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nord_214_2 | Causes of Cerebellar Agenesis | The etiology of cerebellar agenesis is varied (heterogeneous). Acquired (prenatal/perinatal) causes include cerebellar destruction caused by hemorrhage, lack of or diminished blood flow (ischemia), prenatal infection (e.g., cytomegalovirus, Zika virus) or other factors. This has been documented in a minority of children with spina bifida (myelomeningocele), also called “vanishing cerebellum in myelomeningocele”. It is being increasingly recognized in premature babies with very low birth weight (also called “cerebellar disruption of prematurity”) and is often accompanied by additional anomalies of the brain.The exact cause of isolated cerebellar agenesis often remains unknown. Most cases occur randomly for unknown reasons (sporadically).A genetic cause is documented in an extremely rare syndrome of cerebellar agenesis and agenesis of the pancreas, resulting in neonatal diabetes mellitus. This syndrome is caused by changes (variants or mutations) in the PTF1A gene, and it is inherited in an autosomal recessive manner. | Causes of Cerebellar Agenesis. The etiology of cerebellar agenesis is varied (heterogeneous). Acquired (prenatal/perinatal) causes include cerebellar destruction caused by hemorrhage, lack of or diminished blood flow (ischemia), prenatal infection (e.g., cytomegalovirus, Zika virus) or other factors. This has been documented in a minority of children with spina bifida (myelomeningocele), also called “vanishing cerebellum in myelomeningocele”. It is being increasingly recognized in premature babies with very low birth weight (also called “cerebellar disruption of prematurity”) and is often accompanied by additional anomalies of the brain.The exact cause of isolated cerebellar agenesis often remains unknown. Most cases occur randomly for unknown reasons (sporadically).A genetic cause is documented in an extremely rare syndrome of cerebellar agenesis and agenesis of the pancreas, resulting in neonatal diabetes mellitus. This syndrome is caused by changes (variants or mutations) in the PTF1A gene, and it is inherited in an autosomal recessive manner. | 214 | Cerebellar Agenesis |
nord_214_3 | Affects of Cerebellar Agenesis | Cerebellar agenesis appears to affect males and females in equal numbers. The exact incidence and prevalence of the disorder in the general population is unknown. Congenital isolated cerebellar agenesis is considered an extremely rare occurrence. | Affects of Cerebellar Agenesis. Cerebellar agenesis appears to affect males and females in equal numbers. The exact incidence and prevalence of the disorder in the general population is unknown. Congenital isolated cerebellar agenesis is considered an extremely rare occurrence. | 214 | Cerebellar Agenesis |
nord_214_4 | Related disorders of Cerebellar Agenesis | Cerebellar agenesis is defined by neuroimaging and should not be confused with other more prevalent malformations of the cerebellum (e.g., Dandy-Walker malformation and Joubert syndrome) if the detailed neuroimaging pattern is taken into account.Cerebellar agenesis can be interpreted as the most severe end of the spectrum of cerebellar hypoplasia, a general term for a cerebellum of diminished volume. Again, careful analysis of neuroimaging allows distinction from cerebellar hypoplasia, which is a very heterogeneous condition. | Related disorders of Cerebellar Agenesis. Cerebellar agenesis is defined by neuroimaging and should not be confused with other more prevalent malformations of the cerebellum (e.g., Dandy-Walker malformation and Joubert syndrome) if the detailed neuroimaging pattern is taken into account.Cerebellar agenesis can be interpreted as the most severe end of the spectrum of cerebellar hypoplasia, a general term for a cerebellum of diminished volume. Again, careful analysis of neuroimaging allows distinction from cerebellar hypoplasia, which is a very heterogeneous condition. | 214 | Cerebellar Agenesis |
nord_214_5 | Diagnosis of Cerebellar Agenesis | After birth (postnatally) the definite diagnosis of cerebellar agenesis is based on the neuroimaging findings with MRI (magnetic resonance imaging); it cannot be made on clinical grounds. Before birth (prenatally) the diagnosis of cerebellar agenesis is not reliably possible by ultrasound or fetal MRI. Babies have been described with normal brain ultrasound at 20-25 weeks of gestation, with subsequent destruction of the cerebellum during later stages of pregnancy. | Diagnosis of Cerebellar Agenesis. After birth (postnatally) the definite diagnosis of cerebellar agenesis is based on the neuroimaging findings with MRI (magnetic resonance imaging); it cannot be made on clinical grounds. Before birth (prenatally) the diagnosis of cerebellar agenesis is not reliably possible by ultrasound or fetal MRI. Babies have been described with normal brain ultrasound at 20-25 weeks of gestation, with subsequent destruction of the cerebellum during later stages of pregnancy. | 214 | Cerebellar Agenesis |
nord_214_6 | Therapies of Cerebellar Agenesis | Treatment The treatment of cerebellar agenesis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, speech pathologists, and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively.Early intervention is important in ensuring that children with cerebellar abnormalities reach their highest potential. Services that may be beneficial may include physical therapy, occupational therapy and speech therapy. In some children, special remedial education may be of benefit. Adaptive devices may assist individuals with significant motor deficits or speech difficulties. | Therapies of Cerebellar Agenesis. Treatment The treatment of cerebellar agenesis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, speech pathologists, and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively.Early intervention is important in ensuring that children with cerebellar abnormalities reach their highest potential. Services that may be beneficial may include physical therapy, occupational therapy and speech therapy. In some children, special remedial education may be of benefit. Adaptive devices may assist individuals with significant motor deficits or speech difficulties. | 214 | Cerebellar Agenesis |
nord_215_0 | Overview of Cerebral Creatine Deficiency Syndromes | Cerebral creatine deficiency syndromes (CCDS) are inborn errors of creatine metabolism which interrupt the formation or transport of creatine. Creatine is necessary to render available the energy of adenosine triphosphate (ATP) to all cells in the body. Creatine is essential to sustain the high energy levels needed for muscle and brain development.There are three types of CCDS: creatine transporter deficiency (CTD), guanidinoacetate methyltransferase deficiency (GAMT) and arginine: glycine amidinotransferase deficiency (AGAT). | Overview of Cerebral Creatine Deficiency Syndromes. Cerebral creatine deficiency syndromes (CCDS) are inborn errors of creatine metabolism which interrupt the formation or transport of creatine. Creatine is necessary to render available the energy of adenosine triphosphate (ATP) to all cells in the body. Creatine is essential to sustain the high energy levels needed for muscle and brain development.There are three types of CCDS: creatine transporter deficiency (CTD), guanidinoacetate methyltransferase deficiency (GAMT) and arginine: glycine amidinotransferase deficiency (AGAT). | 215 | Cerebral Creatine Deficiency Syndromes |
nord_215_1 | Symptoms of Cerebral Creatine Deficiency Syndromes | The severity of CCDS varies from patient to patient. Global developmental delays affect all children with these disorders and may be the first sign, appearing before other symptoms. Speech delay may be particularly severe and is present in all affected children. Intellectual disability of variable severity is typically present in all older children and adults.Additional symptoms may include seizure disorders, muscle weakness, behavior disorders, autism-like behaviors, movement disorders, gastrointestinal problems, and failure to thrive. | Symptoms of Cerebral Creatine Deficiency Syndromes. The severity of CCDS varies from patient to patient. Global developmental delays affect all children with these disorders and may be the first sign, appearing before other symptoms. Speech delay may be particularly severe and is present in all affected children. Intellectual disability of variable severity is typically present in all older children and adults.Additional symptoms may include seizure disorders, muscle weakness, behavior disorders, autism-like behaviors, movement disorders, gastrointestinal problems, and failure to thrive. | 215 | Cerebral Creatine Deficiency Syndromes |
nord_215_2 | Causes of Cerebral Creatine Deficiency Syndromes | Creatine transporter defect (CTD)
CTD is caused by a change (mutation or variant)) in the creatine transporter gene, SLC6A8. This variant results in a blockage in the transportation of creatine to the brain and muscle. CTD is the most common CCDS. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy, normal GAA, but high creatine: creatinine ratio in urine. Individuals typically present with intellectual disabilities and severe expressive speech delays, seizures and autistic behaviors. The age of diagnosis ranges from 2 to 66 years of age, indicating that life expectancy can be normal. The inheritance pattern for CTD is X-linked. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.Guanidinoacetate methyltransferase deficiency (GAMT)
GAMT deficiency is a caused by a variant in the GAMT gene that codes for the enzyme that transforms guanidinoacetate into creatine, resulting in a shortage of creatine and the accumulation of guanidinoacetate (GAA). It is the most severe of the three CCDS due to the elevation of guanidinoacetate (which is neurotoxic) in addition to creatine deficiency. Affected individuals have cerebral creatine deficiency on MR spectroscopy and high GAA in plasma. People with GAMT deficiency typically present with severe intellectual disabilities, seizure disorders and autistic behaviors. The onset of symptoms is between ages 3 months and 3 years of age.The inheritance pattern for GAMT is autosomal recessive. 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.Arginine: glycine amidinotransferase deficiency (AGAT)
AGAT deficiency impairs the first step of creatine production, resulting in decreased formation of guanidinoacetate, the immediate precursor of creatine. Variants in the GATM gene impair the body’s production of creatine. Out of the three CCDS, AGAT is the least reported. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy and low GAA in plasma. People with AGAT typically present with mild to moderate intellectual disabilities. The inheritance pattern for AGAT is autosomal recessive. | Causes of Cerebral Creatine Deficiency Syndromes. Creatine transporter defect (CTD)
CTD is caused by a change (mutation or variant)) in the creatine transporter gene, SLC6A8. This variant results in a blockage in the transportation of creatine to the brain and muscle. CTD is the most common CCDS. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy, normal GAA, but high creatine: creatinine ratio in urine. Individuals typically present with intellectual disabilities and severe expressive speech delays, seizures and autistic behaviors. The age of diagnosis ranges from 2 to 66 years of age, indicating that life expectancy can be normal. The inheritance pattern for CTD is X-linked. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.Guanidinoacetate methyltransferase deficiency (GAMT)
GAMT deficiency is a caused by a variant in the GAMT gene that codes for the enzyme that transforms guanidinoacetate into creatine, resulting in a shortage of creatine and the accumulation of guanidinoacetate (GAA). It is the most severe of the three CCDS due to the elevation of guanidinoacetate (which is neurotoxic) in addition to creatine deficiency. Affected individuals have cerebral creatine deficiency on MR spectroscopy and high GAA in plasma. People with GAMT deficiency typically present with severe intellectual disabilities, seizure disorders and autistic behaviors. The onset of symptoms is between ages 3 months and 3 years of age.The inheritance pattern for GAMT is autosomal recessive. 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.Arginine: glycine amidinotransferase deficiency (AGAT)
AGAT deficiency impairs the first step of creatine production, resulting in decreased formation of guanidinoacetate, the immediate precursor of creatine. Variants in the GATM gene impair the body’s production of creatine. Out of the three CCDS, AGAT is the least reported. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy and low GAA in plasma. People with AGAT typically present with mild to moderate intellectual disabilities. The inheritance pattern for AGAT is autosomal recessive. | 215 | Cerebral Creatine Deficiency Syndromes |
nord_215_3 | Affects of Cerebral Creatine Deficiency Syndromes | CTD is estimated to account for 1-2% of all unexplained X-linked intellectual disabilities. In regard to GAMT deficiency, there have been estimations from 1 out of 250,000 to 1 out of 550,000. As of 2015, there have only been 110 individuals with GAMT deficiency diagnosed worldwide. The prevalence of AGAT is not known because there have been too few studies on record. | Affects of Cerebral Creatine Deficiency Syndromes. CTD is estimated to account for 1-2% of all unexplained X-linked intellectual disabilities. In regard to GAMT deficiency, there have been estimations from 1 out of 250,000 to 1 out of 550,000. As of 2015, there have only been 110 individuals with GAMT deficiency diagnosed worldwide. The prevalence of AGAT is not known because there have been too few studies on record. | 215 | Cerebral Creatine Deficiency Syndromes |
nord_215_4 | Related disorders of Cerebral Creatine Deficiency Syndromes | CCDS patients are frequently misdiagnosed with cerebral palsy as infants and toddlers. Children are often misdiagnosed with autism or global developmental delays. | Related disorders of Cerebral Creatine Deficiency Syndromes. CCDS patients are frequently misdiagnosed with cerebral palsy as infants and toddlers. Children are often misdiagnosed with autism or global developmental delays. | 215 | Cerebral Creatine Deficiency Syndromes |
nord_215_5 | Diagnosis of Cerebral Creatine Deficiency Syndromes | CCDS screening is non-invasive.Testing in both urine and plasma is recommended for all three types of CCDS by measuring the concentration of creatine (Cr), guanidinoacetate (GAA) and creatinine (Crn). Follow up genomic testing for specific genes and brain MRI with spectroscopy may be ordered to confirm a CCDS diagnosis. GAMT deficiency is also part of the recommended uniform newborn screening panel and children can be identified at birth in states that have adopted it. | Diagnosis of Cerebral Creatine Deficiency Syndromes. CCDS screening is non-invasive.Testing in both urine and plasma is recommended for all three types of CCDS by measuring the concentration of creatine (Cr), guanidinoacetate (GAA) and creatinine (Crn). Follow up genomic testing for specific genes and brain MRI with spectroscopy may be ordered to confirm a CCDS diagnosis. GAMT deficiency is also part of the recommended uniform newborn screening panel and children can be identified at birth in states that have adopted it. | 215 | Cerebral Creatine Deficiency Syndromes |
nord_215_6 | Therapies of Cerebral Creatine Deficiency Syndromes | Treatments
Individuals diagnosed with a CCDS require the coordinated efforts of a team of specialists. A pediatrician or an adult primary care physician, neurologist, geneticist, dietician and a doctor who is familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech, and physical therapists may be necessary to treat developmental disabilities and behavior therapy to address behavior problems.Treatments vary with each CCDS patient. Oral supplementation is available and effective if initiated early for GAMT and AGAT. To date, this type of therapy has not shown to improve outcomes in individuals with CTD. Additional treatments for CTD are under investigation.Oral creatine monohydrate is given to replenish creatine levels in the brain and other tissues in individuals with GAMT and AGAT. A low arginine/protein diet, L-ornithine supplementation and sodium benzoate are used to reduce toxic levels of guanidinoacetate in individuals with GAMT. There may be some clinical benefits to a subset of individuals with CTD when treated with creatine monohydrate, L-arginine, glycine, and betaine. For CCDS patients being treated with creatine monohydrate, a routine measurement of renal function should be considered to detect possible creatine-associated kidney disease (nephropathy).Prevention of Primary Symptoms
Early treatment at the first sign of symptoms in patients with GAMT and AGAT is effective in improving patient’s quality of life. The treatment in newborn siblings of individuals with GAMT or AGAT has been shown to prevent disease manifestation. | Therapies of Cerebral Creatine Deficiency Syndromes. Treatments
Individuals diagnosed with a CCDS require the coordinated efforts of a team of specialists. A pediatrician or an adult primary care physician, neurologist, geneticist, dietician and a doctor who is familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech, and physical therapists may be necessary to treat developmental disabilities and behavior therapy to address behavior problems.Treatments vary with each CCDS patient. Oral supplementation is available and effective if initiated early for GAMT and AGAT. To date, this type of therapy has not shown to improve outcomes in individuals with CTD. Additional treatments for CTD are under investigation.Oral creatine monohydrate is given to replenish creatine levels in the brain and other tissues in individuals with GAMT and AGAT. A low arginine/protein diet, L-ornithine supplementation and sodium benzoate are used to reduce toxic levels of guanidinoacetate in individuals with GAMT. There may be some clinical benefits to a subset of individuals with CTD when treated with creatine monohydrate, L-arginine, glycine, and betaine. For CCDS patients being treated with creatine monohydrate, a routine measurement of renal function should be considered to detect possible creatine-associated kidney disease (nephropathy).Prevention of Primary Symptoms
Early treatment at the first sign of symptoms in patients with GAMT and AGAT is effective in improving patient’s quality of life. The treatment in newborn siblings of individuals with GAMT or AGAT has been shown to prevent disease manifestation. | 215 | Cerebral Creatine Deficiency Syndromes |
nord_216_0 | Overview of Cerebral Folate Deficiency | Cerebral folate deficiency is a neurological syndrome in which development is usually normal in the first year of life, but at approximately 2 years of age, affected children start to lose mental and motor skills (psychomotor regression). Some early symptoms are intellectual disability, speech difficulties, and development of recurrent seizures in a third of affected children. Motor issues such as tremors and lack of muscle control or coordination of voluntary movements (ataxia) can become severe. Cerebral folate deficiency occurs because of a deficiency of vitamin B folate (vitamin B9) in the brain caused by a low level of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid due to a disruption in the function of the folate receptor alpha (FRA). The function of the FRA can be disrupted by several causes. The most common etiology involves one of two autoantibodies blinding to the FRA resulting in a disruption in its function. The FRA is highly dependent on mitochondrial function leading to disrupting in FRA function in mitochondrial and other metabolic disorders. Lastly, rare mutation in the FOLR1 gene can result in an autosomal recessive genetic condition which disrupts FRA function. This condition can be treated with leucovorin calcium (aka folinic acid). | Overview of Cerebral Folate Deficiency. Cerebral folate deficiency is a neurological syndrome in which development is usually normal in the first year of life, but at approximately 2 years of age, affected children start to lose mental and motor skills (psychomotor regression). Some early symptoms are intellectual disability, speech difficulties, and development of recurrent seizures in a third of affected children. Motor issues such as tremors and lack of muscle control or coordination of voluntary movements (ataxia) can become severe. Cerebral folate deficiency occurs because of a deficiency of vitamin B folate (vitamin B9) in the brain caused by a low level of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid due to a disruption in the function of the folate receptor alpha (FRA). The function of the FRA can be disrupted by several causes. The most common etiology involves one of two autoantibodies blinding to the FRA resulting in a disruption in its function. The FRA is highly dependent on mitochondrial function leading to disrupting in FRA function in mitochondrial and other metabolic disorders. Lastly, rare mutation in the FOLR1 gene can result in an autosomal recessive genetic condition which disrupts FRA function. This condition can be treated with leucovorin calcium (aka folinic acid). | 216 | Cerebral Folate Deficiency |
nord_216_1 | Symptoms of Cerebral Folate Deficiency | The symptoms of cerebral folate deficiency may begin as early as four to six months of age with irritability and sleep problems (insomnia). Delays in development may be noted including slow head growth, low muscle tone (hypotonia), ataxia, loss of voluntary movement (dyskinesia), constant contracted muscles (spasticity), speech complications, and epilepsy. Additional signs may involve visual disturbances, hearing loss and autistic features.Even though there may be normal folate levels in the serum and red blood, evaluation of the cerebrospinal fluid shows a decreased level of 5MTHF. The brain may appear normal on an MRI, but in some affected children, a loss of white matter in the brain (leukodystrophy) may be seen. Frontotemporal atrophy and impairment of the protective layer that surrounds nerve fibers in the brain and spinal cord (subcortical demyelination) can be seen as early as 18 months. | Symptoms of Cerebral Folate Deficiency. The symptoms of cerebral folate deficiency may begin as early as four to six months of age with irritability and sleep problems (insomnia). Delays in development may be noted including slow head growth, low muscle tone (hypotonia), ataxia, loss of voluntary movement (dyskinesia), constant contracted muscles (spasticity), speech complications, and epilepsy. Additional signs may involve visual disturbances, hearing loss and autistic features.Even though there may be normal folate levels in the serum and red blood, evaluation of the cerebrospinal fluid shows a decreased level of 5MTHF. The brain may appear normal on an MRI, but in some affected children, a loss of white matter in the brain (leukodystrophy) may be seen. Frontotemporal atrophy and impairment of the protective layer that surrounds nerve fibers in the brain and spinal cord (subcortical demyelination) can be seen as early as 18 months. | 216 | Cerebral Folate Deficiency |
nord_216_2 | Causes of Cerebral Folate Deficiency | Cerebral folate deficiency is caused by a disruption in the function of the folate receptor alpha (FRA). Folate receptor alpha is located inside the cell membrane and binds to folate, which allows it to be transported into the cell. The protein is created in greatest quantities in the choroid plexus in the brain. The choroid plexus releases cerebrospinal fluid that protects the brain and spinal cord. Folate receptor alpha moves folate through the choroid plexus and into the cerebrospinal fluid that will spread to the brain. Folate is important for constructing myelin and chemical messengers (neurotransmitters) that transmit signals in the brain. The absence of folate in the brain triggers the neurological complications associated with this condition.Function of the FRA can result from three main causes. The most common cause results from one of two autoantibodies attaching to the FRA and disrupting its function. Autoantibodies are proteins produced by the immune system that are directed against one or more of an individual's own proteins. One probable mechanism for autoantibody production is that soluble folate receptors from milk may trigger an immune response.Metabolic disorders such as mitochondrial disease are the second most common cause of a disruption in FRA function. The FRA requires energy to function adequately since folate needs to be actively transported into the brain because the folate concentration in the brain is higher than it is in the blood. The mitochondria is important for producing this energy, so any metabolic disorder that disrupts mitochondrial function can interfere with folate transport into the brain. Lastly, mutations in the FOLR1 gene that result in production of abnormal or missing FRA protein are rare causes of the disorder. This form of cerebral folate deficiency is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits 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 altered gene and 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. | Causes of Cerebral Folate Deficiency. Cerebral folate deficiency is caused by a disruption in the function of the folate receptor alpha (FRA). Folate receptor alpha is located inside the cell membrane and binds to folate, which allows it to be transported into the cell. The protein is created in greatest quantities in the choroid plexus in the brain. The choroid plexus releases cerebrospinal fluid that protects the brain and spinal cord. Folate receptor alpha moves folate through the choroid plexus and into the cerebrospinal fluid that will spread to the brain. Folate is important for constructing myelin and chemical messengers (neurotransmitters) that transmit signals in the brain. The absence of folate in the brain triggers the neurological complications associated with this condition.Function of the FRA can result from three main causes. The most common cause results from one of two autoantibodies attaching to the FRA and disrupting its function. Autoantibodies are proteins produced by the immune system that are directed against one or more of an individual's own proteins. One probable mechanism for autoantibody production is that soluble folate receptors from milk may trigger an immune response.Metabolic disorders such as mitochondrial disease are the second most common cause of a disruption in FRA function. The FRA requires energy to function adequately since folate needs to be actively transported into the brain because the folate concentration in the brain is higher than it is in the blood. The mitochondria is important for producing this energy, so any metabolic disorder that disrupts mitochondrial function can interfere with folate transport into the brain. Lastly, mutations in the FOLR1 gene that result in production of abnormal or missing FRA protein are rare causes of the disorder. This form of cerebral folate deficiency is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits 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 altered gene and 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. | 216 | Cerebral Folate Deficiency |
nord_216_3 | Affects of Cerebral Folate Deficiency | Fewer than 20 individuals with cerebral folate deficiency have been reported in scientific literature. The exact prevalence of this condition is unknown. | Affects of Cerebral Folate Deficiency. Fewer than 20 individuals with cerebral folate deficiency have been reported in scientific literature. The exact prevalence of this condition is unknown. | 216 | Cerebral Folate Deficiency |
nord_216_4 | Related disorders of Cerebral Folate Deficiency | Symptoms of the following disorders can be similar to those of cerebral folate deficiency. Comparisons may be useful for a differential diagnosis:Folinic acid-responsive seizures (FARS) is a condition characterized by myoclonic or clonic seizures, trouble breathing (apnea), and irritability within five days after birth. Brain imaging will demonstrate brain atrophy and numerous white matter abnormalities. FARS is caused by mutations in the ALDH7A1 gene.Some people with Kearns–Sayre syndrome who have decreased levels of 5MTHF have a risk of developing secondary cerebral folate deficiency. Folate transport reduction has also been reported in some children with Rett syndrome, Aicardi-Goutiere syndrome and autistic spectrum disorders. | Related disorders of Cerebral Folate Deficiency. Symptoms of the following disorders can be similar to those of cerebral folate deficiency. Comparisons may be useful for a differential diagnosis:Folinic acid-responsive seizures (FARS) is a condition characterized by myoclonic or clonic seizures, trouble breathing (apnea), and irritability within five days after birth. Brain imaging will demonstrate brain atrophy and numerous white matter abnormalities. FARS is caused by mutations in the ALDH7A1 gene.Some people with Kearns–Sayre syndrome who have decreased levels of 5MTHF have a risk of developing secondary cerebral folate deficiency. Folate transport reduction has also been reported in some children with Rett syndrome, Aicardi-Goutiere syndrome and autistic spectrum disorders. | 216 | Cerebral Folate Deficiency |
nord_216_5 | Diagnosis of Cerebral Folate Deficiency | A neurological exam will identify symptoms of cerebral folate deficiency such as hypotonia, ataxia, unsteady walking, and small head circumference. MRI of the brain can help determine if there is irregular subcortical white matter.Cerebral folate deficiency is diagnosed by measuring 5MTHF concentration in the cerebrospinal fluid. This is done with a lumbar puncture (spinal tap), a procedure where a needle is carefully inserted into the spinal canal low in the back.Electroencephalography (EEG), a test used to record electrical activity of the brain, may show unusual arrays that involve high amplitude and irregular waves (hypsarrhythmia). Hearing and ophthalmological examinations may also be conducted.Molecular genetic testing for mutations in the FOLR1 gene is available to confirm the diagnosis.Testing for the two FRA autoantibodies (blocking antibody and binding autoantibody) can be performed to determine if autoantibodies are responsible for cerebral folate deficiency. | Diagnosis of Cerebral Folate Deficiency. A neurological exam will identify symptoms of cerebral folate deficiency such as hypotonia, ataxia, unsteady walking, and small head circumference. MRI of the brain can help determine if there is irregular subcortical white matter.Cerebral folate deficiency is diagnosed by measuring 5MTHF concentration in the cerebrospinal fluid. This is done with a lumbar puncture (spinal tap), a procedure where a needle is carefully inserted into the spinal canal low in the back.Electroencephalography (EEG), a test used to record electrical activity of the brain, may show unusual arrays that involve high amplitude and irregular waves (hypsarrhythmia). Hearing and ophthalmological examinations may also be conducted.Molecular genetic testing for mutations in the FOLR1 gene is available to confirm the diagnosis.Testing for the two FRA autoantibodies (blocking antibody and binding autoantibody) can be performed to determine if autoantibodies are responsible for cerebral folate deficiency. | 216 | Cerebral Folate Deficiency |
nord_216_6 | Therapies of Cerebral Folate Deficiency | Treatment
Oral treatment with leucovorin calcium has been shown to improve symptoms and stabilize the level of 5MTHF in the cerebrospinal fluid. The overall outcome seems to depend on the age at which treatment is initiated, the earlier the treatment, the better outcome. Supplementation with folic acid is not recommended because it is associated with adverse effects such as producing epileptic seizures. No serious adverse effects have been recorded during leucovorin calcium treatment. A milk-free diet in combination with leucovorin Calcium acid has been reported to improve symptoms, especially when used in the early stages of the disease. | Therapies of Cerebral Folate Deficiency. Treatment
Oral treatment with leucovorin calcium has been shown to improve symptoms and stabilize the level of 5MTHF in the cerebrospinal fluid. The overall outcome seems to depend on the age at which treatment is initiated, the earlier the treatment, the better outcome. Supplementation with folic acid is not recommended because it is associated with adverse effects such as producing epileptic seizures. No serious adverse effects have been recorded during leucovorin calcium treatment. A milk-free diet in combination with leucovorin Calcium acid has been reported to improve symptoms, especially when used in the early stages of the disease. | 216 | Cerebral Folate Deficiency |
nord_217_0 | Overview of Cerebrocostomandibular Syndrome | Cerebrocostomandibular syndrome (CCMS) is a disorder that involves a small chin (micrognathia), an opening in the roof of the mouth (cleft palate), a narrow chest, missing ribs, gaps between ribs, and breathing and feeding difficulties. Other common features include scoliosis, developmental delay or intellectual disability, and hearing loss. Other medical problems can be seen as well. Breathing difficulties can lead to death in childhood, and most babies born with CCMS need surgery in the first year of life to help them breathe. These surgeries can include inserting a breathing tube directly into the throat (tracheostomy), surgeries to make the jaw or chest larger, surgery to insert a feeding tube into the stomach, and surgery to repair the hole in the roof of the mouth. CCMS is caused by changes in the SNRPB gene. A damaging change in one of a person’s two copies of the gene can cause the disorder. Most of the time, these changes are new to a child, and do not show up in family members. Rarely, a parent may have the change as well, and may show no symptoms. The diagnosis of CCMS is usually made in the first year of life based on the clinical features (such as a small jaw, rib gaps, narrow chest, and/or breathing difficulties). Imaging techniques like X-ray or MRI may be needed to take a better look at the ribs and spine. Genetic testing can confirm the diagnosis and help parents to better understand the risk for having another child with the disorder. | Overview of Cerebrocostomandibular Syndrome. Cerebrocostomandibular syndrome (CCMS) is a disorder that involves a small chin (micrognathia), an opening in the roof of the mouth (cleft palate), a narrow chest, missing ribs, gaps between ribs, and breathing and feeding difficulties. Other common features include scoliosis, developmental delay or intellectual disability, and hearing loss. Other medical problems can be seen as well. Breathing difficulties can lead to death in childhood, and most babies born with CCMS need surgery in the first year of life to help them breathe. These surgeries can include inserting a breathing tube directly into the throat (tracheostomy), surgeries to make the jaw or chest larger, surgery to insert a feeding tube into the stomach, and surgery to repair the hole in the roof of the mouth. CCMS is caused by changes in the SNRPB gene. A damaging change in one of a person’s two copies of the gene can cause the disorder. Most of the time, these changes are new to a child, and do not show up in family members. Rarely, a parent may have the change as well, and may show no symptoms. The diagnosis of CCMS is usually made in the first year of life based on the clinical features (such as a small jaw, rib gaps, narrow chest, and/or breathing difficulties). Imaging techniques like X-ray or MRI may be needed to take a better look at the ribs and spine. Genetic testing can confirm the diagnosis and help parents to better understand the risk for having another child with the disorder. | 217 | Cerebrocostomandibular Syndrome |
nord_217_1 | Symptoms of Cerebrocostomandibular Syndrome | CCMS is an extremely rare inherited disorder. Its features mainly stem from problems in how the jaw and ribs are formed. People with CCMS have a small jaw with a small chin and mouth (micrognathia). This can cause the tongue to be in the wrong position (glossoptosis). In turn, the abnormal position of the tongue can cause a gap to form in the roof of the mouth (cleft palate) during development in the womb. This set of features (micrognathia, glossoptosis, and cleft palate) is often called Robin sequence. These features can cause feeding difficulties. Nearly all people with CCMS have a small jaw, and most have cleft palate.Individuals with CCMS have large gaps between some of their ribs, especially in the back of the ribcage near the spine. They are typically missing some ribs as well. In one study, people with CCMS had between 7 and 11 ribs per side instead of the typical 12. All had a least one gap on each side. Some patients had gaps between nearly all their ribs. Some of these gaps healed over time. In addition, the ribs of people with CCMS do not connect to the spine in the way they should (abnormal costotransverse articulation). Most people with CCMS also have narrow rib cages. The narrow rib cage and jaw problems can make it difficult for people with CCMS to breathe and eat. These problems usually need treatment in the first year of life. Previously, only about 50% of babies born with CCMS lived until their first birthday. However, treatments have improved, and now about 80% of babies with CCMS live to be at least one-year-old. Many people with CCMS can live full, productive lives. Scoliosis is another common feature in CCMS, though it tends to develop during childhood rather than appearing in infants. Scoliosis may affect about half (50%) of people with CCMS. About half of these patients, or 25% of all CCMS patients, have severe scoliosis. The rib gaps in CCMS cause the scoliosis, but the number of rib gaps cannot predict how severe the scoliosis will be.About half (50%) of people with CCMS have developmental delays or intellectual disability. These delays can often be explained by a lack of oxygen at birth. The delays can be mild, moderate or severe. Severe delays may be related to more severe health problems overall. In some very severe cases of CCMS, babies die within the first year of life. Extra skin at the back of the neck (called redundant neck skin or neck webbing) may be a sign of this more severe form of CCMS.Some other features of CCMS include hearing loss, clubfeet, small head, and low weight and height. They can also have problems with the stomach, heart, kidneys, and urine and genital pathways. Conductive hearing loss occurs in about two thirds (67%) of people with CCMS, where problems in how the ears are formed prevents normal hearing. Another type of hearing loss, called sensorineural hearing loss, has been found in at least one person with CCMS. This involves a problem in how noise signals are sent from the ears to the brain. Around one third (31%) of patients with CCMS have a problem where stomach acid travels back up into the throat (gastroesophageal reflux disease, shortened to GERD in the US and GORD in the UK). About one fourth (25%) are born with a hole in the heart. Problems with the urinary and genital pathways include testicles that remain inside the body (cryptorchidism) or a block in the anus (anal stenosis). During pregnancy, some features of CCMS may be found by ultrasound. Around one fourth (19%) of people with CCMS in one study had a small jaw (micrognathia) on ultrasound. Some other ultrasound findings included slow growth (intrauterine growth restriction, or IUGR), extra amniotic fluid (polyhydramnios), and a thicker pocket of fluid at the back of the baby’s neck (thickened nuchal translucency). If this pocket of fluid becomes very large, it may be called a cystic hygroma. Extra fluid at the back of the neck while in the womb can lead to extra neck skin at birth, and may be linked to more severe problems in babies with CCMS. | Symptoms of Cerebrocostomandibular Syndrome. CCMS is an extremely rare inherited disorder. Its features mainly stem from problems in how the jaw and ribs are formed. People with CCMS have a small jaw with a small chin and mouth (micrognathia). This can cause the tongue to be in the wrong position (glossoptosis). In turn, the abnormal position of the tongue can cause a gap to form in the roof of the mouth (cleft palate) during development in the womb. This set of features (micrognathia, glossoptosis, and cleft palate) is often called Robin sequence. These features can cause feeding difficulties. Nearly all people with CCMS have a small jaw, and most have cleft palate.Individuals with CCMS have large gaps between some of their ribs, especially in the back of the ribcage near the spine. They are typically missing some ribs as well. In one study, people with CCMS had between 7 and 11 ribs per side instead of the typical 12. All had a least one gap on each side. Some patients had gaps between nearly all their ribs. Some of these gaps healed over time. In addition, the ribs of people with CCMS do not connect to the spine in the way they should (abnormal costotransverse articulation). Most people with CCMS also have narrow rib cages. The narrow rib cage and jaw problems can make it difficult for people with CCMS to breathe and eat. These problems usually need treatment in the first year of life. Previously, only about 50% of babies born with CCMS lived until their first birthday. However, treatments have improved, and now about 80% of babies with CCMS live to be at least one-year-old. Many people with CCMS can live full, productive lives. Scoliosis is another common feature in CCMS, though it tends to develop during childhood rather than appearing in infants. Scoliosis may affect about half (50%) of people with CCMS. About half of these patients, or 25% of all CCMS patients, have severe scoliosis. The rib gaps in CCMS cause the scoliosis, but the number of rib gaps cannot predict how severe the scoliosis will be.About half (50%) of people with CCMS have developmental delays or intellectual disability. These delays can often be explained by a lack of oxygen at birth. The delays can be mild, moderate or severe. Severe delays may be related to more severe health problems overall. In some very severe cases of CCMS, babies die within the first year of life. Extra skin at the back of the neck (called redundant neck skin or neck webbing) may be a sign of this more severe form of CCMS.Some other features of CCMS include hearing loss, clubfeet, small head, and low weight and height. They can also have problems with the stomach, heart, kidneys, and urine and genital pathways. Conductive hearing loss occurs in about two thirds (67%) of people with CCMS, where problems in how the ears are formed prevents normal hearing. Another type of hearing loss, called sensorineural hearing loss, has been found in at least one person with CCMS. This involves a problem in how noise signals are sent from the ears to the brain. Around one third (31%) of patients with CCMS have a problem where stomach acid travels back up into the throat (gastroesophageal reflux disease, shortened to GERD in the US and GORD in the UK). About one fourth (25%) are born with a hole in the heart. Problems with the urinary and genital pathways include testicles that remain inside the body (cryptorchidism) or a block in the anus (anal stenosis). During pregnancy, some features of CCMS may be found by ultrasound. Around one fourth (19%) of people with CCMS in one study had a small jaw (micrognathia) on ultrasound. Some other ultrasound findings included slow growth (intrauterine growth restriction, or IUGR), extra amniotic fluid (polyhydramnios), and a thicker pocket of fluid at the back of the baby’s neck (thickened nuchal translucency). If this pocket of fluid becomes very large, it may be called a cystic hygroma. Extra fluid at the back of the neck while in the womb can lead to extra neck skin at birth, and may be linked to more severe problems in babies with CCMS. | 217 | Cerebrocostomandibular Syndrome |
nord_217_2 | Causes of Cerebrocostomandibular Syndrome | The gene that is changed in patients with CCMS is the SNRPB gene. It is possible that there are other rarer causes of CCMS that have not been discovered yet, since some patients with CCMS do not seem to have a change in SNRPB.We have two copies of nearly every gene: one copy from our mother and one copy from our father. A genetic disorder is called “dominant” if it is caused by a change or mutation in only one copy of a gene. The gene change could be passed on from the mother, passed on from the father, or a new change in the person with the disorder. If a person has a changed or mutated gene, they have a 50% chance of passing it on each time they have a child. The chance is the same for each child. It does not matter is the child is male or female.In some individuals, the disorder is due to a new or spontaneous (de novo) genetic change that occurs in the egg or sperm cell. In these cases, the disorder is not inherited from the parents. This is the most common case for children born with CCMS, and is seen in about two thirds (67%) of CCMS patients. However, there have been a few cases where a child with CCMS inherited a genetic mutation from a parent. The parent may or may not show features of CCMS. It is unknown why some people do not show any symptoms of CCMS despite having a genetic change that causes the disorder. This is called incomplete penetrance. This seems to happen in around 20% of parents who have a child with CCMS. Previous reports suggested that CCMS followed autosomal recessive inheritance, where both parents must be carriers for a child to have the disorder. However, since the gene for CCMS was discovered, no cases have been reported where both parents were carriers. The best current explanation for inheritance in CCMS is dominant inheritance with incomplete penetrance, as described above. | Causes of Cerebrocostomandibular Syndrome. The gene that is changed in patients with CCMS is the SNRPB gene. It is possible that there are other rarer causes of CCMS that have not been discovered yet, since some patients with CCMS do not seem to have a change in SNRPB.We have two copies of nearly every gene: one copy from our mother and one copy from our father. A genetic disorder is called “dominant” if it is caused by a change or mutation in only one copy of a gene. The gene change could be passed on from the mother, passed on from the father, or a new change in the person with the disorder. If a person has a changed or mutated gene, they have a 50% chance of passing it on each time they have a child. The chance is the same for each child. It does not matter is the child is male or female.In some individuals, the disorder is due to a new or spontaneous (de novo) genetic change that occurs in the egg or sperm cell. In these cases, the disorder is not inherited from the parents. This is the most common case for children born with CCMS, and is seen in about two thirds (67%) of CCMS patients. However, there have been a few cases where a child with CCMS inherited a genetic mutation from a parent. The parent may or may not show features of CCMS. It is unknown why some people do not show any symptoms of CCMS despite having a genetic change that causes the disorder. This is called incomplete penetrance. This seems to happen in around 20% of parents who have a child with CCMS. Previous reports suggested that CCMS followed autosomal recessive inheritance, where both parents must be carriers for a child to have the disorder. However, since the gene for CCMS was discovered, no cases have been reported where both parents were carriers. The best current explanation for inheritance in CCMS is dominant inheritance with incomplete penetrance, as described above. | 217 | Cerebrocostomandibular Syndrome |
nord_217_3 | Affects of Cerebrocostomandibular Syndrome | CCMS is a very rare disorder that is apparent at birth (congenital). The disorder appears to affect males and females in equal numbers. Over 80 patients have been reported in the medical literature. | Affects of Cerebrocostomandibular Syndrome. CCMS is a very rare disorder that is apparent at birth (congenital). The disorder appears to affect males and females in equal numbers. Over 80 patients have been reported in the medical literature. | 217 | Cerebrocostomandibular Syndrome |
nord_217_4 | Related disorders of Cerebrocostomandibular Syndrome | Symptoms of the following disorders can be similar to those of cerebrocostomandibular syndrome (CCMS). Comparisons may be useful for to distinguish between diagnoses:Robin sequence (also known as Pierre Robin syndrome or Pierre Robin anomaly) is a sequence of problems that can happen on their own or as part of another disorder. It involves small jaws (micrognathia); an improper, downward position of the tongue (glossoptosis); a hole in the roof of the mouth (cleft palate); and/or other problems. When it occurs on its own, Robin sequence is thought to follow autosomal recessive inheritance. (For more information on this disorder, choose “Pierre Robin” as your search term in the Rare Disease Database.)
In diaphanospondylodysostosis, the bones of the ribs and spine take too long to harden do not fully harden at all. People who have this disorder can have narrow chests and rib gaps like people with CCMS. However, they also have tumors and fluid-filled cysts in their kidneys. Finally, they do not have abnormally small jaws (micrognathia) or holes in the roof of their mouths (cleft palates) like in CCMS.Another disorder like CCMS is congenital disorder of glycosylation type IIg. People with this disorder also have rib gaps, slowed growth, and Robin sequence. Unlike CCMS, people with this disorder have fused ribs and many other problems with the formation of the bones in the spine (called vertebrae). They can also have clubfeet (talipes), small ears (microtia), and problems in how the eyes and brain are formed.There may be other disorders that begin before birth and involve small jaws (micrognathia), a hole in the roof of the mouth (cleft palate), problems in how the ribs are formed, and/or other physical features and symptoms like those seen in CCMS. (For more information on these disorders, choose the exact disorder name in question as your search term in the Rare Disease Database.) | Related disorders of Cerebrocostomandibular Syndrome. Symptoms of the following disorders can be similar to those of cerebrocostomandibular syndrome (CCMS). Comparisons may be useful for to distinguish between diagnoses:Robin sequence (also known as Pierre Robin syndrome or Pierre Robin anomaly) is a sequence of problems that can happen on their own or as part of another disorder. It involves small jaws (micrognathia); an improper, downward position of the tongue (glossoptosis); a hole in the roof of the mouth (cleft palate); and/or other problems. When it occurs on its own, Robin sequence is thought to follow autosomal recessive inheritance. (For more information on this disorder, choose “Pierre Robin” as your search term in the Rare Disease Database.)
In diaphanospondylodysostosis, the bones of the ribs and spine take too long to harden do not fully harden at all. People who have this disorder can have narrow chests and rib gaps like people with CCMS. However, they also have tumors and fluid-filled cysts in their kidneys. Finally, they do not have abnormally small jaws (micrognathia) or holes in the roof of their mouths (cleft palates) like in CCMS.Another disorder like CCMS is congenital disorder of glycosylation type IIg. People with this disorder also have rib gaps, slowed growth, and Robin sequence. Unlike CCMS, people with this disorder have fused ribs and many other problems with the formation of the bones in the spine (called vertebrae). They can also have clubfeet (talipes), small ears (microtia), and problems in how the eyes and brain are formed.There may be other disorders that begin before birth and involve small jaws (micrognathia), a hole in the roof of the mouth (cleft palate), problems in how the ribs are formed, and/or other physical features and symptoms like those seen in CCMS. (For more information on these disorders, choose the exact disorder name in question as your search term in the Rare Disease Database.) | 217 | Cerebrocostomandibular Syndrome |
nord_217_5 | Diagnosis of Cerebrocostomandibular Syndrome | In some patients, CCMS may be diagnosed before birth (prenatally) using advanced imaging techniques such as ultrasound. Fetal ultrasounds use reflected sound waves to make a picture of the developing fetus, and can show signs of CCMS (e.g., short, improperly formed ribs; small jaw; etc.).In most patietns, CCMS is diagnosed and/or confirmed after birth (postnatally) based upon a thorough clinical evaluation, classic physical findings, and imaging tests. For example, x-ray studies may confirm or reveal the severity of jaw and rib problems, as well as other features of CCMS. | Diagnosis of Cerebrocostomandibular Syndrome. In some patients, CCMS may be diagnosed before birth (prenatally) using advanced imaging techniques such as ultrasound. Fetal ultrasounds use reflected sound waves to make a picture of the developing fetus, and can show signs of CCMS (e.g., short, improperly formed ribs; small jaw; etc.).In most patietns, CCMS is diagnosed and/or confirmed after birth (postnatally) based upon a thorough clinical evaluation, classic physical findings, and imaging tests. For example, x-ray studies may confirm or reveal the severity of jaw and rib problems, as well as other features of CCMS. | 217 | Cerebrocostomandibular Syndrome |
nord_217_6 | Therapies of Cerebrocostomandibular Syndrome | Treatment
The treatment of CCMS is based on the symptoms that a person with CCMS has. Treatment may require a group effort from a team of specialists. Pediatricians, surgeons, physicians who diagnose and treat abnormalities of the lungs (pulmonologists), specialists who assess and treat hearing problems (audiologists), speech pathologists, and other health care professionals may need to work together to plan a child's treatment.Specific therapies for the treatment of CCMS are meant to ease the burden of specific symptoms. Because infants with the disorder may be prone to breathing problems and infections, doctors may closely watch babies with CCMS, recommend preventive treatments, and aggressively treat infections with antibiotics. In cases of severe breathing problems in the first few months of life, a cut may be made into the windpipe (trachea) to create a temporary opening (tracheostomy) that will allow the baby to breathe more easily. About one third (1/3) will still need breathing support after this procedure. This can include continuous oxygen through a tube under the nose or a small portable breathing machine (continuous positive airway pressure, or CPAP). In addition, special therapies may help babies with feeding problems to get enough food and nutrients. For example, babies born with a hole in the roof of the mouth (cleft palate) need special bottle nipples for feedings, and typically need surgery to repair the roof of the mouth. Most babies born with CCMS need to have a tube placed into their bodies to help with feeding. This can be through the baby’s nose (nasogastric tube, or NG tube) or directly into the baby’s stomach (gastrostomy tube, or G tube). Other surgeries may be considered , such as surgery to make the jaw or chest larger.The vertical expandable prosthetic titanium rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a disorder where severe problems in how the chest, spine, and ribs are formed prevent normal breathing and lung development. The VEPTR is device helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. It is placed inside the body and its size can be adjusted as the patient grows. The titanium rib was developed at the University of Texas Health Science Center in San Antonio. It is made by Synthes Spine Co. Hearing aids may be helpful for people with CCMS who have hearing loss. Early intervention services can help children with CCMS reach their potential. These include special education, speech therapy, and other medical, social, and/or job skills services.Genetic counseling can be helpful for all people with CCMS and their families. Genetic counselors can explain CCMS and the chance that another child in the family will have it. They can also help families connect to resources and other people with CCMs. | Therapies of Cerebrocostomandibular Syndrome. Treatment
The treatment of CCMS is based on the symptoms that a person with CCMS has. Treatment may require a group effort from a team of specialists. Pediatricians, surgeons, physicians who diagnose and treat abnormalities of the lungs (pulmonologists), specialists who assess and treat hearing problems (audiologists), speech pathologists, and other health care professionals may need to work together to plan a child's treatment.Specific therapies for the treatment of CCMS are meant to ease the burden of specific symptoms. Because infants with the disorder may be prone to breathing problems and infections, doctors may closely watch babies with CCMS, recommend preventive treatments, and aggressively treat infections with antibiotics. In cases of severe breathing problems in the first few months of life, a cut may be made into the windpipe (trachea) to create a temporary opening (tracheostomy) that will allow the baby to breathe more easily. About one third (1/3) will still need breathing support after this procedure. This can include continuous oxygen through a tube under the nose or a small portable breathing machine (continuous positive airway pressure, or CPAP). In addition, special therapies may help babies with feeding problems to get enough food and nutrients. For example, babies born with a hole in the roof of the mouth (cleft palate) need special bottle nipples for feedings, and typically need surgery to repair the roof of the mouth. Most babies born with CCMS need to have a tube placed into their bodies to help with feeding. This can be through the baby’s nose (nasogastric tube, or NG tube) or directly into the baby’s stomach (gastrostomy tube, or G tube). Other surgeries may be considered , such as surgery to make the jaw or chest larger.The vertical expandable prosthetic titanium rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a disorder where severe problems in how the chest, spine, and ribs are formed prevent normal breathing and lung development. The VEPTR is device helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. It is placed inside the body and its size can be adjusted as the patient grows. The titanium rib was developed at the University of Texas Health Science Center in San Antonio. It is made by Synthes Spine Co. Hearing aids may be helpful for people with CCMS who have hearing loss. Early intervention services can help children with CCMS reach their potential. These include special education, speech therapy, and other medical, social, and/or job skills services.Genetic counseling can be helpful for all people with CCMS and their families. Genetic counselors can explain CCMS and the chance that another child in the family will have it. They can also help families connect to resources and other people with CCMs. | 217 | Cerebrocostomandibular Syndrome |
nord_218_0 | Overview of Cerebrotendinous Xanthomatosis | Summary Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive genetic disorder caused by an abnormality in the CYP27A1 gene, resulting in a deficiency of the mitochondrial enzyme sterol 27-hydroxylase. The lack of this enzyme prevents cholesterol from being converted into a bile acid called chenodeoxycholic acid. Deposits of cholesterol and a related compound called cholestanol accumulate in the nerve cells and membranes potentially causing damage to the brain, spinal cord, tendons, lens of the eye and arteries. Affected individuals can experience diarrhea and cataracts in childhood and may develop benign, fatty tumors (xanthomas) of the tendons during adolescence. If untreated, CTX can lead to progressive neurologic problems such as seizures, cognitive impairment, and difficulties with coordination and balance (ataxia). Coronary heart disease is common. Some individuals with the later-onset symptoms of CTX experienced cholestatic jaundice during infancy. The specific symptoms and progression of this disorder can vary greatly from one individual to another, even for twins with the same abnormality in the CYP27A1 gene. Long-term therapy with chenodeoxycholic acid has been effective in treating affected individuals. IntroductionCTX was first described in the medical literature in 1937. CTX is classified as a bile acid synthesis disorder (due to the underlying genetic mutation that causes deficiency in an important enzyme in the bile acid synthesis pathway; sterol 27-hydroxylase). Bile acids (chenodeoxycholic and cholic acid) are mostly synthesized in the liver. They are an important component of bile and help the intestine to absorb fats. The disorder can also be classified as a lipid storage disorder (due to fat deposition in various tissues of the body) or a leukodystrophy (due to the involvement of central nervous system white matter). | Overview of Cerebrotendinous Xanthomatosis. Summary Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive genetic disorder caused by an abnormality in the CYP27A1 gene, resulting in a deficiency of the mitochondrial enzyme sterol 27-hydroxylase. The lack of this enzyme prevents cholesterol from being converted into a bile acid called chenodeoxycholic acid. Deposits of cholesterol and a related compound called cholestanol accumulate in the nerve cells and membranes potentially causing damage to the brain, spinal cord, tendons, lens of the eye and arteries. Affected individuals can experience diarrhea and cataracts in childhood and may develop benign, fatty tumors (xanthomas) of the tendons during adolescence. If untreated, CTX can lead to progressive neurologic problems such as seizures, cognitive impairment, and difficulties with coordination and balance (ataxia). Coronary heart disease is common. Some individuals with the later-onset symptoms of CTX experienced cholestatic jaundice during infancy. The specific symptoms and progression of this disorder can vary greatly from one individual to another, even for twins with the same abnormality in the CYP27A1 gene. Long-term therapy with chenodeoxycholic acid has been effective in treating affected individuals. IntroductionCTX was first described in the medical literature in 1937. CTX is classified as a bile acid synthesis disorder (due to the underlying genetic mutation that causes deficiency in an important enzyme in the bile acid synthesis pathway; sterol 27-hydroxylase). Bile acids (chenodeoxycholic and cholic acid) are mostly synthesized in the liver. They are an important component of bile and help the intestine to absorb fats. The disorder can also be classified as a lipid storage disorder (due to fat deposition in various tissues of the body) or a leukodystrophy (due to the involvement of central nervous system white matter). | 218 | Cerebrotendinous Xanthomatosis |
nord_218_1 | Symptoms of Cerebrotendinous Xanthomatosis | The presentation of CTX is highly variable and is associated with a wide range of potential abnormalities. Originally, the disorder was believed only to be a neurological disorder of abnormal fat (lipid) storage not associated with liver disease. It is now known that CTX can occasionally present in childhood with cholestatic liver disease that can be severe or can be mild and resolve on its own in individuals who may later develop other complications of the disorder such as neurological disease. Cholestatic liver disease refers to the interruption or suppression of the flow of bile from the liver (cholestasis). Features of cholestasis include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, and growth deficiency. Enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly) may also occur. Generally, systemic symptoms develop earlier than neurologic symptoms. The first symptom may be chronic diarrhea in infancy. Diarrhea is often resistant to treatment (intractable). Infantile spasms have also been reported as a possible symptom. Juvenile cataracts in the first decades of life are often an initial symptom of CTX. Tendinous xanthomas (fatty tumors) may appear in the second or third decade and can be located on the Achilles tendon, extensor tendons of the elbows and hands, and the knees. Most affected individuals experience a decline in mental function beginning at puberty, but some show impairment beginning in childhood. Cognitive impairment can be mild to severe. CTX is often diagnosed through neurological symptoms of the disease that will continue to get worse without treatment. Seizures and epilepsy have been reported as symptoms. Psychiatric abnormalities including behavioral changes, hallucinations, agitation, aggression, depression, and suicidal tendencies can also occur, although specific expression varies greatly. Increased muscle tone and stiffness (spasticity) can occur. In some patients, additional neurologic findings may occur including impaired coordination of voluntary movements due to underdevelopment (hypoplasia) of the brain’s cerebellum (cerebellar ataxia); symptoms that resemble Parkinson disease (atypical parkinsonism); and dystonia, which is a general term for a large group of movement disorders that vary in their symptoms, causes, progression, and treatments. Dystonia is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Cardiovascular disease has been reported in individuals with CTX, although the exact prevalence of this finding is unknown. Hardening of the arteries (atherosclerosis) and coronary heart disease may occur. Additional symptoms that have been reported include underactivity of the thyroid (hypothyroidism) and skeletal abnormalities such as porous, brittle bones (osteoporosis) and a higher incidence of bone fractures. | Symptoms of Cerebrotendinous Xanthomatosis. The presentation of CTX is highly variable and is associated with a wide range of potential abnormalities. Originally, the disorder was believed only to be a neurological disorder of abnormal fat (lipid) storage not associated with liver disease. It is now known that CTX can occasionally present in childhood with cholestatic liver disease that can be severe or can be mild and resolve on its own in individuals who may later develop other complications of the disorder such as neurological disease. Cholestatic liver disease refers to the interruption or suppression of the flow of bile from the liver (cholestasis). Features of cholestasis include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, and growth deficiency. Enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly) may also occur. Generally, systemic symptoms develop earlier than neurologic symptoms. The first symptom may be chronic diarrhea in infancy. Diarrhea is often resistant to treatment (intractable). Infantile spasms have also been reported as a possible symptom. Juvenile cataracts in the first decades of life are often an initial symptom of CTX. Tendinous xanthomas (fatty tumors) may appear in the second or third decade and can be located on the Achilles tendon, extensor tendons of the elbows and hands, and the knees. Most affected individuals experience a decline in mental function beginning at puberty, but some show impairment beginning in childhood. Cognitive impairment can be mild to severe. CTX is often diagnosed through neurological symptoms of the disease that will continue to get worse without treatment. Seizures and epilepsy have been reported as symptoms. Psychiatric abnormalities including behavioral changes, hallucinations, agitation, aggression, depression, and suicidal tendencies can also occur, although specific expression varies greatly. Increased muscle tone and stiffness (spasticity) can occur. In some patients, additional neurologic findings may occur including impaired coordination of voluntary movements due to underdevelopment (hypoplasia) of the brain’s cerebellum (cerebellar ataxia); symptoms that resemble Parkinson disease (atypical parkinsonism); and dystonia, which is a general term for a large group of movement disorders that vary in their symptoms, causes, progression, and treatments. Dystonia is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Cardiovascular disease has been reported in individuals with CTX, although the exact prevalence of this finding is unknown. Hardening of the arteries (atherosclerosis) and coronary heart disease may occur. Additional symptoms that have been reported include underactivity of the thyroid (hypothyroidism) and skeletal abnormalities such as porous, brittle bones (osteoporosis) and a higher incidence of bone fractures. | 218 | Cerebrotendinous Xanthomatosis |
nord_218_2 | Causes of Cerebrotendinous Xanthomatosis | CTX is caused by a disease-causing (pathogenic) variant in the CYP27A1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a pathogenic variant of a gene occurs, the protein product or enzyme may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. In CTX, the gene variant is inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Disease-causing variants in the CYP27A1 gene result in deficiency of the mitochondrial enzyme sterol 27-hydroxylase. The lack of this enzyme prevents cholesterol from being converted into the bile acid chenodeoxycholic acid. The block in synthesis of this bile acid causes accumulation of bile acid pathway intermediates and cholestanol in blood and tissues of affected individuals. Cholestanol deposits can accumulate in nerve cells and membranes and cause damage to the brain, spinal cord, tendons, lens of the eye and arteries. | Causes of Cerebrotendinous Xanthomatosis. CTX is caused by a disease-causing (pathogenic) variant in the CYP27A1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a pathogenic variant of a gene occurs, the protein product or enzyme may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. In CTX, the gene variant is inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Disease-causing variants in the CYP27A1 gene result in deficiency of the mitochondrial enzyme sterol 27-hydroxylase. The lack of this enzyme prevents cholesterol from being converted into the bile acid chenodeoxycholic acid. The block in synthesis of this bile acid causes accumulation of bile acid pathway intermediates and cholestanol in blood and tissues of affected individuals. Cholestanol deposits can accumulate in nerve cells and membranes and cause damage to the brain, spinal cord, tendons, lens of the eye and arteries. | 218 | Cerebrotendinous Xanthomatosis |
nord_218_3 | Affects of Cerebrotendinous Xanthomatosis | Recent estimates place CTX incidence ranging from 1:134,970 to 1:461,358 in Europeans, 1:263,222 to 1:468,624 in Africans, 1:71,677 to 1:148,914 in Americans, 1:64,267 to 1:64,712 in East Asians and 1:36,072 to 1:75,601 in South Asians.. Despite this, only around three hundred affected individual of CTX have been described worldwide. This suggests many cases may go undiagnosed or are misdiagnosed. Affected individuals have been reported in the USA, Israel, Italy, Japan, the Netherlands, Belgium, Brazil, Canada, France, Iran, Norway, Tunisia, Spain, China and Sweden. Populations with a higher prevalence of CTX exist, for example in an isolated Israeli Druze community a carrier frequency of 1:11 for the deleterious c.355delC variant was determined, leading to an estimated prevalence of CTX at 1:440 individuals. | Affects of Cerebrotendinous Xanthomatosis. Recent estimates place CTX incidence ranging from 1:134,970 to 1:461,358 in Europeans, 1:263,222 to 1:468,624 in Africans, 1:71,677 to 1:148,914 in Americans, 1:64,267 to 1:64,712 in East Asians and 1:36,072 to 1:75,601 in South Asians.. Despite this, only around three hundred affected individual of CTX have been described worldwide. This suggests many cases may go undiagnosed or are misdiagnosed. Affected individuals have been reported in the USA, Israel, Italy, Japan, the Netherlands, Belgium, Brazil, Canada, France, Iran, Norway, Tunisia, Spain, China and Sweden. Populations with a higher prevalence of CTX exist, for example in an isolated Israeli Druze community a carrier frequency of 1:11 for the deleterious c.355delC variant was determined, leading to an estimated prevalence of CTX at 1:440 individuals. | 218 | Cerebrotendinous Xanthomatosis |
nord_218_4 | Related disorders of Cerebrotendinous Xanthomatosis | Symptoms of the following disorders can be similar to those of CTX. Comparisons may be useful for a differential diagnosis. Sitosterolemia is a rare autosomal recessive genetic condition caused by an abnormality in the ABCG8 gene or the ABCG5 gene, resulting in an accumulation of cholesterol and other types of lipids called sterols in body tissues. Symptoms include clusters of fatty tumors in the skin of joints (tuberous xanthomas), on the tendons (tendon xanthomas), plaque deposits in the arteries (atherosclerosis), and coronary artery disease. Joint stiffness and pain can develop. In some cases affected individuals may have low levels of circulating red blood cells due to the premature destruction of red blood cells (hemolytic anemia). (For more information on this disorder, choose “sitosterolemia” as your search term in the Rare Disease Database.) Familial hypercholesterolemia (FH) is characterized by very high levels of total and low-density lipoprotein (LDL) cholesterol, often called the “bad” cholesterol. The levels of another blood lipid, triglycerides, are usually normal and the levels of high-density lipoprotein (HDL) cholesterol (the “good” cholesterol) are typically low or normal. The condition greatly increases the risk of atherosclerosis (hardening of the arteries), which causes heart attacks, strokes and other serious vascular conditions. Untreated men with FH often develop symptoms of coronary heart disease (CHD) in their early forties and women, in their early fifties. If one or more other major risk factors for CHD are present, especially cigarette smoking and diabetes mellitus, the risk of developing symptomatic CHD is greatly increased. Women without other major risk factors for CHD may survive to old age without developing symptomatic disease. Additional symptoms include the formation of fatty tumors of the tendons (tendinous xanthomas), cholesterol deposits on the eyelids (xanthelasmas), and a curved appearance of the corneas of the eyes (corneal arcus). (For more information on this disorder, choose “hypercholesterolemia” as your search term in the Rare Disease Database.) | Related disorders of Cerebrotendinous Xanthomatosis. Symptoms of the following disorders can be similar to those of CTX. Comparisons may be useful for a differential diagnosis. Sitosterolemia is a rare autosomal recessive genetic condition caused by an abnormality in the ABCG8 gene or the ABCG5 gene, resulting in an accumulation of cholesterol and other types of lipids called sterols in body tissues. Symptoms include clusters of fatty tumors in the skin of joints (tuberous xanthomas), on the tendons (tendon xanthomas), plaque deposits in the arteries (atherosclerosis), and coronary artery disease. Joint stiffness and pain can develop. In some cases affected individuals may have low levels of circulating red blood cells due to the premature destruction of red blood cells (hemolytic anemia). (For more information on this disorder, choose “sitosterolemia” as your search term in the Rare Disease Database.) Familial hypercholesterolemia (FH) is characterized by very high levels of total and low-density lipoprotein (LDL) cholesterol, often called the “bad” cholesterol. The levels of another blood lipid, triglycerides, are usually normal and the levels of high-density lipoprotein (HDL) cholesterol (the “good” cholesterol) are typically low or normal. The condition greatly increases the risk of atherosclerosis (hardening of the arteries), which causes heart attacks, strokes and other serious vascular conditions. Untreated men with FH often develop symptoms of coronary heart disease (CHD) in their early forties and women, in their early fifties. If one or more other major risk factors for CHD are present, especially cigarette smoking and diabetes mellitus, the risk of developing symptomatic CHD is greatly increased. Women without other major risk factors for CHD may survive to old age without developing symptomatic disease. Additional symptoms include the formation of fatty tumors of the tendons (tendinous xanthomas), cholesterol deposits on the eyelids (xanthelasmas), and a curved appearance of the corneas of the eyes (corneal arcus). (For more information on this disorder, choose “hypercholesterolemia” as your search term in the Rare Disease Database.) | 218 | Cerebrotendinous Xanthomatosis |
nord_218_5 | Diagnosis of Cerebrotendinous Xanthomatosis | CTX is diagnosed based on a thorough clinical evaluation, a detailed patient and family history, identification of characteristic clinical findings, and specialized tests including genetic testing and biochemical tests on blood and urine. Genetic testing can confirm a diagnosis of CTX by detecting disease-causing (pathogenic) variants in the CYP27A1 gene known to cause the disorder. This type of testing can confirm the presence of gene variants that have already been described in the literature to cause CTX. Sometimes novel (unknown) variants are uncovered by genetic testing and in these cases biochemical testing is helpful to confirm the biochemical defect is present. Certain specialized laboratories can conduct analysis to detect biochemical features that are indicative of CTX. Due to the nature of the biochemical defect, the cholestanol concentration in plasma or serum (derived from blood) is high, while the plasma cholesterol concentration is normal to low. In addition, the concentration of bile acid pathway intermediates is elevated, and the concentration of bile alcohols in plasma, bile and urine is increased. Bile alcohols are formed in an alternative pathway present in CTX that generates some cholic acid. Due to the nature of the biochemical defect in CTX there is little or no formation of chenodeoxycholic acid. CTX has been nominated as a candidate disorder to add the recommended uniform screening panel of disorders (the RUSP) to screen for in newborns. Researchers have developed testing for CTX to identify dried bloodspots from newborns with the disorder and large prospective pilot studies are underway to confirm that the testing is able to identify newborns with CTX. In some cases, specialized imaging techniques may include computerized tomography (CT) scanning of the head and magnetic resonance imaging (MRI) of the brain may assist in assessing disease progression in individuals suspected of CTX. 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. These tests may show cerebellar lesions and white matter damage in individuals with CTX. | Diagnosis of Cerebrotendinous Xanthomatosis. CTX is diagnosed based on a thorough clinical evaluation, a detailed patient and family history, identification of characteristic clinical findings, and specialized tests including genetic testing and biochemical tests on blood and urine. Genetic testing can confirm a diagnosis of CTX by detecting disease-causing (pathogenic) variants in the CYP27A1 gene known to cause the disorder. This type of testing can confirm the presence of gene variants that have already been described in the literature to cause CTX. Sometimes novel (unknown) variants are uncovered by genetic testing and in these cases biochemical testing is helpful to confirm the biochemical defect is present. Certain specialized laboratories can conduct analysis to detect biochemical features that are indicative of CTX. Due to the nature of the biochemical defect, the cholestanol concentration in plasma or serum (derived from blood) is high, while the plasma cholesterol concentration is normal to low. In addition, the concentration of bile acid pathway intermediates is elevated, and the concentration of bile alcohols in plasma, bile and urine is increased. Bile alcohols are formed in an alternative pathway present in CTX that generates some cholic acid. Due to the nature of the biochemical defect in CTX there is little or no formation of chenodeoxycholic acid. CTX has been nominated as a candidate disorder to add the recommended uniform screening panel of disorders (the RUSP) to screen for in newborns. Researchers have developed testing for CTX to identify dried bloodspots from newborns with the disorder and large prospective pilot studies are underway to confirm that the testing is able to identify newborns with CTX. In some cases, specialized imaging techniques may include computerized tomography (CT) scanning of the head and magnetic resonance imaging (MRI) of the brain may assist in assessing disease progression in individuals suspected of CTX. 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. These tests may show cerebellar lesions and white matter damage in individuals with CTX. | 218 | Cerebrotendinous Xanthomatosis |
nord_218_6 | Therapies of Cerebrotendinous Xanthomatosis | Treatment
Because oral bile acid replacement therapy can halt disease progression or prevent symptoms from occurring in asymptomatic individuals, early diagnosis and treatment of CTX is extremely important to prevent disease complications. Researchers have recently shown that CTX patients who started treatment later (after the age of 25 years) had a worse outcome and were significantly more limited in ambulation and more cognitively impaired than those that started treatment earlier (before the age of 25 years). Successful long-term treatment of a number of affected individuals who were asymptomatic in childhood has been reported in the literature. Treatment with chenodeoxycholic acid normalizes the production of cholestanol. The efficacy of treatment with chenodeoxycholic acid can be monitored using biochemical testing to confirm a decrease in blood cholestanol. Treatment can prevent symptoms in asymptomatic individuals and stop the progression of disease symptoms in affected individuals. After significant disease progression, treatment does not readily reverse the neurological deficits that have already occurred. It may be effective to give a drug that inhibits HMG-CoA reductase (an enzyme that plays a role in the creation of cholesterol in the liver) in conjunction with chenodeoxycholic acid. There are concerns that treatment with HMG-CoA reductase inhibitors (better known as statins) could boost the activity of receptors for low-density lipoprotein (LDL) cholesterol, thereby increasing cholesterol uptake and potentially worsening CTX. HMG-CoA reductase inhibitors can also cause muscle damage. In 2009, the U.S. Food and Drug Administration (FDA) re-approved an artificially made (synthetic) form of chenodeoxycholic acid known as Chenodal as a treatment for gallstones. This drug is also used as a first-line therapy to treat individuals with CTX. Chenodal received an orphan drug designation from the FDA for the treatment of CTX in the U.S. Cholic acid, another bile acid, has also been used to treat young children with CTX. Although chenodeoxycholic acid is considered as a first-line therapy to treat CTX, cholic acid lacks the potential toxic effects on the liver (hepatotoxicity) sometimes associated with chenodeoxycholic acid. Additional treatment is symptomatic and supportive. For example, cataract surgery may be necessary before 50 years of age. Genetic counseling is recommended for affected families and individuals | Therapies of Cerebrotendinous Xanthomatosis. Treatment
Because oral bile acid replacement therapy can halt disease progression or prevent symptoms from occurring in asymptomatic individuals, early diagnosis and treatment of CTX is extremely important to prevent disease complications. Researchers have recently shown that CTX patients who started treatment later (after the age of 25 years) had a worse outcome and were significantly more limited in ambulation and more cognitively impaired than those that started treatment earlier (before the age of 25 years). Successful long-term treatment of a number of affected individuals who were asymptomatic in childhood has been reported in the literature. Treatment with chenodeoxycholic acid normalizes the production of cholestanol. The efficacy of treatment with chenodeoxycholic acid can be monitored using biochemical testing to confirm a decrease in blood cholestanol. Treatment can prevent symptoms in asymptomatic individuals and stop the progression of disease symptoms in affected individuals. After significant disease progression, treatment does not readily reverse the neurological deficits that have already occurred. It may be effective to give a drug that inhibits HMG-CoA reductase (an enzyme that plays a role in the creation of cholesterol in the liver) in conjunction with chenodeoxycholic acid. There are concerns that treatment with HMG-CoA reductase inhibitors (better known as statins) could boost the activity of receptors for low-density lipoprotein (LDL) cholesterol, thereby increasing cholesterol uptake and potentially worsening CTX. HMG-CoA reductase inhibitors can also cause muscle damage. In 2009, the U.S. Food and Drug Administration (FDA) re-approved an artificially made (synthetic) form of chenodeoxycholic acid known as Chenodal as a treatment for gallstones. This drug is also used as a first-line therapy to treat individuals with CTX. Chenodal received an orphan drug designation from the FDA for the treatment of CTX in the U.S. Cholic acid, another bile acid, has also been used to treat young children with CTX. Although chenodeoxycholic acid is considered as a first-line therapy to treat CTX, cholic acid lacks the potential toxic effects on the liver (hepatotoxicity) sometimes associated with chenodeoxycholic acid. Additional treatment is symptomatic and supportive. For example, cataract surgery may be necessary before 50 years of age. Genetic counseling is recommended for affected families and individuals | 218 | Cerebrotendinous Xanthomatosis |
nord_219_0 | Overview of Cervical Dystonia | Cervical dystonia, also known as spasmodic torticollis, is a rare neurological disorder that originates in the brain. It is the most common form of focal dystonia in an office setting. Cervical dystonia is characterized by involuntary muscle contractions in the neck that cause abnormal movements and postures of the neck and head. In some cases, these abnormal contractions may be sustained or continuous; in others, they may be present as spasms that can resemble tremor. The severity of cervical dystonia can vary, but the disorder can cause significant pain and discomfort as well as difficulty due to the abnormal postures. It can affect quality of life and activities of daily living including employment. Cervical dystonia typically begins in middle age, and rarely begins in adolescence and young adulthood. The cause of cervical dystonia is unknown, although a genetic susceptibility is thought to underlie some cases. If cervical dystonia begins in infancy or early childhood, secondary causes should be investigated. | Overview of Cervical Dystonia. Cervical dystonia, also known as spasmodic torticollis, is a rare neurological disorder that originates in the brain. It is the most common form of focal dystonia in an office setting. Cervical dystonia is characterized by involuntary muscle contractions in the neck that cause abnormal movements and postures of the neck and head. In some cases, these abnormal contractions may be sustained or continuous; in others, they may be present as spasms that can resemble tremor. The severity of cervical dystonia can vary, but the disorder can cause significant pain and discomfort as well as difficulty due to the abnormal postures. It can affect quality of life and activities of daily living including employment. Cervical dystonia typically begins in middle age, and rarely begins in adolescence and young adulthood. The cause of cervical dystonia is unknown, although a genetic susceptibility is thought to underlie some cases. If cervical dystonia begins in infancy or early childhood, secondary causes should be investigated. | 219 | Cervical Dystonia |
nord_219_1 | Symptoms of Cervical Dystonia | The symptoms of cervical dystonia may begin slowly and can involve any of the muscles of the neck. The head posture in cervical dystonia can vary. The most common abnormal posture associated with cervical dystonia is the twisting of the chin toward a shoulder so that the head rotates sideways (torticollis). Other abnormal postures associated with cervical dystonia including anterocollis, in which the head tips forward; retrocollis, in which the head is tilted backward; or laterocollis, in which the head tilts toward one side. There can also be shifting of the head on the shoulders in a forward (anterior sagittal shift) or backward (posterior sagittal shift) direction. Often cervical dystonia is complex and combines several angles of head movement. In some people with isolated CD, there may also be a postural tremor of the hands. Symptoms of cervical dystonia vary over the course of the disorder. Studies of the natural history of CD are needed to better understand the natural history of this disorder. Symptoms may temporarily worsen with stress or excitement. The dystonia can be activated by certain postures or positions. This varies in individual patients. Symptoms may improve with the performance of sensory tricks, such as touching the cheek or the back of the head. A small percentage of individuals experience a spontaneous recovery (remission) after symptom onset. This remission is often temporary, lasting days to years, with recurrence of symptoms. It is likely that less than 1 percent of affected individuals have permanent remissions.There can be secondary problems arising from cervical dystonia that include cervical spine arthritis, compression of nerve roots, and sometimes narrowing of the spinal cord in the neck (cervical stenosis). Pain related directly to cervical dystonia typically is on the same side as the head turn and is felt as muscular pain in the area of the overactive muscles. Pain can potentially become severe and disabling. | Symptoms of Cervical Dystonia. The symptoms of cervical dystonia may begin slowly and can involve any of the muscles of the neck. The head posture in cervical dystonia can vary. The most common abnormal posture associated with cervical dystonia is the twisting of the chin toward a shoulder so that the head rotates sideways (torticollis). Other abnormal postures associated with cervical dystonia including anterocollis, in which the head tips forward; retrocollis, in which the head is tilted backward; or laterocollis, in which the head tilts toward one side. There can also be shifting of the head on the shoulders in a forward (anterior sagittal shift) or backward (posterior sagittal shift) direction. Often cervical dystonia is complex and combines several angles of head movement. In some people with isolated CD, there may also be a postural tremor of the hands. Symptoms of cervical dystonia vary over the course of the disorder. Studies of the natural history of CD are needed to better understand the natural history of this disorder. Symptoms may temporarily worsen with stress or excitement. The dystonia can be activated by certain postures or positions. This varies in individual patients. Symptoms may improve with the performance of sensory tricks, such as touching the cheek or the back of the head. A small percentage of individuals experience a spontaneous recovery (remission) after symptom onset. This remission is often temporary, lasting days to years, with recurrence of symptoms. It is likely that less than 1 percent of affected individuals have permanent remissions.There can be secondary problems arising from cervical dystonia that include cervical spine arthritis, compression of nerve roots, and sometimes narrowing of the spinal cord in the neck (cervical stenosis). Pain related directly to cervical dystonia typically is on the same side as the head turn and is felt as muscular pain in the area of the overactive muscles. Pain can potentially become severe and disabling. | 219 | Cervical Dystonia |
nord_219_2 | Causes of Cervical Dystonia | Cervical dystonia is classified as an isolated dystonia if there are no other associated abnormal findings, such as spasticity, Parkinsonism or ataxia. Most isolated cervical dystonia had no identifiable underlying causes. However, in some cases, cervical dystonia can arise from another underlying cause and be considered secondary (occurring as consequence of another disorder or condition). In most cases, isolated cervical dystonia is idiopathic although a genetic susceptibility may be present as evidenced by a positive family history in approximately 10-25% of cases. Cervical dystonia is associated with changes (mutations) in several genes (GNAL, THAP1, CIZ1, ANO3 genes) and several possible environmental factors. However, at this time there is no gene test that is recommended for clinical purposes in people with cervical dystonia. Some cases of cervical dystonia may have an identifiable cause (secondary cervical dystonia). In these cases, cervical dystonia may develop due to the use of certain drugs such as anti-psychotics or certain nausea medications with dopamine receptor blocking activity. In most secondary cases, such as those due to toxins or degenerative brain diseases, there are additional signs and symptoms other than cervical dystonia. Whether trauma to the neck could cause cervical dystonia remains controversial. Cervical dystonia is a neurological disorder. However, there are some non-neurological conditions that may mimic cervical dystonia. In children with slippage of the vertebrae in the neck (atlanto-axial subluxation), there may be a twisting of the head that is very painful and requires specialized orthopedic treatments. Some infants are born with a shortening of one of the muscles in the neck (congenital infantile torticollis) that causes a head turn. In some children with esophageal reflux, there can also be posturing of the head. There are additional conditions, including functional movement disorders that may appear similar to cervical dystonia but are non-neurologic in origin. | Causes of Cervical Dystonia. Cervical dystonia is classified as an isolated dystonia if there are no other associated abnormal findings, such as spasticity, Parkinsonism or ataxia. Most isolated cervical dystonia had no identifiable underlying causes. However, in some cases, cervical dystonia can arise from another underlying cause and be considered secondary (occurring as consequence of another disorder or condition). In most cases, isolated cervical dystonia is idiopathic although a genetic susceptibility may be present as evidenced by a positive family history in approximately 10-25% of cases. Cervical dystonia is associated with changes (mutations) in several genes (GNAL, THAP1, CIZ1, ANO3 genes) and several possible environmental factors. However, at this time there is no gene test that is recommended for clinical purposes in people with cervical dystonia. Some cases of cervical dystonia may have an identifiable cause (secondary cervical dystonia). In these cases, cervical dystonia may develop due to the use of certain drugs such as anti-psychotics or certain nausea medications with dopamine receptor blocking activity. In most secondary cases, such as those due to toxins or degenerative brain diseases, there are additional signs and symptoms other than cervical dystonia. Whether trauma to the neck could cause cervical dystonia remains controversial. Cervical dystonia is a neurological disorder. However, there are some non-neurological conditions that may mimic cervical dystonia. In children with slippage of the vertebrae in the neck (atlanto-axial subluxation), there may be a twisting of the head that is very painful and requires specialized orthopedic treatments. Some infants are born with a shortening of one of the muscles in the neck (congenital infantile torticollis) that causes a head turn. In some children with esophageal reflux, there can also be posturing of the head. There are additional conditions, including functional movement disorders that may appear similar to cervical dystonia but are non-neurologic in origin. | 219 | Cervical Dystonia |
nord_219_3 | Affects of Cervical Dystonia | Cervical dystonia affects women approximately twice as often as men. It is the most common form of focal dystonia in an office setting. Cervical dystonia may affect individuals of any age, but typically develops in people between 40 and 60 years of age. Cervical dystonia affects people of all ethnic backgrounds. The exact incidence or prevalence of cervical dystonia in the general population is unknown but is estimated to be about 60,000 people in the United States. | Affects of Cervical Dystonia. Cervical dystonia affects women approximately twice as often as men. It is the most common form of focal dystonia in an office setting. Cervical dystonia may affect individuals of any age, but typically develops in people between 40 and 60 years of age. Cervical dystonia affects people of all ethnic backgrounds. The exact incidence or prevalence of cervical dystonia in the general population is unknown but is estimated to be about 60,000 people in the United States. | 219 | Cervical Dystonia |
nord_219_4 | Related disorders of Cervical Dystonia | Related disorders of Cervical Dystonia. | 219 | Cervical Dystonia |
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nord_219_5 | Diagnosis of Cervical Dystonia | A diagnosis of cervical dystonia is based upon clinical examination, a detailed patient history, and knowledge of the disorder. No specific laboratory or imaging test confirms a diagnosis of cervical dystonia. There are no abnormalities in laboratory or imaging tests. Magnetic resonance imaging (MRI) of the brain is normal, and MRI of the neck does not help with the diagnosis unless compression of the spinal cord is suspected. Electromyography is not indicated unless there are additional signs of nerve irritation. | Diagnosis of Cervical Dystonia. A diagnosis of cervical dystonia is based upon clinical examination, a detailed patient history, and knowledge of the disorder. No specific laboratory or imaging test confirms a diagnosis of cervical dystonia. There are no abnormalities in laboratory or imaging tests. Magnetic resonance imaging (MRI) of the brain is normal, and MRI of the neck does not help with the diagnosis unless compression of the spinal cord is suspected. Electromyography is not indicated unless there are additional signs of nerve irritation. | 219 | Cervical Dystonia |
nord_219_6 | Therapies of Cervical Dystonia | Treatment
Not every treatment option for cervical dystonia is successful for all affected individuals. Therefore, no single strategy is appropriate for every case. Most therapies are symptomatic and are intended to relieve spasms, pain and disturbed postures or functions. Identifying the treatment regimen that is most effective in individual cases may require patience and perseverance on the part of the patient and physician.There are essentially three treatment options: botulinum toxin injections, oral medications, and, in some cases, surgery. These treatments may be used alone or in combination. In addition, physical therapy may provide a helpful complement to medical treatment. In some cases, if there is a trick such as touching the chin, a soft cervical collar may be beneficial.Botulinum toxin injections are the treatment of choice for focal dystonia, which is the neck and head in cervical dystonia. Botulinum toxin is a neurotoxin that is injected into the dystonic neck muscles in small doses. Botulinum toxin works by preventing the nerve from releasing a messenger, called acetylcholine, that tells the muscle to contract. This causes weakness of the muscle. The effect of botulinum toxin on the muscle begins approximately 2-3 days following injection, peaks at around 4 weeks, and provides relief for approximately 2-6 months. Botulinum toxin treatment is not a cure, but rather a symptom treatment. When the effect of botulinum toxin wears off, the symptoms of cervical dystonia recur and another injection is needed to sustain benefit. In order for botulinum toxin injections to be successful, it is critical that the injecting physician be well-versed in cervical dystonia, the functional anatomy of the neck muscles, and the type and doses of botulinum toxin to use.There are now four brands of Botulinum toxin that have been approved by the Food and Drug Administration (FDA) for the treatment of individuals with cervical dystonia. There are three brands of botulinum toxin serotype A, including onabotulinumtoxinA (BOTOX, Allergan Inc.) abobotulinumtoxinA (Dysport, Tercica Inc) and incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals). There is one formulation of botulinum toxin type B called rimabotulinumtoxinB (Myobloc, Solstice, US World Meds). These brands are not interchangeable, and each should be administered as a unique drug. At this time, there is no clinical data that supports the use of one over the other. The most frequent side effects from the injection are swallowing difficulties, pain and sometimes neck weakness. These side effects are usually mild and transient, lasting a few weeks. The FDA has a “black box” warning concerning the use of any of these toxins that indicates that the toxin can spread from the injection site. However, with the doses used for cervical dystonia the clinical effects of spread of toxin are uncommon if administered by an experienced physician.Currently, there are no oral medications that are FDA approved for use in dystonia. Among the oral medications used, dopaminergic agents (levodopa), anticholinergic agents (benztropine, trihexyphenidyl), baclofen and clonazepam are the most frequently used. These drugs are usually most effective in children with generalized dystonia. In adults, the side effects of these agents, including memory problems and sedation, often occur before an effective dose can be reached. Surgical treatments for cervical dystonia are of two types. One is selective peripheral denervation in which the nerves to the dystonic muscles are cut. Although this has been reported to be effective, this approach is limited by the ability to access the nerve involved, the need for considerable expertise of the surgeon, and the potential for side effects. Side effects from the surgery are not uncommon and following surgery, there is a long period of rehabilitation.Deep brain stimulation surgery (DBS) is effective for cervical dystonia and may be appropriate for patients who lose their response to botulinum toxin, or have a form of cervical dystonia that is difficult to treat with the injections, in particular anterocollis. DBS involves the placement of electrodes (thin wires) into the area of the brain called the globus pallidus on both sides. The electrodes are connected to stimulators which send small electrical pulses to the brain. Although the precise mechanism is not clear, the electrical impulses seem to “reset” the brain and improve the dystonic movements. After the DBS is placed, the stimulators are programmed for the optimal outcome.Recently clinical studies have focused on new oral therapies, newer formulations of botulinum toxin and optimization of DBS methodology. | Therapies of Cervical Dystonia. Treatment
Not every treatment option for cervical dystonia is successful for all affected individuals. Therefore, no single strategy is appropriate for every case. Most therapies are symptomatic and are intended to relieve spasms, pain and disturbed postures or functions. Identifying the treatment regimen that is most effective in individual cases may require patience and perseverance on the part of the patient and physician.There are essentially three treatment options: botulinum toxin injections, oral medications, and, in some cases, surgery. These treatments may be used alone or in combination. In addition, physical therapy may provide a helpful complement to medical treatment. In some cases, if there is a trick such as touching the chin, a soft cervical collar may be beneficial.Botulinum toxin injections are the treatment of choice for focal dystonia, which is the neck and head in cervical dystonia. Botulinum toxin is a neurotoxin that is injected into the dystonic neck muscles in small doses. Botulinum toxin works by preventing the nerve from releasing a messenger, called acetylcholine, that tells the muscle to contract. This causes weakness of the muscle. The effect of botulinum toxin on the muscle begins approximately 2-3 days following injection, peaks at around 4 weeks, and provides relief for approximately 2-6 months. Botulinum toxin treatment is not a cure, but rather a symptom treatment. When the effect of botulinum toxin wears off, the symptoms of cervical dystonia recur and another injection is needed to sustain benefit. In order for botulinum toxin injections to be successful, it is critical that the injecting physician be well-versed in cervical dystonia, the functional anatomy of the neck muscles, and the type and doses of botulinum toxin to use.There are now four brands of Botulinum toxin that have been approved by the Food and Drug Administration (FDA) for the treatment of individuals with cervical dystonia. There are three brands of botulinum toxin serotype A, including onabotulinumtoxinA (BOTOX, Allergan Inc.) abobotulinumtoxinA (Dysport, Tercica Inc) and incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals). There is one formulation of botulinum toxin type B called rimabotulinumtoxinB (Myobloc, Solstice, US World Meds). These brands are not interchangeable, and each should be administered as a unique drug. At this time, there is no clinical data that supports the use of one over the other. The most frequent side effects from the injection are swallowing difficulties, pain and sometimes neck weakness. These side effects are usually mild and transient, lasting a few weeks. The FDA has a “black box” warning concerning the use of any of these toxins that indicates that the toxin can spread from the injection site. However, with the doses used for cervical dystonia the clinical effects of spread of toxin are uncommon if administered by an experienced physician.Currently, there are no oral medications that are FDA approved for use in dystonia. Among the oral medications used, dopaminergic agents (levodopa), anticholinergic agents (benztropine, trihexyphenidyl), baclofen and clonazepam are the most frequently used. These drugs are usually most effective in children with generalized dystonia. In adults, the side effects of these agents, including memory problems and sedation, often occur before an effective dose can be reached. Surgical treatments for cervical dystonia are of two types. One is selective peripheral denervation in which the nerves to the dystonic muscles are cut. Although this has been reported to be effective, this approach is limited by the ability to access the nerve involved, the need for considerable expertise of the surgeon, and the potential for side effects. Side effects from the surgery are not uncommon and following surgery, there is a long period of rehabilitation.Deep brain stimulation surgery (DBS) is effective for cervical dystonia and may be appropriate for patients who lose their response to botulinum toxin, or have a form of cervical dystonia that is difficult to treat with the injections, in particular anterocollis. DBS involves the placement of electrodes (thin wires) into the area of the brain called the globus pallidus on both sides. The electrodes are connected to stimulators which send small electrical pulses to the brain. Although the precise mechanism is not clear, the electrical impulses seem to “reset” the brain and improve the dystonic movements. After the DBS is placed, the stimulators are programmed for the optimal outcome.Recently clinical studies have focused on new oral therapies, newer formulations of botulinum toxin and optimization of DBS methodology. | 219 | Cervical Dystonia |
nord_220_0 | Overview of Cervical Teratoma | Cervical teratomas are extremely rare germ cell tumors (neoplasm) that occur in the neck. The majority of teratomas occur in the testes or ovaries (gonads) or the lower back (sacrococcygeal region). In rare cases, other areas such as the neck may be affected. Most cervical tumors occur in children and are non-cancerous (benign). In extremely rare cases, cervical teratomas occur in adults and are usually cancerous (malignant).The term “cancer” refers to a group of diseases characterized by abnormal, uncontrolled cellular growth that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer are be classified based upon the cell type involved, the specific nature of the malignancy, and the disease's clinical course.Teratomas are germ cell tumors that, in rare cases, occur in the head and neck region. Some researchers differentiate between cervical and primary thyroid teratomas. For a diagnosis of primary thyroid teratoma one of three conditions must be met: a tumor must occupy a portion of the thyroid gland, a direct connection must exist between the tumor and the thyroid, or a teratoma is accompanied by the absence of the thyroid. However, most cervical teratomas have some type of relationship with the thyroid and the clinical picture and prognosis between these tumors is the same. Therefore, many researchers have abandoned separating these tumors and classify all neck teratomas as cervical teratomas. | Overview of Cervical Teratoma. Cervical teratomas are extremely rare germ cell tumors (neoplasm) that occur in the neck. The majority of teratomas occur in the testes or ovaries (gonads) or the lower back (sacrococcygeal region). In rare cases, other areas such as the neck may be affected. Most cervical tumors occur in children and are non-cancerous (benign). In extremely rare cases, cervical teratomas occur in adults and are usually cancerous (malignant).The term “cancer” refers to a group of diseases characterized by abnormal, uncontrolled cellular growth that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer are be classified based upon the cell type involved, the specific nature of the malignancy, and the disease's clinical course.Teratomas are germ cell tumors that, in rare cases, occur in the head and neck region. Some researchers differentiate between cervical and primary thyroid teratomas. For a diagnosis of primary thyroid teratoma one of three conditions must be met: a tumor must occupy a portion of the thyroid gland, a direct connection must exist between the tumor and the thyroid, or a teratoma is accompanied by the absence of the thyroid. However, most cervical teratomas have some type of relationship with the thyroid and the clinical picture and prognosis between these tumors is the same. Therefore, many researchers have abandoned separating these tumors and classify all neck teratomas as cervical teratomas. | 220 | Cervical Teratoma |
nord_220_1 | Symptoms of Cervical Teratoma | Symptoms of cervical teratomas may vary from case to case. The tumors may be non-cancerous (benign) or cancerous (malignant). Cervical teratomas are more common in children than adults. In children they are usually benign; in adults they are usually malignant. The specific symptoms associated with cervical teratomas in children vary depending upon the size of the tumor. Small tumors may not cause any symptoms (asymptomatic). However, a large teratoma may cause disfigurement and compress nearby structures such as the windpipe (trachea). Such large tumors may cause additional symptoms including a wheezing or whistling sound when breathing (stridor), difficulty breathing, or shortness of breath (dyspnea). These tumors can also compress the esophagus, inhibiting swallowing. Eventually, compression of vital structures may cause life-threatening complications such as respiratory distress. Cervical teratomas in adults are extremely rare. In most cases, they are malignant and may spread (metastasize) to nearby lymph nodes and other organs of the body, especially the lungs. As in children, cervical teratomas in adults can compress nearby structures such as the windpipe resulting in respiratory distress and additional symptoms. | Symptoms of Cervical Teratoma. Symptoms of cervical teratomas may vary from case to case. The tumors may be non-cancerous (benign) or cancerous (malignant). Cervical teratomas are more common in children than adults. In children they are usually benign; in adults they are usually malignant. The specific symptoms associated with cervical teratomas in children vary depending upon the size of the tumor. Small tumors may not cause any symptoms (asymptomatic). However, a large teratoma may cause disfigurement and compress nearby structures such as the windpipe (trachea). Such large tumors may cause additional symptoms including a wheezing or whistling sound when breathing (stridor), difficulty breathing, or shortness of breath (dyspnea). These tumors can also compress the esophagus, inhibiting swallowing. Eventually, compression of vital structures may cause life-threatening complications such as respiratory distress. Cervical teratomas in adults are extremely rare. In most cases, they are malignant and may spread (metastasize) to nearby lymph nodes and other organs of the body, especially the lungs. As in children, cervical teratomas in adults can compress nearby structures such as the windpipe resulting in respiratory distress and additional symptoms. | 220 | Cervical Teratoma |
nord_220_2 | Causes of Cervical Teratoma | The exact cause of cervical teratomas is unknown. These tumors appear to occur randomly for no apparent reason (sporadic). Investigators are conducting ongoing basic research to learn more about the many factors that may result in tumor formation. Cervical 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 (sacrococcygeal region). When these tumors occur outside of the gonads, they are known as extragonadal tumors. Teratomas consist of cells foreign to the part of the body where the teratoma forms. They consist of cells from 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. Researchers do not know how extragonadal germ cell tumors form. Several theories have been proposed. One theory suggests that germ cells accidentally migrate 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. | Causes of Cervical Teratoma. The exact cause of cervical teratomas is unknown. These tumors appear to occur randomly for no apparent reason (sporadic). Investigators are conducting ongoing basic research to learn more about the many factors that may result in tumor formation. Cervical 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 (sacrococcygeal region). When these tumors occur outside of the gonads, they are known as extragonadal tumors. Teratomas consist of cells foreign to the part of the body where the teratoma forms. They consist of cells from 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. Researchers do not know how extragonadal germ cell tumors form. Several theories have been proposed. One theory suggests that germ cells accidentally migrate 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. | 220 | Cervical Teratoma |
nord_220_3 | Affects of Cervical Teratoma | Cervical teratomas affect men and women in equal numbers. Germ cell tumors account for 3-5 percent of all tumors in childhood. Cervical teratomas are much more common in newborns than adults. Fewer than 50 cases of cervical teratomas in adults have been reported in the medical literature. | Affects of Cervical Teratoma. Cervical teratomas affect men and women in equal numbers. Germ cell tumors account for 3-5 percent of all tumors in childhood. Cervical teratomas are much more common in newborns than adults. Fewer than 50 cases of cervical teratomas in adults have been reported in the medical literature. | 220 | Cervical Teratoma |
nord_220_4 | Related disorders of Cervical Teratoma | Symptoms of the following disorders can be similar to those of cervical teratomas. Comparisons may be useful for a differential diagnosis.Lymphatic malformations are rare non-malignant masses consisting of fluid-filled channels or spaces thought to be caused by the abnormal development of the lymphatic system. These malformations are usually apparent at birth or by two years of age. Lymphatic malformations can affect any area of the body (except the brain), but most commonly affect the head and neck. When evident at birth (congenital), lymphatic malformations tend to be soft, spongy, non-tender masses. The specific symptoms and severity of lymphatic malformations varies based upon the size and specific location of the malformation. Some lymphatic malformations can be massive. Lymphatic malformations regardless of size can potentially cause functional impairment of nearby structures or organs and disfigurement of affected areas. (For more information on this disorder, choose “lymphatic malformations” as your search term in the Rare Disease Database.)Thyroid cancer (carcinoma) is cancer affecting the thyroid gland, a butterfly-shaped structure located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body's activities as well as regulating the heart rate, body temperature, and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body. In many cases, there are no symptoms (asymptomatic) associated with thyroid cancer. Pain in the neck, hoarseness and swollen lymph nodes especially in the neck may be present in some cases. The four main types of thyroid cancer are papillary, follicular, medullary and anaplastic. Although thyroid cancer is a rare, it is most common form of cancer affecting the endocrine system. Most forms rarely cause pain or disability and are easily treated with surgery and follow up therapy. (For more information on this disorder, choose “thyroid cancer” as your search term in the Rare Disease Database.)Hemangioma is a benign tumor consisting of a cluster of small widened (dilated) blood vessels. Most hemangiomas occur in the head and neck region and are often present at birth (congenital). Hemangiomas may grow rapidly, but eventually decrease in size without treatment (spontaneously) – a process called involution. Hemagniomas may leave a birthmark or discolored skin in the affected area. Hemangiomas may ulcerate, resulting in a sore. Large hemangiomas can cause airway obstruction. The exact cause of hemangiomas is unknown. | Related disorders of Cervical Teratoma. Symptoms of the following disorders can be similar to those of cervical teratomas. Comparisons may be useful for a differential diagnosis.Lymphatic malformations are rare non-malignant masses consisting of fluid-filled channels or spaces thought to be caused by the abnormal development of the lymphatic system. These malformations are usually apparent at birth or by two years of age. Lymphatic malformations can affect any area of the body (except the brain), but most commonly affect the head and neck. When evident at birth (congenital), lymphatic malformations tend to be soft, spongy, non-tender masses. The specific symptoms and severity of lymphatic malformations varies based upon the size and specific location of the malformation. Some lymphatic malformations can be massive. Lymphatic malformations regardless of size can potentially cause functional impairment of nearby structures or organs and disfigurement of affected areas. (For more information on this disorder, choose “lymphatic malformations” as your search term in the Rare Disease Database.)Thyroid cancer (carcinoma) is cancer affecting the thyroid gland, a butterfly-shaped structure located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body's activities as well as regulating the heart rate, body temperature, and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body. In many cases, there are no symptoms (asymptomatic) associated with thyroid cancer. Pain in the neck, hoarseness and swollen lymph nodes especially in the neck may be present in some cases. The four main types of thyroid cancer are papillary, follicular, medullary and anaplastic. Although thyroid cancer is a rare, it is most common form of cancer affecting the endocrine system. Most forms rarely cause pain or disability and are easily treated with surgery and follow up therapy. (For more information on this disorder, choose “thyroid cancer” as your search term in the Rare Disease Database.)Hemangioma is a benign tumor consisting of a cluster of small widened (dilated) blood vessels. Most hemangiomas occur in the head and neck region and are often present at birth (congenital). Hemangiomas may grow rapidly, but eventually decrease in size without treatment (spontaneously) – a process called involution. Hemagniomas may leave a birthmark or discolored skin in the affected area. Hemangiomas may ulcerate, resulting in a sore. Large hemangiomas can cause airway obstruction. The exact cause of hemangiomas is unknown. | 220 | Cervical Teratoma |
nord_220_5 | Diagnosis of Cervical Teratoma | The diagnosis of a cervical teratoma is based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient history, and a variety of specialized tests. Such testing includes microscopic evaluation of tumor cells.Prenatal diagnosis of cervical teratomas is possible via ultrasound, a procedure during which reflected sound waves create an image of the developing fetus. Large tumors may be readily apparent on a fetal ultrasound, the neck may appear hyper-extended, or associated findings such as excessive amniotic fluid (polyhydramnios) may be detected. In adults, a mass may be detected in the neck during a routine physical exam.To confirm a diagnosis of cervical teratoma a variety of tests may be performed including fine-needle aspiration (FNA). FNA is a diagnostic technique in which a thin, hollow needle is passed though the skin and inserted into the nodule to withdraw small samples of tissue from the nodule. The collected tissue is then studied under a microscope.In some cases, FNA may prove inconclusive and physicians may perform a biopsy. During a biopsy, a small sample tissue is surgically removed and sent to a pathology laboratory where it is processed and studied to determine its microscopic structure and makeup (histopathology).In addition to ultrasound, additional specialized imaging techniques may be used to help evaluate the size, placement, and extension of a tumor and to serve as an aid for future surgical procedures. 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 approximately 50 percent of cases, the appearance of clusters of calcium (calcifications) can be detected on x-rays, a finding suggestive of a teratoma. Laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases. | Diagnosis of Cervical Teratoma. The diagnosis of a cervical teratoma is based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient history, and a variety of specialized tests. Such testing includes microscopic evaluation of tumor cells.Prenatal diagnosis of cervical teratomas is possible via ultrasound, a procedure during which reflected sound waves create an image of the developing fetus. Large tumors may be readily apparent on a fetal ultrasound, the neck may appear hyper-extended, or associated findings such as excessive amniotic fluid (polyhydramnios) may be detected. In adults, a mass may be detected in the neck during a routine physical exam.To confirm a diagnosis of cervical teratoma a variety of tests may be performed including fine-needle aspiration (FNA). FNA is a diagnostic technique in which a thin, hollow needle is passed though the skin and inserted into the nodule to withdraw small samples of tissue from the nodule. The collected tissue is then studied under a microscope.In some cases, FNA may prove inconclusive and physicians may perform a biopsy. During a biopsy, a small sample tissue is surgically removed and sent to a pathology laboratory where it is processed and studied to determine its microscopic structure and makeup (histopathology).In addition to ultrasound, additional specialized imaging techniques may be used to help evaluate the size, placement, and extension of a tumor and to serve as an aid for future surgical procedures. 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 approximately 50 percent of cases, the appearance of clusters of calcium (calcifications) can be detected on x-rays, a finding suggestive of a teratoma. Laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases. | 220 | Cervical Teratoma |
nord_220_6 | Therapies of Cervical Teratoma | TreatmentThe therapeutic management of individuals with cervical teratomas may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), specialists in maternal-fetal health (perinatologists), specialists in the ear, nose and throat (otolaryngologists), pediatric surgeons, oncology nurses, and other specialists.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; 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, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.In most individuals with a cervical teratoma, surgical removal of the tumor and affected tissue is performed. Although most teratomas in children are benign, they can compress the windpipe and nearby structures necessitating their removal.In cases diagnosed before birth (prenatally), a procedure known as ex utero intrapartum treatment (EXIT) may be performed. In this procedure, surgery is performed as an affected baby is born via Cesarean section. The baby remains attached to the placenta so normal blood flow exchange occurs while physicians perform necessary surgical procedures.In order to secure the airway, physicians may need to insert a breathing tube (endotracheal tube). In some cases, physicians may perform a tracheostomy, a surgical procedure in which an incision is made in the windpipe (trachea) to create a temporary opening to allow the passage of air.Adults with a cervical teratoma are treated by complete surgical removal of the tumor. Radiation therapy may be used before surgery (to decrease tumor size) or after surgery as an adjuvant therapy. Chemotherapy immediately after surgery has also been used to treat individuals with cervical teratomas.Surgical removal of a cervical teratoma may involve the removal of a portion of or the entire thyroid. In such cases, affected individuals must go on hormone replacement therapy to obtain the hormones normally produced by the thyroid.Infants with a benign cervical teratoma rarely experience recurrence of the tumor. Malignant cervical teratomas such as those found in adults recur more often. Affected individuals must be monitored periodically to check for recurrence. | Therapies of Cervical Teratoma. TreatmentThe therapeutic management of individuals with cervical teratomas may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), specialists in maternal-fetal health (perinatologists), specialists in the ear, nose and throat (otolaryngologists), pediatric surgeons, oncology nurses, and other specialists.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; 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, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.In most individuals with a cervical teratoma, surgical removal of the tumor and affected tissue is performed. Although most teratomas in children are benign, they can compress the windpipe and nearby structures necessitating their removal.In cases diagnosed before birth (prenatally), a procedure known as ex utero intrapartum treatment (EXIT) may be performed. In this procedure, surgery is performed as an affected baby is born via Cesarean section. The baby remains attached to the placenta so normal blood flow exchange occurs while physicians perform necessary surgical procedures.In order to secure the airway, physicians may need to insert a breathing tube (endotracheal tube). In some cases, physicians may perform a tracheostomy, a surgical procedure in which an incision is made in the windpipe (trachea) to create a temporary opening to allow the passage of air.Adults with a cervical teratoma are treated by complete surgical removal of the tumor. Radiation therapy may be used before surgery (to decrease tumor size) or after surgery as an adjuvant therapy. Chemotherapy immediately after surgery has also been used to treat individuals with cervical teratomas.Surgical removal of a cervical teratoma may involve the removal of a portion of or the entire thyroid. In such cases, affected individuals must go on hormone replacement therapy to obtain the hormones normally produced by the thyroid.Infants with a benign cervical teratoma rarely experience recurrence of the tumor. Malignant cervical teratomas such as those found in adults recur more often. Affected individuals must be monitored periodically to check for recurrence. | 220 | Cervical Teratoma |
nord_221_0 | Overview of Chanarin-Dorfman Syndrome | SummaryChanarin-Dorfman syndrome (CDS) is an extremely rare genetic disorder characterized by dry, scaly skin at birth as well as progressive fatty liver disease and various degrees of muscular involvement. Vision problems, hearing loss, short stature and mild intellectual disability are also associated with this condition. The skin abnormalities are present at birth but the disease is often diagnosed a few years later in childhood when more symptoms become apparent. The current treatment options are limited, mostly for the skin symptoms. An early initiation of low fat diet with MCT (medium chain triglycerides) might improve the liver condition. Motor rehabilitation is necessary in patients with muscle disease (myopathy).IntroductionChanarin-Dorfman syndrome was first described in 1974 in Jerusalem. Over 128 CDS patients have been reported worldwide, especially in the Mediterranean and Middle East area. CDS is a type of neutral lipid storage disease, but is also a considered a hereditary skin disease in the ‘ichthyotic’ group. It is named according to the first researchers who described patients: M.L Dorfman in 1974 and I. Chanarin in 1975. | Overview of Chanarin-Dorfman Syndrome. SummaryChanarin-Dorfman syndrome (CDS) is an extremely rare genetic disorder characterized by dry, scaly skin at birth as well as progressive fatty liver disease and various degrees of muscular involvement. Vision problems, hearing loss, short stature and mild intellectual disability are also associated with this condition. The skin abnormalities are present at birth but the disease is often diagnosed a few years later in childhood when more symptoms become apparent. The current treatment options are limited, mostly for the skin symptoms. An early initiation of low fat diet with MCT (medium chain triglycerides) might improve the liver condition. Motor rehabilitation is necessary in patients with muscle disease (myopathy).IntroductionChanarin-Dorfman syndrome was first described in 1974 in Jerusalem. Over 128 CDS patients have been reported worldwide, especially in the Mediterranean and Middle East area. CDS is a type of neutral lipid storage disease, but is also a considered a hereditary skin disease in the ‘ichthyotic’ group. It is named according to the first researchers who described patients: M.L Dorfman in 1974 and I. Chanarin in 1975. | 221 | Chanarin-Dorfman Syndrome |
nord_221_1 | Symptoms of Chanarin-Dorfman Syndrome | Chanarin-Dorfman syndrome can affect many systems. All patients have skin findings that are usually present at birth: redness, fine scaling, dark pigmentation and severe itching which leads to scratching and skin-picking (excoriation). The skin appearance is referred to “ichthyosiform nonbullous erythroderma”. Patients also have liver disease with lipid storage which can lead to liver failure. About 60% of patients also have muscle problems. They have slowly progressive weakness of the proximal arms and legs. When the muscles are affected they release their enzymes in the blood, which can be detected by the presence of a CK elevation. Exercise intolerance has never been reported, but many patients reported early fatigability.Less commonly, other systems can be involved. Around 40% of patients have eye problems consisting mainly in cataracts or eyelids pointing outwards (ectropion). Approximately 25% of patients have progressive hearing loss. Around 25% have cognitive impairment. Short stature and growth retardation have also been reported. Some patients have intestinal problems such as fatty diarrhea (steatorrhea) and enlarged spleen. Some have orthopedic problems and kidney dysfunction. | Symptoms of Chanarin-Dorfman Syndrome. Chanarin-Dorfman syndrome can affect many systems. All patients have skin findings that are usually present at birth: redness, fine scaling, dark pigmentation and severe itching which leads to scratching and skin-picking (excoriation). The skin appearance is referred to “ichthyosiform nonbullous erythroderma”. Patients also have liver disease with lipid storage which can lead to liver failure. About 60% of patients also have muscle problems. They have slowly progressive weakness of the proximal arms and legs. When the muscles are affected they release their enzymes in the blood, which can be detected by the presence of a CK elevation. Exercise intolerance has never been reported, but many patients reported early fatigability.Less commonly, other systems can be involved. Around 40% of patients have eye problems consisting mainly in cataracts or eyelids pointing outwards (ectropion). Approximately 25% of patients have progressive hearing loss. Around 25% have cognitive impairment. Short stature and growth retardation have also been reported. Some patients have intestinal problems such as fatty diarrhea (steatorrhea) and enlarged spleen. Some have orthopedic problems and kidney dysfunction. | 221 | Chanarin-Dorfman Syndrome |
nord_221_2 | Causes of Chanarin-Dorfman Syndrome | Chanarin-Dorfman syndrome is caused by changes (mutations) in the ABHD5 gene located on chromosome 3. This gene produces a protein involved in fat metabolism called CGI-58. This protein is called a co-factor because it helps the activity of the main enzyme, which is adipose triacylglycerol lipase (ATGL). The function of this enzyme is to break down a type of fat called triacylglycerol (TAG). This process is disturbed when either the enzyme or the helper protein doesn’t work properly. When the fat (triacylglycerol) cannot be broken down, it accumulates in various parts of the body as lipid droplets and causes different symptoms. This is what happens in a group of disorders called ‘neutral lipid storage disease’. It comprises two entities:When the mutation occurs in the gene for the main enzyme (ATGL), the disease is called ‘neutral lipid storage disease with myopathy’.When the mutation occurs in the gene for the helper protein (CGI-58), the disease is called ‘neutral lipid storage disease with itchthyosis’, or Chanarin-Dorfman syndrome.It is important to distinguish between the two because the clinical presentations are very different. In the first one, patients usually present in early adulthood with muscle abnormalities caused by the accumulation of fat. In Chanarin-Dorfman syndrome, patients primarily have skin abnormalities that are apparent at birth. For this reason, Chanarin-Dorfman syndrome is also part of a group of diseases called ‘itchthyoses’, which are characterized by skin abnormalities. Another difference is the absence of heart problems (cardiomyopathy) in Chanarin-Dorfman syndrome, whereas they are present in first one.The genetic mutation in Chanarin-Dorfman syndrome leads to abnormal accumulation of fat (lipid droplets) in many cells, especially in the skin, liver and white blood cells. The effect on the skin is an abnormal permeability, which leads to a characteristic rash and intense itching. In the liver, the lipid droplet accumulation leads to fatty change called “steatosis” that can eventually progress to cirrhosis and liver failure.Chanarin-Dorfman syndrome is inherited in an autosomal recessive pattern, which means the 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. | Causes of Chanarin-Dorfman Syndrome. Chanarin-Dorfman syndrome is caused by changes (mutations) in the ABHD5 gene located on chromosome 3. This gene produces a protein involved in fat metabolism called CGI-58. This protein is called a co-factor because it helps the activity of the main enzyme, which is adipose triacylglycerol lipase (ATGL). The function of this enzyme is to break down a type of fat called triacylglycerol (TAG). This process is disturbed when either the enzyme or the helper protein doesn’t work properly. When the fat (triacylglycerol) cannot be broken down, it accumulates in various parts of the body as lipid droplets and causes different symptoms. This is what happens in a group of disorders called ‘neutral lipid storage disease’. It comprises two entities:When the mutation occurs in the gene for the main enzyme (ATGL), the disease is called ‘neutral lipid storage disease with myopathy’.When the mutation occurs in the gene for the helper protein (CGI-58), the disease is called ‘neutral lipid storage disease with itchthyosis’, or Chanarin-Dorfman syndrome.It is important to distinguish between the two because the clinical presentations are very different. In the first one, patients usually present in early adulthood with muscle abnormalities caused by the accumulation of fat. In Chanarin-Dorfman syndrome, patients primarily have skin abnormalities that are apparent at birth. For this reason, Chanarin-Dorfman syndrome is also part of a group of diseases called ‘itchthyoses’, which are characterized by skin abnormalities. Another difference is the absence of heart problems (cardiomyopathy) in Chanarin-Dorfman syndrome, whereas they are present in first one.The genetic mutation in Chanarin-Dorfman syndrome leads to abnormal accumulation of fat (lipid droplets) in many cells, especially in the skin, liver and white blood cells. The effect on the skin is an abnormal permeability, which leads to a characteristic rash and intense itching. In the liver, the lipid droplet accumulation leads to fatty change called “steatosis” that can eventually progress to cirrhosis and liver failure.Chanarin-Dorfman syndrome is inherited in an autosomal recessive pattern, which means the 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. | 221 | Chanarin-Dorfman Syndrome |
nord_221_3 | Affects of Chanarin-Dorfman Syndrome | There have been over 128 patients reported worldwide, especially in the Mediterranean and Middle East region. Many of the reported patients have been children born to couples who are related by blood (consanguineous). This condition affects males and females equally. | Affects of Chanarin-Dorfman Syndrome. There have been over 128 patients reported worldwide, especially in the Mediterranean and Middle East region. Many of the reported patients have been children born to couples who are related by blood (consanguineous). This condition affects males and females equally. | 221 | Chanarin-Dorfman Syndrome |
nord_221_4 | Related disorders of Chanarin-Dorfman Syndrome | There are a few disorders other than Chanarin-Dorfman syndrome that have similar skin changes at birth and involve many systems. Among those, there is Neherton syndrome, Sjögren-Larsson syndrome, Conradi-Heunermann-Happle syndrome, Ichthyosis follicularis, atrichia and photophobia (IFAP) syndrome and Refsum syndrome.Neherton syndrome is characterized by congenital ichthyosis and predisposition to allergic features such as chronic hives, asthma, rhinitis and hay fever (referred to as atopy). A unique feature is “bamboo hair”, which are short, sparse, dry and not lustrous.Sjögren-Larsson syndrome is characterized by congenital ichthyosis, paralysis of lower limbs and severe intellectual disability. Conradi-Heunermann-Happle syndrome manifests as skin changes at birth, in addition to skeletal abnormalities (asymmetrical shortening of limbs, kyphoscoliosis), short stature and cataracts.IFAP is characterized by icthyotic skin changes and loss of hair on the entire scalp (alopecia totalis). There is also extreme sensitivity to light, short stature, intellectual disability and convulsions.Refsum syndrome develops during childhood and adolescence. In addition to the skin findings, there is functional disorder of the nervous system with ataxia, inflammation of the nerves (peripheral neuritis) and inflammation of the retina in the eyes (retinitis pigmentosa). | Related disorders of Chanarin-Dorfman Syndrome. There are a few disorders other than Chanarin-Dorfman syndrome that have similar skin changes at birth and involve many systems. Among those, there is Neherton syndrome, Sjögren-Larsson syndrome, Conradi-Heunermann-Happle syndrome, Ichthyosis follicularis, atrichia and photophobia (IFAP) syndrome and Refsum syndrome.Neherton syndrome is characterized by congenital ichthyosis and predisposition to allergic features such as chronic hives, asthma, rhinitis and hay fever (referred to as atopy). A unique feature is “bamboo hair”, which are short, sparse, dry and not lustrous.Sjögren-Larsson syndrome is characterized by congenital ichthyosis, paralysis of lower limbs and severe intellectual disability. Conradi-Heunermann-Happle syndrome manifests as skin changes at birth, in addition to skeletal abnormalities (asymmetrical shortening of limbs, kyphoscoliosis), short stature and cataracts.IFAP is characterized by icthyotic skin changes and loss of hair on the entire scalp (alopecia totalis). There is also extreme sensitivity to light, short stature, intellectual disability and convulsions.Refsum syndrome develops during childhood and adolescence. In addition to the skin findings, there is functional disorder of the nervous system with ataxia, inflammation of the nerves (peripheral neuritis) and inflammation of the retina in the eyes (retinitis pigmentosa). | 221 | Chanarin-Dorfman Syndrome |
nord_221_5 | Diagnosis of Chanarin-Dorfman Syndrome | Newborns usually have characteristic skin changes (ichthyosiform changes), but the combination of skin appearance, liver abnormalities and other system involvement is what raises the suspicion for Chanarin-Dorfman syndrome. The suspected diagnosis is made with a peripheral blood smear test, where fat deposits (lipid droplets) are seen in white blood cells (called Jordan’s anomaly). Molecular genetic testing for mutations in the ABHD5 gene is available to confirm the diagnosis. Clinical Testing and Work-UpMost findings can be detected by a blood test: the initial diagnosis requires a peripheral blood smear, liver involvement can be detected with abnormal liver enzymes, and muscle involvement can be detected with elevated muscle enzymes and neurological clinical examination. Ultrasound of the abdomen is virtually always done to evaluate liver changes. Electromyography (EMG) can be done to evaluate the muscle changes. Biopsies of the skin, liver and muscle can be done to examine the changes under the microscope. Other systems can be examined and evaluated depending on the symptoms. | Diagnosis of Chanarin-Dorfman Syndrome. Newborns usually have characteristic skin changes (ichthyosiform changes), but the combination of skin appearance, liver abnormalities and other system involvement is what raises the suspicion for Chanarin-Dorfman syndrome. The suspected diagnosis is made with a peripheral blood smear test, where fat deposits (lipid droplets) are seen in white blood cells (called Jordan’s anomaly). Molecular genetic testing for mutations in the ABHD5 gene is available to confirm the diagnosis. Clinical Testing and Work-UpMost findings can be detected by a blood test: the initial diagnosis requires a peripheral blood smear, liver involvement can be detected with abnormal liver enzymes, and muscle involvement can be detected with elevated muscle enzymes and neurological clinical examination. Ultrasound of the abdomen is virtually always done to evaluate liver changes. Electromyography (EMG) can be done to evaluate the muscle changes. Biopsies of the skin, liver and muscle can be done to examine the changes under the microscope. Other systems can be examined and evaluated depending on the symptoms. | 221 | Chanarin-Dorfman Syndrome |
nord_221_6 | Therapies of Chanarin-Dorfman Syndrome | Treatment
There is no effective treatment for Chanarin-Dorfman syndrome. However, it is recommended to have a low fat diet (specifically low long-chain fatty acid and minimal saturated fat), enriched with medium-chain triglycerides, ursodiol (a bile acid) and vitamin E. This would decrease the liver size and normalize the liver enzymes. This diet has no effect on skin symptoms. To alleviate itching and other skin symptoms, it is recommended to apply moisturizers on the skin. Vitamin A derivatives like acitretin are useful for skin and muscle manifestations, but are often considered contraindicated if the liver enzymes are impaired, which is commonly the case. However, improvement in skin symptoms without deleterious effect on liver function has been reported with the use of acitretin. There is no consensus about the use of retinoid in Chanarin-Dorfman syndrome with abnormal liver function. One case of liver transplant followed by the usual dietary modifications has been reported with stabilisation of the skin and intellectual disability deterioration after 1 year, but there are insufficient studies to conclude the effectiveness and the long-term effects of liver transplantation. | Therapies of Chanarin-Dorfman Syndrome. Treatment
There is no effective treatment for Chanarin-Dorfman syndrome. However, it is recommended to have a low fat diet (specifically low long-chain fatty acid and minimal saturated fat), enriched with medium-chain triglycerides, ursodiol (a bile acid) and vitamin E. This would decrease the liver size and normalize the liver enzymes. This diet has no effect on skin symptoms. To alleviate itching and other skin symptoms, it is recommended to apply moisturizers on the skin. Vitamin A derivatives like acitretin are useful for skin and muscle manifestations, but are often considered contraindicated if the liver enzymes are impaired, which is commonly the case. However, improvement in skin symptoms without deleterious effect on liver function has been reported with the use of acitretin. There is no consensus about the use of retinoid in Chanarin-Dorfman syndrome with abnormal liver function. One case of liver transplant followed by the usual dietary modifications has been reported with stabilisation of the skin and intellectual disability deterioration after 1 year, but there are insufficient studies to conclude the effectiveness and the long-term effects of liver transplantation. | 221 | Chanarin-Dorfman Syndrome |
nord_222_0 | Overview of Chandler’s Syndrome | Chandler's syndrome (CS) is a rare eye disorder in which the endothelium, the single layer of cells lining the interior of the cornea, proliferates causing corneal edema, distortion of the iris, and unusually high pressure in the eye (glaucoma). CS is one of three syndromes affecting the eyes (progressive iris atrophy and Cogan-Reese syndrome are the other two) that make up the iridocorneal endothelial syndrome (ICE syndrome). The spectrum is an acquired, unilateral disorder, which typically occurs in early to middle adulthood and predominantly affects women. Chandler's syndrome is the most commonly encountered clinical variant of this spectrum.Most often the condition affects one eye only, but the fellow eye often has subclinical involvement. The combination of high pressure within the eye (glaucoma) and corneal edema can result in reduced vision, frequently requiring surgical intervention with variable success rates. | Overview of Chandler’s Syndrome. Chandler's syndrome (CS) is a rare eye disorder in which the endothelium, the single layer of cells lining the interior of the cornea, proliferates causing corneal edema, distortion of the iris, and unusually high pressure in the eye (glaucoma). CS is one of three syndromes affecting the eyes (progressive iris atrophy and Cogan-Reese syndrome are the other two) that make up the iridocorneal endothelial syndrome (ICE syndrome). The spectrum is an acquired, unilateral disorder, which typically occurs in early to middle adulthood and predominantly affects women. Chandler's syndrome is the most commonly encountered clinical variant of this spectrum.Most often the condition affects one eye only, but the fellow eye often has subclinical involvement. The combination of high pressure within the eye (glaucoma) and corneal edema can result in reduced vision, frequently requiring surgical intervention with variable success rates. | 222 | Chandler’s Syndrome |
nord_222_1 | Symptoms of Chandler’s Syndrome | Chandler’s syndrome is characterized by proliferation of the cells lining the cornea, swelling of the cornea with distortion of the iris and glaucoma (optic nerve damage from high pressure) within the eye.The pupil of the eye appears to be out of place, i.e. located in an out-of-the-ordinary position and distorted in shape and size (corectopia). In Chandler’s syndrome, whatever iris atrophy occurs is mild when compared to that associated with progressive iris atrophy and Cogan-Reese syndrome. Typically, the corneal endothelium presents as a hammered, silver surface on the back of the cornea. Because iris alternations may be minimal in the early stage of the disease, CS is often not recognized initially by the clinicians.The disorder may cause blurred vision, pain in the eye with eventual loss of vision. Usually only one eye is affected; however, the other eye may, very rarely, be clinically involved. | Symptoms of Chandler’s Syndrome. Chandler’s syndrome is characterized by proliferation of the cells lining the cornea, swelling of the cornea with distortion of the iris and glaucoma (optic nerve damage from high pressure) within the eye.The pupil of the eye appears to be out of place, i.e. located in an out-of-the-ordinary position and distorted in shape and size (corectopia). In Chandler’s syndrome, whatever iris atrophy occurs is mild when compared to that associated with progressive iris atrophy and Cogan-Reese syndrome. Typically, the corneal endothelium presents as a hammered, silver surface on the back of the cornea. Because iris alternations may be minimal in the early stage of the disease, CS is often not recognized initially by the clinicians.The disorder may cause blurred vision, pain in the eye with eventual loss of vision. Usually only one eye is affected; however, the other eye may, very rarely, be clinically involved. | 222 | Chandler’s Syndrome |
nord_222_2 | Causes of Chandler’s Syndrome | The single layer of cells lining the inside of the surface of the cornea is known as the endothelium. One of the roles played by the endothelium is to pump aqueous humor (fluid inside the eye) from the cornea. If the behavior of the endothelium is interrupted (as in Chandler’s syndrome), the pumping action fails, and fluid accumulates in the cornea (corneal edema) resulting in blurred vision. In addition, the abnormal endothelial cells can migrate as a membrane over adjacent structures, including the iris and the trabecular meshwork (the drainage canal of the eye). Contraction of this membrane leads to associated iris changes (corectopia) and iridotrabecular synechiae causing obstruction of aqueous outflow in the trabecular meshwork resulting in secondary glaucoma. The exact cause of Chandler’s syndrome is not known. Some researchers suspect that inflammation or chronic viral infection may be the cause of the disease. Herpes simplex virus DNA has been demonstrated with polymerase chain reaction in corneal specimens obtained from patients with ICE syndrome. | Causes of Chandler’s Syndrome. The single layer of cells lining the inside of the surface of the cornea is known as the endothelium. One of the roles played by the endothelium is to pump aqueous humor (fluid inside the eye) from the cornea. If the behavior of the endothelium is interrupted (as in Chandler’s syndrome), the pumping action fails, and fluid accumulates in the cornea (corneal edema) resulting in blurred vision. In addition, the abnormal endothelial cells can migrate as a membrane over adjacent structures, including the iris and the trabecular meshwork (the drainage canal of the eye). Contraction of this membrane leads to associated iris changes (corectopia) and iridotrabecular synechiae causing obstruction of aqueous outflow in the trabecular meshwork resulting in secondary glaucoma. The exact cause of Chandler’s syndrome is not known. Some researchers suspect that inflammation or chronic viral infection may be the cause of the disease. Herpes simplex virus DNA has been demonstrated with polymerase chain reaction in corneal specimens obtained from patients with ICE syndrome. | 222 | Chandler’s Syndrome |
nord_222_3 | Affects of Chandler’s Syndrome | Chandler’s syndrome is a very rare disorder that affects females more often than it does males. The disorder usually appears during young adult to middle aged years. However, its occurrence in a child and a teenager has been reported. ICE syndrome has been described in different ethnic groups, although the prevalence of the 3 clinical variants may vary among ethnicities. | Affects of Chandler’s Syndrome. Chandler’s syndrome is a very rare disorder that affects females more often than it does males. The disorder usually appears during young adult to middle aged years. However, its occurrence in a child and a teenager has been reported. ICE syndrome has been described in different ethnic groups, although the prevalence of the 3 clinical variants may vary among ethnicities. | 222 | Chandler’s Syndrome |
nord_222_4 | Related disorders of Chandler’s Syndrome | Symptoms of the following disorders can be similar to those of Chandler’s syndrome. Comparisons may be useful for a differential diagnosis:Progressive (or essential) iris atrophy is a very similar disorder to Chandler’s syndrome and their symptoms may even overlap. Progressive iris atrophy is characterized by gross distortion of the pupil eye and the development of holes in the iris. This condition also causes increased intraocular pressure and corneal edema. If left untreated, vision loss may occur.Cogan-Reese syndrome is characterized by distortion of iris tissue and the development of small wart-like growths on the iris. Increased pressure within the eye and corneal swelling are also evident. This disorder differs from Cogan corneal dystrophy, which is inherited as an autosomal dominant disorder. (For more information on this disorder, choose “Cogan-Reese” as your search term in the Rare Disease Database.)
The prevalence of glaucoma in ICE syndrome has been reported to be as high as 82%. Glaucoma appears to be more frequent and severe in patients with progressive iris atrophy and Cogan-Reese syndrome as compared with Chandler’s syndrome. The anterior chamber angle is usually open early in the disease process, and some patients may develop glaucoma at this stage. As the disease progresses and contraction of the abnormal basement membrane occurs, broad peripheral anterior synechiae (broad iris strands to the drainage angle structures, including trabecular meshwork and Schwalbe’s line) lead to aqueous humor outflow obstruction and secondary angle closure glaucoma. If left untreated, the increased pressure may affect the optic nerve, resulting in eventual blindness. Some symptoms for persons to be aware of are: blurred vision, rainbow colored halos around lights, and loss of side vision resulting in “tunnel vision”. A simple test can measure the pressure in a person’s eye, and this testing is recommended annually for persons over age 40, along with a complete eye exam. Treatment may consist of medicated eye drops and if these are unsuccessful surgery may be necessary. | Related disorders of Chandler’s Syndrome. Symptoms of the following disorders can be similar to those of Chandler’s syndrome. Comparisons may be useful for a differential diagnosis:Progressive (or essential) iris atrophy is a very similar disorder to Chandler’s syndrome and their symptoms may even overlap. Progressive iris atrophy is characterized by gross distortion of the pupil eye and the development of holes in the iris. This condition also causes increased intraocular pressure and corneal edema. If left untreated, vision loss may occur.Cogan-Reese syndrome is characterized by distortion of iris tissue and the development of small wart-like growths on the iris. Increased pressure within the eye and corneal swelling are also evident. This disorder differs from Cogan corneal dystrophy, which is inherited as an autosomal dominant disorder. (For more information on this disorder, choose “Cogan-Reese” as your search term in the Rare Disease Database.)
The prevalence of glaucoma in ICE syndrome has been reported to be as high as 82%. Glaucoma appears to be more frequent and severe in patients with progressive iris atrophy and Cogan-Reese syndrome as compared with Chandler’s syndrome. The anterior chamber angle is usually open early in the disease process, and some patients may develop glaucoma at this stage. As the disease progresses and contraction of the abnormal basement membrane occurs, broad peripheral anterior synechiae (broad iris strands to the drainage angle structures, including trabecular meshwork and Schwalbe’s line) lead to aqueous humor outflow obstruction and secondary angle closure glaucoma. If left untreated, the increased pressure may affect the optic nerve, resulting in eventual blindness. Some symptoms for persons to be aware of are: blurred vision, rainbow colored halos around lights, and loss of side vision resulting in “tunnel vision”. A simple test can measure the pressure in a person’s eye, and this testing is recommended annually for persons over age 40, along with a complete eye exam. Treatment may consist of medicated eye drops and if these are unsuccessful surgery may be necessary. | 222 | Chandler’s Syndrome |
nord_222_5 | Diagnosis of Chandler’s Syndrome | Diagnosis of Chandler’s Syndrome. | 222 | Chandler’s Syndrome |
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nord_222_6 | Therapies of Chandler’s Syndrome | TreatmentTreatment of Chandler's syndrome usually involves the use of drops in the eyes to control the glaucoma and swelling (edema). Mild cases or corneal edema are often managed with soft contact lenses and hypertonic saline solutions. In advanced cases penetrating or endothelial keratoplasty may be required, although the failure rate is high with need for repeat corneal grafts. In some individuals, the corneal edema may be improved with reduction in intraocular pressure. Medical therapy for glaucoma is usually initiated with aqueous suppressants, including beta blockers, alpha-2 agonists and carbonic anhydrase inhibitors. Prostaglandin analogues may be helpful in some cases. Surgical intervention for glaucoma is eventually required in a high percentage of patients with ICE syndrome. The most commonly performed procedure is trabeculectomy, with variable success rates. Glaucoma drainage devices have shown favorable outcomes in a small number of patients, but further studies are warranted to validate these results in a large series. Laser surgery is rarely effective. | Therapies of Chandler’s Syndrome. TreatmentTreatment of Chandler's syndrome usually involves the use of drops in the eyes to control the glaucoma and swelling (edema). Mild cases or corneal edema are often managed with soft contact lenses and hypertonic saline solutions. In advanced cases penetrating or endothelial keratoplasty may be required, although the failure rate is high with need for repeat corneal grafts. In some individuals, the corneal edema may be improved with reduction in intraocular pressure. Medical therapy for glaucoma is usually initiated with aqueous suppressants, including beta blockers, alpha-2 agonists and carbonic anhydrase inhibitors. Prostaglandin analogues may be helpful in some cases. Surgical intervention for glaucoma is eventually required in a high percentage of patients with ICE syndrome. The most commonly performed procedure is trabeculectomy, with variable success rates. Glaucoma drainage devices have shown favorable outcomes in a small number of patients, but further studies are warranted to validate these results in a large series. Laser surgery is rarely effective. | 222 | Chandler’s Syndrome |
nord_223_0 | Overview of Charcot-Marie-Tooth Disease | Charcot-Marie-Tooth (CMT) disease is a group of disorders in which the motor and/or sensory peripheral nerves are affected, resulting in muscle weakness and atrophy as well as sensory loss. Symptoms occur first in the distal legs and later in the hands. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. In CMT specific gene mutations are responsible for the abnormal function of the peripheral nerves. In many forms of CMT these genes are known and in others, while the condition is known to be inherited, the specific gene has not yet been identified. | Overview of Charcot-Marie-Tooth Disease. Charcot-Marie-Tooth (CMT) disease is a group of disorders in which the motor and/or sensory peripheral nerves are affected, resulting in muscle weakness and atrophy as well as sensory loss. Symptoms occur first in the distal legs and later in the hands. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. In CMT specific gene mutations are responsible for the abnormal function of the peripheral nerves. In many forms of CMT these genes are known and in others, while the condition is known to be inherited, the specific gene has not yet been identified. | 223 | Charcot-Marie-Tooth Disease |
nord_223_1 | Symptoms of Charcot-Marie-Tooth Disease | Symptoms of CMT disease usually begin gradually in adolescence, but can begin earlier or later. In almost all patients, the longest nerve fibers are affected first. Over time, affected individuals may lose the normal use of their feet, hands, legs and arms. Common early signs and symptoms can include decreased sensitivity to heat, touch or pain, muscle weakness in the hand, foot or lower leg, trouble with fine motor skills, high-stepped gait (foot drop), loss of muscle mass in the lower leg, frequent tripping or falling, hammertoe, high foot arch and flat feet. Stretch reflexes may be lost. The disease is slowly progressive and variable, and those affected may remain active for years and live a normal life span. In the most severe cases, breathing difficulties can hasten death. | Symptoms of Charcot-Marie-Tooth Disease. Symptoms of CMT disease usually begin gradually in adolescence, but can begin earlier or later. In almost all patients, the longest nerve fibers are affected first. Over time, affected individuals may lose the normal use of their feet, hands, legs and arms. Common early signs and symptoms can include decreased sensitivity to heat, touch or pain, muscle weakness in the hand, foot or lower leg, trouble with fine motor skills, high-stepped gait (foot drop), loss of muscle mass in the lower leg, frequent tripping or falling, hammertoe, high foot arch and flat feet. Stretch reflexes may be lost. The disease is slowly progressive and variable, and those affected may remain active for years and live a normal life span. In the most severe cases, breathing difficulties can hasten death. | 223 | Charcot-Marie-Tooth Disease |
nord_223_2 | Causes of Charcot-Marie-Tooth Disease | CMT is known to be a genetic condition caused by genes that have abnormal changes affecting their function. There are now over 100 genes that are known to be responsible for various forms of CMT. A single gene, PMP22, when duplicated, is the cause of around 50% of cases of CMT, while damaging changes in some genes that cause CMT can be extremely rare and found only in a few families. In around 40% of cases of CMT, no responsible gene has yet been identified.Genetic diseases are caused by changes in a single gene or in a combination of genes for a particular trait that are on the chromosomes received from the father and the mother. At this time, genetic causes for CMT can only be identified when a single gene is responsible for the condition, but not when the effect of several genes with damaging changes, known as polygenic inheritance, is suspected. Single genes that cause CMT can be inherited in an autosomal dominant, autosomal recessive, X-linked or X-linked dominant pattern.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.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.X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.X-linked dominant disorders are caused by a non-working gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the non-working gene for a particular disease. Males with a non-working gene for an X-linked dominant disorder are more severely affected than females and often do not survive.The common naming system for CMT disease is a subdivision into several major types termed CMT1, CMT2, CMT3, CMT4, CMTX, CMTDI and CMTRI. If a responsible gene has been identified, a letter is added to the name, such as CMT1A, CMT1B etc. Recently, new naming schemes have been proposed to simplify this by basing names on inheritance pattern, whether the cause is demyelinating, axonal or intermediate and if the causative gene if known. Table 1 lists CMT types using the common nomenclature and lists causative genes. Some of the types were named before genetic causes were well understood, so there is some redundancy in this naming system and some types have proven to be inaccurately attributed to a specific gene making certain subtype names obsolete. For these reasons some names are no longer in common use.CMT1 is the most common form of CMT and is characterized by abnormalities in nerve myelin that leads to decreased nerve conduction velocities. Peripheral nerve myelin is formed by Schwann cells, and abnormal changes in genes involved in formation and function of these Schwann cells leads to demyelination. CMT1 is inherited in an autosomal dominant pattern. CMT1 has been further subdivided into subtypes from CMT1A – 1F based on specific gene abnormalities. CMT1A is by far the most common single subtype of CMT accounting for around 50% of all cases of CMT and is caused by a duplication of the PMP22 gene. Other subtypes of CMT1 and responsible genes are listed in Table 1.CMT2 is a form of the condition in which nerve conduction velocities are usually normal or slightly slower than normal but nerve signal strength is reduced. CMT2 is caused by abnormal genes involved in the structure and function of axons. CMT2 includes primarily autosomal dominant inheritance patterns. CMT2 has been further subdivided into CMT2A – 2Z based on mutations in specific genes. CMT2A is the most common and is caused by mutations in the MFN2 gene. Other subtypes of CMT2 and responsible genes are listed in Table 1. While CMT2 is meant to indicate autosomal dominant inheritance patterns, some subtypes feature autosomal recessive inheritance.CMT4 is a classification strictly for autosomal recessive forms of CMT. CMT4A is caused by an abnormality in the GDAP1 gene; however the GDAP1 gene is also responsible for CMT2H and CMT2K when the damaging changes to it are sufficient to be transmitted through an autosomal dominant inheritance pattern. Other subtypes of CMT4 and responsible genes are listed in Table 1. SORD-related CMT is the current name for an autosomal recessive axonal form of CMT caused by changes in the SORD gene. This gene was only recently found to be responsible for CMT but may be the most common genetic cause of autosomal recessive CMT. It has not yet been given a classification in the common naming system.CMTX is an X-linked dominant form of the condition caused by abnormalities in genes located on the X chromosome. CMTX1 (aka CMT1X), caused by changes in the GJB1 gene, accounts for approximately 90% of CMTX. Other subtypes of CMTX and responsible genes are listed in Table 1. Because GJB1 and these other known and unknown genes that cause CMTX are located on the X-chromosome, CMTX primarily affects males, however in CMTX1 and CMTX6 feature an X-linked dominant inheritance with males being more severely affected than females. In CMTX1 and CMTX6, affected females usually have a later onset than males and a milder condition at every age, or may even be asymptomatic, probably due to X inactivation in the myelinating Schwann cells.Intermediate CMTs include those with “intermediate” conduction velocities and thus an uncertainty regarding whether the neuropathy is primarily axonal or demyelinating. There are both dominant (CMTDI) and recessive (CMTRI) forms of Intermediate CMT. Known causative genes for the subtypes of CMTDI and CMTRI are included in Table 1.Hereditary neuropathy with liability to pressure palsies (HNPP) is another condition in the CMT group of conditions. HNPP is inherited in an autosomal dominant pattern. Like CMT1A, HNPP is caused by changes to the PMP22 gene. Unlike CMT1A, where the PMP22 gene is usually duplicated, in HNPP one of the PMP22 genes is deleted, so instead of having two copies of PMP22 (one from each parent), HNPP patients only have one copy. This means that patients with HNPP do not produce enough of the PMP22 proteins.CMT3, also called Dejerine-Sottas disease, is no longer a commonly used name because individuals with this condition have been found to have a gene mutation in one of the genes responsible for CMT1A, CMT1B, CMT1D or CMT4. CMT5 and CMT6 are also historically used terms now attributed to damaging changes in the MFN2 gene that is now known to cause CMT2A2A. Historical names for subtypes that are no longer in use are included in parenthesis next to the contemporary subtype name in Table1.Hereditary sensory neuropathies (HSN or HSAN) are sometimes included in the CMT group of conditions. Some forms of HSN are related to or identical to forms of CMT and there is overlap with genes responsible for these conditions. Hereditary motor neuropathies (dHMN) are similar to CMT and some experts consider these conditions to be in the same group.Table 1 Subtypes of CMT, causative genes and inheritance pattern (adapted from Nam,Choi, 2019)
| Causes of Charcot-Marie-Tooth Disease. CMT is known to be a genetic condition caused by genes that have abnormal changes affecting their function. There are now over 100 genes that are known to be responsible for various forms of CMT. A single gene, PMP22, when duplicated, is the cause of around 50% of cases of CMT, while damaging changes in some genes that cause CMT can be extremely rare and found only in a few families. In around 40% of cases of CMT, no responsible gene has yet been identified.Genetic diseases are caused by changes in a single gene or in a combination of genes for a particular trait that are on the chromosomes received from the father and the mother. At this time, genetic causes for CMT can only be identified when a single gene is responsible for the condition, but not when the effect of several genes with damaging changes, known as polygenic inheritance, is suspected. Single genes that cause CMT can be inherited in an autosomal dominant, autosomal recessive, X-linked or X-linked dominant pattern.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.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.X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.X-linked dominant disorders are caused by a non-working gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the non-working gene for a particular disease. Males with a non-working gene for an X-linked dominant disorder are more severely affected than females and often do not survive.The common naming system for CMT disease is a subdivision into several major types termed CMT1, CMT2, CMT3, CMT4, CMTX, CMTDI and CMTRI. If a responsible gene has been identified, a letter is added to the name, such as CMT1A, CMT1B etc. Recently, new naming schemes have been proposed to simplify this by basing names on inheritance pattern, whether the cause is demyelinating, axonal or intermediate and if the causative gene if known. Table 1 lists CMT types using the common nomenclature and lists causative genes. Some of the types were named before genetic causes were well understood, so there is some redundancy in this naming system and some types have proven to be inaccurately attributed to a specific gene making certain subtype names obsolete. For these reasons some names are no longer in common use.CMT1 is the most common form of CMT and is characterized by abnormalities in nerve myelin that leads to decreased nerve conduction velocities. Peripheral nerve myelin is formed by Schwann cells, and abnormal changes in genes involved in formation and function of these Schwann cells leads to demyelination. CMT1 is inherited in an autosomal dominant pattern. CMT1 has been further subdivided into subtypes from CMT1A – 1F based on specific gene abnormalities. CMT1A is by far the most common single subtype of CMT accounting for around 50% of all cases of CMT and is caused by a duplication of the PMP22 gene. Other subtypes of CMT1 and responsible genes are listed in Table 1.CMT2 is a form of the condition in which nerve conduction velocities are usually normal or slightly slower than normal but nerve signal strength is reduced. CMT2 is caused by abnormal genes involved in the structure and function of axons. CMT2 includes primarily autosomal dominant inheritance patterns. CMT2 has been further subdivided into CMT2A – 2Z based on mutations in specific genes. CMT2A is the most common and is caused by mutations in the MFN2 gene. Other subtypes of CMT2 and responsible genes are listed in Table 1. While CMT2 is meant to indicate autosomal dominant inheritance patterns, some subtypes feature autosomal recessive inheritance.CMT4 is a classification strictly for autosomal recessive forms of CMT. CMT4A is caused by an abnormality in the GDAP1 gene; however the GDAP1 gene is also responsible for CMT2H and CMT2K when the damaging changes to it are sufficient to be transmitted through an autosomal dominant inheritance pattern. Other subtypes of CMT4 and responsible genes are listed in Table 1. SORD-related CMT is the current name for an autosomal recessive axonal form of CMT caused by changes in the SORD gene. This gene was only recently found to be responsible for CMT but may be the most common genetic cause of autosomal recessive CMT. It has not yet been given a classification in the common naming system.CMTX is an X-linked dominant form of the condition caused by abnormalities in genes located on the X chromosome. CMTX1 (aka CMT1X), caused by changes in the GJB1 gene, accounts for approximately 90% of CMTX. Other subtypes of CMTX and responsible genes are listed in Table 1. Because GJB1 and these other known and unknown genes that cause CMTX are located on the X-chromosome, CMTX primarily affects males, however in CMTX1 and CMTX6 feature an X-linked dominant inheritance with males being more severely affected than females. In CMTX1 and CMTX6, affected females usually have a later onset than males and a milder condition at every age, or may even be asymptomatic, probably due to X inactivation in the myelinating Schwann cells.Intermediate CMTs include those with “intermediate” conduction velocities and thus an uncertainty regarding whether the neuropathy is primarily axonal or demyelinating. There are both dominant (CMTDI) and recessive (CMTRI) forms of Intermediate CMT. Known causative genes for the subtypes of CMTDI and CMTRI are included in Table 1.Hereditary neuropathy with liability to pressure palsies (HNPP) is another condition in the CMT group of conditions. HNPP is inherited in an autosomal dominant pattern. Like CMT1A, HNPP is caused by changes to the PMP22 gene. Unlike CMT1A, where the PMP22 gene is usually duplicated, in HNPP one of the PMP22 genes is deleted, so instead of having two copies of PMP22 (one from each parent), HNPP patients only have one copy. This means that patients with HNPP do not produce enough of the PMP22 proteins.CMT3, also called Dejerine-Sottas disease, is no longer a commonly used name because individuals with this condition have been found to have a gene mutation in one of the genes responsible for CMT1A, CMT1B, CMT1D or CMT4. CMT5 and CMT6 are also historically used terms now attributed to damaging changes in the MFN2 gene that is now known to cause CMT2A2A. Historical names for subtypes that are no longer in use are included in parenthesis next to the contemporary subtype name in Table1.Hereditary sensory neuropathies (HSN or HSAN) are sometimes included in the CMT group of conditions. Some forms of HSN are related to or identical to forms of CMT and there is overlap with genes responsible for these conditions. Hereditary motor neuropathies (dHMN) are similar to CMT and some experts consider these conditions to be in the same group.Table 1 Subtypes of CMT, causative genes and inheritance pattern (adapted from Nam,Choi, 2019)
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nord_223_3 | Affects of Charcot-Marie-Tooth Disease | CMT is found worldwide in people of all races and ethnic groups. Prevalence rate estimates from epidemiological studies are highly variable due in part to the wide variation of clinical symptoms and different disease forms as well as discrepancies in what conditions are included within CMT. Recent prevalence estimates range from 9 to 28 per 100,000. Symptoms of CMT usually begin gradually in adolescence, early adulthood or middle age. | Affects of Charcot-Marie-Tooth Disease. CMT is found worldwide in people of all races and ethnic groups. Prevalence rate estimates from epidemiological studies are highly variable due in part to the wide variation of clinical symptoms and different disease forms as well as discrepancies in what conditions are included within CMT. Recent prevalence estimates range from 9 to 28 per 100,000. Symptoms of CMT usually begin gradually in adolescence, early adulthood or middle age. | 223 | Charcot-Marie-Tooth Disease |
nord_223_4 | Related disorders of Charcot-Marie-Tooth Disease | Peripheral neuropathy is part of at least 100 inherited syndromes, though it is typically overshadowed by other manifestations. Expert opinions differ on exactly which disorders are similar to but separate from, the same as, or have some overlap with conditions within the CMT group of disorders.Hereditary sensory (and autonomic) neuropathies (HSN or HSAN), include conditions where sensory (and variably autonomic) neurons/axons are affected, with relative or complete sparing of motor neurons/axons. Dominant and recessive mutations in neuronally expressed genes cause HSAN and related disorders. There are over 15 forms of HSAN and they can be inherited in dominant and recessive patterns. Some experts consider these conditions within the same group of conditions as CMT.Distal hereditary motor neuropathies (DHMN) are conditions where motor neurons/axons are affected but sensory fibers are spared. These are a clinically and genetically heterogeneous group of disorders that share genetic causes with distal spinal muscular atrophy (DMSA). They can be inherited in dominant or recessive patterns. Some experts consider these within the same group of conditions as CMT.Other conditions that feature hereditary neuropathy generally considered to be outside of the CMT group include:There are many distal myopathies that share some features with CMT but are also considered outside of the CMT group of conditions. These include: | Related disorders of Charcot-Marie-Tooth Disease. Peripheral neuropathy is part of at least 100 inherited syndromes, though it is typically overshadowed by other manifestations. Expert opinions differ on exactly which disorders are similar to but separate from, the same as, or have some overlap with conditions within the CMT group of disorders.Hereditary sensory (and autonomic) neuropathies (HSN or HSAN), include conditions where sensory (and variably autonomic) neurons/axons are affected, with relative or complete sparing of motor neurons/axons. Dominant and recessive mutations in neuronally expressed genes cause HSAN and related disorders. There are over 15 forms of HSAN and they can be inherited in dominant and recessive patterns. Some experts consider these conditions within the same group of conditions as CMT.Distal hereditary motor neuropathies (DHMN) are conditions where motor neurons/axons are affected but sensory fibers are spared. These are a clinically and genetically heterogeneous group of disorders that share genetic causes with distal spinal muscular atrophy (DMSA). They can be inherited in dominant or recessive patterns. Some experts consider these within the same group of conditions as CMT.Other conditions that feature hereditary neuropathy generally considered to be outside of the CMT group include:There are many distal myopathies that share some features with CMT but are also considered outside of the CMT group of conditions. These include: | 223 | Charcot-Marie-Tooth Disease |
nord_223_5 | Diagnosis of Charcot-Marie-Tooth Disease | The diagnosis of CMT disease can be challenging. Diagnosis is based on physical symptoms, family history and clinical tests. Clinical tests include nerve conduction velocity (NCV) which measures the speed at which impulses travel along the nerves and electromyogram (EMG) which records the electrical activity of muscle cell. With recent advances in molecular genetic testing using both deletion duplication analysis and next generation sequencing (NGS) for patients with a clinical diagnosis of CMT, a genetic cause can be found in about 60% of patients. For CMT1 a genetic cause can be identified in 56-92% of patients. For axonal CMT, genetic causes can be found 17-44% of the time. Panels to test multiple genes can include from 7 to 150 genes, while abnormalities in 4 genes, (PMP22 duplication, GJB1, MFN2, and MPZ) account for about 90% of these genetic diagnoses. | Diagnosis of Charcot-Marie-Tooth Disease. The diagnosis of CMT disease can be challenging. Diagnosis is based on physical symptoms, family history and clinical tests. Clinical tests include nerve conduction velocity (NCV) which measures the speed at which impulses travel along the nerves and electromyogram (EMG) which records the electrical activity of muscle cell. With recent advances in molecular genetic testing using both deletion duplication analysis and next generation sequencing (NGS) for patients with a clinical diagnosis of CMT, a genetic cause can be found in about 60% of patients. For CMT1 a genetic cause can be identified in 56-92% of patients. For axonal CMT, genetic causes can be found 17-44% of the time. Panels to test multiple genes can include from 7 to 150 genes, while abnormalities in 4 genes, (PMP22 duplication, GJB1, MFN2, and MPZ) account for about 90% of these genetic diagnoses. | 223 | Charcot-Marie-Tooth Disease |
nord_223_6 | Therapies of Charcot-Marie-Tooth Disease | TreatmentTreatment of CMT disease is symptomatic and supportive. A cure is not available so it is important to minimize or stall the symptoms. Comprehensive treatments include physical therapy, shoe orthotics, leg braces and surgery to correct deformities. Complementary therapies may help psychologically, relieve pain and discomfort, and improve overall quality of life. Vocational counseling, anticipating progression of the disorder, may be useful for young patients. Genetic counseling can be helpful with many aspects including genetic diagnosis, connecting with research and support groups and in understanding of recurrence risk. | Therapies of Charcot-Marie-Tooth Disease. TreatmentTreatment of CMT disease is symptomatic and supportive. A cure is not available so it is important to minimize or stall the symptoms. Comprehensive treatments include physical therapy, shoe orthotics, leg braces and surgery to correct deformities. Complementary therapies may help psychologically, relieve pain and discomfort, and improve overall quality of life. Vocational counseling, anticipating progression of the disorder, may be useful for young patients. Genetic counseling can be helpful with many aspects including genetic diagnosis, connecting with research and support groups and in understanding of recurrence risk. | 223 | Charcot-Marie-Tooth Disease |
nord_224_0 | Overview of CHARGE Syndrome | CHARGE syndrome is a rare disorder that arises during early fetal development and affects multiple organ systems. The CHARGE acronym comes from the first letter of some of the more common features seen in these children: (C) = coloboma (usually retinochoroidal) and cranial nerve defects (80-90%) (H) = heart defects in 75-85%, especially tetralogy of Fallot (A) = atresia of the choanae (blocked nasal breathing passages) (50-60%) (R) = retardation of growth (70-80%) and development (G) = genital underdevelopment due to hypogonadotropic hypogonadism (E) = ear abnormalities and sensorineural hearing loss (>90%). Diagnosis is based on a specific set of features (see below). In addition to the CHARGE features above, most children with CHARGE syndrome have other features, including characteristic facial features: asymmetric facial nerve palsy, cleft lip or palate, esophageal atresia (blind-ending food pipe) or tracheoesophageal fistula (connection between the wind pipe and the food pipe). The symptoms of CHARGE syndrome vary greatly from one child to another. The cause of CHARGE is usually a new mutation (change) in the CHD7 gene, or rarely, genomic alterations in the region of chromosome 8q12.2 where the CHD7 gene is located. Among 119 French children with CHARGE syndrome, CHD7 mutations were found in 83% of typical CHARGE syndrome individuals, and 58% of atypical cases. The following cardinal symptoms were found among CHD7+ cases: coloboma 73%; heart defects 63%; choanal atresia 43%; IUGR 24%; genital abnormalities 56%; semicircular canal agenesis/hypoplasia 99%; deafness 97%; external ear anomalies 86%; internal ear anomalies (SCC defects excluded) 65%; anosmia 83%; olfactory bulb agenesis 76%; cranial nerve defects 74%; intellectual disability 62%; CNS defects 51%; kidney 31%; esophageal anomalies 24%; and cleft lip and/or palate 20%. Postnatal growth failure and swallowing problems are very frequent associated with cranial nerve dysfunctions. Three-dimensional reconstructions of MRI scans showed temporal bone abnormalities in over 85%. | Overview of CHARGE Syndrome. CHARGE syndrome is a rare disorder that arises during early fetal development and affects multiple organ systems. The CHARGE acronym comes from the first letter of some of the more common features seen in these children: (C) = coloboma (usually retinochoroidal) and cranial nerve defects (80-90%) (H) = heart defects in 75-85%, especially tetralogy of Fallot (A) = atresia of the choanae (blocked nasal breathing passages) (50-60%) (R) = retardation of growth (70-80%) and development (G) = genital underdevelopment due to hypogonadotropic hypogonadism (E) = ear abnormalities and sensorineural hearing loss (>90%). Diagnosis is based on a specific set of features (see below). In addition to the CHARGE features above, most children with CHARGE syndrome have other features, including characteristic facial features: asymmetric facial nerve palsy, cleft lip or palate, esophageal atresia (blind-ending food pipe) or tracheoesophageal fistula (connection between the wind pipe and the food pipe). The symptoms of CHARGE syndrome vary greatly from one child to another. The cause of CHARGE is usually a new mutation (change) in the CHD7 gene, or rarely, genomic alterations in the region of chromosome 8q12.2 where the CHD7 gene is located. Among 119 French children with CHARGE syndrome, CHD7 mutations were found in 83% of typical CHARGE syndrome individuals, and 58% of atypical cases. The following cardinal symptoms were found among CHD7+ cases: coloboma 73%; heart defects 63%; choanal atresia 43%; IUGR 24%; genital abnormalities 56%; semicircular canal agenesis/hypoplasia 99%; deafness 97%; external ear anomalies 86%; internal ear anomalies (SCC defects excluded) 65%; anosmia 83%; olfactory bulb agenesis 76%; cranial nerve defects 74%; intellectual disability 62%; CNS defects 51%; kidney 31%; esophageal anomalies 24%; and cleft lip and/or palate 20%. Postnatal growth failure and swallowing problems are very frequent associated with cranial nerve dysfunctions. Three-dimensional reconstructions of MRI scans showed temporal bone abnormalities in over 85%. | 224 | CHARGE Syndrome |
nord_224_1 | Symptoms of CHARGE Syndrome | CHARGE syndrome affects multiple organ systems, resulting in multiple problems apparent at birth. Other characteristics of CHARGE syndrome may not become apparent until later in life. The diagnosis of CHARGE syndrome should be made by a medical geneticist based on the presence of at least one major criterion and several minor and/or occasional criteria of CHARGE syndrome (see below).Major Diagnostic Criteria (The 4 C’s):
Features seen commonly in CHARGE, rarely in other conditions: Coloboma, Cranial nerve abnormalities, Choanal atresia, typical CHARGE Ear.Coloboma
A coloboma is a cleft or failure to close of the eyeball during fetal development. This can result in a keyhole-shaped pupil (iris coloboma) and/or abnormalities in the retina, macula or optic nerve. Very small eyes (microphthalmia) or missing eyes (anophthalmia) can be severe forms of coloboma. Colobomas of the retina or optic nerve may result in significant vision loss, including blind spots, problems with depth perception or legal blindness. Colobomas occur most frequently in the retina and are present in at least 70-90% of patients with CHARGE syndrome. Examination of 38 eyes in 19 patients with CHARGE syndrome and confirmed CHD7 mutations revealed colobomata affected the posterior segment of 35 eyes in 18 patients. Both retinochoroidal and optic disk colobomata were observed bilaterally in 15 patients and unilaterally in 3 patients. The coloboma involved the macula totally or partially in 21 eyes of 13 patients. Bilateral large retinochoroidal colobomata are the typical ophthalmic feature of CHARGE syndrome in patients with confirmed CHD7 mutations; however, even eyes with large colobomata can form maculas. Many children with colobomas (even just an iris coloboma) may be sensitive to bright light (photophobia). Surgery cannot correct ocular colobomas. Near-sightedness or far-sightedness can be helped with glasses. Sunglasses and a hat with a protective bill can help the photophobia.Cranial nerve abnormalities
Sensorineural (nerve) hearing loss in CHARGE is due to abnormalities in cranial nerve VIII. Cranial CT scan often reveals a hypoplastic cochlea (81%) with absent semicircular canals in most cases. Hearing loss and difficulty with balance are the most common features associated with cochlear hypoplasia and absent semicircular canals. CHARGE syndrome is associated with characteristic external ears that tend to protrude and lack lobes. The hearing loss can range from a mild hearing loss to profound deafness. Hearing loss can be very difficult to measure in young children. Many children with CHARGE receive cochlear implants to aid their sensorineural hearing loss. Most also have balance problems (vestibular abnormalities) associated with absent semicircular canals, which is a key finding in making the diagnosis of CHARGE syndrome.Most children with CHARGE have swallowing problems (cranial nerves IX/X). These swallowing problems include the inability to coordinate suck and swallow, leading to gagging and aspiration of food into the lungs (which can cause pneumonia). Many children require feeding via a gastrostomy tube (tube directly into the stomach through the abdominal wall) until they are able to swallow safely.Many children with CHARGE have asymmetric facial palsy resulting in paralysis of one side of the face (cranial nerve VII). This results in a lack of facial expression, which is important when a child is working with teachers or therapists.Most children with CHARGE have an absent or reduced sense of smell (cranial nerve I), which complicates learning to eat normally. Most patients with CHARGE syndrome have absent or abnormal olfactory bulbs in MRI, leading to a diminished sense of smell. Smell-testing can predict the presence of hypogonadotropic hypogonadism. The combination of defective olfaction (anosmia or hyposmia) with hypogonadotropic hypogonadism (termed Kallman syndrome) results in small external genitalia. This is very common in CHARGE syndrome and warrants consultation with an endocrinologist.Choanal atresia
Choanae are the passages from the back of the nose to the throat that make it possible to breathe through the nose. In about half of all children with CHARGE, these passages may be blocked (atresia) or narrowed (stenosis). Among 12 patients with bilateral choanal atresia, 10 had related malformations, 3 of which had CHARGE syndrome. Surgery can often correct these defects. Patients with unilateral atresia can usually be corrected with 1 surgical procedure at a later age (median 6 years, range 6 months to 18 years), while patients with the bilateral form need a median of 2.85 interventions at an early age (median 25 days, range 6 days-6 years). If both sides are affected, immediate measures must be taken to allow the newborn to breathe properly and prevent respiratory failure.CHARGE ear
Most children with CHARGE have unusual external ears. The “typical CHARGE ear” is short and wide with little or no earlobe. The helix (outer fold) may end abruptly in mid-ear. The center of the ear (concha) is often very triangular in shape. The ears are often floppy and may stick out due to weak cartilage. The two ears often look different from each other. There are also typical findings in the middle ear in CHARGE, including malformed bones of the middle ear (93%) and incomplete cochlea (Mondini defect), which is diagnosed with an MRI scan. In many cases, the external ear can be unique enough to suspect the diagnosis of CHARGE before examining other features, and a temporal bone CT scan to look for absent semicircular canals and evaluate the choanae for atresia or stenosis should prompt mutation analysis of CHD7 to confirm the diagnosis.Minor Diagnostic Criteria:
Features less specific to CHARGE syndrome and/or not consistent enough to be considered major: heart defects, genital abnormalities, kidney abnormalities, cleft lip or palate, TE fistula or esophageal atresia, poor growth, hypotonia, typical CHARGE face, and typical CHARGE hand.Heart defects
About 75-80% of children with CHARGE syndrome have congenital heart defects. Although all types of heart defects have been seen in children with CHARGE syndrome, the most common are tetralogy of Fallot (33%), VSD (ventricular septal defect), AV (atriventricular) canal defect, and aortic arch anomalies. The heart defects can range from an innocent murmur to life-threatening heart defects involving the outflow tracts of the heart. Most require medication and/or surgery. Severe heart defects are a major cause of death in children with CHARGE. The heart defects in CHARGE are similar to those seen in Deletion 22q11.2 syndrome.Genital abnormalities
Most boys with CHARGE syndrome have a small penis, often with undescended testes (cryptorchidism). The urethral opening may not be at the end of the penis (hypospadias). Girls may have small labia. Among 46 boys with hypogonadotropic hypogonadism, 14 (30.4%) had Kallmann syndrome, 4 (8.7%) had CHARGE syndrome and 28 (60.9%) had hypogonadotropic hypogonadism without an olfaction deficit or olfactory bulb hypoplasia. Most children with CHARGE require hormone therapy to achieve puberty due to hypogonadotropic hypogonadism, and a pediatric endocrinologist should evaluate their pituitary gonadal axis.Kidney abnormalities
About 40% of children with CHARGE syndrome have kidney abnormalities. These can include hydronephrosis (extra fluid in the kidneys) or reflux (backflow into the kidneys); horseshoe kidney; small or absent kidney; or multicystic dysplastic kidneys. All children with CHARGE should have a kidney ultrasound.Cleft lip and/or cleft palate
About 25% of children with CHARGE have a cleft lip or cleft palate. The cleft lip can be one-sided or two-sided and may or not include the palate. A positive family history of any individual with an apparently isolated unilateral major CHARGE anomaly, or someone with a few of the minor features, should precipitate testing the affected child and both parents for CHD7. Some have cleft palate without cleft lip. Submucous cleft palate (just the muscle, not the bone in the roof of the mouth) may be hard to diagnose.Tracheoesophageal Fistula/Esophageal atresia
About 15-20% of children with CHARGE are born with an esophageal atresia (EA), where the food pipe is not connected to the stomach or with tracheoesophageal fistula (TEF), where there is a connection between the windpipe (trachea) and the food pipe (esophagus). Both of these conditions require surgery. In addition, the trachea may be weak or floppy due to weak cartilage. This can complicate surgery to treat these conditions.Poor growth
Although birth weight is usually normal, many children with CHARGE are small after birth. Sometimes this is due to nutrition problems, heart problems or multiple illnesses. Some children with CHARGE have growth hormone insufficiency, which can be evaluated with a growth hormone stimulation test.Hypotonia of the trunk
Most children with CHARGE syndrome have upper body hypotonia (weakness). They are weak, especially in the trunk, and may have sloping shoulders. This weakness, especially combined with balance problems and/or vision problems, will delay walking. The average age of walking is about 3 or 4 years in children with CHARGE syndrome, and this results from the combination of hypotonia and diminished balance due to their underdeveloped semicircular canals.Typical CHARGE face
Children with CHARGE syndrome often look similar to one another. The typical child has a square face, with broad prominent forehead, arched eyebrows, large eyes, occasional droopy eyelids, a prominent nasal bridge with square root, small nostrils, prominent nasal columella, flat midface, small mouth, occasional small chin, which improves with age. The face is often very asymmetric.Typical CHARGE hand
Many children with CHARGE have a small thumb, broad palm with “hockey-stick” palmar crease, and short fingers.Other Common Findings
These features may be important for management, but not very helpful in making the diagnosis. Brain abnormalities, including small head (microcephaly), enlarged cerebral ventricles or other abnormalities identified by brain imaging such as MRI or CT scan are occasionally seen. Apnea and seizures are rarely seen in children with CHARGE. Weak cartilage (as seen in the ears) can also affect the trachea (windpipe) making it weak. Sometimes the baby has a very weak cry due to laryngomalacia (weak vocal cords). A few children with CHARGE syndrome have missing or extra nipples. Some have a relatively wide neck, with occasional cervical vertebral abnormalities. Rarely, children with CHARGE have an umbilical hernia, omphalocele or limb abnormalities, such as abnormal thumbs or extra fingers.A few children with CHARGE have DiGeorge sequence, consisting of a complex heart defect, immune deficiency, and abnormalities of the thyroid and parathyroid glands. Because these features are also seen in VCF, children with possible CHARGE and no mutation in CHD7 should have array comparative genomic hybridization testing done. Some children with CHARGE appear to have a poor immune response even, and the presence of hypocalcemia should prompt an immunologic evaluation. Most children with CHARGE syndrome and immunodeficiency have T-cell deficiency.Many children with CHARGE develop scoliosis, even as relatively young children. This may be due in part to their weak upper body, but a skeletal survey should be carried out to exclude skeletal anomalies, particularly those of the cervical spine.Developmental Features as Signs of CHARGE Syndrome
Most young children with CHARGE are developmentally delayed. Often, this is primarily due to sensory deficits (vision and/or hearing loss) and frequent illnesses and hospitalizations as infants and young children. Although developmentally delayed, many children with CHARGE will show significant catch up in later childhood, manifesting normal intellectual abilities, and ending up as independent adults. It is not possible to predict eventual development for any one child, and early intervention with a deaf-blind specialist is essential to remediate their sensory deficits and prevent behavioral problems. Regardless of the extent of inner ear anomalies and intellectual faculties, cochlear implantation with careful treatment planning can be a highly effective option for hearing rehabilitation in children with sensorineural hearing loss and CHARGE syndrome.As children with CHARGE grow older, challenging behaviors can emerge. Some children display autistic-like behaviors such as hand waving or head banging. Often, these are attempts at communication by a child who has not yet developed language or other communication skills due to hearing and vision problems. These behaviors occur less often when a communication system (speech, signs, or a combination of both) is established. Older individuals with CHARGE may show signs of obsessive-compulsive disorder. Many children with CHARGE begin communication using sign language or some form of gestures and communication boards. Those with cochlear implants or hearing aids that bring hearing into the normal range will usually switch over to oral speech at some point. Learning signs first does not keep children from speaking later. | Symptoms of CHARGE Syndrome. CHARGE syndrome affects multiple organ systems, resulting in multiple problems apparent at birth. Other characteristics of CHARGE syndrome may not become apparent until later in life. The diagnosis of CHARGE syndrome should be made by a medical geneticist based on the presence of at least one major criterion and several minor and/or occasional criteria of CHARGE syndrome (see below).Major Diagnostic Criteria (The 4 C’s):
Features seen commonly in CHARGE, rarely in other conditions: Coloboma, Cranial nerve abnormalities, Choanal atresia, typical CHARGE Ear.Coloboma
A coloboma is a cleft or failure to close of the eyeball during fetal development. This can result in a keyhole-shaped pupil (iris coloboma) and/or abnormalities in the retina, macula or optic nerve. Very small eyes (microphthalmia) or missing eyes (anophthalmia) can be severe forms of coloboma. Colobomas of the retina or optic nerve may result in significant vision loss, including blind spots, problems with depth perception or legal blindness. Colobomas occur most frequently in the retina and are present in at least 70-90% of patients with CHARGE syndrome. Examination of 38 eyes in 19 patients with CHARGE syndrome and confirmed CHD7 mutations revealed colobomata affected the posterior segment of 35 eyes in 18 patients. Both retinochoroidal and optic disk colobomata were observed bilaterally in 15 patients and unilaterally in 3 patients. The coloboma involved the macula totally or partially in 21 eyes of 13 patients. Bilateral large retinochoroidal colobomata are the typical ophthalmic feature of CHARGE syndrome in patients with confirmed CHD7 mutations; however, even eyes with large colobomata can form maculas. Many children with colobomas (even just an iris coloboma) may be sensitive to bright light (photophobia). Surgery cannot correct ocular colobomas. Near-sightedness or far-sightedness can be helped with glasses. Sunglasses and a hat with a protective bill can help the photophobia.Cranial nerve abnormalities
Sensorineural (nerve) hearing loss in CHARGE is due to abnormalities in cranial nerve VIII. Cranial CT scan often reveals a hypoplastic cochlea (81%) with absent semicircular canals in most cases. Hearing loss and difficulty with balance are the most common features associated with cochlear hypoplasia and absent semicircular canals. CHARGE syndrome is associated with characteristic external ears that tend to protrude and lack lobes. The hearing loss can range from a mild hearing loss to profound deafness. Hearing loss can be very difficult to measure in young children. Many children with CHARGE receive cochlear implants to aid their sensorineural hearing loss. Most also have balance problems (vestibular abnormalities) associated with absent semicircular canals, which is a key finding in making the diagnosis of CHARGE syndrome.Most children with CHARGE have swallowing problems (cranial nerves IX/X). These swallowing problems include the inability to coordinate suck and swallow, leading to gagging and aspiration of food into the lungs (which can cause pneumonia). Many children require feeding via a gastrostomy tube (tube directly into the stomach through the abdominal wall) until they are able to swallow safely.Many children with CHARGE have asymmetric facial palsy resulting in paralysis of one side of the face (cranial nerve VII). This results in a lack of facial expression, which is important when a child is working with teachers or therapists.Most children with CHARGE have an absent or reduced sense of smell (cranial nerve I), which complicates learning to eat normally. Most patients with CHARGE syndrome have absent or abnormal olfactory bulbs in MRI, leading to a diminished sense of smell. Smell-testing can predict the presence of hypogonadotropic hypogonadism. The combination of defective olfaction (anosmia or hyposmia) with hypogonadotropic hypogonadism (termed Kallman syndrome) results in small external genitalia. This is very common in CHARGE syndrome and warrants consultation with an endocrinologist.Choanal atresia
Choanae are the passages from the back of the nose to the throat that make it possible to breathe through the nose. In about half of all children with CHARGE, these passages may be blocked (atresia) or narrowed (stenosis). Among 12 patients with bilateral choanal atresia, 10 had related malformations, 3 of which had CHARGE syndrome. Surgery can often correct these defects. Patients with unilateral atresia can usually be corrected with 1 surgical procedure at a later age (median 6 years, range 6 months to 18 years), while patients with the bilateral form need a median of 2.85 interventions at an early age (median 25 days, range 6 days-6 years). If both sides are affected, immediate measures must be taken to allow the newborn to breathe properly and prevent respiratory failure.CHARGE ear
Most children with CHARGE have unusual external ears. The “typical CHARGE ear” is short and wide with little or no earlobe. The helix (outer fold) may end abruptly in mid-ear. The center of the ear (concha) is often very triangular in shape. The ears are often floppy and may stick out due to weak cartilage. The two ears often look different from each other. There are also typical findings in the middle ear in CHARGE, including malformed bones of the middle ear (93%) and incomplete cochlea (Mondini defect), which is diagnosed with an MRI scan. In many cases, the external ear can be unique enough to suspect the diagnosis of CHARGE before examining other features, and a temporal bone CT scan to look for absent semicircular canals and evaluate the choanae for atresia or stenosis should prompt mutation analysis of CHD7 to confirm the diagnosis.Minor Diagnostic Criteria:
Features less specific to CHARGE syndrome and/or not consistent enough to be considered major: heart defects, genital abnormalities, kidney abnormalities, cleft lip or palate, TE fistula or esophageal atresia, poor growth, hypotonia, typical CHARGE face, and typical CHARGE hand.Heart defects
About 75-80% of children with CHARGE syndrome have congenital heart defects. Although all types of heart defects have been seen in children with CHARGE syndrome, the most common are tetralogy of Fallot (33%), VSD (ventricular septal defect), AV (atriventricular) canal defect, and aortic arch anomalies. The heart defects can range from an innocent murmur to life-threatening heart defects involving the outflow tracts of the heart. Most require medication and/or surgery. Severe heart defects are a major cause of death in children with CHARGE. The heart defects in CHARGE are similar to those seen in Deletion 22q11.2 syndrome.Genital abnormalities
Most boys with CHARGE syndrome have a small penis, often with undescended testes (cryptorchidism). The urethral opening may not be at the end of the penis (hypospadias). Girls may have small labia. Among 46 boys with hypogonadotropic hypogonadism, 14 (30.4%) had Kallmann syndrome, 4 (8.7%) had CHARGE syndrome and 28 (60.9%) had hypogonadotropic hypogonadism without an olfaction deficit or olfactory bulb hypoplasia. Most children with CHARGE require hormone therapy to achieve puberty due to hypogonadotropic hypogonadism, and a pediatric endocrinologist should evaluate their pituitary gonadal axis.Kidney abnormalities
About 40% of children with CHARGE syndrome have kidney abnormalities. These can include hydronephrosis (extra fluid in the kidneys) or reflux (backflow into the kidneys); horseshoe kidney; small or absent kidney; or multicystic dysplastic kidneys. All children with CHARGE should have a kidney ultrasound.Cleft lip and/or cleft palate
About 25% of children with CHARGE have a cleft lip or cleft palate. The cleft lip can be one-sided or two-sided and may or not include the palate. A positive family history of any individual with an apparently isolated unilateral major CHARGE anomaly, or someone with a few of the minor features, should precipitate testing the affected child and both parents for CHD7. Some have cleft palate without cleft lip. Submucous cleft palate (just the muscle, not the bone in the roof of the mouth) may be hard to diagnose.Tracheoesophageal Fistula/Esophageal atresia
About 15-20% of children with CHARGE are born with an esophageal atresia (EA), where the food pipe is not connected to the stomach or with tracheoesophageal fistula (TEF), where there is a connection between the windpipe (trachea) and the food pipe (esophagus). Both of these conditions require surgery. In addition, the trachea may be weak or floppy due to weak cartilage. This can complicate surgery to treat these conditions.Poor growth
Although birth weight is usually normal, many children with CHARGE are small after birth. Sometimes this is due to nutrition problems, heart problems or multiple illnesses. Some children with CHARGE have growth hormone insufficiency, which can be evaluated with a growth hormone stimulation test.Hypotonia of the trunk
Most children with CHARGE syndrome have upper body hypotonia (weakness). They are weak, especially in the trunk, and may have sloping shoulders. This weakness, especially combined with balance problems and/or vision problems, will delay walking. The average age of walking is about 3 or 4 years in children with CHARGE syndrome, and this results from the combination of hypotonia and diminished balance due to their underdeveloped semicircular canals.Typical CHARGE face
Children with CHARGE syndrome often look similar to one another. The typical child has a square face, with broad prominent forehead, arched eyebrows, large eyes, occasional droopy eyelids, a prominent nasal bridge with square root, small nostrils, prominent nasal columella, flat midface, small mouth, occasional small chin, which improves with age. The face is often very asymmetric.Typical CHARGE hand
Many children with CHARGE have a small thumb, broad palm with “hockey-stick” palmar crease, and short fingers.Other Common Findings
These features may be important for management, but not very helpful in making the diagnosis. Brain abnormalities, including small head (microcephaly), enlarged cerebral ventricles or other abnormalities identified by brain imaging such as MRI or CT scan are occasionally seen. Apnea and seizures are rarely seen in children with CHARGE. Weak cartilage (as seen in the ears) can also affect the trachea (windpipe) making it weak. Sometimes the baby has a very weak cry due to laryngomalacia (weak vocal cords). A few children with CHARGE syndrome have missing or extra nipples. Some have a relatively wide neck, with occasional cervical vertebral abnormalities. Rarely, children with CHARGE have an umbilical hernia, omphalocele or limb abnormalities, such as abnormal thumbs or extra fingers.A few children with CHARGE have DiGeorge sequence, consisting of a complex heart defect, immune deficiency, and abnormalities of the thyroid and parathyroid glands. Because these features are also seen in VCF, children with possible CHARGE and no mutation in CHD7 should have array comparative genomic hybridization testing done. Some children with CHARGE appear to have a poor immune response even, and the presence of hypocalcemia should prompt an immunologic evaluation. Most children with CHARGE syndrome and immunodeficiency have T-cell deficiency.Many children with CHARGE develop scoliosis, even as relatively young children. This may be due in part to their weak upper body, but a skeletal survey should be carried out to exclude skeletal anomalies, particularly those of the cervical spine.Developmental Features as Signs of CHARGE Syndrome
Most young children with CHARGE are developmentally delayed. Often, this is primarily due to sensory deficits (vision and/or hearing loss) and frequent illnesses and hospitalizations as infants and young children. Although developmentally delayed, many children with CHARGE will show significant catch up in later childhood, manifesting normal intellectual abilities, and ending up as independent adults. It is not possible to predict eventual development for any one child, and early intervention with a deaf-blind specialist is essential to remediate their sensory deficits and prevent behavioral problems. Regardless of the extent of inner ear anomalies and intellectual faculties, cochlear implantation with careful treatment planning can be a highly effective option for hearing rehabilitation in children with sensorineural hearing loss and CHARGE syndrome.As children with CHARGE grow older, challenging behaviors can emerge. Some children display autistic-like behaviors such as hand waving or head banging. Often, these are attempts at communication by a child who has not yet developed language or other communication skills due to hearing and vision problems. These behaviors occur less often when a communication system (speech, signs, or a combination of both) is established. Older individuals with CHARGE may show signs of obsessive-compulsive disorder. Many children with CHARGE begin communication using sign language or some form of gestures and communication boards. Those with cochlear implants or hearing aids that bring hearing into the normal range will usually switch over to oral speech at some point. Learning signs first does not keep children from speaking later. | 224 | CHARGE Syndrome |
nord_224_2 | Causes of CHARGE Syndrome | The cause of CHARGE is usually a new mutation (change) in the CHD7 gene, or rarely, genomic alterations in the region of chromosome 8 (8q12.2) where the CHD7 gene is located. CHD7 function is required for the development of the retina and cranial motor neurons. Over 90 % of typical CHARGE patients have mutations in the CHD7 gene, while 65 %-70 % of all typical and suspected cases combined are demonstrate CHD7 mutations. The mutations are equally distributed along the coding region of CHD7 and most are nonsense or frameshift mutations. Pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5′ and 3′ regions. CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations. Intragenic or promotor sequence complex genomic rearrangements can be missed by current sequencing without duplication/deletion or MLPA analysis. Most cases of CHARGE syndrome occur sporadically, often in association with older paternal age. In 12 out of 13 families, the mutation affected the paternal allele (92.3%), with a mean paternal age at birth of 32.92 years. In rare cases, CHARGE has run in families, either two affected children or a parent and child affected, either because of parental mosaicism for a CHD7 mutation, which results in a parent being mildly affected or not affected at all.There are no known teratogens (exposures during pregnancy) that have been associated with CHARGE syndrome. Retinoic acid or isotretonin (a medicine taken for severe acne) can cause similar malformations when taken during the first trimester of pregnancy. | Causes of CHARGE Syndrome. The cause of CHARGE is usually a new mutation (change) in the CHD7 gene, or rarely, genomic alterations in the region of chromosome 8 (8q12.2) where the CHD7 gene is located. CHD7 function is required for the development of the retina and cranial motor neurons. Over 90 % of typical CHARGE patients have mutations in the CHD7 gene, while 65 %-70 % of all typical and suspected cases combined are demonstrate CHD7 mutations. The mutations are equally distributed along the coding region of CHD7 and most are nonsense or frameshift mutations. Pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5′ and 3′ regions. CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations. Intragenic or promotor sequence complex genomic rearrangements can be missed by current sequencing without duplication/deletion or MLPA analysis. Most cases of CHARGE syndrome occur sporadically, often in association with older paternal age. In 12 out of 13 families, the mutation affected the paternal allele (92.3%), with a mean paternal age at birth of 32.92 years. In rare cases, CHARGE has run in families, either two affected children or a parent and child affected, either because of parental mosaicism for a CHD7 mutation, which results in a parent being mildly affected or not affected at all.There are no known teratogens (exposures during pregnancy) that have been associated with CHARGE syndrome. Retinoic acid or isotretonin (a medicine taken for severe acne) can cause similar malformations when taken during the first trimester of pregnancy. | 224 | CHARGE Syndrome |
nord_224_3 | Affects of CHARGE Syndrome | CHARGE syndrome is a rare disorder, affecting 0.1-1.2/10,000 live births. It affects males and females in equal numbers and has been seen in all races and on every continent. There are far more cases of CHARGE than those described in the medical literature. Many cases are misdiagnosed or undiagnosed, especially in children with fewer problems. Although many features of CHARGE are apparent at birth, some features will not become apparent for weeks, months, or perhaps years later. The recurrence risk of CHARGE for parents with one affected child is low, around 2-3 percent. The recurrence risk for an adult with CHARGE to have an affected child may be as high as 50 percent. | Affects of CHARGE Syndrome. CHARGE syndrome is a rare disorder, affecting 0.1-1.2/10,000 live births. It affects males and females in equal numbers and has been seen in all races and on every continent. There are far more cases of CHARGE than those described in the medical literature. Many cases are misdiagnosed or undiagnosed, especially in children with fewer problems. Although many features of CHARGE are apparent at birth, some features will not become apparent for weeks, months, or perhaps years later. The recurrence risk of CHARGE for parents with one affected child is low, around 2-3 percent. The recurrence risk for an adult with CHARGE to have an affected child may be as high as 50 percent. | 224 | CHARGE Syndrome |
nord_224_4 | Related disorders of CHARGE Syndrome | Symptoms of the following disorders can be similar to those of CHARGE syndrome. Comparisons may be useful for a differential diagnosis.DiGeorge sequence, which consists of complex heart defects, immunodeficiency and abnormalities of the thyroid and parathyroid glands, may occur in CHARGE syndrome, with 72% manifesting hypocalcemia and 60% demonstrating lymphopenia. Some children with CHARGE appear to have poor immune responses to infections. Because these features are also seen in 22q11.2 deletion syndrome, children with possible CHARGE should have array comparative hybridization testing if mutation analysis of CHD7 is negative. A variety of chromosome abnormalities can result in features that overlap with CHARGE. Most have different ear anomalies and facial features, and many of these disorders can be ruled out by array comparative hybridization, which is a more advanced form or chromosome analysis.Deletion 22q11.2 syndrome (Velocardiofacial syndrome, Shprintzen syndrome) is far more common than CHARGE syndrome. There are many overlapping features in these two disorders. VCF is characterized by velopharyngeal incompetence (cleft palate and/or swallowing problems), cardiac (heart) defects, and a typical face (long and narrow). Many children with VCF also have DiGeorge sequence. The overwhelming majority of children with VCF have a microdeletion (tiny missing piece) of chromosome 22 (deletion 22q11.2) which can also be detected by a special lab technique called FISH (fluorescent in-situ hybridization) or chromosomal microarray (which is a broader test which shows the size of the deletion and detects other chromosomal abnormalities too). There are at least 7 published patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and typical 22q11.2 deletion features were found in 3.7% of 802 CHD7 mutation-positive patients with CHARGE syndrome. It is recommended to perform CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 deletion, and conversely, to perform a genome-wide chromosomal microarray in CHARGE syndrome patients without a CHD7 mutation.The heart defects and swallowing problems seen in deletion 22q11.2 can be nearly identical to those seen in CHARGE. However, the characteristic ears, face and temporal bone findings are distinctly different, as are the hands (long and slender hands in VCF vs. short and broad in CHARGE; long face in VCF, square face in CHARGE). Only about 5 percent of children with CHARGE have complete DiGeorge sequence as part of CHARGE. Conversely, of all the children with DiGeorge sequence, about 85 percent have VCF with a chromosome 22q11.2 deletion, 5 percent have CHARGE and 10 percent have something else. To date, there has not been a single individual with definite CHARGE who had a FISH test that was positive for the 22q11 deletion. (For more information on this disorder, choose Shprintzen-VCF as your search term in the Rare Disease Database).Kabuki syndrome is a rare multisystem disorder characterized by five cardinal manifestations including typical facial features, skeletal anomalies, dermatoglyphic abnormalities, mild to moderate intellectual disability, and postnatal growth deficiency. Germline mutations in KMT2D underlie the molecular pathogenesis of 52-76% of patients with Kabuki syndrome. There is clearly a phenotypic overlap between Kabuki syndrome and CHARGE syndrome, so it is important to consider the possibility of a diagnosis of Kabuki syndrome in CHD7-negative patients present with typical symptoms who meet diagnostic criteria of CHARGE syndrome. CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7) and lysine (K) methyltransferase 2D (KMT2D), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. DNA methylation signatures are able to differentiate pathogenic mutations in these two genes from controls and from each other with common gene targets, including homeobox A5 (HOXA5), which could account for some of the clinical overlap in CHARGE and Kabuki syndromes.Retinoic acid embryopathy is a very rare disorder caused by exposure of a fetus to retinoic acid (or isotretonin, which is used to treat acne) during pregnancy. The ear malformations of this syndrome can be similar to CHARGE ears. However, other features are different. (For more information on this disorder, choose Fetal Retinoid Syndrome as your search term in the Rare Disease Database). | Related disorders of CHARGE Syndrome. Symptoms of the following disorders can be similar to those of CHARGE syndrome. Comparisons may be useful for a differential diagnosis.DiGeorge sequence, which consists of complex heart defects, immunodeficiency and abnormalities of the thyroid and parathyroid glands, may occur in CHARGE syndrome, with 72% manifesting hypocalcemia and 60% demonstrating lymphopenia. Some children with CHARGE appear to have poor immune responses to infections. Because these features are also seen in 22q11.2 deletion syndrome, children with possible CHARGE should have array comparative hybridization testing if mutation analysis of CHD7 is negative. A variety of chromosome abnormalities can result in features that overlap with CHARGE. Most have different ear anomalies and facial features, and many of these disorders can be ruled out by array comparative hybridization, which is a more advanced form or chromosome analysis.Deletion 22q11.2 syndrome (Velocardiofacial syndrome, Shprintzen syndrome) is far more common than CHARGE syndrome. There are many overlapping features in these two disorders. VCF is characterized by velopharyngeal incompetence (cleft palate and/or swallowing problems), cardiac (heart) defects, and a typical face (long and narrow). Many children with VCF also have DiGeorge sequence. The overwhelming majority of children with VCF have a microdeletion (tiny missing piece) of chromosome 22 (deletion 22q11.2) which can also be detected by a special lab technique called FISH (fluorescent in-situ hybridization) or chromosomal microarray (which is a broader test which shows the size of the deletion and detects other chromosomal abnormalities too). There are at least 7 published patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and typical 22q11.2 deletion features were found in 3.7% of 802 CHD7 mutation-positive patients with CHARGE syndrome. It is recommended to perform CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 deletion, and conversely, to perform a genome-wide chromosomal microarray in CHARGE syndrome patients without a CHD7 mutation.The heart defects and swallowing problems seen in deletion 22q11.2 can be nearly identical to those seen in CHARGE. However, the characteristic ears, face and temporal bone findings are distinctly different, as are the hands (long and slender hands in VCF vs. short and broad in CHARGE; long face in VCF, square face in CHARGE). Only about 5 percent of children with CHARGE have complete DiGeorge sequence as part of CHARGE. Conversely, of all the children with DiGeorge sequence, about 85 percent have VCF with a chromosome 22q11.2 deletion, 5 percent have CHARGE and 10 percent have something else. To date, there has not been a single individual with definite CHARGE who had a FISH test that was positive for the 22q11 deletion. (For more information on this disorder, choose Shprintzen-VCF as your search term in the Rare Disease Database).Kabuki syndrome is a rare multisystem disorder characterized by five cardinal manifestations including typical facial features, skeletal anomalies, dermatoglyphic abnormalities, mild to moderate intellectual disability, and postnatal growth deficiency. Germline mutations in KMT2D underlie the molecular pathogenesis of 52-76% of patients with Kabuki syndrome. There is clearly a phenotypic overlap between Kabuki syndrome and CHARGE syndrome, so it is important to consider the possibility of a diagnosis of Kabuki syndrome in CHD7-negative patients present with typical symptoms who meet diagnostic criteria of CHARGE syndrome. CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7) and lysine (K) methyltransferase 2D (KMT2D), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. DNA methylation signatures are able to differentiate pathogenic mutations in these two genes from controls and from each other with common gene targets, including homeobox A5 (HOXA5), which could account for some of the clinical overlap in CHARGE and Kabuki syndromes.Retinoic acid embryopathy is a very rare disorder caused by exposure of a fetus to retinoic acid (or isotretonin, which is used to treat acne) during pregnancy. The ear malformations of this syndrome can be similar to CHARGE ears. However, other features are different. (For more information on this disorder, choose Fetal Retinoid Syndrome as your search term in the Rare Disease Database). | 224 | CHARGE Syndrome |
nord_224_5 | Diagnosis of CHARGE Syndrome | A medical geneticist or other specialist familiar with CHARGE syndrome should do a complete physical exam and order tests to look for the major and minor features of CHARGE listed above. Other similar disorders such as 22q11.2 deletion syndrome, Mowat-Wilson syndrome, Kabuki syndrome, Kallman syndrome, and EFTUD2 haploinsufficiency (multiple congenital anomalies/intellectual disability syndrome characterized by the association of mandibulofacial dysostosis with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, esophageal atresia, congenital heart defects, and radial ray defects) need to be ruled out as well. Among 28 Mowat-Wilson syndrome patients with molecular confirmation of a ZEB2 mutation, 2 patients had clinical features of CHARGE syndrome (choanal atresia, coloboma, cardiac defects, genitourinary anomaly, and severe intellectual disability). Cases of Kabuki syndrome have presented with atypical features, consisting of bilateral microphthalmia, coloboma, anal atresia and panhypopituitarism, showing considerable phenotypic overlap with CHARGE syndrome. Mutations in the KMT2D gene, which encodes a H3K4 histone methyltransferase, are the major cause of Kabuki syndrome. Another patient, who was initially diagnosed with CHARGE syndrome (choanal hypoplasia, heart defect, anal atresia, vision problems and conductive hearing impairment), but sequencing and MLPA analysis of all coding exons of CHD7 revealed no pathogenic mutation, while sequence analysis of the KMT2D gene identified the heterozygous de novo nonsense mutation confirming a diagnosis of Kabuki syndrome. CHD7 and KMT2D function in the same chromatin modification machinery, providing a probable explanation for the phenotypic overlap between Kabuki and CHARGE syndromes.Molecular Genetic testing is available for mutations in the CHD7 gene associated with the condition, and if this is negative, a SNP chromosomal microarray should be done, because in a few cases, there has been a submicroscopic genomic alteration of chromosome 8q12.2. If both these tests are negative, whole genome exome sequencing should be done, since other genetic disorders share some clinical features with CHARGE syndrome, and de novo mutations in ZEB2, KMT2D and EFTUD2 have been detected in children previously diagnosed as having CHARGE syndrome. | Diagnosis of CHARGE Syndrome. A medical geneticist or other specialist familiar with CHARGE syndrome should do a complete physical exam and order tests to look for the major and minor features of CHARGE listed above. Other similar disorders such as 22q11.2 deletion syndrome, Mowat-Wilson syndrome, Kabuki syndrome, Kallman syndrome, and EFTUD2 haploinsufficiency (multiple congenital anomalies/intellectual disability syndrome characterized by the association of mandibulofacial dysostosis with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, esophageal atresia, congenital heart defects, and radial ray defects) need to be ruled out as well. Among 28 Mowat-Wilson syndrome patients with molecular confirmation of a ZEB2 mutation, 2 patients had clinical features of CHARGE syndrome (choanal atresia, coloboma, cardiac defects, genitourinary anomaly, and severe intellectual disability). Cases of Kabuki syndrome have presented with atypical features, consisting of bilateral microphthalmia, coloboma, anal atresia and panhypopituitarism, showing considerable phenotypic overlap with CHARGE syndrome. Mutations in the KMT2D gene, which encodes a H3K4 histone methyltransferase, are the major cause of Kabuki syndrome. Another patient, who was initially diagnosed with CHARGE syndrome (choanal hypoplasia, heart defect, anal atresia, vision problems and conductive hearing impairment), but sequencing and MLPA analysis of all coding exons of CHD7 revealed no pathogenic mutation, while sequence analysis of the KMT2D gene identified the heterozygous de novo nonsense mutation confirming a diagnosis of Kabuki syndrome. CHD7 and KMT2D function in the same chromatin modification machinery, providing a probable explanation for the phenotypic overlap between Kabuki and CHARGE syndromes.Molecular Genetic testing is available for mutations in the CHD7 gene associated with the condition, and if this is negative, a SNP chromosomal microarray should be done, because in a few cases, there has been a submicroscopic genomic alteration of chromosome 8q12.2. If both these tests are negative, whole genome exome sequencing should be done, since other genetic disorders share some clinical features with CHARGE syndrome, and de novo mutations in ZEB2, KMT2D and EFTUD2 have been detected in children previously diagnosed as having CHARGE syndrome. | 224 | CHARGE Syndrome |
nord_224_6 | Therapies of CHARGE Syndrome | Treatment
Although these children have many problems, they can survive and become healthy, happy citizens. Many of the structural abnormalities (choanal atresia, heart defects, cleft lip, etc.) can be surgically corrected. Others, such as feeding problems and speech and language deficits may require years of therapy and other interventions. Infants diagnosed with CHARGE syndrome will need to be followed by a number of medical and developmental specialists, depending on their individual needs. Some of the medical specialists who often follow children with CHARGE syndrome include genetics, cardiology, audiology and ENT, ophthalmology, urology, and endocrinology.More than 50% of children with CHARGE syndrome experience sleep disturbances, and obstructive sleep apnea appears to be prevalent in children with CHARGE syndrome. All conventional treatments for obstructive sleep apnea reduce symptoms. Botulinum toxin A (Botox) has been used to reduce excess salivary secretions in a ventilator-dependant infant with CHARGE syndrome who would have required a tracheotomy. Venous anomalies of the temporal bone were present in 10 of 18 (56%) patients with CHARGE syndrome. The pattern of venous abnormality suggests that there is a failure of the sigmoid sinus/jugular bulb to fully develop, resulting in persistence of emissary veins. Recognition of these abnormal venous structures during otologic surgery is critical to avoiding potentially catastrophic bleeding.Analysis of CHD7 in 12 patients with semicircular canal dysplasia and variable clinical features of CHARGE syndrome revealed 6 CHD7 mutations, 5 of which occurred in patients who fulfilled diagnostic criteria for typical CHARGE syndrome, and three of which were previously undiagnosed. Among 7 children with CHARGE and congenital profound hearing loss, all had hypoplastic or absent auditory nerves, affecting their outcomes with cochlear implants. Of 30 ears evaluated with CT, 28 (93%) had major abnormalities of the inner ear including hypoplasia or aplasia of the semicircular canals and abnormalities of the cochlea and vestibule. CT imaging revealed cochlear aperture narrowing or occlusion in 16 ears, one of which had normal hearing. Among 8 patients with profound sensorineural hearing loss who underwent magnetic resonance imaging 13 of 14 ears were noted to have absent or deficient cochlear nerves. Because of the implications of cochlear nerve deficiency in therapeutic decision-making regarding cochlear implantation, MRI evaluation of the eighth nerve should be considered in CHARGE patients with profound sensorineural hearing loss. In patients with markedly abnormal middle ear anatomy, CT image guided surgery was helpful. These children were offered a bilingual early intervention approach, using sign language and verbal language, to ensure best language outcomes. Children with CHARGE syndrome and progressive profound hearing loss did well with cochlear implants and continued to use verbal language. Numerous patients have undergone cochlear implantation, with most patients demonstrating favorable outcomes. Larger diameter of the cochleovestibular nerve on imaging and absence of severe intellectual disability were factors related to better outcomes after cochlear implantation, rather than the type of CHD7 mutations. Auditory brainstem implantation may be a viable option in patients with CHARGE syndrome who have failed to benefit from cochlear implantation.A novel mouse model of CHD7 dysfunction, termed Looper, harbors a nonsense mutation within the Chd7 gene. Looper mice exhibit growth retardation, facial asymmetry, vestibular defects, eye anomalies, hyperactivity, ossicle malformation, hearing loss and vestibular dysfunction. Chd7 also regulates genes involved in neural crest cell guidance, demonstrating a significant role in the pathogenesis of CHARGE syndrome. Mice with heterozygous Chd7 mutations exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis. Chd7 is highly expressed in mature inner and outer hair cells, spiral ganglion neurons, vestibular sensory epithelia and middle ear ossicles.Among 202 patients with CHD7 mutations and CHARGE syndrome, a wide range of heart defects in 74% this cohort of patients. Conotruncal defects and atrioventricular septal defects were over-represented in patients with CHD7 mutations compared with patients with non-syndromic heart defects. However, CHD7 mutations are not a major cause of atrioventricular septal and conotruncal heart defects. Work with mouse models demonstrate that CHD7 plays an important role in the cardiogenic mesoderm during cardiovascular development.Among 25 patients with CHARGE syndrome, 76% of subjects had some type of endocrine disorder: short stature (72%), hypogonadotropic hypogonadism (60%), hypothyroidism (16%), and combined hypopituitarism (8%). A mutation in CHD7 was found in 80% of these subjects. Analysis of growth in 19 children with CHARGE syndrome, revealed a significant loss of median body length, at around 4 weeks of age from -0.5 to -2.3 standard deviations (SDS). At 1 year, the median length was -2.6 SDS and it remained low until 5 years of age when the lowest value was found to be -2.8 SDS. There was a significant increase in median body mass index (BMI) from -1.15 SDS at 1 year to -0.15 SDS at 5 years. Children with CHARGE syndrome displayed almost normal length and weight data at birth, with just one of the 19 infants having below average length for gestational age. Among 16 children with CHARGE syndrome, short stature, and decreased levels of serum growth hormone (GH), conventional doses of GH had a positive effect on short-term growth velocity without any safety issues or adverse effect on BMI. At the start of GH therapy, height was -3.6 SDS and after 2.7 years of GH therapy, height increased to -2.2 SDS in these patients with CHARGE syndrome. Hormonal management also helps treat symptoms of hypogonadism. Among 209 Kallman syndrome patients who had not been diagnosed with CHARGE syndrome, mutations in CHD7 were found in 24 patients (11.5%). Among 783 patients with isolated gonadotropin-releasing hormone deficiency lacking full CHARGE features, CHD7 variants were found in 5.2% of this cohort (73% missense and 27% splice variants), of which 75% were deleterious. Chd7 mutant mouse embryos have CHD7 dosage-dependent reductions in expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode suggesting that that CHD7 plays a critical role in the development and maintenance of gonadotropin-releasing hormone neurons for regulating puberty and reproduction.Others involved in the treatment of children with CHARGE include deaf/blind specialists, occupational therapy, physical therapy and speech therapy. Appropriate therapies and educational interventions must take into account any hearing and vision loss, which is present. The intelligence of children with CHARGE is often underestimated due to the combined hearing and vision problems. A deaf/blind specialist (not just a vision specialist and a hearing specialist) is critical for any child with someone with both vision loss and some hearing loss.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. A team approach is essential for these complex children. | Therapies of CHARGE Syndrome. Treatment
Although these children have many problems, they can survive and become healthy, happy citizens. Many of the structural abnormalities (choanal atresia, heart defects, cleft lip, etc.) can be surgically corrected. Others, such as feeding problems and speech and language deficits may require years of therapy and other interventions. Infants diagnosed with CHARGE syndrome will need to be followed by a number of medical and developmental specialists, depending on their individual needs. Some of the medical specialists who often follow children with CHARGE syndrome include genetics, cardiology, audiology and ENT, ophthalmology, urology, and endocrinology.More than 50% of children with CHARGE syndrome experience sleep disturbances, and obstructive sleep apnea appears to be prevalent in children with CHARGE syndrome. All conventional treatments for obstructive sleep apnea reduce symptoms. Botulinum toxin A (Botox) has been used to reduce excess salivary secretions in a ventilator-dependant infant with CHARGE syndrome who would have required a tracheotomy. Venous anomalies of the temporal bone were present in 10 of 18 (56%) patients with CHARGE syndrome. The pattern of venous abnormality suggests that there is a failure of the sigmoid sinus/jugular bulb to fully develop, resulting in persistence of emissary veins. Recognition of these abnormal venous structures during otologic surgery is critical to avoiding potentially catastrophic bleeding.Analysis of CHD7 in 12 patients with semicircular canal dysplasia and variable clinical features of CHARGE syndrome revealed 6 CHD7 mutations, 5 of which occurred in patients who fulfilled diagnostic criteria for typical CHARGE syndrome, and three of which were previously undiagnosed. Among 7 children with CHARGE and congenital profound hearing loss, all had hypoplastic or absent auditory nerves, affecting their outcomes with cochlear implants. Of 30 ears evaluated with CT, 28 (93%) had major abnormalities of the inner ear including hypoplasia or aplasia of the semicircular canals and abnormalities of the cochlea and vestibule. CT imaging revealed cochlear aperture narrowing or occlusion in 16 ears, one of which had normal hearing. Among 8 patients with profound sensorineural hearing loss who underwent magnetic resonance imaging 13 of 14 ears were noted to have absent or deficient cochlear nerves. Because of the implications of cochlear nerve deficiency in therapeutic decision-making regarding cochlear implantation, MRI evaluation of the eighth nerve should be considered in CHARGE patients with profound sensorineural hearing loss. In patients with markedly abnormal middle ear anatomy, CT image guided surgery was helpful. These children were offered a bilingual early intervention approach, using sign language and verbal language, to ensure best language outcomes. Children with CHARGE syndrome and progressive profound hearing loss did well with cochlear implants and continued to use verbal language. Numerous patients have undergone cochlear implantation, with most patients demonstrating favorable outcomes. Larger diameter of the cochleovestibular nerve on imaging and absence of severe intellectual disability were factors related to better outcomes after cochlear implantation, rather than the type of CHD7 mutations. Auditory brainstem implantation may be a viable option in patients with CHARGE syndrome who have failed to benefit from cochlear implantation.A novel mouse model of CHD7 dysfunction, termed Looper, harbors a nonsense mutation within the Chd7 gene. Looper mice exhibit growth retardation, facial asymmetry, vestibular defects, eye anomalies, hyperactivity, ossicle malformation, hearing loss and vestibular dysfunction. Chd7 also regulates genes involved in neural crest cell guidance, demonstrating a significant role in the pathogenesis of CHARGE syndrome. Mice with heterozygous Chd7 mutations exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis. Chd7 is highly expressed in mature inner and outer hair cells, spiral ganglion neurons, vestibular sensory epithelia and middle ear ossicles.Among 202 patients with CHD7 mutations and CHARGE syndrome, a wide range of heart defects in 74% this cohort of patients. Conotruncal defects and atrioventricular septal defects were over-represented in patients with CHD7 mutations compared with patients with non-syndromic heart defects. However, CHD7 mutations are not a major cause of atrioventricular septal and conotruncal heart defects. Work with mouse models demonstrate that CHD7 plays an important role in the cardiogenic mesoderm during cardiovascular development.Among 25 patients with CHARGE syndrome, 76% of subjects had some type of endocrine disorder: short stature (72%), hypogonadotropic hypogonadism (60%), hypothyroidism (16%), and combined hypopituitarism (8%). A mutation in CHD7 was found in 80% of these subjects. Analysis of growth in 19 children with CHARGE syndrome, revealed a significant loss of median body length, at around 4 weeks of age from -0.5 to -2.3 standard deviations (SDS). At 1 year, the median length was -2.6 SDS and it remained low until 5 years of age when the lowest value was found to be -2.8 SDS. There was a significant increase in median body mass index (BMI) from -1.15 SDS at 1 year to -0.15 SDS at 5 years. Children with CHARGE syndrome displayed almost normal length and weight data at birth, with just one of the 19 infants having below average length for gestational age. Among 16 children with CHARGE syndrome, short stature, and decreased levels of serum growth hormone (GH), conventional doses of GH had a positive effect on short-term growth velocity without any safety issues or adverse effect on BMI. At the start of GH therapy, height was -3.6 SDS and after 2.7 years of GH therapy, height increased to -2.2 SDS in these patients with CHARGE syndrome. Hormonal management also helps treat symptoms of hypogonadism. Among 209 Kallman syndrome patients who had not been diagnosed with CHARGE syndrome, mutations in CHD7 were found in 24 patients (11.5%). Among 783 patients with isolated gonadotropin-releasing hormone deficiency lacking full CHARGE features, CHD7 variants were found in 5.2% of this cohort (73% missense and 27% splice variants), of which 75% were deleterious. Chd7 mutant mouse embryos have CHD7 dosage-dependent reductions in expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode suggesting that that CHD7 plays a critical role in the development and maintenance of gonadotropin-releasing hormone neurons for regulating puberty and reproduction.Others involved in the treatment of children with CHARGE include deaf/blind specialists, occupational therapy, physical therapy and speech therapy. Appropriate therapies and educational interventions must take into account any hearing and vision loss, which is present. The intelligence of children with CHARGE is often underestimated due to the combined hearing and vision problems. A deaf/blind specialist (not just a vision specialist and a hearing specialist) is critical for any child with someone with both vision loss and some hearing loss.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. A team approach is essential for these complex children. | 224 | CHARGE Syndrome |
nord_225_0 | Overview of Chediak Higashi Syndrome | Chediak-Higashi syndrome (CHS) is a rare, inherited, complex, immune disorder that usually occurs in childhood characterized by reduced pigment in the skin and eyes (oculocutaneous albinism), immune deficiency with an increased susceptibility to infections, and a tendency to bruise and bleed easily. Neurological deficits are also common. CHS is transmitted as an autosomal recessive genetic condition. | Overview of Chediak Higashi Syndrome. Chediak-Higashi syndrome (CHS) is a rare, inherited, complex, immune disorder that usually occurs in childhood characterized by reduced pigment in the skin and eyes (oculocutaneous albinism), immune deficiency with an increased susceptibility to infections, and a tendency to bruise and bleed easily. Neurological deficits are also common. CHS is transmitted as an autosomal recessive genetic condition. | 225 | Chediak Higashi Syndrome |
nord_225_1 | Symptoms of Chediak Higashi Syndrome | The symptoms of CHS may be apparent during early infancy. Hair is typically blond or light brown with a silvery tint. Affected children may be abnormally sensitive to light (photosensitivity) because of the reduced pigment in the eyes and skin, and may exhibit rapid, involuntary, eye movements (nystagmus). More important and more serious are the effects of CHS on the patient's immune and nervous systems.In CHS, white blood cells contain abnormal granules that are markedly enlarged. These granules can be seen by looking at the blood cells under the microscope, and if present, are diagnostic of CHS. These abnormal granules affect the ability of the white blood cells to fight infection. Children are susceptible to frequent bacterial, viral, and fungal infections, particularly of the skin and respiratory tract. Children with CHS can also have abnormally low levels of white blood cells. Children with this disorder may bruise easily or bleed excessively when injured. Platelet numbers are usually normal, but the platelets do not function properly causing easy bruising or prolonged bleeding.The disease can be categorized into classic and atypical (mild) forms. Individuals with the atypical form may have fewer or less severe, infections and milder symptoms. Children with the classic form of the disease are at risk for developing the accelerated phase. The accelerated phase occurs in up to 85% of patients and can occur at any age. The accelerated phase is caused by an excess production of lymphocytes by the immune system. Patients can develop symptoms such as fever, swollen lymph nodes, enlargement of the liver and spleen, anemia, low WBC count, and low blood platelet count. This is a serious condition and needs to be treated right away.Neurological symptoms occur in early adulthood. Symptoms involving the nervous system include an unsteady posture and walk (ataxia) and loss of sensation in the arms and legs (peripheral neuropathy).This can progress to physical weakness and disability. Some patients can have symptoms that resemble Parkinson’s disease. | Symptoms of Chediak Higashi Syndrome. The symptoms of CHS may be apparent during early infancy. Hair is typically blond or light brown with a silvery tint. Affected children may be abnormally sensitive to light (photosensitivity) because of the reduced pigment in the eyes and skin, and may exhibit rapid, involuntary, eye movements (nystagmus). More important and more serious are the effects of CHS on the patient's immune and nervous systems.In CHS, white blood cells contain abnormal granules that are markedly enlarged. These granules can be seen by looking at the blood cells under the microscope, and if present, are diagnostic of CHS. These abnormal granules affect the ability of the white blood cells to fight infection. Children are susceptible to frequent bacterial, viral, and fungal infections, particularly of the skin and respiratory tract. Children with CHS can also have abnormally low levels of white blood cells. Children with this disorder may bruise easily or bleed excessively when injured. Platelet numbers are usually normal, but the platelets do not function properly causing easy bruising or prolonged bleeding.The disease can be categorized into classic and atypical (mild) forms. Individuals with the atypical form may have fewer or less severe, infections and milder symptoms. Children with the classic form of the disease are at risk for developing the accelerated phase. The accelerated phase occurs in up to 85% of patients and can occur at any age. The accelerated phase is caused by an excess production of lymphocytes by the immune system. Patients can develop symptoms such as fever, swollen lymph nodes, enlargement of the liver and spleen, anemia, low WBC count, and low blood platelet count. This is a serious condition and needs to be treated right away.Neurological symptoms occur in early adulthood. Symptoms involving the nervous system include an unsteady posture and walk (ataxia) and loss of sensation in the arms and legs (peripheral neuropathy).This can progress to physical weakness and disability. Some patients can have symptoms that resemble Parkinson’s disease. | 225 | Chediak Higashi Syndrome |
nord_225_2 | Causes of Chediak Higashi Syndrome | Chediak-Higashi syndrome is inherited as an autosomal recessive genetic trait. The responsible gene has been mapped to chromosomal locus 1q42.1-q42.2 and is known as LYST gene.The abnormal gene affects the “traffic patterns” or movement of proteins within the cells. Proteins (or enzymes) that are meant to go from one part of the cell to another may be misdirected or fail to be transported.For example, a granule in which the skin pigment (melanin) is made is interfered with so that the pigment cannot be transported to the appropriate skin cell. Similarly, a defect in the transport within a white blood cell (WBC) renders the cell helpless in killing infective agents like viruses or bacteria and causing the immune problems.
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 1q42.1” refers to band 42.1 on the long arm of chromosome 1. 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, which 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 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 defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 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. | Causes of Chediak Higashi Syndrome. Chediak-Higashi syndrome is inherited as an autosomal recessive genetic trait. The responsible gene has been mapped to chromosomal locus 1q42.1-q42.2 and is known as LYST gene.The abnormal gene affects the “traffic patterns” or movement of proteins within the cells. Proteins (or enzymes) that are meant to go from one part of the cell to another may be misdirected or fail to be transported.For example, a granule in which the skin pigment (melanin) is made is interfered with so that the pigment cannot be transported to the appropriate skin cell. Similarly, a defect in the transport within a white blood cell (WBC) renders the cell helpless in killing infective agents like viruses or bacteria and causing the immune problems.
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 1q42.1” refers to band 42.1 on the long arm of chromosome 1. 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, which 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 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 defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 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. | 225 | Chediak Higashi Syndrome |
nord_225_3 | Affects of Chediak Higashi Syndrome | Chediak-Higashi syndrome is a very rare disorder that affects males and females in equal numbers. It is often obvious at birth or shortly thereafter. There does not appear to be a higher risk for any particular ethnic or racial group. There are less than 500 cases of the disease on record. 85% of affected individuals progress to the accelerated phase. | Affects of Chediak Higashi Syndrome. Chediak-Higashi syndrome is a very rare disorder that affects males and females in equal numbers. It is often obvious at birth or shortly thereafter. There does not appear to be a higher risk for any particular ethnic or racial group. There are less than 500 cases of the disease on record. 85% of affected individuals progress to the accelerated phase. | 225 | Chediak Higashi Syndrome |
nord_225_4 | Related disorders of Chediak Higashi Syndrome | Symptoms of the following disorders can be similar to those of Chediak- Higashi syndrome. Comparisons may be useful for a differential diagnosis:Griscelli syndrome, also known as Chediak-Higashi-like syndrome, is a rare inherited disorder characterized by partial albinism and abnormalities of platelets and white blood cells. The symptoms are similar to those of CHS. There are 3 different types of Griscelli syndrome. Type 2 is very similar to CHS as patients have reduced pigment and immune abnormalities. These patients are also at risk for the accelerated phase. On laboratory analysis, the white blood cells do not have the giant granules like those seen in Chediak- Higashi syndrome; therefore, the diagnoses are made differentially based on these WBC granules.Hermansky-Pudlak syndrome is a rare inherited disorder characterized by reduced skin, hair, and/or eye pigmentation (albinism), abnormal platelets, and the excessive storage of a fatty substance (ceroid) in various parts of the body. The symptoms of Hermansky-Pudlak syndrome include reduced color in the skin, hair, and eyes, impaired vision, and excessive bleeding. Fatty deposits of ceroid in the lungs, intestines, heart, and/or kidneys may cause impaired function in many organs of the body. One type of Hermansky-Pudlak syndrome can also have immune abnormalities. Frequently the first symptoms of Hermansky-Pudlak syndrome in a child include easy bruising, bleeding gums, nosebleeds, and excessive bleeding after surgery or injury. (For more information on this disorder, choose “Hermansky-Pudlak” as your search term in the Rare Disease Database.)Oculocutaneous albinism is a disease that results in visual impairment and iris/retinal depigmentation. Depigmentation can range from reduced to complete loss. This can be diagnosed independent of CHS due to the lack of infectious history or neurologic abnormalities.Familial hemophagocytic lymphohistiocytosis (FLH) is characterized by highly active macrophages and T-lymphocytes that act as acute illnesses with fevers, reduction in blood cell count, and enlarged spleens and livers. There is variable age of onset. Neurological symptoms also may present in the form of pressure in the brain, irritability, stiff neck, low muscle tone, spastic muscles, convulsions, cranial nerve palsies, loss of muscle control (ataxia), hemi/quadriplegia, blindness, and coma. Liver dysfunction and immune cell destruction are also symptoms. Median survival for children is less than two months usually due to infection. This disease is autosomal recessive and caused by a mutation in one of the FHL1-FHL5 genes.Vici syndrome is characterized by a lack of pigment, immunodeficiency, lack of development of the corpus callosum, cataracts of both eyes, and cleft lip and palate. Cognitive impairment, seizures, and severe respiratory infections have also been observed with this syndrome. | Related disorders of Chediak Higashi Syndrome. Symptoms of the following disorders can be similar to those of Chediak- Higashi syndrome. Comparisons may be useful for a differential diagnosis:Griscelli syndrome, also known as Chediak-Higashi-like syndrome, is a rare inherited disorder characterized by partial albinism and abnormalities of platelets and white blood cells. The symptoms are similar to those of CHS. There are 3 different types of Griscelli syndrome. Type 2 is very similar to CHS as patients have reduced pigment and immune abnormalities. These patients are also at risk for the accelerated phase. On laboratory analysis, the white blood cells do not have the giant granules like those seen in Chediak- Higashi syndrome; therefore, the diagnoses are made differentially based on these WBC granules.Hermansky-Pudlak syndrome is a rare inherited disorder characterized by reduced skin, hair, and/or eye pigmentation (albinism), abnormal platelets, and the excessive storage of a fatty substance (ceroid) in various parts of the body. The symptoms of Hermansky-Pudlak syndrome include reduced color in the skin, hair, and eyes, impaired vision, and excessive bleeding. Fatty deposits of ceroid in the lungs, intestines, heart, and/or kidneys may cause impaired function in many organs of the body. One type of Hermansky-Pudlak syndrome can also have immune abnormalities. Frequently the first symptoms of Hermansky-Pudlak syndrome in a child include easy bruising, bleeding gums, nosebleeds, and excessive bleeding after surgery or injury. (For more information on this disorder, choose “Hermansky-Pudlak” as your search term in the Rare Disease Database.)Oculocutaneous albinism is a disease that results in visual impairment and iris/retinal depigmentation. Depigmentation can range from reduced to complete loss. This can be diagnosed independent of CHS due to the lack of infectious history or neurologic abnormalities.Familial hemophagocytic lymphohistiocytosis (FLH) is characterized by highly active macrophages and T-lymphocytes that act as acute illnesses with fevers, reduction in blood cell count, and enlarged spleens and livers. There is variable age of onset. Neurological symptoms also may present in the form of pressure in the brain, irritability, stiff neck, low muscle tone, spastic muscles, convulsions, cranial nerve palsies, loss of muscle control (ataxia), hemi/quadriplegia, blindness, and coma. Liver dysfunction and immune cell destruction are also symptoms. Median survival for children is less than two months usually due to infection. This disease is autosomal recessive and caused by a mutation in one of the FHL1-FHL5 genes.Vici syndrome is characterized by a lack of pigment, immunodeficiency, lack of development of the corpus callosum, cataracts of both eyes, and cleft lip and palate. Cognitive impairment, seizures, and severe respiratory infections have also been observed with this syndrome. | 225 | Chediak Higashi Syndrome |
nord_225_5 | Diagnosis of Chediak Higashi Syndrome | The diagnosis of CHS is usually made by the presence of ‘giant granules' in microscopic analysis of white blood cells. ‘Giant inclusion bodies' can also be seen in the cells that develop into white blood cells (leukocyte precursor cells) in the bone marrow.Pigment clumping in hair that can be seen under light microscopy is another method for diagnosis that would be done if a blood smear showed enlarged granules. | Diagnosis of Chediak Higashi Syndrome. The diagnosis of CHS is usually made by the presence of ‘giant granules' in microscopic analysis of white blood cells. ‘Giant inclusion bodies' can also be seen in the cells that develop into white blood cells (leukocyte precursor cells) in the bone marrow.Pigment clumping in hair that can be seen under light microscopy is another method for diagnosis that would be done if a blood smear showed enlarged granules. | 225 | Chediak Higashi Syndrome |
nord_225_6 | Therapies of Chediak Higashi Syndrome | TreatmentManagement varies depending of the stage of the disease at the time of diagnosis. Ideally, bone marrow transplant should be performed before the patient develops the accelerated phase. Bone marrow transplant corrects the immune and bleeding abnormalities and prevents the development of the accelerated phase. If the accelerated phase occurs, hemophagocytosis must be in remission before a bone marrow transplant can occur. Those patients are given chemotherapy to get the accelerated phase into remission. Bone marrow transplant can occur after the patient is in remission. Before major procedures, a drug to prevent excessive bleeding, DDVAP, can be administered.Other than these options, treatment of CHS is symptomatic. When bacterial or fungal infections occur, they should be vigorously treated with antibiotic or antifungal drugs. Acute viral infections may be treated with the anti-viral drugs. Platelet transfusions may be necessary if bleeding becomes excessive after injury or surgery.People with CHS should minimize unprotected sun exposure. When affected individuals are exposed to sunlight, sunglasses and sunscreens applied to the skin can be helpful. Genetic counseling may be of benefit for people with CHS and their families. | Therapies of Chediak Higashi Syndrome. TreatmentManagement varies depending of the stage of the disease at the time of diagnosis. Ideally, bone marrow transplant should be performed before the patient develops the accelerated phase. Bone marrow transplant corrects the immune and bleeding abnormalities and prevents the development of the accelerated phase. If the accelerated phase occurs, hemophagocytosis must be in remission before a bone marrow transplant can occur. Those patients are given chemotherapy to get the accelerated phase into remission. Bone marrow transplant can occur after the patient is in remission. Before major procedures, a drug to prevent excessive bleeding, DDVAP, can be administered.Other than these options, treatment of CHS is symptomatic. When bacterial or fungal infections occur, they should be vigorously treated with antibiotic or antifungal drugs. Acute viral infections may be treated with the anti-viral drugs. Platelet transfusions may be necessary if bleeding becomes excessive after injury or surgery.People with CHS should minimize unprotected sun exposure. When affected individuals are exposed to sunlight, sunglasses and sunscreens applied to the skin can be helpful. Genetic counseling may be of benefit for people with CHS and their families. | 225 | Chediak Higashi Syndrome |
nord_226_0 | Overview of Chiari Frommel Syndrome | Chiari-Frommel Syndrome is a rare endocrine disorder that affects women who have recently given birth (postpartum) and is characterized by the over-production of breast milk (galactorrhea), lack of ovulation (anovulation), and the absence of regular menstrual periods (amenorrhea). In Chiari-Frommel Syndrome, these symptoms persist long (for more than six months) after childbirth. The absence of normal hormonal cycles may result in reduced size of the uterus (atrophy). Some cases of Chiari-Frommel Syndrome resolve completely without treatment (spontaneously); hormone levels and reproductive function return to normal. | Overview of Chiari Frommel Syndrome. Chiari-Frommel Syndrome is a rare endocrine disorder that affects women who have recently given birth (postpartum) and is characterized by the over-production of breast milk (galactorrhea), lack of ovulation (anovulation), and the absence of regular menstrual periods (amenorrhea). In Chiari-Frommel Syndrome, these symptoms persist long (for more than six months) after childbirth. The absence of normal hormonal cycles may result in reduced size of the uterus (atrophy). Some cases of Chiari-Frommel Syndrome resolve completely without treatment (spontaneously); hormone levels and reproductive function return to normal. | 226 | Chiari Frommel Syndrome |
nord_226_1 | Symptoms of Chiari Frommel Syndrome | Chiari-Frommel Syndrome is a rare disorder characterized by the abnormal production of breast milk (galactorrhea), and the absence of regular menstrual periods (amenorrhea) and ovulation (anovulatory) for more than 6 months after childbirth. These symptoms occur even though the mother is not nursing the baby. The pregnancy which precedes the onset of Chiari-Frommel Syndrome is usually normal, and childbirth and initial lactation are uneventful. However, normal menstrual periods and ovulation do not resume, and persistent discharge from the nipples occurs, which can sometimes last for years. Other symptoms may include emotional distress, anxiety, headaches, backaches, abdominal pain, impaired vision, and occasionally obesity. Women who have Chiari-Frommel Syndrome for a long time may also have a loss of muscle tone in the uterus and diminished uterine size (atrophy). | Symptoms of Chiari Frommel Syndrome. Chiari-Frommel Syndrome is a rare disorder characterized by the abnormal production of breast milk (galactorrhea), and the absence of regular menstrual periods (amenorrhea) and ovulation (anovulatory) for more than 6 months after childbirth. These symptoms occur even though the mother is not nursing the baby. The pregnancy which precedes the onset of Chiari-Frommel Syndrome is usually normal, and childbirth and initial lactation are uneventful. However, normal menstrual periods and ovulation do not resume, and persistent discharge from the nipples occurs, which can sometimes last for years. Other symptoms may include emotional distress, anxiety, headaches, backaches, abdominal pain, impaired vision, and occasionally obesity. Women who have Chiari-Frommel Syndrome for a long time may also have a loss of muscle tone in the uterus and diminished uterine size (atrophy). | 226 | Chiari Frommel Syndrome |
nord_226_2 | Causes of Chiari Frommel Syndrome | The exact cause of Chiari-Frommel Syndrome is not fully understood but may be related to an abnormality of the hypothalamus and/or pituitary glands. Some research suggests that microscopic tumors of the pituitary gland (microadenomas), stimulated by the hormones associated with pregnancy (e.g., prolactin, a stimulator of lactation) are responsible. When such microtumors grow, they may be detected by imaging techniques (CT scan or MRI). Approximately 50 percent of affected women eventually resume normal menstruation over a period of months or years.The cause of the abnormal hormonal relationship between the pituitary and hypothalamus gland associated with Chiari-Frommel Syndrome is not known. Some studies suggest that microscopic lesions of the hypothalamus may also cause Chiari-Frommel Syndrome. An association with the use of oral contraceptives has also been suggested. | Causes of Chiari Frommel Syndrome. The exact cause of Chiari-Frommel Syndrome is not fully understood but may be related to an abnormality of the hypothalamus and/or pituitary glands. Some research suggests that microscopic tumors of the pituitary gland (microadenomas), stimulated by the hormones associated with pregnancy (e.g., prolactin, a stimulator of lactation) are responsible. When such microtumors grow, they may be detected by imaging techniques (CT scan or MRI). Approximately 50 percent of affected women eventually resume normal menstruation over a period of months or years.The cause of the abnormal hormonal relationship between the pituitary and hypothalamus gland associated with Chiari-Frommel Syndrome is not known. Some studies suggest that microscopic lesions of the hypothalamus may also cause Chiari-Frommel Syndrome. An association with the use of oral contraceptives has also been suggested. | 226 | Chiari Frommel Syndrome |
nord_226_3 | Affects of Chiari Frommel Syndrome | Chiari-Frommel Syndrome is a rare disorder that affects females who have recently given birth (postpartum). | Affects of Chiari Frommel Syndrome. Chiari-Frommel Syndrome is a rare disorder that affects females who have recently given birth (postpartum). | 226 | Chiari Frommel Syndrome |
nord_226_4 | Related disorders of Chiari Frommel Syndrome | Symptoms of the following disorders can be similar to those of Chiari-Frommel Syndrome. Comparisons may be useful for a differential diagnosis:Forbes-Albright Syndrome is one of a group of rare endocrine disorders characterized by abnormally high levels of the hormone prolactin due to a tumor of the pituitary gland. Symptoms include the production and secretion of milk from the breasts (lactation) without associated childbirth or nursing (galactorrhea), and the absence of a regular menstrual period (amenorrhea). Women with Forbes-Albright Syndrome generally have breasts and nipples of normal size and appearance, but the pattern of body hair and sexual drive may be reduced. (For more information on this disorder, choose “Forbes-Albright” as your search term in the Rare Disease Database.)Ahumada-del Castillo Syndrome is a rare endocrine disorder characterized by the abnormal function of the hypothalamus and pituitary glands affecting the secretion of hormones. This disorder affects only women and is not related to pregnancy. The two major symptoms of this disorder include the production and expression of milk from the breasts not associated with childbirth or nursing, and the lack of regular menstruation. There is normal development of secondary sexual characteristics. (For more information on this disorder, choose “Ahumada-del Castillo” as your search term in the Rare Disease Database.) | Related disorders of Chiari Frommel Syndrome. Symptoms of the following disorders can be similar to those of Chiari-Frommel Syndrome. Comparisons may be useful for a differential diagnosis:Forbes-Albright Syndrome is one of a group of rare endocrine disorders characterized by abnormally high levels of the hormone prolactin due to a tumor of the pituitary gland. Symptoms include the production and secretion of milk from the breasts (lactation) without associated childbirth or nursing (galactorrhea), and the absence of a regular menstrual period (amenorrhea). Women with Forbes-Albright Syndrome generally have breasts and nipples of normal size and appearance, but the pattern of body hair and sexual drive may be reduced. (For more information on this disorder, choose “Forbes-Albright” as your search term in the Rare Disease Database.)Ahumada-del Castillo Syndrome is a rare endocrine disorder characterized by the abnormal function of the hypothalamus and pituitary glands affecting the secretion of hormones. This disorder affects only women and is not related to pregnancy. The two major symptoms of this disorder include the production and expression of milk from the breasts not associated with childbirth or nursing, and the lack of regular menstruation. There is normal development of secondary sexual characteristics. (For more information on this disorder, choose “Ahumada-del Castillo” as your search term in the Rare Disease Database.) | 226 | Chiari Frommel Syndrome |
nord_226_5 | Diagnosis of Chiari Frommel Syndrome | Diagnosis of Chiari Frommel Syndrome. | 226 | Chiari Frommel Syndrome |
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nord_226_6 | Therapies of Chiari Frommel Syndrome | Some women with Chiari-Frommel Syndrome may have abnormally high levels of prolactin in the blood. Other women have normal prolactin levels. Additional laboratory findings may include abnormally low levels of estrogen and other hormones (gonadotropins) in the urine.The drug bromocriptine may be prescribed to help reduce prolactin levels. When these levels are reduced, normal ovulation cycles may be restored along with regular menstrual periods.If the symptoms persist for a long period of time, affected individuals should be monitored (CT scan or MRI) for the presence of a pituitary tumor. If a tumor is discovered, it may be difficult to treat if it is very small. Larger tumors may be surgically removed. | Therapies of Chiari Frommel Syndrome. Some women with Chiari-Frommel Syndrome may have abnormally high levels of prolactin in the blood. Other women have normal prolactin levels. Additional laboratory findings may include abnormally low levels of estrogen and other hormones (gonadotropins) in the urine.The drug bromocriptine may be prescribed to help reduce prolactin levels. When these levels are reduced, normal ovulation cycles may be restored along with regular menstrual periods.If the symptoms persist for a long period of time, affected individuals should be monitored (CT scan or MRI) for the presence of a pituitary tumor. If a tumor is discovered, it may be difficult to treat if it is very small. Larger tumors may be surgically removed. | 226 | Chiari Frommel Syndrome |
nord_227_0 | Overview of Chiari Malformations | Chiari malformations are a group of complex brain abnormalities that affect the area in lower posterior skull where the brain and spinal cord connect. The underlying anatomy of Chiari malformations is thought to be present at birth (congenital), although in many cases they may not become clinically apparent until adulthood. In extremely rare cases, a Chiari malformation may be acquired during life. The exact cause of Chiari malformations are not known, but often the cavity near the base of the skull (posterior fossa) is narrow and abnormally small in relation to the size of the cerebellum, which this portion of the skull encloses. Researchers believe that in some cases the small posterior fossa may cause the developing brain, specifically the cerebellum and the brainstem, to be pushed downward. Part of the cerebellum (known as the cerebellar tonsils) may protrude (herniate) through the foramen magnum, which is the normal opening found in the occipital bone at the base of the skull. The tonsils may thus interfere with the flow of cerebrospinal fluid (CSF) to and from the skull and spinal canal, potentially leading to accumulation of cerebral spinal fluid in the subarachnoid spaces of the brain and spine. A Chiari malformation can also cause pressure on the brain and produce hydrocephalus (pressure due to excessive cerebrospinal fluid accumulation in the brain) and the spinal cord, potentially causing a wide variety of symptoms. In fact, no two cases of Chiari malformation are exactly alike and the associated symptoms are highly variable. The severity of Chiari malformations can vary dramatically as well. In some cases, affected individuals may not develop any symptoms (asymptomatic); in others, severe, potentially debilitating or life-threatening symptoms can develop.Traditionally, Chiari malformations have been defined and classified by how much of the cerebellar tonsils protrude through the foramen magnum. A diagnosis of a Chiari malformation usually signifies that the cerebellar tonsils protrude below the foramen magnum (often cited as at least 5 millimeters, though this is controversial). However, researchers have determined that the length of tonsil descent in a Chiari malformation does not always correspond to the severity of symptoms or to the response to treatment. In fact, some individuals are classified as having Chiari malformation type 0, in which there is minimal or no descent of the cerebellar tonsils. These individuals still have symptoms associated with a Chiari malformation, most likely due to abnormalities in the flow of cerebrospinal fluid within the skull and spinal canal. Research is ongoing to understand the complex, underlying mechanisms that cause Chiari malformations.Chiari malformations are named for Hans Chiari, an Austrian pathologist, who first identified type I-III in 1891. Julius Arnold further expanded the definition of Chiari malformation type II and some medical sources began using the name Arnold-Chiari malformation. Nowadays, some medical sources use Arnold-Chiari malformation as a broad term for all forms. Chiari malformations have also been known as congenital tonsillar herniation, tonsillar ectopia or tonsillar descent. | Overview of Chiari Malformations. Chiari malformations are a group of complex brain abnormalities that affect the area in lower posterior skull where the brain and spinal cord connect. The underlying anatomy of Chiari malformations is thought to be present at birth (congenital), although in many cases they may not become clinically apparent until adulthood. In extremely rare cases, a Chiari malformation may be acquired during life. The exact cause of Chiari malformations are not known, but often the cavity near the base of the skull (posterior fossa) is narrow and abnormally small in relation to the size of the cerebellum, which this portion of the skull encloses. Researchers believe that in some cases the small posterior fossa may cause the developing brain, specifically the cerebellum and the brainstem, to be pushed downward. Part of the cerebellum (known as the cerebellar tonsils) may protrude (herniate) through the foramen magnum, which is the normal opening found in the occipital bone at the base of the skull. The tonsils may thus interfere with the flow of cerebrospinal fluid (CSF) to and from the skull and spinal canal, potentially leading to accumulation of cerebral spinal fluid in the subarachnoid spaces of the brain and spine. A Chiari malformation can also cause pressure on the brain and produce hydrocephalus (pressure due to excessive cerebrospinal fluid accumulation in the brain) and the spinal cord, potentially causing a wide variety of symptoms. In fact, no two cases of Chiari malformation are exactly alike and the associated symptoms are highly variable. The severity of Chiari malformations can vary dramatically as well. In some cases, affected individuals may not develop any symptoms (asymptomatic); in others, severe, potentially debilitating or life-threatening symptoms can develop.Traditionally, Chiari malformations have been defined and classified by how much of the cerebellar tonsils protrude through the foramen magnum. A diagnosis of a Chiari malformation usually signifies that the cerebellar tonsils protrude below the foramen magnum (often cited as at least 5 millimeters, though this is controversial). However, researchers have determined that the length of tonsil descent in a Chiari malformation does not always correspond to the severity of symptoms or to the response to treatment. In fact, some individuals are classified as having Chiari malformation type 0, in which there is minimal or no descent of the cerebellar tonsils. These individuals still have symptoms associated with a Chiari malformation, most likely due to abnormalities in the flow of cerebrospinal fluid within the skull and spinal canal. Research is ongoing to understand the complex, underlying mechanisms that cause Chiari malformations.Chiari malformations are named for Hans Chiari, an Austrian pathologist, who first identified type I-III in 1891. Julius Arnold further expanded the definition of Chiari malformation type II and some medical sources began using the name Arnold-Chiari malformation. Nowadays, some medical sources use Arnold-Chiari malformation as a broad term for all forms. Chiari malformations have also been known as congenital tonsillar herniation, tonsillar ectopia or tonsillar descent. | 227 | Chiari Malformations |
nord_227_1 | Symptoms of Chiari Malformations | The signs and symptoms of Chiari malformation can vary greatly from one person to another. Some individuals may not have any symptoms (asymptomatic) upon diagnosis as an incidental finding; others may have serious manifestations such as neurological deficits. Symptoms may go through periods of exacerbation and remission. Chiari malformations are highly variable conditions that will affect every individual person differently. Specific symptoms can occur in different combinations and generally reflect dysfunction of the cerebellum, the brainstem, the spinal cord and lower cranial nerves. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The most common symptom associated with a Chiari malformation is occipital headaches. These headaches are felt near the base of the skull and may radiate to cause pain in the neck and shoulders. They can be severe and may be described as sharp, brief, throbbing or pulsating. Occipital headaches can be brought on or worsened by coughing, straining or sneezing.Abnormalities affecting the eyes can also affect individuals with a Chiari malformation including double vision (diplopia), abnormal sensitivity to light (photophobia), blurred vision, involuntary eye movements (nystagmus) and pain behind the eyes. Vertigo, dizziness, ringing in the ears (tinnitus) and bilateral hearing impairment can also develop.Additional symptoms associated with a Chiari malformation may include poor coordination and balance problems, muscle weakness, difficulties swallowing (dysphagia) or speaking (dysarthria), palpitations, fainting episodes (syncope) and tingling or burning sensations in the fingers, toes or lips (paresthesias). Sleep disorders, especially sleep apnea and chronic fatigue, have also been described in individuals with Chiari malformations.Affected individuals may also develop a fluid-filled cavity or cyst in the spinal cord (syrinx), a condition known as syringomyelia. This condition is chronic and a syrinx can expand over time. Syringomyelia can be associated with a variety of symptoms depending upon the size and specific location of the syrinx. Potential symptoms include loss of muscle mass, muscle weakness, numbness or decreased sensation especially to hot and cold, abnormal curvature of the spine (scoliosis), loss of bowel and bladder control, chronic pain, muscle contractions, uncoordinated movements (ataxia), and spasms and tightening of the muscles of the legs (spasticity).Some individuals have a condition related to syringomyelia known as hydromyelia, which is characterized by abnormal widening of the central canal of the spinal cord (the small canal running through the center of the spinal cord). These small cavities are filled with cerebrospinal fluid and their significance, if any, is not known. Some physicians use the terms syringomyelia or hydromyelia interchangeably. However, hydromyelia cavities connect to the fourth ventricle (an area in the brain that normally contains cerebrospinal fluid). Hydromyelia may also be present in infants and young children with or without brain abnormalities, such as Chiari malformation type II. The fluid-filled cavities in cases of syringomyelia often do not connect to any other fluid-filled areas or spaces and occur more often in adults than children.CHIARI MALFORMATION TYPE IChiari malformation type I is the most common cause of syringomyelia. It may not cause any symptoms and often goes unrecognized until adolescence or adulthood. Consequently, this form is sometimes referred to as adult Chiari malformation. Chiari malformation type I is usually not associated with other neurological abnormalities, although it can cause neurological symptoms due to compression of the brainstem and spinal cord.CHIARI MALFORMATION TYPE IIChiari malformation type II is usually more severe than type I and generally symptoms become apparent during childhood. The severity of Chiari malformation type II can vary greatly. The disorder can potentially cause severe, life-threatening complications during infancy or childhood.In Chiari malformation type II, cerebellar tissue protrudes all the way into the spinal canal. Affected individuals may have some of the symptoms described above. However, additional findings such as hydrocephalus may also occur. Hydrocephalus is a condition in which accumulation of excessive cerebrospinal fluid in the brain ventricles causes pressure on the tissues of the brain. Hydrocephalus can cause an abnormally enlarged head (macrocephaly), vomiting, irritability, seizures, and delays in attaining developmental milestones. The specific symptoms associated with hydrocephalus can vary from one child to another.Chiari malformation type II is almost invariably associated with a form of spina bifida, frequently presenting as myelomeningocele. Spina bifida is a birth defect due to incomplete closure of the posterior spinal cord and bony vertebral arch (lamina). Many cases with this anomaly leave a portion of the spinal cord exposed through the spinal canal, typically forming a sac filled with cerebrospinal fluid, meninges, and portions of the spinal cord and nerves (myelomeningocele). Myelomeningocele can be associated with partial or complete paralysis below the spinal opening, including lack of bladder and bowel control.Chiari malformation type II can be associated with other significant neurological conditions including complex anomalies of the brain. Chiari malformation type II is sometimes referred to as pediatric Chiari malformation and requires surgical intervention during infancy or early childhood.CHIARI MALFORMATION TYPE IIIChiari malformation type III is extremely rare and more severe than Chiari malformations types I and II. This form is associated with an encephalocele, a condition in which a portion of the brain and its surrounding membranes (meninges) protrude through a defect in the skull.Affected individuals have many of the symptoms associated with Chiari malformation type II, but also have additional symptoms. Chiari malformation type III is often associated with debilitating and life-threatening complications in infancy.CHIARI MALFORMATION TYPE IVUnlike types I-III, Chiari malformation type IV is not associated with herniation of the brain through the foramen magnum. In this condition, the brain is underdeveloped (hypoplastic) or fails to develop (aplastic). Chiari malformation type IV is the most severe form and is usually fatal during infancy. Because of the lack of cerebellar tonsillar herniation, some researchers do not consider this condition a form of Chiari malformation.CHIARI MALFORMATION TYPE 0Researchers have determined that some individuals with a Chiari malformation have minimal or no herniation of the cerebellar tonsils through the foramen magnum. These individuals often have syringomyelia despite the lack of cerebellar tonsil herniation. Occipital headaches may also occur. Symptoms in these cases are most likely due to abnormalities in the flow of cerebrospinal fluid at the level of the foramen magnum at the skull base, although there is often no identifiable cause. Individuals with this condition have improved after decompression surgery. The addition of Chiari malformation type 0 as a classification for Chiari malformations is controversial; some physicians believe that, for a diagnosis of a Chiari malformation, tonsillar herniation must be present. | Symptoms of Chiari Malformations. The signs and symptoms of Chiari malformation can vary greatly from one person to another. Some individuals may not have any symptoms (asymptomatic) upon diagnosis as an incidental finding; others may have serious manifestations such as neurological deficits. Symptoms may go through periods of exacerbation and remission. Chiari malformations are highly variable conditions that will affect every individual person differently. Specific symptoms can occur in different combinations and generally reflect dysfunction of the cerebellum, the brainstem, the spinal cord and lower cranial nerves. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The most common symptom associated with a Chiari malformation is occipital headaches. These headaches are felt near the base of the skull and may radiate to cause pain in the neck and shoulders. They can be severe and may be described as sharp, brief, throbbing or pulsating. Occipital headaches can be brought on or worsened by coughing, straining or sneezing.Abnormalities affecting the eyes can also affect individuals with a Chiari malformation including double vision (diplopia), abnormal sensitivity to light (photophobia), blurred vision, involuntary eye movements (nystagmus) and pain behind the eyes. Vertigo, dizziness, ringing in the ears (tinnitus) and bilateral hearing impairment can also develop.Additional symptoms associated with a Chiari malformation may include poor coordination and balance problems, muscle weakness, difficulties swallowing (dysphagia) or speaking (dysarthria), palpitations, fainting episodes (syncope) and tingling or burning sensations in the fingers, toes or lips (paresthesias). Sleep disorders, especially sleep apnea and chronic fatigue, have also been described in individuals with Chiari malformations.Affected individuals may also develop a fluid-filled cavity or cyst in the spinal cord (syrinx), a condition known as syringomyelia. This condition is chronic and a syrinx can expand over time. Syringomyelia can be associated with a variety of symptoms depending upon the size and specific location of the syrinx. Potential symptoms include loss of muscle mass, muscle weakness, numbness or decreased sensation especially to hot and cold, abnormal curvature of the spine (scoliosis), loss of bowel and bladder control, chronic pain, muscle contractions, uncoordinated movements (ataxia), and spasms and tightening of the muscles of the legs (spasticity).Some individuals have a condition related to syringomyelia known as hydromyelia, which is characterized by abnormal widening of the central canal of the spinal cord (the small canal running through the center of the spinal cord). These small cavities are filled with cerebrospinal fluid and their significance, if any, is not known. Some physicians use the terms syringomyelia or hydromyelia interchangeably. However, hydromyelia cavities connect to the fourth ventricle (an area in the brain that normally contains cerebrospinal fluid). Hydromyelia may also be present in infants and young children with or without brain abnormalities, such as Chiari malformation type II. The fluid-filled cavities in cases of syringomyelia often do not connect to any other fluid-filled areas or spaces and occur more often in adults than children.CHIARI MALFORMATION TYPE IChiari malformation type I is the most common cause of syringomyelia. It may not cause any symptoms and often goes unrecognized until adolescence or adulthood. Consequently, this form is sometimes referred to as adult Chiari malformation. Chiari malformation type I is usually not associated with other neurological abnormalities, although it can cause neurological symptoms due to compression of the brainstem and spinal cord.CHIARI MALFORMATION TYPE IIChiari malformation type II is usually more severe than type I and generally symptoms become apparent during childhood. The severity of Chiari malformation type II can vary greatly. The disorder can potentially cause severe, life-threatening complications during infancy or childhood.In Chiari malformation type II, cerebellar tissue protrudes all the way into the spinal canal. Affected individuals may have some of the symptoms described above. However, additional findings such as hydrocephalus may also occur. Hydrocephalus is a condition in which accumulation of excessive cerebrospinal fluid in the brain ventricles causes pressure on the tissues of the brain. Hydrocephalus can cause an abnormally enlarged head (macrocephaly), vomiting, irritability, seizures, and delays in attaining developmental milestones. The specific symptoms associated with hydrocephalus can vary from one child to another.Chiari malformation type II is almost invariably associated with a form of spina bifida, frequently presenting as myelomeningocele. Spina bifida is a birth defect due to incomplete closure of the posterior spinal cord and bony vertebral arch (lamina). Many cases with this anomaly leave a portion of the spinal cord exposed through the spinal canal, typically forming a sac filled with cerebrospinal fluid, meninges, and portions of the spinal cord and nerves (myelomeningocele). Myelomeningocele can be associated with partial or complete paralysis below the spinal opening, including lack of bladder and bowel control.Chiari malformation type II can be associated with other significant neurological conditions including complex anomalies of the brain. Chiari malformation type II is sometimes referred to as pediatric Chiari malformation and requires surgical intervention during infancy or early childhood.CHIARI MALFORMATION TYPE IIIChiari malformation type III is extremely rare and more severe than Chiari malformations types I and II. This form is associated with an encephalocele, a condition in which a portion of the brain and its surrounding membranes (meninges) protrude through a defect in the skull.Affected individuals have many of the symptoms associated with Chiari malformation type II, but also have additional symptoms. Chiari malformation type III is often associated with debilitating and life-threatening complications in infancy.CHIARI MALFORMATION TYPE IVUnlike types I-III, Chiari malformation type IV is not associated with herniation of the brain through the foramen magnum. In this condition, the brain is underdeveloped (hypoplastic) or fails to develop (aplastic). Chiari malformation type IV is the most severe form and is usually fatal during infancy. Because of the lack of cerebellar tonsillar herniation, some researchers do not consider this condition a form of Chiari malformation.CHIARI MALFORMATION TYPE 0Researchers have determined that some individuals with a Chiari malformation have minimal or no herniation of the cerebellar tonsils through the foramen magnum. These individuals often have syringomyelia despite the lack of cerebellar tonsil herniation. Occipital headaches may also occur. Symptoms in these cases are most likely due to abnormalities in the flow of cerebrospinal fluid at the level of the foramen magnum at the skull base, although there is often no identifiable cause. Individuals with this condition have improved after decompression surgery. The addition of Chiari malformation type 0 as a classification for Chiari malformations is controversial; some physicians believe that, for a diagnosis of a Chiari malformation, tonsillar herniation must be present. | 227 | Chiari Malformations |
nord_227_2 | Causes of Chiari Malformations | The exact cause of Chiari malformations is unknown. These malformations and the associated central nervous system abnormalities are extremely complex. Chiari malformations appear to be due to a developmental failure of the brainstem and upper spinal cord (cervical region) within a developing fetus with no known cause. Some investigators believe that an abnormally small posterior fossa, which is the space in which the cerebellum normally resides, contributes to the development of a Chiari malformation. In many individuals, the posterior fossa is abnormally small, which may lead to the growing brain being pushed down through the normal opening (foramen magnum) where the brain and spinal cord meet.The specific parts of the cerebellum that are affected are the cerebellar tonsils. The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movements. The cerebellar tonsils are small peg-like structures at the base of the cerebellum. When the tonsils protrude through the foramen magnum, they block the proper flow of cerebrospinal fluid between the skull and the spinal cord, potentially compressing the brainstem (pons medulla) and the upper portion of the spinal cord.There have been numerous reports in the medical literature of families in which more than one family member was affected by a Chiari malformation. This suggests that in some cases genetic factors play a role in the development of a Chiari malformation. Research is ongoing to determine the specific genetic components (e.g., gene mutations) that influence the development of Chiari malformations in some people.In extremely rare cases, Chiari malformations have been acquired during life. Generally, any condition that takes up space within the skull, especially within the posterior fossa of the skull, can cause an acquired Chiari malformation. Such conditions include tumors, an arachnoid cyst, and hematomas. Hydrocephalus and intracranial hypertension (pseudotumor cerebri) have also been linked to Chiari malformations. Abnormalities that affect the upper cervical portion of the spine, such as basilar invagination, can also cause a Chiari malformation. Basilar invagination occurs when the upper vertebrae are located upward, blocking the foramen magnum and thereby blocking the flow of cerebrospinal fluid.Leakage or drainage of CSF including the prolonged use of a lumboperitoneal shunt, which is often used to treat hydrocephalus, has been linked to the development of an acquired Chiari malformation. One theory states that if too much cerebrospinal fluid is drained, it might create a pressure imbalance between the cranial and spinal fluid compartments. Consequently, this pressure imbalance is theorized to suck or draw the cerebellar tonsils downward through the foramen magnum.Some researchers have speculated that, in a specific subset of individuals, a Chiari malformation may be caused by a tethered cord. Such individuals have a normal-sized posterior fossa. Tethered cord syndrome is a stretch-induced functional disorder associated with the fixation (tethering) effect of inelastic tissue (filum terminale) on the lower end of the spinal cord, limiting its normal upward movement. This abnormal attachment is associated with progressive stretching and increased tension of the spinal cord as a child grows, potentially resulting in a variety of neurological and other symptoms. While some individuals have both a tethered cord and a Chiari malformation, the exact relationship between these two disorders is not understood. Whether tethered cord syndrome is a distinct cause of Chiari malformations in certain cases is unproven and controversial.Chiari malformations can also occur as part of a larger syndrome such as Goldenhar syndrome, Albright hereditary osteodystrophy (pseudohypoparathyroidism), Hajdu-Cheney syndrome, achondroplasia and hereditary connective tissue diseases such as Ehlers-Danlos syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Many of the symptoms of a Chiari malformation are believed to be due to abnormalities affecting the flow of cerebrospinal fluid (CSF) in the skull and spinal canal. Syringomyelia, which is often associated with a Chiari malformation, most likely develops due to partial obstruction of the normal flow of CSF between the brain and spinal cord. Some symptoms associated with a Chiari malformation or syringomyelia result from direct compression of portions of the brainstem or spinal cord. Researchers have determined that the length of herniation (i.e., the amount of the cerebellar tonsils that protrudes through the foramen magnum) does not necessarily correspond to the severity of a Chiari malformation. | Causes of Chiari Malformations. The exact cause of Chiari malformations is unknown. These malformations and the associated central nervous system abnormalities are extremely complex. Chiari malformations appear to be due to a developmental failure of the brainstem and upper spinal cord (cervical region) within a developing fetus with no known cause. Some investigators believe that an abnormally small posterior fossa, which is the space in which the cerebellum normally resides, contributes to the development of a Chiari malformation. In many individuals, the posterior fossa is abnormally small, which may lead to the growing brain being pushed down through the normal opening (foramen magnum) where the brain and spinal cord meet.The specific parts of the cerebellum that are affected are the cerebellar tonsils. The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movements. The cerebellar tonsils are small peg-like structures at the base of the cerebellum. When the tonsils protrude through the foramen magnum, they block the proper flow of cerebrospinal fluid between the skull and the spinal cord, potentially compressing the brainstem (pons medulla) and the upper portion of the spinal cord.There have been numerous reports in the medical literature of families in which more than one family member was affected by a Chiari malformation. This suggests that in some cases genetic factors play a role in the development of a Chiari malformation. Research is ongoing to determine the specific genetic components (e.g., gene mutations) that influence the development of Chiari malformations in some people.In extremely rare cases, Chiari malformations have been acquired during life. Generally, any condition that takes up space within the skull, especially within the posterior fossa of the skull, can cause an acquired Chiari malformation. Such conditions include tumors, an arachnoid cyst, and hematomas. Hydrocephalus and intracranial hypertension (pseudotumor cerebri) have also been linked to Chiari malformations. Abnormalities that affect the upper cervical portion of the spine, such as basilar invagination, can also cause a Chiari malformation. Basilar invagination occurs when the upper vertebrae are located upward, blocking the foramen magnum and thereby blocking the flow of cerebrospinal fluid.Leakage or drainage of CSF including the prolonged use of a lumboperitoneal shunt, which is often used to treat hydrocephalus, has been linked to the development of an acquired Chiari malformation. One theory states that if too much cerebrospinal fluid is drained, it might create a pressure imbalance between the cranial and spinal fluid compartments. Consequently, this pressure imbalance is theorized to suck or draw the cerebellar tonsils downward through the foramen magnum.Some researchers have speculated that, in a specific subset of individuals, a Chiari malformation may be caused by a tethered cord. Such individuals have a normal-sized posterior fossa. Tethered cord syndrome is a stretch-induced functional disorder associated with the fixation (tethering) effect of inelastic tissue (filum terminale) on the lower end of the spinal cord, limiting its normal upward movement. This abnormal attachment is associated with progressive stretching and increased tension of the spinal cord as a child grows, potentially resulting in a variety of neurological and other symptoms. While some individuals have both a tethered cord and a Chiari malformation, the exact relationship between these two disorders is not understood. Whether tethered cord syndrome is a distinct cause of Chiari malformations in certain cases is unproven and controversial.Chiari malformations can also occur as part of a larger syndrome such as Goldenhar syndrome, Albright hereditary osteodystrophy (pseudohypoparathyroidism), Hajdu-Cheney syndrome, achondroplasia and hereditary connective tissue diseases such as Ehlers-Danlos syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Many of the symptoms of a Chiari malformation are believed to be due to abnormalities affecting the flow of cerebrospinal fluid (CSF) in the skull and spinal canal. Syringomyelia, which is often associated with a Chiari malformation, most likely develops due to partial obstruction of the normal flow of CSF between the brain and spinal cord. Some symptoms associated with a Chiari malformation or syringomyelia result from direct compression of portions of the brainstem or spinal cord. Researchers have determined that the length of herniation (i.e., the amount of the cerebellar tonsils that protrudes through the foramen magnum) does not necessarily correspond to the severity of a Chiari malformation. | 227 | Chiari Malformations |
nord_227_3 | Affects of Chiari Malformations | Chiari malformations affect individuals of every race and ethnicity. Some studies suggest that females are affected more often than males. In most cases, a Chiari malformation is thought to be present at birth (congenital), although some cases may not be discovered until adulthood (sometimes incidentally when a brain scan is done for another reason). The incidence and prevalence of Chiari malformations are unknown. Some cases may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of these disorders in the general population. | Affects of Chiari Malformations. Chiari malformations affect individuals of every race and ethnicity. Some studies suggest that females are affected more often than males. In most cases, a Chiari malformation is thought to be present at birth (congenital), although some cases may not be discovered until adulthood (sometimes incidentally when a brain scan is done for another reason). The incidence and prevalence of Chiari malformations are unknown. Some cases may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of these disorders in the general population. | 227 | Chiari Malformations |
nord_227_4 | Related disorders of Chiari Malformations | Symptoms of the following disorders can be similar to those of Chiari malformation. Comparisons may be useful for a differential diagnosis.There are a wide variety of conditions that can be considered in the differential diagnosis of a Chiari malformation. The symptoms commonly associated with a Chiari malformation are vague and common to numerous other conditions. Some disorders are common misdiagnoses for individuals with a Chiari malformation. Such conditions include multiple sclerosis, chronic fatigue syndrome, fibromyalgia and spinal cord tumors. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Chiari Malformations. Symptoms of the following disorders can be similar to those of Chiari malformation. Comparisons may be useful for a differential diagnosis.There are a wide variety of conditions that can be considered in the differential diagnosis of a Chiari malformation. The symptoms commonly associated with a Chiari malformation are vague and common to numerous other conditions. Some disorders are common misdiagnoses for individuals with a Chiari malformation. Such conditions include multiple sclerosis, chronic fatigue syndrome, fibromyalgia and spinal cord tumors. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 227 | Chiari Malformations |
nord_227_5 | Diagnosis of Chiari Malformations | A diagnosis of a Chiari malformation is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a neurological exam that includes a variety of specialized tests including specialized imaging techniques.Clinical Testing and Work-UpImaging techniques may include magnetic resonance imaging (MRI), cine MRI and plain X-rays. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI can reveal excess CSF and loss of neural tissue. A cine MRI is like a traditional MRI, but can be used to measure and assess CSF flow. Interpreting a cine MRI is difficult and the procedure is best at diagnosing obvious CSF flow abnormalities (as opposed to borderline cases). Consequently, not all physicians advocate its use.A plain X-ray can reveal skeletal malformations such as skull defects, abnormalities of cervical vertebrae or abnormal curvature or abnormal motion of the spine. Computed tomography (CT) scans may be helpful in clarifying congenital bony abnormalities at the skull base. Additional tests may be performed to detect or assess other complications potentially associated with a Chiari malformation. Such tests may include a swallowing test to assess how well someone can drink fluids or swallow thickened food and sleep studies to detect sleep disorders potentially associated with Chiari malformations. | Diagnosis of Chiari Malformations. A diagnosis of a Chiari malformation is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a neurological exam that includes a variety of specialized tests including specialized imaging techniques.Clinical Testing and Work-UpImaging techniques may include magnetic resonance imaging (MRI), cine MRI and plain X-rays. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI can reveal excess CSF and loss of neural tissue. A cine MRI is like a traditional MRI, but can be used to measure and assess CSF flow. Interpreting a cine MRI is difficult and the procedure is best at diagnosing obvious CSF flow abnormalities (as opposed to borderline cases). Consequently, not all physicians advocate its use.A plain X-ray can reveal skeletal malformations such as skull defects, abnormalities of cervical vertebrae or abnormal curvature or abnormal motion of the spine. Computed tomography (CT) scans may be helpful in clarifying congenital bony abnormalities at the skull base. Additional tests may be performed to detect or assess other complications potentially associated with a Chiari malformation. Such tests may include a swallowing test to assess how well someone can drink fluids or swallow thickened food and sleep studies to detect sleep disorders potentially associated with Chiari malformations. | 227 | Chiari Malformations |
nord_227_6 | Therapies of Chiari Malformations | TreatmentThe treatment of a Chiari malformation is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurosurgeons, neurologists, eye specialists (ophthalmologists) and other healthcare professionals may need to systematically and comprehensively plan a patient's treatment.Treatment procedures and interventions may vary, depending upon numerous factors, such as disease progression; the presence or absence of certain symptoms; the relationship of the malformation to the main physical symptoms; the impact of symptoms on overall quality of life; an individual's age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient and should be based upon the specifics of his or her case, a thorough discussion of the potential benefits and risks including possible side effects and long-term effects, patient preference, and other appropriate factors.Neurosurgeons and other physicians may disagree as to the best approach to treat a Chiari malformation. There is no specific, agreed-upon therapy or treatment regimen. Different neurosurgeons may recommend different surgical techniques or treatment regimens.Generally, individuals with no symptoms are not treated, but are regularly monitored to see whether the disorder progresses. If mild symptoms are present such as neck pain or headaches, physicians may recommend conservative treatment such as pain medications, massage therapy or a reduction in activities, particularly those involving heavy lifting or straining. Physical therapy may be tried in some cases, but some physicians argue against its use stating that physical therapy for individuals with a Chiari malformation is not always effective.Symptomatic Chiari malformations are most often treated by surgery. There are no specific criteria or objective tests that can be used to determine when to undergo surgery or the best procedures to choose. The procedure that is best may differ for children and adults. The most common surgery is known as posterior fossa decompression. With this procedure, a surgeon creates room by removing small pieces of bone in the back of the skull, thereby enlarging the foramen magnum. This relieves pressure and reduces compression on the brainstem, and may allow the cerebellar tonsils to move back to a more normal position.There are usually a few steps during the surgical decompression of the posterior fossa including,Removal of a piece of the skull (craniectomy). This can relieve pressure and give more room for cerebrospinal fluid circulation. A craniectomy may be enough in some cases of mild tonsillar descent. However, many cases require the additional procedures described below.Removal of part of the bony covering of the spinal canal (laminectomy) in order to provide more room for cerebrospinal fluid circulation and to remove scar tissue. In most instances, the laminectomy is limited to C1, the first cervical vertebra.Cutting open of the tough outer membrane covering the brain and spinal cord (dura) and sewing in a patch to make it bigger (duraplasty). The patch used in a duraplasty may be made from artificial material or from tissue harvested from another area of the body. A duraplasty is performed to provide even more room for decompression, although some physicians argue against the necessity of this step. It may not be necessary in children.Shrinking of the cerebellar tonsils. Some neurosurgeons advocate cauterizing (applying a small amount of electricity) to the cerebellar tonsils, which causes tonsillar tissue to shrink and retract. This is more invasive and is not advocated by all neurosurgeons, but appears necessary for at least some patients.Insertion of an artificial plate over the area where the skull was removed.Surgical treatment of a Chiari malformation has variable results. One study found that more than 80 percent of adults reported significant improvement in symptoms after surgery. However, response to therapy is highly variable. Symptoms related to a Chiari malformation may respond differently from symptoms related to an associated syringomyelia. Although some individuals experience significant improvement, others may have symptoms that persist including residual pain, muscle weakness, and loss of sensation. In addition, surgery carries risks such as leakage of cerebrospinal fluid or infection.Individuals with hydrocephalus may be treated by the implantation of a tube (shunt) to drain excessive cerebrospinal fluid away from the skull and brain to another part of the body where the CSF can be absorbed. In some cases, shunts may relieve CSF pressure and improve symptoms. In other cases, individuals require surgical intervention as described above. Before surgery can be performed, the excessive fluid may need to be drained via shunt insertion.A myelomeningocele, which is usually associated with Chiari malformation type II, requires surgical repair.Syringomyelia associated with a Chiari malformation usually does not require direct treatment. In most cases, syringomyelia improves on its own after surgery to correct a Chiari malformation because the normal flow of cerebrospinal fluid is restored.An acquired Chiari malformation requires treatment of the underlying condition. In many cases, a Chiari malformation may resolve without further treatment in such cases.Genetic counseling may be of benefit for affected individuals and their families. Additional treatment is symptomatic and supportive.Individuals require periodic follow up after surgical treatment for a Chiari malformation. Symptoms may recur after a successful surgery, usually within the first two years. Most likely, this is due to the development of scar tissue or an opening around the duraplasty covering the brain. Children required periodic MRI examinations because of the normal continued growth of the brain and skull. | Therapies of Chiari Malformations. TreatmentThe treatment of a Chiari malformation is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurosurgeons, neurologists, eye specialists (ophthalmologists) and other healthcare professionals may need to systematically and comprehensively plan a patient's treatment.Treatment procedures and interventions may vary, depending upon numerous factors, such as disease progression; the presence or absence of certain symptoms; the relationship of the malformation to the main physical symptoms; the impact of symptoms on overall quality of life; an individual's age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient and should be based upon the specifics of his or her case, a thorough discussion of the potential benefits and risks including possible side effects and long-term effects, patient preference, and other appropriate factors.Neurosurgeons and other physicians may disagree as to the best approach to treat a Chiari malformation. There is no specific, agreed-upon therapy or treatment regimen. Different neurosurgeons may recommend different surgical techniques or treatment regimens.Generally, individuals with no symptoms are not treated, but are regularly monitored to see whether the disorder progresses. If mild symptoms are present such as neck pain or headaches, physicians may recommend conservative treatment such as pain medications, massage therapy or a reduction in activities, particularly those involving heavy lifting or straining. Physical therapy may be tried in some cases, but some physicians argue against its use stating that physical therapy for individuals with a Chiari malformation is not always effective.Symptomatic Chiari malformations are most often treated by surgery. There are no specific criteria or objective tests that can be used to determine when to undergo surgery or the best procedures to choose. The procedure that is best may differ for children and adults. The most common surgery is known as posterior fossa decompression. With this procedure, a surgeon creates room by removing small pieces of bone in the back of the skull, thereby enlarging the foramen magnum. This relieves pressure and reduces compression on the brainstem, and may allow the cerebellar tonsils to move back to a more normal position.There are usually a few steps during the surgical decompression of the posterior fossa including,Removal of a piece of the skull (craniectomy). This can relieve pressure and give more room for cerebrospinal fluid circulation. A craniectomy may be enough in some cases of mild tonsillar descent. However, many cases require the additional procedures described below.Removal of part of the bony covering of the spinal canal (laminectomy) in order to provide more room for cerebrospinal fluid circulation and to remove scar tissue. In most instances, the laminectomy is limited to C1, the first cervical vertebra.Cutting open of the tough outer membrane covering the brain and spinal cord (dura) and sewing in a patch to make it bigger (duraplasty). The patch used in a duraplasty may be made from artificial material or from tissue harvested from another area of the body. A duraplasty is performed to provide even more room for decompression, although some physicians argue against the necessity of this step. It may not be necessary in children.Shrinking of the cerebellar tonsils. Some neurosurgeons advocate cauterizing (applying a small amount of electricity) to the cerebellar tonsils, which causes tonsillar tissue to shrink and retract. This is more invasive and is not advocated by all neurosurgeons, but appears necessary for at least some patients.Insertion of an artificial plate over the area where the skull was removed.Surgical treatment of a Chiari malformation has variable results. One study found that more than 80 percent of adults reported significant improvement in symptoms after surgery. However, response to therapy is highly variable. Symptoms related to a Chiari malformation may respond differently from symptoms related to an associated syringomyelia. Although some individuals experience significant improvement, others may have symptoms that persist including residual pain, muscle weakness, and loss of sensation. In addition, surgery carries risks such as leakage of cerebrospinal fluid or infection.Individuals with hydrocephalus may be treated by the implantation of a tube (shunt) to drain excessive cerebrospinal fluid away from the skull and brain to another part of the body where the CSF can be absorbed. In some cases, shunts may relieve CSF pressure and improve symptoms. In other cases, individuals require surgical intervention as described above. Before surgery can be performed, the excessive fluid may need to be drained via shunt insertion.A myelomeningocele, which is usually associated with Chiari malformation type II, requires surgical repair.Syringomyelia associated with a Chiari malformation usually does not require direct treatment. In most cases, syringomyelia improves on its own after surgery to correct a Chiari malformation because the normal flow of cerebrospinal fluid is restored.An acquired Chiari malformation requires treatment of the underlying condition. In many cases, a Chiari malformation may resolve without further treatment in such cases.Genetic counseling may be of benefit for affected individuals and their families. Additional treatment is symptomatic and supportive.Individuals require periodic follow up after surgical treatment for a Chiari malformation. Symptoms may recur after a successful surgery, usually within the first two years. Most likely, this is due to the development of scar tissue or an opening around the duraplasty covering the brain. Children required periodic MRI examinations because of the normal continued growth of the brain and skull. | 227 | Chiari Malformations |
nord_228_0 | Overview of Chikungunya | Chikungunya is a rare viral infection transmitted by the bite of an infected mosquito. It is characterized by a rash, fever, and severe joint pain (arthralgias) that usually lasts for three to seven days. Because of its effect on the joints, Chikungunya has been classified among the Arthritic Viruses. It primarily occurs in tropical areas of the world. | Overview of Chikungunya. Chikungunya is a rare viral infection transmitted by the bite of an infected mosquito. It is characterized by a rash, fever, and severe joint pain (arthralgias) that usually lasts for three to seven days. Because of its effect on the joints, Chikungunya has been classified among the Arthritic Viruses. It primarily occurs in tropical areas of the world. | 228 | Chikungunya |
nord_228_1 | Symptoms of Chikungunya | The early symptoms of Chikungunya include fever, headache, and joint pain (arthralgias) that may be so severe that they may be disabling. The knees, elbows, wrists, ankles, and/or fingers are generally effected. Joint pain increases with movement and is worse in the morning. However, it may take several weeks before the symptoms improve. Chikungunya is not associated with permanent joint damage.Other symptoms may include abnormal sensitivity to light (photophobia), sore throat, lack of appetite (anorexia), and vomiting. Backache and rash on the face and neck are also common in people with Chikungunya. Occasionally the membranes that line the eyes may become inflamed (conjunctivitis) and lymph glands may become swollen (lymphadenopathy). The fever usually subsides before the 10th day. | Symptoms of Chikungunya. The early symptoms of Chikungunya include fever, headache, and joint pain (arthralgias) that may be so severe that they may be disabling. The knees, elbows, wrists, ankles, and/or fingers are generally effected. Joint pain increases with movement and is worse in the morning. However, it may take several weeks before the symptoms improve. Chikungunya is not associated with permanent joint damage.Other symptoms may include abnormal sensitivity to light (photophobia), sore throat, lack of appetite (anorexia), and vomiting. Backache and rash on the face and neck are also common in people with Chikungunya. Occasionally the membranes that line the eyes may become inflamed (conjunctivitis) and lymph glands may become swollen (lymphadenopathy). The fever usually subsides before the 10th day. | 228 | Chikungunya |
nord_228_2 | Causes of Chikungunya | Chikungunya is an infectious tropical disease caused by a virus that belongs to the group of A arboviruses. It is transmitted by various species of mosquitoes. Monkeys may also be infected with this virus. Some cases of this infection appear to have occurred through casual human to human contact, but it is not known how it is transmitted among humans. | Causes of Chikungunya. Chikungunya is an infectious tropical disease caused by a virus that belongs to the group of A arboviruses. It is transmitted by various species of mosquitoes. Monkeys may also be infected with this virus. Some cases of this infection appear to have occurred through casual human to human contact, but it is not known how it is transmitted among humans. | 228 | Chikungunya |
nord_228_3 | Affects of Chikungunya | Chikungunya is a viral disease that affects males and females in equal numbers. It primarily affects children and young adults in Africa, Southeast Asia, and India. A large outbreak of Chikungunya occurred in Tanganyika, Africa in 1953. This disorder is rare outside of tropical areas of the world. | Affects of Chikungunya. Chikungunya is a viral disease that affects males and females in equal numbers. It primarily affects children and young adults in Africa, Southeast Asia, and India. A large outbreak of Chikungunya occurred in Tanganyika, Africa in 1953. This disorder is rare outside of tropical areas of the world. | 228 | Chikungunya |
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