the arms and legs.) As a result, the growing end (epiphysis) of the long bone may flatten and fragment. Such flattening of the epiphysis of the thighbone (femur) may contribute to or occur in association with abnormal development of the hipbone (hip dysplasia).Additional skeletal abnormalities may also occur in children with classical Schwartz-Jampel syndrome. Affected individuals may have an abnormally short neck, malformation of the hip (hip dysplasia), and/or a sideways and front-to-back curvature of the spine (kyphoscoliosis). In addition, the breastbone (sternum) may be abnormally prominent (“pigeon breast” or pectus carinatum).Some researchers suggest that the classical form of SJS may be divided into two distinct subgroups, depending upon the severity of associated skeletal abnormalities. SJS type 1A, which may be recognized during early childhood, is characterized by mild skeletal changes (skeletal dysplasia) that occur secondary to skeletal muscle abnormalities. Type 1B may be recognized at birth or early infancy based upon primary, more pronounced abnormalities of bone development (primary skeletal dysplasia) in association with muscle defects.Many of the musculoskeletal abnormalities occurring in association with classical SJS (e.g., myotonia, joint contractures, hip dysplasia, etc.) may make it difficult for affected individuals to perform certain voluntary movements. For example, many may have difficulty walking independently.Within the first or second year of life, facial abnormalities associated with classical SJS also become apparent. The mouth and chin may appear abnormally small; the face may appear flat; facial expressions may seem fixed or mask-like; and the face may have a characteristic “pinched” appearance. In addition, the entire face may seem small in relation to the size of the head. Affected individuals may also have abnormally low-set ears.Many individuals with classical SJS also have several eye (ocular) abnormalities. The front transparent region of the eye through which light passes may be small (microcornea) or the entire eye may appear unusually small (microphthalmia). The opening between the upper and lower eyelids (palpebral fissures) may be narrow and short (blepharophimosis), and the lids may have two or more rows of eyelashes. Affected individuals may also have nearsightedness (myopia), clouding of the lenses of the eyes (juvenile cataracts), and/or intermittent, involuntary contractions or spasms of the muscles around the eyes (blepharospasm). Such eye abnormalities may result in varying degrees of visual impairment. In cases of blepharospasm, an inability to open the eyelids due to involuntary muscle spasms may result in functional blindness. The degree of visual impairment in affected individuals depends upon the severity and/or combination of eye abnormalities present. (For more information on blepharospasm, please see the Related Disorders section below.)In some cases, individuals with classical SJS may have additional abnormalities. Affected individuals may have high-pitched voices and their speech may be difficult to understand. In some cases, there may be protrusion of portions of the large intestine through an abnormal opening in muscles of the groin (inguinal hernia) or the abdominal wall where the umbilical cord joins the fetal abdomen (umbilical hernia). In addition, some affected males may have unusually small testes. Individuals with the disorder may also be prone to repeated respiratory infections.Some individuals with SJS may be at risk for malignant hyperthermia, a condition in which exposure to certain anesthetics or muscle relaxants may cause a sudden rise in body temperature (hyperthermia), muscle twitching and stiffness, and other symptoms. Without appropriate treatment, life-threatening symptoms may result. (For more information on this condition, please see the Related Disorders section of this report.)As mentioned above, researchers have recognized a second, more severe form of Schwartz-Jampel syndrome, known as SJS type 2. Because this form of the disorder is apparent at birth, it is also often referred to as “neonatal” SJS. SJS type 2 is characterized by distinctive facial abnormalities, including a “pursed” appearance of the mouth; muscle weakness; and abnormalities of the growing ends of the long bones (metaphyses) of the arms and legs (limbs), associated bowing of the limbs (campomelic-metaphyseal skeletal dysplasia), and short stature. Additional findings typically include permanent bending or extension of several joints in various fixed postures (joint contractures) at birth. Affected infants may also have feeding, swallowing, and breathing difficulties and be prone to sudden and severe rises in body temperature (hyperthermia), potentially leading to life-threatening complications. Many researchers suggest that SJS type 2 and a disorder known as Stuve-Wiedemann syndrome are the same disease entity.
Symptoms of Schwartz Jampel Syndrome. SJS is primarily characterized by abnormalities of skeletal muscle, bone, and cartilage; malformations of the eyes and the face; and growth delays. In some cases, additional abnormalities may also be present. The range and severity of associated symptoms and physical findings varies from person to person, depending upon the form of the disorder present and other factors. Two forms of the disorder have been recognized, which are known as SJS types 1 and 2. SJS type 1, which is considered the classical form of the disorder, may be recognized during early to late infancy or childhood, whereas SJS type 2 is apparent at birth (congenital).Infants with classical or type 1 SJS may have a normal or low birth weight. From the first or second year of life through childhood, an affected child’s growth rate may be below the normal range. Although the growth rate may increase during puberty, adult height may still be below the normal range; as a result, such affected individuals may have abnormally short stature (dwarfism). In addition to possible growth delays, most infants with SJS are delayed in reaching developmental milestones, such as crawling, sitting, walking, etc. (delayed motor development). However, after the age of about two years, their motor abilities may improve. Mental development is generally normal.The skeletal muscle abnormalities associated with SJS may be recognized at birth or infancy or may become apparent within the second year of life. Affected children may have muscle stiffness and weakness, an inability to relax certain muscles after they have contracted (myotonic myopathy), and abnormally small skeletal muscles. In addition, several joints may become fixed in a permanently bent or extended position (joint contractures) due to shortening of muscle fibers. In some cases, the symptoms of myotonic myopathy associated with SJS may gradually diminish.Most individuals with classical SJS also have abnormalities of bone and cartilage growth (chondrodystrophy). The layers of cartilage that separate the shaft of a long bone (diaphysis) from its growing end (epiphyseal plate or growth plate) may develop abnormally (epiphyseal dysplasia). (Long bone refers to bones in the arms and legs.) As a result, the growing end (epiphysis) of the long bone may flatten and fragment. Such flattening of the epiphysis of the thighbone (femur) may contribute to or occur in association with abnormal development of the hipbone (hip dysplasia).Additional skeletal abnormalities may also occur in children with classical Schwartz-Jampel syndrome. Affected individuals may have an abnormally short neck, malformation of the hip (hip dysplasia), and/or a sideways and front-to-back curvature of the spine (kyphoscoliosis). In addition, the breastbone (sternum) may be abnormally prominent (“pigeon breast” or pectus carinatum).Some researchers suggest that the classical form of SJS may be divided into two distinct subgroups, depending upon the severity of associated skeletal abnormalities. SJS type 1A, which may be recognized during early childhood, is characterized by mild skeletal changes (skeletal dysplasia) that occur secondary to skeletal muscle abnormalities. Type 1B may be recognized at birth or early infancy based upon primary, more pronounced abnormalities of bone development (primary skeletal dysplasia) in association with muscle defects.Many of the musculoskeletal abnormalities occurring in association with classical SJS (e.g., myotonia, joint contractures, hip dysplasia, etc.) may make it difficult for affected individuals to perform certain voluntary movements. For example, many may have difficulty walking independently.Within the first or second year of life, facial abnormalities associated with classical SJS also become apparent. The mouth and chin may appear abnormally small; the face may appear flat; facial expressions may seem fixed or mask-like; and the face may have a characteristic “pinched” appearance. In addition, the entire face may seem small in relation to the size of the head. Affected individuals may also have abnormally low-set ears.Many individuals with classical SJS also have several eye (ocular) abnormalities. The front transparent region of the eye through which light passes may be small (microcornea) or the entire eye may appear unusually small (microphthalmia). The opening between the upper and lower eyelids (palpebral fissures) may be narrow and short (blepharophimosis), and the lids may have two or more rows of eyelashes. Affected individuals may also have nearsightedness (myopia), clouding of the lenses of the eyes (juvenile cataracts), and/or intermittent, involuntary contractions or spasms of the muscles around the eyes (blepharospasm). Such eye abnormalities may result in varying degrees of visual impairment. In cases of blepharospasm, an inability to open the eyelids due to involuntary muscle spasms may result in functional blindness. The degree of visual impairment in affected individuals depends upon the severity and/or combination of eye abnormalities present. (For more information on blepharospasm, please see the Related Disorders section below.)In some cases, individuals with classical SJS may have additional abnormalities. Affected individuals may have high-pitched voices and their speech may be difficult to understand. In some cases, there may be protrusion of portions of the large intestine through an abnormal opening in muscles of the groin (inguinal hernia) or the abdominal wall where the umbilical cord joins the fetal abdomen (umbilical hernia). In addition, some affected males may have unusually small testes. Individuals with the disorder may also be prone to repeated respiratory infections.Some individuals with SJS may be at risk for malignant hyperthermia, a condition in which exposure to certain anesthetics or muscle relaxants may cause a sudden rise in body temperature (hyperthermia), muscle twitching and stiffness, and other symptoms. Without appropriate treatment, life-threatening symptoms may result. (For more information on this condition, please see the Related Disorders section of this report.)As mentioned above, researchers have recognized a second, more severe form of Schwartz-Jampel syndrome, known as SJS type 2. Because this form of the disorder is apparent at birth, it is also often referred to as “neonatal” SJS. SJS type 2 is characterized by distinctive facial abnormalities, including a “pursed” appearance of the mouth; muscle weakness; and abnormalities of the growing ends of the long bones (metaphyses) of the arms and legs (limbs), associated bowing of the limbs (campomelic-metaphyseal skeletal dysplasia), and short stature. Additional findings typically include permanent bending or extension of several joints in various fixed postures (joint contractures) at birth. Affected infants may also have feeding, swallowing, and breathing difficulties and be prone to sudden and severe rises in body temperature (hyperthermia), potentially leading to life-threatening complications. Many researchers suggest that SJS type 2 and a disorder known as Stuve-Wiedemann syndrome are the same disease entity.
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Causes of Schwartz Jampel Syndrome
SJS types 1 and 2 are both thought to have autosomal recessive inheritance. Genetic diseases are determined by two genes, one received from the father and one from 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%.Some individuals with SJS types 1 and 2 have had parents who were related by blood (consanguineous). All individuals carry abnormal genes and genetic variations. 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.Researchers have determined that the classical form of SJS may be caused by changes (mutations) of a gene encoding perlecan located on the short arm (p) of chromosome 1 (1p36.1-p34). Perlecan is a large heparin sulfate proteoglycan and plays a role in neuromuscular function and cartilage formation. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into many bands that are numbered.Genetic evaluation of at least three families (kindreds) with individuals affected by the severe neonatal form of SJS (type 2) has determined that those with the disorder did not have mutations of the disease gene located at 1p36.1-p34 (discussed above). Accordingly, researchers indicate that SJS may result from mutations of different genes (genetic heterogeneity).
Causes of Schwartz Jampel Syndrome. SJS types 1 and 2 are both thought to have autosomal recessive inheritance. Genetic diseases are determined by two genes, one received from the father and one from 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%.Some individuals with SJS types 1 and 2 have had parents who were related by blood (consanguineous). All individuals carry abnormal genes and genetic variations. 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.Researchers have determined that the classical form of SJS may be caused by changes (mutations) of a gene encoding perlecan located on the short arm (p) of chromosome 1 (1p36.1-p34). Perlecan is a large heparin sulfate proteoglycan and plays a role in neuromuscular function and cartilage formation. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into many bands that are numbered.Genetic evaluation of at least three families (kindreds) with individuals affected by the severe neonatal form of SJS (type 2) has determined that those with the disorder did not have mutations of the disease gene located at 1p36.1-p34 (discussed above). Accordingly, researchers indicate that SJS may result from mutations of different genes (genetic heterogeneity).
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Affects of Schwartz Jampel Syndrome
SJS (SJS) types 1 and 2 are rare disorders that appear to affect males and females in equal numbers. More than 85 cases have been reported in the medical literature, including individuals affected by the classical (type 1) and the more severe neonatal form (type 2) of the disorder. SJS type 2 appears to be most common in individuals of United Arab Emirates descent. Depending upon the form of the disorder present, associated symptoms and findings may be recognized at birth or may become apparent during infancy or within the second year of life.
Affects of Schwartz Jampel Syndrome. SJS (SJS) types 1 and 2 are rare disorders that appear to affect males and females in equal numbers. More than 85 cases have been reported in the medical literature, including individuals affected by the classical (type 1) and the more severe neonatal form (type 2) of the disorder. SJS type 2 appears to be most common in individuals of United Arab Emirates descent. Depending upon the form of the disorder present, associated symptoms and findings may be recognized at birth or may become apparent during infancy or within the second year of life.
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Related disorders of Schwartz Jampel Syndrome
Symptoms of the following disorders may be similar to those of SJS. Comparisons may be useful for a differential diagnosis:Stuve-Wiedemann syndrome is a rare skeletal disorder present at birth (congenital). It is characterized by short stature, bowing of the long bones of the arms and legs (campomelia), and fingers or toes that are permanently flexed (camptodactyly) outward away from the thumb (ulnar deviation). Affected infants may develop life-threatening complications such as episodes where there is a sudden rise in body temperature (hyperthermia) or respiratory distress. Stuve-Wiedemann syndrome is inherited as an autosomal recessive trait. Some researchers believe that Stuve-Wiedemann syndrome and SJS type II are the same disorder. SJS was previously believed to be the newborn (neonatal) form of SJS. However, the clinical and radiographic pictures of Stuve-Wiedemann and SJS type II are nearly identical leading many researchers to believe the two disorders are a single entity. (For more information on this disorder, choose “Stuve-Wiedemann” as your search term in the Rare Disease Database.)Freeman-Sheldon syndrome, also known as craniocarpotarsal dystrophy, is a rare inherited disorder characterized by a flattened, masklike face; deep-set eyes; a slightly shortened opening between the upper and lower eyelids (blepharophimosis); full cheeks; a small mouth (microstomia) that has a “whistling” appearance; and other craniofacial abnormalities. Skeletal abnormalities may also be present, such as a short neck, fingers that are permanently flexed (camptodactyly), and/or a foot that is twisted out of shape (club foot or talipes equinovarus). Freeman-Sheldon syndrome is inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Freeman-Sheldon” as your search term in the Rare Disease Database.)Marden-Walker syndrome is a rare connective tissue disorder that is inherited as an autosomal recessive genetic trait. Affected individuals may exhibit abnormalities of the head and facial (craniofacial) area including a masklike face, a flat nasal bridge, a small jaw (micrognathia), droopy upper eyelids (ptosis), an abnormally narrow opening between the upper and lower eyelids (blepharophimosis), and/or low-set ears. Individuals with Marden-Walker syndrome may also exhibit incomplete closure of the roof of the mouth (cleft palate) and/or a vertical groove in the upper lip (cleft lip). In addition, affected individuals may exhibit growth delay, reduced muscle mass, joints that are in a fixed position (joint contractures), and/or limited control of muscle movement. In some individuals, skeletal abnormalities may be present, such as a sideways (scoliosis) or front-to-back curvature of the spine (kyphosis) and/or a breast bone that is abnormally prominent (pigeon breast or pectus carinatum) or appears to sink inward (funnel chest or pectus excavatum). (For more information on this disorder, choose “Marden-Walker” as your search term in the Rare Disease Database.)Morquio syndrome, also known as mucopolysaccharidosis IV (MPS IV), exists in two forms (Morquio syndromes A and B), and is caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulfatase and beta-galactosidase, respectively. A deficiency of either enzyme leads to the accumulation of keratan sulfate in the body, abnormal musculoskeletal development, and other symptoms. The clinical features of MPS IV-B are usually fewer and milder than those associated with MPS IV-A. Symptoms may include growth retardation, a prominent lower face, an abnormally short neck, knees that are abnormally close together (knock knees or genu valgum), flat feet, a sideways and front-to-back curvature of the spine (kyphoscoliosis), abnormal development of the growing ends of the long bones (epiphyses), and/or a prominent breast bone (pectus carinatum). Hearing loss, weakness of the legs, and/or other abnormalities also often occurs. Morquio syndromes A and B are inherited as autosomal recessive genetic traits. (For more information on these disorders, choose “Morquio” as your search term in the Rare Disease Database.)King syndrome, an extremely rare disorder, is a form of malignant hyperthermia. Exposure to certain anesthetics or muscle relaxants may cause a sudden rise in an affected individual’s body temperature, muscle stiffness, and other symptoms. (For more information, see “malignant hyperthermia” below.) Individuals with King syndrome also exhibit several characteristic physical abnormalities. These include abnormalities of the head and facial (craniofacial) area, such as low-set ears and/or incomplete development of the middle portion of the face (midface hypoplasia). In addition, the upper eyelids may droop (ptosis) and the opening between the upper and lower eyelids (palpebral fissures) may slant downward. Skeletal abnormalities may also be present, including a sideways and front-to-back curvature of the spine (kyphoscoliosis), abnormally short stature, and/or an unusually prominent breastbone (pigeon breast or pectus carinatum). In some cases, mild muscle weakness may be present, and/or certain joints may be fixed in a permanently flexed position due to shortening of muscle fibers (joint contractures). King syndrome is believed to result from a spontaneous genetic change that occurs for unknown reasons (sporadic); in addition, some researchers believe that King syndrome may be inherited as an autosomal recessive trait.Van Dyke-Hanson syndrome is a rare inherited neuromuscular disorder. In Some affected individuals may exhibit permanently flexed, fixed joints in the hands and feet at birth (congenital joint contractures). During early childhood, those with the disorder may begin to experience one- to two-minute attacks characterized by impaired coordination of voluntary movement (periodic ataxia) affecting the central part of the body (trunk) and/or the head (titubation); in addition, affected individuals may also experience uncontrolled jerking movements of the arms, legs, and head during the attacks. Such episodes may be triggered by abrupt changes in posture, events that bring on a strong emotional response, and/or other factors. The disorder may also be characterized by short, spontaneous spasms and contractions within groups of muscle fibers (myokymia) in the facial area, arms, and legs. Continuous electrical activity is apparent within muscle fibers, even while at rest. It is believed that Van Dyke-Hanson syndrome is inherited as an autosomal dominant trait.The following disorders may be associated with SJS as secondary characteristics. They are not necessary for a differential diagnosis:Malignant hyperthermia (MH) is a group of inherited disorders in which exposure to certain anesthetics (e.g., halothane or cyclopropane) or particular muscle relaxants (e.g., succinylcholine) may cause a dangerous, sudden rise in body temperature (hyperthermia), muscle twitching and stiffness, headache, nausea, vomiting, low blood pressure (hypotension), rapid heartbeat (tachycardia) and/or irregular heartbeat (cardiac arrhythmias). Without appropriate treatment, life-threatening symptoms may result. In some cases, a predisposition to malignant hyperthermia may be inherited as an autosomal dominant genetic trait; in this form, individuals may exhibit no symptoms or physical abnormalities between MH episodes. Other forms of malignant hyperthermia may occur spontaneously and/or be inherited as an autosomal recessive genetic trait (see “King Syndrome” above). Researchers believe that malignant hyperthermia may be caused by the interaction of many genes, possibly in combination with environmental factors (multifactorial inheritance). (For more information on this condition, choose “malignant hyperthermia” as your search term in the Rare Disease Database.)Blepharospasm is a condition characterized by intermittent, involuntary contractions or spasms of the muscles around the eyes. An inability to open the eyelids due to the involuntary muscle spasms may result in functional blindness. Blepharospasm may be due to an abnormal tissue change (lesion) of the eye; impairment of one of the nerves that arises from the brain and innervates the eyes [trigeminal (5th cranial) nerve]; or psychological stress or may occur due to or in association with a number of different underlying disorders. (For more information on this condition, use “blepharospasm” as your search term in the Rare Disease Database.)
Related disorders of Schwartz Jampel Syndrome. Symptoms of the following disorders may be similar to those of SJS. Comparisons may be useful for a differential diagnosis:Stuve-Wiedemann syndrome is a rare skeletal disorder present at birth (congenital). It is characterized by short stature, bowing of the long bones of the arms and legs (campomelia), and fingers or toes that are permanently flexed (camptodactyly) outward away from the thumb (ulnar deviation). Affected infants may develop life-threatening complications such as episodes where there is a sudden rise in body temperature (hyperthermia) or respiratory distress. Stuve-Wiedemann syndrome is inherited as an autosomal recessive trait. Some researchers believe that Stuve-Wiedemann syndrome and SJS type II are the same disorder. SJS was previously believed to be the newborn (neonatal) form of SJS. However, the clinical and radiographic pictures of Stuve-Wiedemann and SJS type II are nearly identical leading many researchers to believe the two disorders are a single entity. (For more information on this disorder, choose “Stuve-Wiedemann” as your search term in the Rare Disease Database.)Freeman-Sheldon syndrome, also known as craniocarpotarsal dystrophy, is a rare inherited disorder characterized by a flattened, masklike face; deep-set eyes; a slightly shortened opening between the upper and lower eyelids (blepharophimosis); full cheeks; a small mouth (microstomia) that has a “whistling” appearance; and other craniofacial abnormalities. Skeletal abnormalities may also be present, such as a short neck, fingers that are permanently flexed (camptodactyly), and/or a foot that is twisted out of shape (club foot or talipes equinovarus). Freeman-Sheldon syndrome is inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Freeman-Sheldon” as your search term in the Rare Disease Database.)Marden-Walker syndrome is a rare connective tissue disorder that is inherited as an autosomal recessive genetic trait. Affected individuals may exhibit abnormalities of the head and facial (craniofacial) area including a masklike face, a flat nasal bridge, a small jaw (micrognathia), droopy upper eyelids (ptosis), an abnormally narrow opening between the upper and lower eyelids (blepharophimosis), and/or low-set ears. Individuals with Marden-Walker syndrome may also exhibit incomplete closure of the roof of the mouth (cleft palate) and/or a vertical groove in the upper lip (cleft lip). In addition, affected individuals may exhibit growth delay, reduced muscle mass, joints that are in a fixed position (joint contractures), and/or limited control of muscle movement. In some individuals, skeletal abnormalities may be present, such as a sideways (scoliosis) or front-to-back curvature of the spine (kyphosis) and/or a breast bone that is abnormally prominent (pigeon breast or pectus carinatum) or appears to sink inward (funnel chest or pectus excavatum). (For more information on this disorder, choose “Marden-Walker” as your search term in the Rare Disease Database.)Morquio syndrome, also known as mucopolysaccharidosis IV (MPS IV), exists in two forms (Morquio syndromes A and B), and is caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulfatase and beta-galactosidase, respectively. A deficiency of either enzyme leads to the accumulation of keratan sulfate in the body, abnormal musculoskeletal development, and other symptoms. The clinical features of MPS IV-B are usually fewer and milder than those associated with MPS IV-A. Symptoms may include growth retardation, a prominent lower face, an abnormally short neck, knees that are abnormally close together (knock knees or genu valgum), flat feet, a sideways and front-to-back curvature of the spine (kyphoscoliosis), abnormal development of the growing ends of the long bones (epiphyses), and/or a prominent breast bone (pectus carinatum). Hearing loss, weakness of the legs, and/or other abnormalities also often occurs. Morquio syndromes A and B are inherited as autosomal recessive genetic traits. (For more information on these disorders, choose “Morquio” as your search term in the Rare Disease Database.)King syndrome, an extremely rare disorder, is a form of malignant hyperthermia. Exposure to certain anesthetics or muscle relaxants may cause a sudden rise in an affected individual’s body temperature, muscle stiffness, and other symptoms. (For more information, see “malignant hyperthermia” below.) Individuals with King syndrome also exhibit several characteristic physical abnormalities. These include abnormalities of the head and facial (craniofacial) area, such as low-set ears and/or incomplete development of the middle portion of the face (midface hypoplasia). In addition, the upper eyelids may droop (ptosis) and the opening between the upper and lower eyelids (palpebral fissures) may slant downward. Skeletal abnormalities may also be present, including a sideways and front-to-back curvature of the spine (kyphoscoliosis), abnormally short stature, and/or an unusually prominent breastbone (pigeon breast or pectus carinatum). In some cases, mild muscle weakness may be present, and/or certain joints may be fixed in a permanently flexed position due to shortening of muscle fibers (joint contractures). King syndrome is believed to result from a spontaneous genetic change that occurs for unknown reasons (sporadic); in addition, some researchers believe that King syndrome may be inherited as an autosomal recessive trait.Van Dyke-Hanson syndrome is a rare inherited neuromuscular disorder. In Some affected individuals may exhibit permanently flexed, fixed joints in the hands and feet at birth (congenital joint contractures). During early childhood, those with the disorder may begin to experience one- to two-minute attacks characterized by impaired coordination of voluntary movement (periodic ataxia) affecting the central part of the body (trunk) and/or the head (titubation); in addition, affected individuals may also experience uncontrolled jerking movements of the arms, legs, and head during the attacks. Such episodes may be triggered by abrupt changes in posture, events that bring on a strong emotional response, and/or other factors. The disorder may also be characterized by short, spontaneous spasms and contractions within groups of muscle fibers (myokymia) in the facial area, arms, and legs. Continuous electrical activity is apparent within muscle fibers, even while at rest. It is believed that Van Dyke-Hanson syndrome is inherited as an autosomal dominant trait.The following disorders may be associated with SJS as secondary characteristics. They are not necessary for a differential diagnosis:Malignant hyperthermia (MH) is a group of inherited disorders in which exposure to certain anesthetics (e.g., halothane or cyclopropane) or particular muscle relaxants (e.g., succinylcholine) may cause a dangerous, sudden rise in body temperature (hyperthermia), muscle twitching and stiffness, headache, nausea, vomiting, low blood pressure (hypotension), rapid heartbeat (tachycardia) and/or irregular heartbeat (cardiac arrhythmias). Without appropriate treatment, life-threatening symptoms may result. In some cases, a predisposition to malignant hyperthermia may be inherited as an autosomal dominant genetic trait; in this form, individuals may exhibit no symptoms or physical abnormalities between MH episodes. Other forms of malignant hyperthermia may occur spontaneously and/or be inherited as an autosomal recessive genetic trait (see “King Syndrome” above). Researchers believe that malignant hyperthermia may be caused by the interaction of many genes, possibly in combination with environmental factors (multifactorial inheritance). (For more information on this condition, choose “malignant hyperthermia” as your search term in the Rare Disease Database.)Blepharospasm is a condition characterized by intermittent, involuntary contractions or spasms of the muscles around the eyes. An inability to open the eyelids due to the involuntary muscle spasms may result in functional blindness. Blepharospasm may be due to an abnormal tissue change (lesion) of the eye; impairment of one of the nerves that arises from the brain and innervates the eyes [trigeminal (5th cranial) nerve]; or psychological stress or may occur due to or in association with a number of different underlying disorders. (For more information on this condition, use “blepharospasm” as your search term in the Rare Disease Database.)
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Diagnosis of Schwartz Jampel Syndrome
In rare cases, SJS may be diagnosed before birth (prenatally) through the use of specialized tests such as ultrasound. During ultrasonography, reflected sound waves are used to create an image of the developing fetus. Such imaging studies may reveal characteristic findings that suggest SJS or other developmental abnormalities in the fetus.SJS is usually diagnosed at birth or within the first or second year of life. Such a diagnosis may be confirmed based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. The presence of myotonic myopathy, a primary finding associated with the disorder, may be confirmed through several tests, including electromyograms (EMG). An EMG is a test that records electrical activity in skeletal muscles at rest and during muscle contraction. In cases of myotonic myopathy, an EMG may demonstrate continuous electrical activity within muscle fibers, even while at rest. Other specialized tests used to confirm myotonic myopathy may include studies that measure the levels of certain enzymes in the fluid portion of the blood (serum enzymes) and/or the surgical removal (biopsy) and microscopic examination (light and/or electron microscopy) of small samples of muscle tissue. The presence of skeletal abnormalities often associated with SJS may be confirmed by specialized imaging studies and other testing.
Diagnosis of Schwartz Jampel Syndrome. In rare cases, SJS may be diagnosed before birth (prenatally) through the use of specialized tests such as ultrasound. During ultrasonography, reflected sound waves are used to create an image of the developing fetus. Such imaging studies may reveal characteristic findings that suggest SJS or other developmental abnormalities in the fetus.SJS is usually diagnosed at birth or within the first or second year of life. Such a diagnosis may be confirmed based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. The presence of myotonic myopathy, a primary finding associated with the disorder, may be confirmed through several tests, including electromyograms (EMG). An EMG is a test that records electrical activity in skeletal muscles at rest and during muscle contraction. In cases of myotonic myopathy, an EMG may demonstrate continuous electrical activity within muscle fibers, even while at rest. Other specialized tests used to confirm myotonic myopathy may include studies that measure the levels of certain enzymes in the fluid portion of the blood (serum enzymes) and/or the surgical removal (biopsy) and microscopic examination (light and/or electron microscopy) of small samples of muscle tissue. The presence of skeletal abnormalities often associated with SJS may be confirmed by specialized imaging studies and other testing.
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Therapies of Schwartz Jampel Syndrome
TreatmentThe treatment of SJS is directed toward the specific symptoms that are apparent in each individual. Pediatricians; physicians who diagnose and treat diseases of the eye (ophthalmologists); specialists who diagnose and treat skeletal abnormalities (orthopedists); surgeons; physical therapists; and/or other health care professionals may need to work together to ensure a comprehensive approach to treatment.Specific therapies for the treatment of SJS are symptomatic and supportive. In some infants with the severe neonatal form of the disorder (SJS Type 2), treatment may require special supportive therapies to ensure the appropriate intake of nutrients, oxygen therapy, measures to help prevent or appropriately treat episodes of hyperthermia, and other therapies as required.In individuals with SJS, various orthopedic techniques, including surgery, may be used to help treat and/or correct musculoskeletal abnormalities, such as joint contractures, kyphoscoliosis, and/or hip dysplasia. Because the skeletal changes associated with hip dysplasia may worsen during childhood, early orthopedic treatment may be essential in preventing such a progression of symptoms. In some cases of hip dysplasia, an artificial device (prosthetic) may be used to replace the hip joint. Physical therapy in combination with such surgical and supportive measures may improve an affected individual's ability to walk and perform other movements independently (mobility). In addition, in some individuals with SJS, depending upon the visual abnormalities that are present, corrective glasses, contact lenses, other supportive methods, and/or surgery may be used to help improve vision.Additional therapeutic and/or supportive measures may be necessary in some cases. Physicians may regularly monitor affected individuals and recommend preventive measures for those who may be prone to respiratory infections. In individuals with protrusion of portions of the large intestine through an abnormal opening in muscles of the groin (inguinal hernia), surgical correction of the hernia may be necessary. If there is a small, abnormal opening in muscles of the abdominal wall where the umbilical cord joined the fetal abdomen (umbilical hernia), the abnormal opening may close on its own (spontaneously) within one or two years; however, if the umbilical hernia is large, surgery may be required.Some individuals with SJS may be at risk for malignant hyperthermia when exposed to certain anesthetics or muscle relaxants. This risk must be taken into consideration by surgeons, anesthesiologists, dentists, and other health care workers when making decisions concerning potential surgery and use of particular anesthetics. It must also be considered by primary care physicians and other health professionals when prescribing certain medications.Early intervention is important in ensuring that children with SJS reach their potential. Special services that may be beneficial to affected children may include special remedial education, speech therapy, and other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Therapies of Schwartz Jampel Syndrome. TreatmentThe treatment of SJS is directed toward the specific symptoms that are apparent in each individual. Pediatricians; physicians who diagnose and treat diseases of the eye (ophthalmologists); specialists who diagnose and treat skeletal abnormalities (orthopedists); surgeons; physical therapists; and/or other health care professionals may need to work together to ensure a comprehensive approach to treatment.Specific therapies for the treatment of SJS are symptomatic and supportive. In some infants with the severe neonatal form of the disorder (SJS Type 2), treatment may require special supportive therapies to ensure the appropriate intake of nutrients, oxygen therapy, measures to help prevent or appropriately treat episodes of hyperthermia, and other therapies as required.In individuals with SJS, various orthopedic techniques, including surgery, may be used to help treat and/or correct musculoskeletal abnormalities, such as joint contractures, kyphoscoliosis, and/or hip dysplasia. Because the skeletal changes associated with hip dysplasia may worsen during childhood, early orthopedic treatment may be essential in preventing such a progression of symptoms. In some cases of hip dysplasia, an artificial device (prosthetic) may be used to replace the hip joint. Physical therapy in combination with such surgical and supportive measures may improve an affected individual's ability to walk and perform other movements independently (mobility). In addition, in some individuals with SJS, depending upon the visual abnormalities that are present, corrective glasses, contact lenses, other supportive methods, and/or surgery may be used to help improve vision.Additional therapeutic and/or supportive measures may be necessary in some cases. Physicians may regularly monitor affected individuals and recommend preventive measures for those who may be prone to respiratory infections. In individuals with protrusion of portions of the large intestine through an abnormal opening in muscles of the groin (inguinal hernia), surgical correction of the hernia may be necessary. If there is a small, abnormal opening in muscles of the abdominal wall where the umbilical cord joined the fetal abdomen (umbilical hernia), the abnormal opening may close on its own (spontaneously) within one or two years; however, if the umbilical hernia is large, surgery may be required.Some individuals with SJS may be at risk for malignant hyperthermia when exposed to certain anesthetics or muscle relaxants. This risk must be taken into consideration by surgeons, anesthesiologists, dentists, and other health care workers when making decisions concerning potential surgery and use of particular anesthetics. It must also be considered by primary care physicians and other health professionals when prescribing certain medications.Early intervention is important in ensuring that children with SJS reach their potential. Special services that may be beneficial to affected children may include special remedial education, speech therapy, and other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Schwartz Jampel Syndrome
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Overview of Scleroderma
Scleroderma is a rare autoimmune connective tissue disorder characterized by abnormal thickening of the skin. Connective tissue is composed of collagen, which supports and binds other body tissues. There are several types of scleroderma. Some types affect certain, specific parts of the body, while other types can affect the whole body and internal organs (systemic). Scleroderma is also known as progressive systemic sclerosis. The exact cause of scleroderma is unknown.
Overview of Scleroderma. Scleroderma is a rare autoimmune connective tissue disorder characterized by abnormal thickening of the skin. Connective tissue is composed of collagen, which supports and binds other body tissues. There are several types of scleroderma. Some types affect certain, specific parts of the body, while other types can affect the whole body and internal organs (systemic). Scleroderma is also known as progressive systemic sclerosis. The exact cause of scleroderma is unknown.
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Symptoms of Scleroderma
The early symptoms of scleroderma vary considerably. Distinctive abnormalities on the skin (cutaneous lesions) usually appear later in the course of the disease. Common symptoms of scleroderma may include painful joints (arthralgia), morning stiffness, fatigue, and/or weight loss. The intermittent loss (triggered by cold temperatures) of blood supply to the fingers, toes, nose, and/or ears (Raynaud's phenomenon) is an early and frequent complaint of people with scleroderma.People with scleroderma have areas of skin that become hard and leathery (indurated). These areas of hardness are widespread and typically appear on both sides of the body. Eventually, tissue loss (atrophy) occurs and the skin becomes more highly colored (hyperpigmentation).Morphea, or localized scleroderma, usually begins between the ages of 20 to 50 years as patches of yellowish or ivory-colored rigid, dry skin (inflammatory stage). These are followed by the appearance of firm, hard, oval-shaped plaques with ivory centers that are encircled by a violet ring. These spots generally appear on the trunk, face, and/or extremities. Many patients with localized morphea improve spontaneously (without treatment). Generalized morphea is more rare and serious, and involves the skin (dermis) but not the internal organs.Linear scleroderma appears as a band-like thickening of skin on the arms or legs. This type of scleroderma is most likely to be on one side of the body (unilateral) but may be on both sides (bilateral). Linear scleroderma generally appears in young children and is characterized by the failure of one limb (i.e., arm or leg) to grow as rapidly as its counterpart. The band of thick skin may extend from the hip to the heel or from the shoulder to the hand. Deep tissue loss may occur along this band.Systemic scleroderma includes a wide range of symptoms including inflammatory diseases of the muscles (i.e., polymyositis or dermatomyositis), swelling (edema) of the fingers and/or hands, microvascular abnormalities, lung disease (i.e., progressive interstitial fibrotic pulmonary disease), kidney dysfunction (i.e., rapidly progressive renal failure), cardiovascular problems (i.e., myocardial accelerated hypertension), gastrointestinal malfunction (i.e., lack of mobility of the esophagus and colon), and/or abnormalities of the immune system. (For more information, choose “Polymyositis” and “Dermatomyositis” as your search terms in the Rare Disease Database.)
Symptoms of Scleroderma. The early symptoms of scleroderma vary considerably. Distinctive abnormalities on the skin (cutaneous lesions) usually appear later in the course of the disease. Common symptoms of scleroderma may include painful joints (arthralgia), morning stiffness, fatigue, and/or weight loss. The intermittent loss (triggered by cold temperatures) of blood supply to the fingers, toes, nose, and/or ears (Raynaud's phenomenon) is an early and frequent complaint of people with scleroderma.People with scleroderma have areas of skin that become hard and leathery (indurated). These areas of hardness are widespread and typically appear on both sides of the body. Eventually, tissue loss (atrophy) occurs and the skin becomes more highly colored (hyperpigmentation).Morphea, or localized scleroderma, usually begins between the ages of 20 to 50 years as patches of yellowish or ivory-colored rigid, dry skin (inflammatory stage). These are followed by the appearance of firm, hard, oval-shaped plaques with ivory centers that are encircled by a violet ring. These spots generally appear on the trunk, face, and/or extremities. Many patients with localized morphea improve spontaneously (without treatment). Generalized morphea is more rare and serious, and involves the skin (dermis) but not the internal organs.Linear scleroderma appears as a band-like thickening of skin on the arms or legs. This type of scleroderma is most likely to be on one side of the body (unilateral) but may be on both sides (bilateral). Linear scleroderma generally appears in young children and is characterized by the failure of one limb (i.e., arm or leg) to grow as rapidly as its counterpart. The band of thick skin may extend from the hip to the heel or from the shoulder to the hand. Deep tissue loss may occur along this band.Systemic scleroderma includes a wide range of symptoms including inflammatory diseases of the muscles (i.e., polymyositis or dermatomyositis), swelling (edema) of the fingers and/or hands, microvascular abnormalities, lung disease (i.e., progressive interstitial fibrotic pulmonary disease), kidney dysfunction (i.e., rapidly progressive renal failure), cardiovascular problems (i.e., myocardial accelerated hypertension), gastrointestinal malfunction (i.e., lack of mobility of the esophagus and colon), and/or abnormalities of the immune system. (For more information, choose “Polymyositis” and “Dermatomyositis” as your search terms in the Rare Disease Database.)
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Causes of Scleroderma
The exact cause of scleroderma is unknown. The immune system and vascular system as well as connective tissue metabolism are known to play some role in the disease process. Researchers believe that several factors interact to produce scleroderma. These include abnormal immune activity, potential environmental triggers, and genetic makeup. Scleroderma is not thought to be passed on from parent to child, but it is believed that the presence of certain genes may make it more likely that a person will develop the disease (genetic predisposition).Abnormal immune activity refers to when the body's natural defenses (antibodies) against invading or “foreign” organisms begin to attack the body's own tissue, often for unknown reasons (autoimmunity).Some cases of scleroderma have been associated with silica dust, organic solvents, and L-tryptophan.
Causes of Scleroderma. The exact cause of scleroderma is unknown. The immune system and vascular system as well as connective tissue metabolism are known to play some role in the disease process. Researchers believe that several factors interact to produce scleroderma. These include abnormal immune activity, potential environmental triggers, and genetic makeup. Scleroderma is not thought to be passed on from parent to child, but it is believed that the presence of certain genes may make it more likely that a person will develop the disease (genetic predisposition).Abnormal immune activity refers to when the body's natural defenses (antibodies) against invading or “foreign” organisms begin to attack the body's own tissue, often for unknown reasons (autoimmunity).Some cases of scleroderma have been associated with silica dust, organic solvents, and L-tryptophan.
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Scleroderma
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Affects of Scleroderma
The systemic form of scleroderma is thought to affect from 40,000 to 165,000 people in the United States. The disease is three to four times more common in females than in males. Scleroderma may occur at any age but the symptoms most frequently begin during midlife.
Affects of Scleroderma. The systemic form of scleroderma is thought to affect from 40,000 to 165,000 people in the United States. The disease is three to four times more common in females than in males. Scleroderma may occur at any age but the symptoms most frequently begin during midlife.
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Related disorders of Scleroderma
Symptoms of the following disorders can be similar to those of scleroderma. Comparisons may be useful for a differential diagnosis:Mixed connective tissue disease (MCTD) is a rare inflammatory disorder of the connective tissue. The symptoms of this disorder overlap with those of lupus (systemic lupus erythematosus), scleroderma, and polymyositis/dermatomyositis. Early symptoms may include a fever of unknown origin, painfully cold fingers in response to cold (Raynaud's phenomenon), swollen hands, fatigue, and/or non-deforming arthritis. Arthritis occurs in almost every case of mixed connective tissue disease, but rarely results in deformities similar to those seen in rheumatoid arthritis. People with mixed connective tissue disease commonly experience muscle pain and skin rashes. (For more information on this disorder, choose “Mixed Connective Tissue Disease” as your search term in the Rare Disease Database.)Lupus (systemic lupus erythematosus or SLE) is a rare inflammatory connective tissue disease. The initial symptom of this disease is usually excessive fatigue. Most people with Lupus experience inflammation and swelling of the joints (arthritis), joint pain (arthralgia), and generalized muscle pain (myalgia). Skin rashes are common in people with lupus. About 50 percent of people with lupus exhibit a classic red “butterfly” rash across the bridge of the nose and cheeks. Other early symptoms may include fever, swollen glands, loss of appetite, weight loss, headaches, loss of hair, and swelling due to fluid retention. (For more information on this disorder, choose “Lupus” as your search term in the Rare Disease Database.)Polymyositis is a rare inflammatory disorder characterized by the inflammation and degeneration of muscle and the supporting collagen connective tissue. The cause of this disorder is not known. The major early symptom of this disorder is muscle weakness, usually in the neck, trunk, and shoulders. Eventually, it may become difficult to rise from a sitting position, climb stairs, lift objects, and/or reach overhead. Occasionally, joint pain and tenderness also occur. Other symptoms may include inflammation of the lungs (interstitial pneumonitis), difficulty breathing, coughing, painfully cold fingers in response to cold (Raynaud's phenomenon), digestive problems, heart irregularities, and kidney failure. (For more information on this disorder, choose “Polymyositis” as your search term in the Rare Disease Database.)Dermatomyositis is a rare inflammatory connective tissue disease. The cause is unknown. Dermatomyositis is identical to polymyositis but with the addition of a characteristic red skin rash. These red rashes generally occur before the muscle weakness occurs and usually appear on the face, knees, shoulders, and hands. In some affected individuals, the skin changes caused by dermatomyositis are similar to those associated with scleroderma. The skin may become dry and hard and have a brownish color. (For more information on this disorder, choose “Dermatomyositis” as your search term in the Rare Disease Database.)Raynaud's disease is a rare disorder characterized by spasms of the blood vessels in the fingers, toes, nose, and ears (Raynaud's phenomenon) usually in response to cold. Raynaud's disease includes the symptoms of Raynaud's phenomenon along with other systemic disorders. The major symptom of this disorder is a dramatic stark white pallor of the affected fingers and toes when exposed to cold, although a blue or red color may also be present from time to time. Other symptoms in the affected fingers and toes vary in response to cold and may include a feeling of numbness, severe aching or pain, tingling or throbbing, a sensation of tightness, “pins and needles,” and/or a profound loss of sensation. (For more information on this disorder, choose “Raynaud's” as your search term in the Rare Disease Database.)CREST syndrome is an acronym for calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly and telangiectasia. Calcinosis is the abnormal accumulation of calcium salts under the skin and in many other organs. Raynaud's phenomenon is a vascular disorder characterized by the intermittent loss of blood to various parts of the body, particularly the fingers, toes, nose, and/or ears. This typically occurs after exposure to cold and causes tingling sensations, numbness, and/or pain. Dysfunction of the lower esophagus results in heartburn (acid reflux into the throat and mouth) and possible scarring. The esophagus may eventually have areas that are narrowed (strictures), and swallowing may become difficult. The small intestine may also lose the ability to push food through to the large intestine (peristalsis), leading to malabsorption and increased bacterial growth in the small intestine. Sclerodactyly, a condition in which the skin becomes thin, shiny, and bright, results in decreased function of the fingers and toes. Affected individuals may also exhibit telangiectasia, meaning the appearance of small blood vessels near the surface of the skin. Individuals with CREST syndrome are at increased risk of developing pulmonary hypertension, a progressive disorder characterized by high blood pressure (hypertension) of the main artery of the lungs (pulmonary artery). (For more information, choose “Raynaud” and “Pulmonary Hypertension” as your search terms in the Rare Disease Database.)
Related disorders of Scleroderma. Symptoms of the following disorders can be similar to those of scleroderma. Comparisons may be useful for a differential diagnosis:Mixed connective tissue disease (MCTD) is a rare inflammatory disorder of the connective tissue. The symptoms of this disorder overlap with those of lupus (systemic lupus erythematosus), scleroderma, and polymyositis/dermatomyositis. Early symptoms may include a fever of unknown origin, painfully cold fingers in response to cold (Raynaud's phenomenon), swollen hands, fatigue, and/or non-deforming arthritis. Arthritis occurs in almost every case of mixed connective tissue disease, but rarely results in deformities similar to those seen in rheumatoid arthritis. People with mixed connective tissue disease commonly experience muscle pain and skin rashes. (For more information on this disorder, choose “Mixed Connective Tissue Disease” as your search term in the Rare Disease Database.)Lupus (systemic lupus erythematosus or SLE) is a rare inflammatory connective tissue disease. The initial symptom of this disease is usually excessive fatigue. Most people with Lupus experience inflammation and swelling of the joints (arthritis), joint pain (arthralgia), and generalized muscle pain (myalgia). Skin rashes are common in people with lupus. About 50 percent of people with lupus exhibit a classic red “butterfly” rash across the bridge of the nose and cheeks. Other early symptoms may include fever, swollen glands, loss of appetite, weight loss, headaches, loss of hair, and swelling due to fluid retention. (For more information on this disorder, choose “Lupus” as your search term in the Rare Disease Database.)Polymyositis is a rare inflammatory disorder characterized by the inflammation and degeneration of muscle and the supporting collagen connective tissue. The cause of this disorder is not known. The major early symptom of this disorder is muscle weakness, usually in the neck, trunk, and shoulders. Eventually, it may become difficult to rise from a sitting position, climb stairs, lift objects, and/or reach overhead. Occasionally, joint pain and tenderness also occur. Other symptoms may include inflammation of the lungs (interstitial pneumonitis), difficulty breathing, coughing, painfully cold fingers in response to cold (Raynaud's phenomenon), digestive problems, heart irregularities, and kidney failure. (For more information on this disorder, choose “Polymyositis” as your search term in the Rare Disease Database.)Dermatomyositis is a rare inflammatory connective tissue disease. The cause is unknown. Dermatomyositis is identical to polymyositis but with the addition of a characteristic red skin rash. These red rashes generally occur before the muscle weakness occurs and usually appear on the face, knees, shoulders, and hands. In some affected individuals, the skin changes caused by dermatomyositis are similar to those associated with scleroderma. The skin may become dry and hard and have a brownish color. (For more information on this disorder, choose “Dermatomyositis” as your search term in the Rare Disease Database.)Raynaud's disease is a rare disorder characterized by spasms of the blood vessels in the fingers, toes, nose, and ears (Raynaud's phenomenon) usually in response to cold. Raynaud's disease includes the symptoms of Raynaud's phenomenon along with other systemic disorders. The major symptom of this disorder is a dramatic stark white pallor of the affected fingers and toes when exposed to cold, although a blue or red color may also be present from time to time. Other symptoms in the affected fingers and toes vary in response to cold and may include a feeling of numbness, severe aching or pain, tingling or throbbing, a sensation of tightness, “pins and needles,” and/or a profound loss of sensation. (For more information on this disorder, choose “Raynaud's” as your search term in the Rare Disease Database.)CREST syndrome is an acronym for calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly and telangiectasia. Calcinosis is the abnormal accumulation of calcium salts under the skin and in many other organs. Raynaud's phenomenon is a vascular disorder characterized by the intermittent loss of blood to various parts of the body, particularly the fingers, toes, nose, and/or ears. This typically occurs after exposure to cold and causes tingling sensations, numbness, and/or pain. Dysfunction of the lower esophagus results in heartburn (acid reflux into the throat and mouth) and possible scarring. The esophagus may eventually have areas that are narrowed (strictures), and swallowing may become difficult. The small intestine may also lose the ability to push food through to the large intestine (peristalsis), leading to malabsorption and increased bacterial growth in the small intestine. Sclerodactyly, a condition in which the skin becomes thin, shiny, and bright, results in decreased function of the fingers and toes. Affected individuals may also exhibit telangiectasia, meaning the appearance of small blood vessels near the surface of the skin. Individuals with CREST syndrome are at increased risk of developing pulmonary hypertension, a progressive disorder characterized by high blood pressure (hypertension) of the main artery of the lungs (pulmonary artery). (For more information, choose “Raynaud” and “Pulmonary Hypertension” as your search terms in the Rare Disease Database.)
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Diagnosis of Scleroderma
Diagnosis of Scleroderma.
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Therapies of Scleroderma
Treatment of scleroderma is symptomatic and supportive. Medications used to control the hardening of the skin and internal organs (fibrosis) are D- penicillamine and cholchicine. Other skin care may include lubricating creams or antibiotic ointments for infected ulcerations.Captopril and enalapril, angiotensin-converting enzyme inhibitors that inhibit the formation of angiotensin, are the drugs of choice for the treatment of kidney disease associated with scleroderma. Other vasodilators or beta-adrenergic blockers also have been used with some success. These agents are effective in controlling hypertension and can preserve kidney function.If Raynaud's phenomenon occurs with scleroderma, drug therapy may help widen (dilate) blood vessels. Vasodilators, including the drugs nifedipine (Procardia), reserpine (Serpasil), guanethidine (Ismelin), phenoxybenzamine (Dibenzyline), nicotinic acid, diltiazem, verapamil, and/or prazosin (Minipress) may be prescribed.In rare cases of scleroderma, abnormal accumulation of calcium salts under the skin and in other organs (calcinosis) may require surgical intervention. For joint pain or arthritis, anti-inflammatory drugs are generally prescribed including aspirin, indomethadin (Indocin), and naproxen (Naprosyn). Some individuals may require low doses of corticosteroid drugs to control these symptoms.The management of symptoms of scleroderma related to pulmonary hypertension involves the use of supplemental oxygen.The orphan drug Tracleer (bosentan) has been approved by the Food and Drug Administration (FDA) for treatment of pulmonary hypertension. Pulmonary hypertension occurs in some individuals with scleroderma. The drug improves the exercise ability of individuals with primary pulmonary hypertension allowing them to exert themselves physically without shortness of breath. Tracleer is manufactured by Actelion Pharmaceuticals US, Inc. of San Francisco, California.Epoprostenol sodium (Flolan) was approved by the FDA in 2000 as a treatment for pulmonary hypertension in scleroderma. For information on Flolan, contact its manufacturer, GlaxoSmithKline.When abnormalities of the heart (myocardial perfusions) occur as a result of scleroderma, the drugs nifedipine and dipyridamole may be administered. Nonsteroidal anti-inflammatory or corticosteroid drugs are typically used to treat the symptoms relating to the inflammation of the membranes of the heart (pericarditis).When scleroderma causes the esophagus and/or gastrointestinal tract to become inflamed or ulcerated, the treatments of choice are drugs known as H2 blockers such as cimetidine or ranitidine; omeprazole may also be used. Metoclopramide has been beneficial in treating the symptoms associated with gastrointestinal dysmotility. Gastrointestinal dysmotility refers to problems with the muscular contractions of the stomach wall that are necessary to move or squeeze contents forward. Acid reflux from the stomach into the esophagus may be partially controlled by dietary regulation. Individuals are urged to avoid certain foods such as fats, spices, tea, coffee, and alcohol. Several small and frequent meals per day lighten the work of the gastrointestinal system. Sitting upright for at least 2 hours after eating aids the digestive process.Good oral hygiene is important because gum disease is common in scleroderma. Some affected individuals may experience excessive dryness of the mouth and eyes. The combination of dry mouth and dry eyes is known as Sjogren's syndrome. (For more information, choose "Sjogren" as your search term in the Rare Disease Database.)
Therapies of Scleroderma. Treatment of scleroderma is symptomatic and supportive. Medications used to control the hardening of the skin and internal organs (fibrosis) are D- penicillamine and cholchicine. Other skin care may include lubricating creams or antibiotic ointments for infected ulcerations.Captopril and enalapril, angiotensin-converting enzyme inhibitors that inhibit the formation of angiotensin, are the drugs of choice for the treatment of kidney disease associated with scleroderma. Other vasodilators or beta-adrenergic blockers also have been used with some success. These agents are effective in controlling hypertension and can preserve kidney function.If Raynaud's phenomenon occurs with scleroderma, drug therapy may help widen (dilate) blood vessels. Vasodilators, including the drugs nifedipine (Procardia), reserpine (Serpasil), guanethidine (Ismelin), phenoxybenzamine (Dibenzyline), nicotinic acid, diltiazem, verapamil, and/or prazosin (Minipress) may be prescribed.In rare cases of scleroderma, abnormal accumulation of calcium salts under the skin and in other organs (calcinosis) may require surgical intervention. For joint pain or arthritis, anti-inflammatory drugs are generally prescribed including aspirin, indomethadin (Indocin), and naproxen (Naprosyn). Some individuals may require low doses of corticosteroid drugs to control these symptoms.The management of symptoms of scleroderma related to pulmonary hypertension involves the use of supplemental oxygen.The orphan drug Tracleer (bosentan) has been approved by the Food and Drug Administration (FDA) for treatment of pulmonary hypertension. Pulmonary hypertension occurs in some individuals with scleroderma. The drug improves the exercise ability of individuals with primary pulmonary hypertension allowing them to exert themselves physically without shortness of breath. Tracleer is manufactured by Actelion Pharmaceuticals US, Inc. of San Francisco, California.Epoprostenol sodium (Flolan) was approved by the FDA in 2000 as a treatment for pulmonary hypertension in scleroderma. For information on Flolan, contact its manufacturer, GlaxoSmithKline.When abnormalities of the heart (myocardial perfusions) occur as a result of scleroderma, the drugs nifedipine and dipyridamole may be administered. Nonsteroidal anti-inflammatory or corticosteroid drugs are typically used to treat the symptoms relating to the inflammation of the membranes of the heart (pericarditis).When scleroderma causes the esophagus and/or gastrointestinal tract to become inflamed or ulcerated, the treatments of choice are drugs known as H2 blockers such as cimetidine or ranitidine; omeprazole may also be used. Metoclopramide has been beneficial in treating the symptoms associated with gastrointestinal dysmotility. Gastrointestinal dysmotility refers to problems with the muscular contractions of the stomach wall that are necessary to move or squeeze contents forward. Acid reflux from the stomach into the esophagus may be partially controlled by dietary regulation. Individuals are urged to avoid certain foods such as fats, spices, tea, coffee, and alcohol. Several small and frequent meals per day lighten the work of the gastrointestinal system. Sitting upright for at least 2 hours after eating aids the digestive process.Good oral hygiene is important because gum disease is common in scleroderma. Some affected individuals may experience excessive dryness of the mouth and eyes. The combination of dry mouth and dry eyes is known as Sjogren's syndrome. (For more information, choose "Sjogren" as your search term in the Rare Disease Database.)
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