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nord_200_0 | Overview of Carnitine Palmitoyltransferase 1A Deficiency | SummaryCarnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of fatty acid oxidation, the process by which the body breaks down fatty acids from food for energy. Fatty acids come from animal and vegetable fats. People with CPT1A deficiency may experience liver failure which can cause damage to the nervous system (hepatic encephalopathy) as a result of fatty acids not being properly broken down. CPT1A deficiency is caused by harmful DNA changes (mutations) in the CPT1A gene. The CPT1A gene produces the carnitine palmitoyltransferase 1 enzyme, which breaks down long fatty acids. CPT1A deficiency is an autosomal recessive condition, which means that a harmful change in the CPT1A gene was inherited from both parents. | Overview of Carnitine Palmitoyltransferase 1A Deficiency. SummaryCarnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of fatty acid oxidation, the process by which the body breaks down fatty acids from food for energy. Fatty acids come from animal and vegetable fats. People with CPT1A deficiency may experience liver failure which can cause damage to the nervous system (hepatic encephalopathy) as a result of fatty acids not being properly broken down. CPT1A deficiency is caused by harmful DNA changes (mutations) in the CPT1A gene. The CPT1A gene produces the carnitine palmitoyltransferase 1 enzyme, which breaks down long fatty acids. CPT1A deficiency is an autosomal recessive condition, which means that a harmful change in the CPT1A gene was inherited from both parents. | 200 | Carnitine Palmitoyltransferase 1A Deficiency |
nord_200_1 | Symptoms of Carnitine Palmitoyltransferase 1A Deficiency | CPT1A deficiency in a developing baby can cause abnormal findings during pregnancy, including maternal fatty liver, low blood sugar (hypoglycemia), abnormal liver enzymes, high amounts of ammonia (hyperammonenmia), and increased susceptibility to bleeding due to abnormal liver function. CPT1A deficiency can be identified on newborn screening, a blood test performed on newborns shortly after birth. Newborn screening can detect levels of fatty acid oxidation products, and abnormal levels can indicate that a newborn has CPT1A deficiency. However, newborn screening is not diagnostic, and further testing is needed to confirm a diagnosis. CPT1A deficiency symptoms typically appear after times of stress, like fasting or illness. These symptoms include low blood glucose and no ketone bodies in urine (hypoketotic hypoglycemia). Ketone bodies are molecules that are produced by the liver after fatty acids are broken down. Additionally, CPT1A deficiency can cause sudden liver failure. Liver failure can lead to damage to the nervous system (hepatic encephalopathy). Additionally, there can be other abnormal laboratory findings which may include increased liver enzymes, ammonia (hyperammonemia), and carnitine in blood. | Symptoms of Carnitine Palmitoyltransferase 1A Deficiency. CPT1A deficiency in a developing baby can cause abnormal findings during pregnancy, including maternal fatty liver, low blood sugar (hypoglycemia), abnormal liver enzymes, high amounts of ammonia (hyperammonenmia), and increased susceptibility to bleeding due to abnormal liver function. CPT1A deficiency can be identified on newborn screening, a blood test performed on newborns shortly after birth. Newborn screening can detect levels of fatty acid oxidation products, and abnormal levels can indicate that a newborn has CPT1A deficiency. However, newborn screening is not diagnostic, and further testing is needed to confirm a diagnosis. CPT1A deficiency symptoms typically appear after times of stress, like fasting or illness. These symptoms include low blood glucose and no ketone bodies in urine (hypoketotic hypoglycemia). Ketone bodies are molecules that are produced by the liver after fatty acids are broken down. Additionally, CPT1A deficiency can cause sudden liver failure. Liver failure can lead to damage to the nervous system (hepatic encephalopathy). Additionally, there can be other abnormal laboratory findings which may include increased liver enzymes, ammonia (hyperammonemia), and carnitine in blood. | 200 | Carnitine Palmitoyltransferase 1A Deficiency |
nord_200_2 | Causes of Carnitine Palmitoyltransferase 1A Deficiency | CPT1A deficiency is caused by harmful changes (mutations) in the CPT1A gene that codes for the carnitine palmitoyltransferase 1 enzyme. This enzyme breaks down long fatty acids. If fats cannot be properly processed, then energy production is decreased. CPT1A deficiency is an autosomal recessive condition. Autosomal recessive conditions occur when both parents carry a mutation on the same gene (carrier) and each parent passes the mutated gene on to the child, giving the child no normally functioning gene to compensate for the mutations. 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 mutation 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 and to not carry mutations from either parent that particular trait is 25%. The risk is the same for males and females. | Causes of Carnitine Palmitoyltransferase 1A Deficiency. CPT1A deficiency is caused by harmful changes (mutations) in the CPT1A gene that codes for the carnitine palmitoyltransferase 1 enzyme. This enzyme breaks down long fatty acids. If fats cannot be properly processed, then energy production is decreased. CPT1A deficiency is an autosomal recessive condition. Autosomal recessive conditions occur when both parents carry a mutation on the same gene (carrier) and each parent passes the mutated gene on to the child, giving the child no normally functioning gene to compensate for the mutations. 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 mutation 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 and to not carry mutations from either parent that particular trait is 25%. The risk is the same for males and females. | 200 | Carnitine Palmitoyltransferase 1A Deficiency |
nord_200_3 | Affects of Carnitine Palmitoyltransferase 1A Deficiency | CPT1A deficiency has been reported in approximately 60 individuals. The incidence of this condition may be higher in the Hutterite populations in the northern United States and Canada and the Inuit populations in northern Canada, Alaska and Greenland. This condition occurs in both males and females equally. | Affects of Carnitine Palmitoyltransferase 1A Deficiency. CPT1A deficiency has been reported in approximately 60 individuals. The incidence of this condition may be higher in the Hutterite populations in the northern United States and Canada and the Inuit populations in northern Canada, Alaska and Greenland. This condition occurs in both males and females equally. | 200 | Carnitine Palmitoyltransferase 1A Deficiency |
nord_200_4 | Related disorders of Carnitine Palmitoyltransferase 1A Deficiency | CPT1A deficiency belongs to a category of conditions called fatty acid oxidation disorders (FODs), in which the body cannot properly break down fatty acids to create energy in the body. The fats that are not broken down cannot be used for energy, and the increased fat by-products can become toxic and cause problems in the body. Other FODs can have similar symptoms to CPT1A deficiency such as:(For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)While CPT1A deficiency is rare, FAODs are estimated to affect one in every 5,000 to 10,000 live births, with MCADD deficiency being the most commonly seen FAOD.Another condition that can have similar symptoms to CPTA1 deficiency is Reye syndrome. Reye syndrome is a disorder that is characterized by low blood sugar, liver and brain problems. Usually, these symptoms occur after a viral illness like chicken pox or flu. Other symptoms include vomiting, lack of energy (lethargy), diarrhea, and/or high rate of breathing. The exact cause of Reye syndrome is unknown. Unlike the previously mentioned conditions, Reye syndrome is not a disorder of fatty acid oxidation. For more information on this disorder, choose “Reye” as your search term in the Rare Disease Database.) | Related disorders of Carnitine Palmitoyltransferase 1A Deficiency. CPT1A deficiency belongs to a category of conditions called fatty acid oxidation disorders (FODs), in which the body cannot properly break down fatty acids to create energy in the body. The fats that are not broken down cannot be used for energy, and the increased fat by-products can become toxic and cause problems in the body. Other FODs can have similar symptoms to CPT1A deficiency such as:(For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)While CPT1A deficiency is rare, FAODs are estimated to affect one in every 5,000 to 10,000 live births, with MCADD deficiency being the most commonly seen FAOD.Another condition that can have similar symptoms to CPTA1 deficiency is Reye syndrome. Reye syndrome is a disorder that is characterized by low blood sugar, liver and brain problems. Usually, these symptoms occur after a viral illness like chicken pox or flu. Other symptoms include vomiting, lack of energy (lethargy), diarrhea, and/or high rate of breathing. The exact cause of Reye syndrome is unknown. Unlike the previously mentioned conditions, Reye syndrome is not a disorder of fatty acid oxidation. For more information on this disorder, choose “Reye” as your search term in the Rare Disease Database.) | 200 | Carnitine Palmitoyltransferase 1A Deficiency |
nord_200_5 | Diagnosis of Carnitine Palmitoyltransferase 1A Deficiency | CPT1A deficiency can be diagnosed by using genetic testing to find two mutations in the CPT1A gene. Additionally, the level of carnitine palmitoyltransferase 1 (CPT1) enzyme can be measured from skin cells. Other laboratory findings can support this diagnosis, including low levels of ketones, elevated liver enzymes, elevated ammonia, and elevated carnitine in blood. Some state newborn screening programs perform screening for CPT1A deficiency by measuring the ratio of free to total carnitine in blood plasma or serum. | Diagnosis of Carnitine Palmitoyltransferase 1A Deficiency. CPT1A deficiency can be diagnosed by using genetic testing to find two mutations in the CPT1A gene. Additionally, the level of carnitine palmitoyltransferase 1 (CPT1) enzyme can be measured from skin cells. Other laboratory findings can support this diagnosis, including low levels of ketones, elevated liver enzymes, elevated ammonia, and elevated carnitine in blood. Some state newborn screening programs perform screening for CPT1A deficiency by measuring the ratio of free to total carnitine in blood plasma or serum. | 200 | Carnitine Palmitoyltransferase 1A Deficiency |
nord_200_6 | Therapies of Carnitine Palmitoyltransferase 1A Deficiency | Treatment
Without proper treatment and management, people with CPT1A deficiency can have severe hypoglycemia. Prevention of hypoglycemia is recommended to reduce the risk of neurological effects, such as seizures, unconsciousness, brain damage, and death. Hypoglycemia can be prevented with a high carbohydrate, low fat diet and frequent feeding. If acute hypoglycemia occurs, intravenous dextrose should be provided. Individuals with CPT1A deficiency should have regular liver function testing performed. Female carriers of an abnormal CPT1A gene should be informed about the possibility of complications if they become pregnant. | Therapies of Carnitine Palmitoyltransferase 1A Deficiency. Treatment
Without proper treatment and management, people with CPT1A deficiency can have severe hypoglycemia. Prevention of hypoglycemia is recommended to reduce the risk of neurological effects, such as seizures, unconsciousness, brain damage, and death. Hypoglycemia can be prevented with a high carbohydrate, low fat diet and frequent feeding. If acute hypoglycemia occurs, intravenous dextrose should be provided. Individuals with CPT1A deficiency should have regular liver function testing performed. Female carriers of an abnormal CPT1A gene should be informed about the possibility of complications if they become pregnant. | 200 | Carnitine Palmitoyltransferase 1A Deficiency |
nord_201_0 | Overview of Carnosinemia | Carnosinemia is a very rare inherited metabolic disorder characterized by developmental delays and seizures. Symptoms can begin during infancy and may include drowsiness, seizures that may be accompanied by involuntary jerking muscle movements of the arms, legs, or head (myoclonic seizures), and intellectual disability. | Overview of Carnosinemia. Carnosinemia is a very rare inherited metabolic disorder characterized by developmental delays and seizures. Symptoms can begin during infancy and may include drowsiness, seizures that may be accompanied by involuntary jerking muscle movements of the arms, legs, or head (myoclonic seizures), and intellectual disability. | 201 | Carnosinemia |
nord_201_1 | Symptoms of Carnosinemia | The symptoms of carnosinemia include extreme drowsiness and seizures that can occur in children under the age of one year. Slow growth, low muscle tone, motor delays, and delayed intellectual development also occur in children with this disorder. Seizures may be accompanied by myoclonic seizures. By approximately 2 years of age, affected children show variable degrees of intellectual deficit leading to intellectual disabilities and developmental regression. Some affected children also have muscle weakness (congenital myopathy). Electroencephalogram (EEG), a test that detects electrical activity in the brain, may be abnormal. A few patients reported with this condition have few or no symptoms. | Symptoms of Carnosinemia. The symptoms of carnosinemia include extreme drowsiness and seizures that can occur in children under the age of one year. Slow growth, low muscle tone, motor delays, and delayed intellectual development also occur in children with this disorder. Seizures may be accompanied by myoclonic seizures. By approximately 2 years of age, affected children show variable degrees of intellectual deficit leading to intellectual disabilities and developmental regression. Some affected children also have muscle weakness (congenital myopathy). Electroencephalogram (EEG), a test that detects electrical activity in the brain, may be abnormal. A few patients reported with this condition have few or no symptoms. | 201 | Carnosinemia |
nord_201_2 | Causes of Carnosinemia | The exact nature of the biochemical abnormality that causes carnosinemia is not clear, but carnosinase, the enzyme responsible for carnosine breakdown, is known to be present in the brain, as well as the blood. Studies of muscle tissue from affected individuals suggest that the metabolism of two dipeptides present in meats, carnosine and anserine, by the enzyme carnosinase, is abnormal. The role of the enzyme carnosinase is to break down carnosine into two basic elements. Affected individuals usually have abnormally high levels of carnosine in their urine (carnosinuria) and abnormally low levels of the enzyme carnosinase in their blood. It remains unclear how the neurological signs of this disorder are related to the low level of carnosinase and/or high level of the carnosine in the body.Carnosinase, the enzyme responsible for degrading histidine-containing dipeptides, such as carnosine, anserine and homocarnosine, is encoded by the CNDP1 gene. Loss of carnosinase function has been reported in a small number of patients with highly elevated blood carnosine concentrations, but it is unclear whether the variety of clinical symptoms in these individuals is causally related to carnosinase deficiency. Carnosinemia is thought to be inherited in an autosomal recessive inheritance pattern.
Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | Causes of Carnosinemia. The exact nature of the biochemical abnormality that causes carnosinemia is not clear, but carnosinase, the enzyme responsible for carnosine breakdown, is known to be present in the brain, as well as the blood. Studies of muscle tissue from affected individuals suggest that the metabolism of two dipeptides present in meats, carnosine and anserine, by the enzyme carnosinase, is abnormal. The role of the enzyme carnosinase is to break down carnosine into two basic elements. Affected individuals usually have abnormally high levels of carnosine in their urine (carnosinuria) and abnormally low levels of the enzyme carnosinase in their blood. It remains unclear how the neurological signs of this disorder are related to the low level of carnosinase and/or high level of the carnosine in the body.Carnosinase, the enzyme responsible for degrading histidine-containing dipeptides, such as carnosine, anserine and homocarnosine, is encoded by the CNDP1 gene. Loss of carnosinase function has been reported in a small number of patients with highly elevated blood carnosine concentrations, but it is unclear whether the variety of clinical symptoms in these individuals is causally related to carnosinase deficiency. Carnosinemia is thought to be inherited in an autosomal recessive inheritance pattern.
Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | 201 | Carnosinemia |
nord_201_3 | Affects of Carnosinemia | Carnosinemia is a very rare disorder that affects males and females in equal numbers. Approximately 30 individuals with carnosinemia have been reported in the medical literature world-wide. | Affects of Carnosinemia. Carnosinemia is a very rare disorder that affects males and females in equal numbers. Approximately 30 individuals with carnosinemia have been reported in the medical literature world-wide. | 201 | Carnosinemia |
nord_201_4 | Related disorders of Carnosinemia | Symptoms of the following disorder can be similar to those of carnosinemia. Comparisons may be useful for a differential diagnosis:Gamma-amino butyric acid (GABA) transaminase deficiency is an extremely rare autosomal recessive genetic disorder caused by mutations in the ABAT gene. Symptoms can include slow growth, motor delays, low muscle tone, hyperactive responses, lethargy, seizures, and abnormalities on an EEG. | Related disorders of Carnosinemia. Symptoms of the following disorder can be similar to those of carnosinemia. Comparisons may be useful for a differential diagnosis:Gamma-amino butyric acid (GABA) transaminase deficiency is an extremely rare autosomal recessive genetic disorder caused by mutations in the ABAT gene. Symptoms can include slow growth, motor delays, low muscle tone, hyperactive responses, lethargy, seizures, and abnormalities on an EEG. | 201 | Carnosinemia |
nord_201_5 | Diagnosis of Carnosinemia | The diagnosis of carnosinemia may be made by testing the levels of amino acids in blood and/or urine, which reveals abnormally high levels of carnosine and anserine in the serum and urine. Very specialized testing of the blood will detect very low activity of the enzyme carnosinase in the blood. Diagnosis is based on amino acid analysis of serum and/or urine after exclusion of meat from the diet. | Diagnosis of Carnosinemia. The diagnosis of carnosinemia may be made by testing the levels of amino acids in blood and/or urine, which reveals abnormally high levels of carnosine and anserine in the serum and urine. Very specialized testing of the blood will detect very low activity of the enzyme carnosinase in the blood. Diagnosis is based on amino acid analysis of serum and/or urine after exclusion of meat from the diet. | 201 | Carnosinemia |
nord_201_6 | Therapies of Carnosinemia | Treatment
The treatment of carnosinemia is symptomatic and supportive as there has not been an effective drug treatment thus far. A vegetarian diet will reduce the amount of carnosine and anserine presented to the body, and may lower serum carnosine levels. However, it remains unclear whether this will have any effect of symptoms or progression of the disease.Genetic counseling is recommended for people with carnosinemia and their families. | Therapies of Carnosinemia. Treatment
The treatment of carnosinemia is symptomatic and supportive as there has not been an effective drug treatment thus far. A vegetarian diet will reduce the amount of carnosine and anserine presented to the body, and may lower serum carnosine levels. However, it remains unclear whether this will have any effect of symptoms or progression of the disease.Genetic counseling is recommended for people with carnosinemia and their families. | 201 | Carnosinemia |
nord_202_0 | Overview of Caroli Disease | SummaryCaroli disease is a rare genetic condition that causes the bile ducts in the liver to be wider than usual. Widening (dilation) of the bile ducts in the liver (intrahepatic bile ducts) can cause bile duct stones to form, which can lead to yellowing of the skin (jaundice) and flu-like symptoms. People with Caroli disease can have many episodes of these symptoms over their lifetime.A different type of Caroli disease is called Caroli syndrome. It is common to group these two conditions together because they share features. People with Caroli syndrome have scarring on their liver (congenital hepatic fibrosis) which can cause high blood pressure in the veins in the liver (portal hypertension) as well as problems with the bile ducts in the liver. Sometimes, people with Caroli syndrome can develop cysts on their kidneys (polycystic kidney disease). Symptoms of Caroli syndrome are similar to Caroli disease, but can also include blood in the stools, frequent illnesses, and pain in the abdomen. Symptoms of these two conditions usually begin by the age of 30, but can happen at any age. Treatment may involve antibiotics or surgery to remove part of the liver, depending on symptoms and the parts of the liver that are damaged. Caroli disease and Caroli syndrome are thought to be genetic conditions.IntroductionCaroli disease was first described in 1958 by a French physician named Dr. Jacques Caroli. He was a gastroenterologist who learned that some people had dilated bile ducts in their liver. He also noticed that some people had scarring on their liver in addition to having dilated bile ducts. Those who just had wider bile ducts were then known to have Caroli disease and those who had liver scarring would be known to have Caroli syndrome. Caroli disease is referred to as congenital dilation of intrahepatic bile duct, which means that somebody is born with wider than normal bile ducts in their liver.Bile is made inside of the liver and sent to the digestive system through ducts to help break down fatty foods for the body to use as energy. These bile ducts are important because they need to be able to transport the bile to other parts of the body. If these bile ducts become too wide, bile will begin to collect and can make the bile ducts inside of the liver swollen (cholangitis). Cholangitis can cause pain in the stomach, fever, tiredness, and nausea and vomiting.Caroli disease is usually diagnosed after a person first experiences the symptoms listed above. Having a diagnosis can help the medical team stop bile from collecting in the bile ducts in the future. Medication such as antibiotics can be used to prevent irritation, as well. Surgery is typically put off until symptoms start, since it is an invasive procedure. Surgery can be used to remove part of the liver where the bile ducts are too wide (hemi-hepatectomy) and if the patient is having too many episodes of cholangitis.The other type of Caroli disease, Caroli syndrome, causes the tissue in the liver to scar (congenital hepatic fibrosis) which also causes the bile ducts to be wider than usual. This can also cause the blood pressure in the portal vein, which is blood vessels of the liver, to be high (portal hypertension). Medications such as beta-blockers can be added to help with portal hypertension. People with Caroli syndrome are at an increased risk to develop many cysts or growths on their kidneys (polycystic kidney disease), so they may need medication and surgery to help their kidneys work properly. | Overview of Caroli Disease. SummaryCaroli disease is a rare genetic condition that causes the bile ducts in the liver to be wider than usual. Widening (dilation) of the bile ducts in the liver (intrahepatic bile ducts) can cause bile duct stones to form, which can lead to yellowing of the skin (jaundice) and flu-like symptoms. People with Caroli disease can have many episodes of these symptoms over their lifetime.A different type of Caroli disease is called Caroli syndrome. It is common to group these two conditions together because they share features. People with Caroli syndrome have scarring on their liver (congenital hepatic fibrosis) which can cause high blood pressure in the veins in the liver (portal hypertension) as well as problems with the bile ducts in the liver. Sometimes, people with Caroli syndrome can develop cysts on their kidneys (polycystic kidney disease). Symptoms of Caroli syndrome are similar to Caroli disease, but can also include blood in the stools, frequent illnesses, and pain in the abdomen. Symptoms of these two conditions usually begin by the age of 30, but can happen at any age. Treatment may involve antibiotics or surgery to remove part of the liver, depending on symptoms and the parts of the liver that are damaged. Caroli disease and Caroli syndrome are thought to be genetic conditions.IntroductionCaroli disease was first described in 1958 by a French physician named Dr. Jacques Caroli. He was a gastroenterologist who learned that some people had dilated bile ducts in their liver. He also noticed that some people had scarring on their liver in addition to having dilated bile ducts. Those who just had wider bile ducts were then known to have Caroli disease and those who had liver scarring would be known to have Caroli syndrome. Caroli disease is referred to as congenital dilation of intrahepatic bile duct, which means that somebody is born with wider than normal bile ducts in their liver.Bile is made inside of the liver and sent to the digestive system through ducts to help break down fatty foods for the body to use as energy. These bile ducts are important because they need to be able to transport the bile to other parts of the body. If these bile ducts become too wide, bile will begin to collect and can make the bile ducts inside of the liver swollen (cholangitis). Cholangitis can cause pain in the stomach, fever, tiredness, and nausea and vomiting.Caroli disease is usually diagnosed after a person first experiences the symptoms listed above. Having a diagnosis can help the medical team stop bile from collecting in the bile ducts in the future. Medication such as antibiotics can be used to prevent irritation, as well. Surgery is typically put off until symptoms start, since it is an invasive procedure. Surgery can be used to remove part of the liver where the bile ducts are too wide (hemi-hepatectomy) and if the patient is having too many episodes of cholangitis.The other type of Caroli disease, Caroli syndrome, causes the tissue in the liver to scar (congenital hepatic fibrosis) which also causes the bile ducts to be wider than usual. This can also cause the blood pressure in the portal vein, which is blood vessels of the liver, to be high (portal hypertension). Medications such as beta-blockers can be added to help with portal hypertension. People with Caroli syndrome are at an increased risk to develop many cysts or growths on their kidneys (polycystic kidney disease), so they may need medication and surgery to help their kidneys work properly. | 202 | Caroli Disease |
nord_202_1 | Symptoms of Caroli Disease | Bile needs to be able to move through the bile ducts without getting stuck. When these ducts become too wide, bile can collect easily. As bile collects over time, the build-up can cause small stones to form. These small stones usually do not cause symptoms unless they block the bile duct. When a bile duct is blocked due to stones, the bile ducts become swollen (cholangitis). This can cause pain on the right side of the body, vomiting, fever, and yellowing of the skin (jaundice). People with Caroli disease experience many episodes of cholangitis. Rarely, tumors called cholangiocarcinomas can form in the bile duct due to the build-up of bile. Usually, symptoms happen before the age of 30, but can happen at any age. Some people with Caroli disease may only have one episode of cholangitis, so it is important to understand how the disease impacts a person’s life. The liver has its own bile ducts and its own blood vessels that make up the hepatic portal system. The portal system carries blood from the digestive organs to the liver in order for the liver to filter out waste. The liver needs to form correctly in order to work. Sometimes, people are born with a condition that causes their liver to have scarring and to be larger than normal (congenital hepatic fibrosis). This also changes the way their bile ducts in the liver are formed, putting them at a higher risk to have cholangitis. Since the hepatic portal system is also not formed correctly, blood pressure in these veins is higher than normal. People with Caroli syndrome have congenital hepatic fibrosis. Caroli syndrome is progressive meaning that damage to the liver is done over time. This condition can lead to liver failure and polycystic kidney disease. | Symptoms of Caroli Disease. Bile needs to be able to move through the bile ducts without getting stuck. When these ducts become too wide, bile can collect easily. As bile collects over time, the build-up can cause small stones to form. These small stones usually do not cause symptoms unless they block the bile duct. When a bile duct is blocked due to stones, the bile ducts become swollen (cholangitis). This can cause pain on the right side of the body, vomiting, fever, and yellowing of the skin (jaundice). People with Caroli disease experience many episodes of cholangitis. Rarely, tumors called cholangiocarcinomas can form in the bile duct due to the build-up of bile. Usually, symptoms happen before the age of 30, but can happen at any age. Some people with Caroli disease may only have one episode of cholangitis, so it is important to understand how the disease impacts a person’s life. The liver has its own bile ducts and its own blood vessels that make up the hepatic portal system. The portal system carries blood from the digestive organs to the liver in order for the liver to filter out waste. The liver needs to form correctly in order to work. Sometimes, people are born with a condition that causes their liver to have scarring and to be larger than normal (congenital hepatic fibrosis). This also changes the way their bile ducts in the liver are formed, putting them at a higher risk to have cholangitis. Since the hepatic portal system is also not formed correctly, blood pressure in these veins is higher than normal. People with Caroli syndrome have congenital hepatic fibrosis. Caroli syndrome is progressive meaning that damage to the liver is done over time. This condition can lead to liver failure and polycystic kidney disease. | 202 | Caroli Disease |
nord_202_2 | Causes of Caroli Disease | Caroli disease and Caroli syndrome are thought to be genetic conditions. Caroli disease usually occurs sporadically, but has been reported to follow autosomal dominant inheritance in some families. Caroli syndrome, on the other hand, is associated with genetic changes (mutations) in the PKHD1 gene. This gene makes a protein that helps build the bile ducts as well as the kidneys. Mutations in this gene are also associated with a kidney condition called polycystic kidney disease. Since this disease has been linked to Caroli syndrome, it may be that PKHD1 is linked to Caroli disease, although it is not certain. 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. People who are related (consanguineous) have a greater chance of being carriers for the same condition and have an increased chance of having a child with a recessive condition. 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 mutated (changed) 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. | Causes of Caroli Disease. Caroli disease and Caroli syndrome are thought to be genetic conditions. Caroli disease usually occurs sporadically, but has been reported to follow autosomal dominant inheritance in some families. Caroli syndrome, on the other hand, is associated with genetic changes (mutations) in the PKHD1 gene. This gene makes a protein that helps build the bile ducts as well as the kidneys. Mutations in this gene are also associated with a kidney condition called polycystic kidney disease. Since this disease has been linked to Caroli syndrome, it may be that PKHD1 is linked to Caroli disease, although it is not certain. 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. People who are related (consanguineous) have a greater chance of being carriers for the same condition and have an increased chance of having a child with a recessive condition. 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 mutated (changed) 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. | 202 | Caroli Disease |
nord_202_3 | Affects of Caroli Disease | Caroli disease and Caroli syndrome can affect people of all ethnic and ancestral backgrounds. Symptoms typically start in adulthood, but can sometimes start in childhood. Caroli disease is rarer than Caroli syndrome, but it is estimated that 1 out of 1,000,000 individuals are affected by Caroli disease. Caroli syndrome has been estimated to affect 1 out of 100,000 individuals, but it is difficult to identify people with Caroli syndrome since features can overlap with other conditions. | Affects of Caroli Disease. Caroli disease and Caroli syndrome can affect people of all ethnic and ancestral backgrounds. Symptoms typically start in adulthood, but can sometimes start in childhood. Caroli disease is rarer than Caroli syndrome, but it is estimated that 1 out of 1,000,000 individuals are affected by Caroli disease. Caroli syndrome has been estimated to affect 1 out of 100,000 individuals, but it is difficult to identify people with Caroli syndrome since features can overlap with other conditions. | 202 | Caroli Disease |
nord_202_4 | Related disorders of Caroli Disease | Many conditions have similar symptoms to both Caroli disease and Caroli syndrome. It is important to know the conditions that could be confused for the two types of Caroli disease: Choledochal cysts are growths on the bile duct that are present from birth. A cysts or growth can form anywhere in the bile duct which then causes bile to back up into the liver and the pancreas, which can cause cholangitis and swelling of the pancreas (pancreatitis). Symptoms can occur in childhood or later. Symptoms include jaundice, abdominal mass, fever, and pain in the right upper abdomen. Cholangiocarcinomas may also form. Recurrent pyogenic cholangitis is a chronic infection that causes cholangitis. It is caused by parasites known as Ascaris lumbricoides and C. sinesis Ascaris lumbricoides. It mainly occurs in people who have lived or are currently living in southeastern Asia. Primary sclerosing cholangitis (PSC) is an autoimmune condition that causes the bile ducts of the liver to become harder and inflamed over time. This condition can lead to end-stage liver disease, portal hypertension, and has been associated with inflammatory bowel disease. People with PSC are at an increased risk to develop colorectal cancer as well as cholangiocarcinomas. (For more information about this condition, search for “PSC” in the Rare Disease Database.) | Related disorders of Caroli Disease. Many conditions have similar symptoms to both Caroli disease and Caroli syndrome. It is important to know the conditions that could be confused for the two types of Caroli disease: Choledochal cysts are growths on the bile duct that are present from birth. A cysts or growth can form anywhere in the bile duct which then causes bile to back up into the liver and the pancreas, which can cause cholangitis and swelling of the pancreas (pancreatitis). Symptoms can occur in childhood or later. Symptoms include jaundice, abdominal mass, fever, and pain in the right upper abdomen. Cholangiocarcinomas may also form. Recurrent pyogenic cholangitis is a chronic infection that causes cholangitis. It is caused by parasites known as Ascaris lumbricoides and C. sinesis Ascaris lumbricoides. It mainly occurs in people who have lived or are currently living in southeastern Asia. Primary sclerosing cholangitis (PSC) is an autoimmune condition that causes the bile ducts of the liver to become harder and inflamed over time. This condition can lead to end-stage liver disease, portal hypertension, and has been associated with inflammatory bowel disease. People with PSC are at an increased risk to develop colorectal cancer as well as cholangiocarcinomas. (For more information about this condition, search for “PSC” in the Rare Disease Database.) | 202 | Caroli Disease |
nord_202_5 | Diagnosis of Caroli Disease | Based on symptoms, imaging may be done to see if there are any problems with the liver or bile ducts. Ultrasounds, CT scans, ERCPs, MRCPs, and MRIs are needed to make a diagnosis. ERCP (endoscopic retrograde cholangiopancreatography) is a procedure that is done using a small, bendable tube (endoscope) that is placed through the mouth and into the stomach. ERCP is able to see the bile ducts and the liver to see if there are any scars or masses. ERCP is an invasive procedure, but it can help rule out other conditions. It is accurate in diagnosing Caroli disease and Caroli syndrome. MRCP (magnetic resonance cholangiopancreatography) is a special type of test that can measure how wide the bile ducts are. MRCP can also see if there are any bile duct stones. Other types of imaging, including CT scans, can see if there are scars on the liver. It is difficult to tell if liver scars are due to Caroli syndrome or another unrelated condition. A complete blood count (CBC) is a blood test that may also be done to see if someone has Caroli disease or Caroli syndrome. People with Caroli syndrome may have lower white blood cells, lower red blood cells, or lower platelets than people with Caroli disease. Combining imaging and blood work can help determine what type of Caroli disease a person has, since the symptoms are similar. Clinical Testing and Work-Up Tests are ordered based on the type of symptoms a person has. If someone has symptoms of Caroli disease, they will have an ERCP, an MRCP, a CT scan, or another type of scan. It is important to measure the bile ducts in the liver to see if they are wider than usual, since that is the main sign of Caroli disease. Having these types of tests can rule out Caroli syndrome. | Diagnosis of Caroli Disease. Based on symptoms, imaging may be done to see if there are any problems with the liver or bile ducts. Ultrasounds, CT scans, ERCPs, MRCPs, and MRIs are needed to make a diagnosis. ERCP (endoscopic retrograde cholangiopancreatography) is a procedure that is done using a small, bendable tube (endoscope) that is placed through the mouth and into the stomach. ERCP is able to see the bile ducts and the liver to see if there are any scars or masses. ERCP is an invasive procedure, but it can help rule out other conditions. It is accurate in diagnosing Caroli disease and Caroli syndrome. MRCP (magnetic resonance cholangiopancreatography) is a special type of test that can measure how wide the bile ducts are. MRCP can also see if there are any bile duct stones. Other types of imaging, including CT scans, can see if there are scars on the liver. It is difficult to tell if liver scars are due to Caroli syndrome or another unrelated condition. A complete blood count (CBC) is a blood test that may also be done to see if someone has Caroli disease or Caroli syndrome. People with Caroli syndrome may have lower white blood cells, lower red blood cells, or lower platelets than people with Caroli disease. Combining imaging and blood work can help determine what type of Caroli disease a person has, since the symptoms are similar. Clinical Testing and Work-Up Tests are ordered based on the type of symptoms a person has. If someone has symptoms of Caroli disease, they will have an ERCP, an MRCP, a CT scan, or another type of scan. It is important to measure the bile ducts in the liver to see if they are wider than usual, since that is the main sign of Caroli disease. Having these types of tests can rule out Caroli syndrome. | 202 | Caroli Disease |
nord_202_6 | Therapies of Caroli Disease | Treatment
Treatment for Caroli disease is based on where the wide bile ducts are located inside of the liver. If the wider bile ducts are on the left or right half of the liver, then that portion of the liver can be removed through surgery. People who have part of their liver removed (hemi-hepatectomy) in order to treat Caroli disease often do not experience future symptoms. If the dilated bile ducts are located throughout the liver, using antibiotics may be able to prevent cholangitis. Surgeries can also be done to help get the bile out of the liver (internal biliary bypass). For some people, this is difficult to manage, so a liver transplant may be the best option. People with Caroli disease are usually followed by a care team made up of doctors who specialize in diseases of the digestive tract (gastroenterologists), doctors who specialize in diseases of the liver (hepatologists), and doctors who perform surgeries. They may also be cared for by a surgeon that specializes in liver transplants (transplant hepatologist). | Therapies of Caroli Disease. Treatment
Treatment for Caroli disease is based on where the wide bile ducts are located inside of the liver. If the wider bile ducts are on the left or right half of the liver, then that portion of the liver can be removed through surgery. People who have part of their liver removed (hemi-hepatectomy) in order to treat Caroli disease often do not experience future symptoms. If the dilated bile ducts are located throughout the liver, using antibiotics may be able to prevent cholangitis. Surgeries can also be done to help get the bile out of the liver (internal biliary bypass). For some people, this is difficult to manage, so a liver transplant may be the best option. People with Caroli disease are usually followed by a care team made up of doctors who specialize in diseases of the digestive tract (gastroenterologists), doctors who specialize in diseases of the liver (hepatologists), and doctors who perform surgeries. They may also be cared for by a surgeon that specializes in liver transplants (transplant hepatologist). | 202 | Caroli Disease |
nord_203_0 | Overview of Carpenter Syndrome | Carpenter syndrome belongs to a group of rare genetic disorders known as “acrocephalopolysyndactyly” (ACPS) disorders. All forms of ACPS are characterized by premature closure of the fibrous joints (cranial sutures) between certain bones of the skull (craniosynostosis), causing the top of the head to appear pointed (acrocephaly); webbing or fusion (syndactyly) of certain fingers or toes (digits); and/or more than the normal number of digits (polydactyly). Carpenter syndrome is also known as ACPS type II.Carpenter syndrome is typically evident at or shortly after birth. Due to craniosynostosis, the top of the head may appear unusually conical (acrocephaly) or the head may seem short and broad (brachycephaly). In addition, the cranial sutures often fuse unevenly, causing the head and face to appear dissimilar from one side to the other (craniofacial asymmetry). Additional malformations of the skull and facial (craniofacial) region may include downslanting eyelid folds (palpebral fissures); a flat nasal bridge; malformed (dysplastic), low-set ears; and a small, underdeveloped (hypoplastic) upper and/or lower jaw (maxilla and/or mandible).Individuals may also have unusually short fingers and toes (brachydactyly); partial fusion of the soft tissues (cutaneous syndactyly) between certain digits; and the presence of extra (supernumerary) toes or, less commonly, additional fingers (polydactyly). In some instances, additional physical abnormalities are present, such as short stature, structural heart malformations (congenital heart defects), mild to moderate obesity, weakening in the abdominal wall near the navel through which the intestine may protrude (umbilical hernia), or failure of the testes to descend into the scrotum (cryptorchidism) in affected males. In addition, many individuals with the disorder are affected by mild to moderate intellectual disability. However, intelligence is normal in some instances. Most cases are caused by mutations in the RAB23 gene. In several affected individuals, Carpenter syndrome was caused by mutations in the MEGF8 gene; these individuals are referred to as having Carpenter syndrome type 2. Both types of Carpenter syndrome are inherited in an autosomal recessive manner.Carpenter syndrome was originally described in the medical literature in 1901 (Carpenter G) in two sisters and one brother. However, Carpenter syndrome was not recognized as a distinct disease entity until 1966 (Temtamy SA). | Overview of Carpenter Syndrome. Carpenter syndrome belongs to a group of rare genetic disorders known as “acrocephalopolysyndactyly” (ACPS) disorders. All forms of ACPS are characterized by premature closure of the fibrous joints (cranial sutures) between certain bones of the skull (craniosynostosis), causing the top of the head to appear pointed (acrocephaly); webbing or fusion (syndactyly) of certain fingers or toes (digits); and/or more than the normal number of digits (polydactyly). Carpenter syndrome is also known as ACPS type II.Carpenter syndrome is typically evident at or shortly after birth. Due to craniosynostosis, the top of the head may appear unusually conical (acrocephaly) or the head may seem short and broad (brachycephaly). In addition, the cranial sutures often fuse unevenly, causing the head and face to appear dissimilar from one side to the other (craniofacial asymmetry). Additional malformations of the skull and facial (craniofacial) region may include downslanting eyelid folds (palpebral fissures); a flat nasal bridge; malformed (dysplastic), low-set ears; and a small, underdeveloped (hypoplastic) upper and/or lower jaw (maxilla and/or mandible).Individuals may also have unusually short fingers and toes (brachydactyly); partial fusion of the soft tissues (cutaneous syndactyly) between certain digits; and the presence of extra (supernumerary) toes or, less commonly, additional fingers (polydactyly). In some instances, additional physical abnormalities are present, such as short stature, structural heart malformations (congenital heart defects), mild to moderate obesity, weakening in the abdominal wall near the navel through which the intestine may protrude (umbilical hernia), or failure of the testes to descend into the scrotum (cryptorchidism) in affected males. In addition, many individuals with the disorder are affected by mild to moderate intellectual disability. However, intelligence is normal in some instances. Most cases are caused by mutations in the RAB23 gene. In several affected individuals, Carpenter syndrome was caused by mutations in the MEGF8 gene; these individuals are referred to as having Carpenter syndrome type 2. Both types of Carpenter syndrome are inherited in an autosomal recessive manner.Carpenter syndrome was originally described in the medical literature in 1901 (Carpenter G) in two sisters and one brother. However, Carpenter syndrome was not recognized as a distinct disease entity until 1966 (Temtamy SA). | 203 | Carpenter Syndrome |
nord_203_1 | Symptoms of Carpenter Syndrome | Primary findings associated with Carpenter syndrome include premature closure of the fibrous joints (cranial sutures) between particular bones in the skull (craniosynostosis), characteristic facial abnormalities, and/or malformations of the fingers and toes (digits). However, associated features may vary in range and severity from one person to another, even among affected members of the same family.Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their child, potential associated symptoms and overall prognosis.The symptoms of Carpenter syndrome types 1 and 2 are extremely similar and have significant overlap. Because only several individuals have been reported with Carpenter syndrome type 2, researchers are unable to determine whether the different associated genes lead to different symptoms or a different severity of symptoms. Craniosynostosis is almost always present. The severity and degree of skull (cranial) malformation may be variable, depending on the cranial sutures involved as well as the rate and order of progression. In many affected infants and children, craniosynostosis initially involves the sutures between bones forming the upper sides and the back of the skull (i.e., sagittal and lambdoidal sutures); this is often followed by early closure of the sutures (i.e., coronal sutures) between bones forming the forehead (frontal bone) and the upper sides of the cranium (parietal bones). Such abnormalities may cause the upper portion of the skull or “skullcap” (calvaria) to appear variable in shape and, in some cases, may result in severe malformation. In many cases, the top of the head appears pointed (acrocephaly) or the head seems unusually short and broad (brachycephaly). In addition, involvement of certain sutures on one side of the skull (e.g., unilateral involvement of lambdoidal and/or coronal sutures) may cause the head and face to appear dissimilar from one side to the other (cranial asymmetry). Rarely, due to involvement of multiple cranial sutures (Kleeblattschadel type craniosynostosis), the skull appears to be abnormally divided into three lobes (cloverleaf skull deformity). In some instances, early closure of certain cranial sutures may lead to abnormally increased pressure within the skull (intracranial pressure).Many infants and children have additional malformations of the skull and facial (craniofacial) area, resulting in a distinctive facial appearance. Such abnormalities include unusually small, underdeveloped ridges above the eyes (hypoplastic supraorbital ridges); downslanting eyelid folds (palpebral fissures); vertical skin folds (epicanthal folds) that may cover the eyes’ inner corners; and broad cheeks. Additional craniofacial malformations are also often present, such as a flat nasal bridge; an unusually narrow or highly arched roof of the mouth (palate); an underdeveloped lower and/or upper jaw (hypoplastic mandible and/or maxilla); relatively low-set, malformed ears; and a short neck. Carpenter syndrome may also be associated with eye (ocular) abnormalities. These may include smallness, improper development, and/or clouding of the front, normally transparent regions of the eyes (corneas); degeneration of the nerves that transmit impulses from the nerve-rich innermost membranes of the eyes (retinas) to the brain (optic atrophy); and/or other ocular defects.Carpenter syndrome is also typically characterized by distinctive malformations of the fingers and toes (digits). Affected individuals have unusually short fingers and toes (brachydactyly) due to shortness or absence of the middle bones of the digits (middle phalanges). There may be partial fusion of the soft tissues (cutaneous syndactyly) between certain fingers, particularly the third and fourth digits. Some individuals may also have partial fusion of soft tissues between certain toes. Some affected individuals may also have more than the normal number of digits (polydactyly). In most cases, affected individuals have additional (supernumerary) great toes (halluces) or second toes (preaxial polydactyly) that may also be webbed or partially fused. Less commonly, there may be additional fingers, such as duplication of the fifth fingers or “pinkies” (postaxial polydactyly). Those with the disorder may also have abnormal flexion (camptodactyly) and deviation (clinodactyly) of certain fingers and/or a deformity in which the heels of the feet are turned inward (talipes varus). Additional abnormalities may also be present, including abnormal skin ridge patterns of the hands; deformity of the hip (coxa valga); it also may be present a malformation in which the knees are abnormally close together and the ankles are unusually far apart (genu valgum); and/or an abnormal curvature of the spine (kyphoscoliosis).Mild short stature and mild to moderate obesity of the face, neck, trunk, forearms, and thighs are common findings. Many individuals are affected by mild intellectual disability. However, normal intelligence has also been reported. In some individuals, hearing loss may occur due to improper conduction of sound from the outer or middle ear to the inner ear (conductive hearing loss); abnormalities of the nerves (i.e., acoustic nerves) that transmit sound impulses to the brain (sensorineural hearing loss); or both (mixed hearing loss). Some individuals with Carpenter syndrome may also have structural heart malformations at birth (congenital heart defects). Such defects commonly include an abnormal opening in the fibrous partition (septum) that separates the lower or upper chambers of the heart (ventricular or atrial septal defects). In some cases, there may be an abnormal opening (i.e., patent ductus arteriosus) between the artery that transports oxygen-rich blood to most of the body (aorta) and the pulmonary artery, which carries oxygen-deficient blood to the lungs. Additional congenital heart defects may include abnormal narrowing of the opening between the pulmonary artery and the lower right chamber of the heart (i.e., pulmonary stenosis) or a deformity known as tetralogy of Fallot. The latter describes a combination of heart defects, including pulmonary stenosis; an abnormal opening in the partition between the lower chambers of the heart (ventricular septal defect); displacement of the aorta, enabling oxygen-deficient blood to flow from the right ventricle to the aorta; and enlargement of the right ventricle (hypertrophy). In some instances, other congenital heart defects may also be present.Additional findings may include failure of the testes to descend into the scrotum (cryptorchidism); deficient functioning of the testes (hypogonadism); and/or protrusion (herniation) of portions of the intestine through an abnormal opening in the abdominal wall into the inguinal canal or the passageway through which the testes normally descend into the scrotum. In addition, in some cases, there may be bulging of the intestine through an abdominal wall defect near the navel (umbilical hernia) or a defect in the abdominal wall from which loops of the intestine and other abdominal organs may protrude, covered by a thin, membrane-like sac (omphalocele). | Symptoms of Carpenter Syndrome. Primary findings associated with Carpenter syndrome include premature closure of the fibrous joints (cranial sutures) between particular bones in the skull (craniosynostosis), characteristic facial abnormalities, and/or malformations of the fingers and toes (digits). However, associated features may vary in range and severity from one person to another, even among affected members of the same family.Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their child, potential associated symptoms and overall prognosis.The symptoms of Carpenter syndrome types 1 and 2 are extremely similar and have significant overlap. Because only several individuals have been reported with Carpenter syndrome type 2, researchers are unable to determine whether the different associated genes lead to different symptoms or a different severity of symptoms. Craniosynostosis is almost always present. The severity and degree of skull (cranial) malformation may be variable, depending on the cranial sutures involved as well as the rate and order of progression. In many affected infants and children, craniosynostosis initially involves the sutures between bones forming the upper sides and the back of the skull (i.e., sagittal and lambdoidal sutures); this is often followed by early closure of the sutures (i.e., coronal sutures) between bones forming the forehead (frontal bone) and the upper sides of the cranium (parietal bones). Such abnormalities may cause the upper portion of the skull or “skullcap” (calvaria) to appear variable in shape and, in some cases, may result in severe malformation. In many cases, the top of the head appears pointed (acrocephaly) or the head seems unusually short and broad (brachycephaly). In addition, involvement of certain sutures on one side of the skull (e.g., unilateral involvement of lambdoidal and/or coronal sutures) may cause the head and face to appear dissimilar from one side to the other (cranial asymmetry). Rarely, due to involvement of multiple cranial sutures (Kleeblattschadel type craniosynostosis), the skull appears to be abnormally divided into three lobes (cloverleaf skull deformity). In some instances, early closure of certain cranial sutures may lead to abnormally increased pressure within the skull (intracranial pressure).Many infants and children have additional malformations of the skull and facial (craniofacial) area, resulting in a distinctive facial appearance. Such abnormalities include unusually small, underdeveloped ridges above the eyes (hypoplastic supraorbital ridges); downslanting eyelid folds (palpebral fissures); vertical skin folds (epicanthal folds) that may cover the eyes’ inner corners; and broad cheeks. Additional craniofacial malformations are also often present, such as a flat nasal bridge; an unusually narrow or highly arched roof of the mouth (palate); an underdeveloped lower and/or upper jaw (hypoplastic mandible and/or maxilla); relatively low-set, malformed ears; and a short neck. Carpenter syndrome may also be associated with eye (ocular) abnormalities. These may include smallness, improper development, and/or clouding of the front, normally transparent regions of the eyes (corneas); degeneration of the nerves that transmit impulses from the nerve-rich innermost membranes of the eyes (retinas) to the brain (optic atrophy); and/or other ocular defects.Carpenter syndrome is also typically characterized by distinctive malformations of the fingers and toes (digits). Affected individuals have unusually short fingers and toes (brachydactyly) due to shortness or absence of the middle bones of the digits (middle phalanges). There may be partial fusion of the soft tissues (cutaneous syndactyly) between certain fingers, particularly the third and fourth digits. Some individuals may also have partial fusion of soft tissues between certain toes. Some affected individuals may also have more than the normal number of digits (polydactyly). In most cases, affected individuals have additional (supernumerary) great toes (halluces) or second toes (preaxial polydactyly) that may also be webbed or partially fused. Less commonly, there may be additional fingers, such as duplication of the fifth fingers or “pinkies” (postaxial polydactyly). Those with the disorder may also have abnormal flexion (camptodactyly) and deviation (clinodactyly) of certain fingers and/or a deformity in which the heels of the feet are turned inward (talipes varus). Additional abnormalities may also be present, including abnormal skin ridge patterns of the hands; deformity of the hip (coxa valga); it also may be present a malformation in which the knees are abnormally close together and the ankles are unusually far apart (genu valgum); and/or an abnormal curvature of the spine (kyphoscoliosis).Mild short stature and mild to moderate obesity of the face, neck, trunk, forearms, and thighs are common findings. Many individuals are affected by mild intellectual disability. However, normal intelligence has also been reported. In some individuals, hearing loss may occur due to improper conduction of sound from the outer or middle ear to the inner ear (conductive hearing loss); abnormalities of the nerves (i.e., acoustic nerves) that transmit sound impulses to the brain (sensorineural hearing loss); or both (mixed hearing loss). Some individuals with Carpenter syndrome may also have structural heart malformations at birth (congenital heart defects). Such defects commonly include an abnormal opening in the fibrous partition (septum) that separates the lower or upper chambers of the heart (ventricular or atrial septal defects). In some cases, there may be an abnormal opening (i.e., patent ductus arteriosus) between the artery that transports oxygen-rich blood to most of the body (aorta) and the pulmonary artery, which carries oxygen-deficient blood to the lungs. Additional congenital heart defects may include abnormal narrowing of the opening between the pulmonary artery and the lower right chamber of the heart (i.e., pulmonary stenosis) or a deformity known as tetralogy of Fallot. The latter describes a combination of heart defects, including pulmonary stenosis; an abnormal opening in the partition between the lower chambers of the heart (ventricular septal defect); displacement of the aorta, enabling oxygen-deficient blood to flow from the right ventricle to the aorta; and enlargement of the right ventricle (hypertrophy). In some instances, other congenital heart defects may also be present.Additional findings may include failure of the testes to descend into the scrotum (cryptorchidism); deficient functioning of the testes (hypogonadism); and/or protrusion (herniation) of portions of the intestine through an abnormal opening in the abdominal wall into the inguinal canal or the passageway through which the testes normally descend into the scrotum. In addition, in some cases, there may be bulging of the intestine through an abdominal wall defect near the navel (umbilical hernia) or a defect in the abdominal wall from which loops of the intestine and other abdominal organs may protrude, covered by a thin, membrane-like sac (omphalocele). | 203 | Carpenter Syndrome |
nord_203_2 | Causes of Carpenter Syndrome | In most instances Carpenter syndrome are caused by a mutation in the RAB23 gene. In a small subset of people, Carpenter syndrome is caused by a mutation in the MEGF8 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The RAB23 gene is located on the short arm of the chromosome 6 (6p12.1) and different mutations in the gene have been reported in the studied families. It is possible to read (sequence) this gene in some diagnostic and research laboratories to confirm the diagnosis if it is not clear clinically. Affected individuals in the same family with the same mutations may have different symptoms and variable severity (intrafamilial variability). Mutations in the RAB23 gene are not present in all affected individuals. In several individuals a mutation in a different gene, MEGF8, has been identified as a cause of a subtype of Carpenter syndrome. The mutations that cause Carpenter syndrome are inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. 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. All individuals carry (on one of their two copies) altered versions of around 5 genes, that if present in double dose would cause serious developmental abnormalities. 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 Carpenter Syndrome. In most instances Carpenter syndrome are caused by a mutation in the RAB23 gene. In a small subset of people, Carpenter syndrome is caused by a mutation in the MEGF8 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The RAB23 gene is located on the short arm of the chromosome 6 (6p12.1) and different mutations in the gene have been reported in the studied families. It is possible to read (sequence) this gene in some diagnostic and research laboratories to confirm the diagnosis if it is not clear clinically. Affected individuals in the same family with the same mutations may have different symptoms and variable severity (intrafamilial variability). Mutations in the RAB23 gene are not present in all affected individuals. In several individuals a mutation in a different gene, MEGF8, has been identified as a cause of a subtype of Carpenter syndrome. The mutations that cause Carpenter syndrome are inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. 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. All individuals carry (on one of their two copies) altered versions of around 5 genes, that if present in double dose would cause serious developmental abnormalities. 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. | 203 | Carpenter Syndrome |
nord_203_3 | Affects of Carpenter Syndrome | Carpenter syndrome appears to affect males and females in relatively equal numbers. More than 70 cases of the disorder have been recorded. In 10 patients that had sequence analysis for the disease causing gene, homozygosity (two copies) for the same nonsense mutation, (a change in the DNA that causes a change in the protein) was found. This is indicative of a founder effect in patients of northern European descent, which means that a high prevalence of a genetic disorder in an isolated or inbred population is due to the fact that many members of the population are derived from a common ancestor who had the disease causing mutation. | Affects of Carpenter Syndrome. Carpenter syndrome appears to affect males and females in relatively equal numbers. More than 70 cases of the disorder have been recorded. In 10 patients that had sequence analysis for the disease causing gene, homozygosity (two copies) for the same nonsense mutation, (a change in the DNA that causes a change in the protein) was found. This is indicative of a founder effect in patients of northern European descent, which means that a high prevalence of a genetic disorder in an isolated or inbred population is due to the fact that many members of the population are derived from a common ancestor who had the disease causing mutation. | 203 | Carpenter Syndrome |
nord_203_4 | Related disorders of Carpenter Syndrome | Symptoms of the following disorders may be similar to those of Carpenter syndrome. Comparisons may be useful for a differential diagnosis:Pfeiffer syndrome is a rare genetic disorder characterized by abnormalities of the skull and facial (craniofacial) region and distinctive malformations of the fingers and toes (digits). Also known as acrocephalosyndactyly (ACS) type V, Pfeiffer syndrome is generally accepted to be the same disease entity as Noack syndrome (acrocephalopolysyndactyly [ACPS] type I). Researchers have described three major subtypes of Pfeiffer syndrome: i.e., Pfeiffer syndrome types I, II, and III. Findings that may be associated with all subtypes include premature closure of the fibrous joints between particular bones of the skull (craniosynostosis); unusually broad, deviating thumbs and great toes; and webbing or fusion (syndactyly) of certain fingers and toes. Pfeiffer syndrome may result from new (sporadic) genetic changes (mutations) or be inherited as an autosomal dominant trait. Evidence suggests that the disorder may be caused by specific mutations in a gene known as fibroblast growth factor receptor-2 (FGFR2) or another gene called fibroblast growth factor receptor-1 (FGFR1). Individuals with FGFR1 mutations usually have milder craniofacial features compared to those with FGFR2 mutations.In the classic form of Pfeiffer syndrome (type I), craniosynostosis causes the head to appear short and unusually pointed at the top (turribrachycephaly). Additional craniofacial malformations often include a high, full forehead; unusually flat, underdeveloped midfacial regions (midface hypoplasia); widely spaced eyes (ocular hypertelorism); a small upper jaw (hypoplastic maxilla); a prominent lower jaw; and dental abnormalities. Intelligence is typically normal. Pfeiffer syndrome type I may result from spontaneous genetic mutations or be inherited as an autosomal dominant trait.In Pfeiffer syndrome type II, early closure of multiple cranial sutures (Kleeblattschadel type craniosynostosis) causes the skull to be abnormally divided into three lobes (cloverleaf skull deformity). Additional physical malformations may include severe protrusion of the eyes (proptosis); abnormal fixation and restricted movement of the elbow joints; malformations of internal organs in the abdominal area (visceral anomalies); and progressive hydrocephalus. The latter is a condition characterized by impaired flow or absorption of the fluid that circulates through cavities (ventricles) of the brain and the spinal canal (cerebrospinal fluid [CSF]), potentially leading to increasing fluid pressure in the brain and other associated findings. Infants with Pfeiffer syndrome type II often experience impaired mental development and neurological problems due to severe involvement of the brain. Pfeiffer syndrome type II appears to be caused by new genetic mutations that occur spontaneously. Certain mutations in the FGFR2 gene have been implicated in some instances of Pfeiffer syndrome type II.Pfeiffer syndrome type III is characterized by symptoms similar to those associated with type II, with the exception of the cloverleaf skull deformity. Additional abnormalities may include a shortened base of the skull; severe protrusion of the eyes (proptosis) due to shallowness of the eye cavities (orbits); and/or various malformations of internal organs in the abdominal area. As seen with type II, infants with type III often have impaired mental development and neurological problems due to severe brain involvement. Pfeiffer syndrome type III is thought to result from new (sporadic) genetic mutations. (For further information on Pfeiffer syndrome types I, II, or III, choose “Pfeiffer” as your search term in the Rare Disease Database.)Sakati syndrome, also known as acrocephalopolysyndactyly (ACPS) type III, is a rare genetic disorder characterized by early closure of certain cranial sutures (craniosynostosis), causing the head to appear unusually pointed at the top (acrocephaly). Affected individuals may also have additional craniofacial malformations, such as a prominent forehead; an elongated, “beak-like” nose; protrusion of the eyes (proptosis) due to unusually shallow eye cavities; a small upper jaw (maxillary hypoplasia); crowding of the upper teeth; and malformed, low-set ears. The disorder may also be characterized by more than the normal number of fingers and toes (polydactyly); unusually short, broad hands; webbing or fusion of certain toes; short arms; and leg deformities. These may include bowed thigh bones (femurs); malformed, displaced calf bones (fibulas); and underdeveloped shin bones (hypoplastic tibias). Additional physical abnormalities may also be present, including congenital heart disease. Intelligence is usually normal. Sakati syndrome appears to result from new (sporadic) genetic mutations. (For further information, choose “Sakati” as your search term in the Rare Disease Database.)Goodman syndrome (ACPS type IV) and Summitt syndromes are extremely rare genetic disorders that are apparent at birth (congenital). Due to premature closure of certain cranial sutures, the head appears pointed at the top (acrocephaly). Additional craniofacial malformations and skeletal abnormalities may also occur. Only a handful of cases of each one of these two disorders have been described in the medical literature. Many researchers suggest that Goodman syndrome and Summitt syndromes are actually variants of Carpenter syndrome rather than distinct disease entities. The acrocephalosyndactyly (ACS) disorders are a group of rare genetic disorders including Apert syndrome (type I), Apert-Crouzon disease (type II), and Saethre-Chotzen syndrome (type III). All are characterized by premature closure of the fibrous joints (cranial sutures) between certain bones of the skull (craniosynostosis), causing the top of the head to appear pointed (acrocephaly), and/or webbing or fusion (syndactyly) of certain fingers or toes (digits). Such disorders may result from new (sporadic) genetic mutations or be transmitted as autosomal dominant traits. (For further information on these disorders, choose “Apert,” “Apert Crouzon,” “Saethre Chotzen,” or “acrocephalosyndactyly” as your search term in the Rare Disease Database.)Greig cephalopolysyndactyly syndrome, caused by mutations in the GLI3 gene, is characterized by a combination of craniofacial and limb features. The facial appearance may include large head (macrocephaly), prominent or broad forehead with frontal bossing, a broad base to the nose and a wide nasal bridge, associated with limb malformations including both pre-axial and post-axial polydactyly with broad or duplicated thumbs, broad or duplicated big toes, post-axial polydactyly of hands and feet and cutaneous syndactyly of the fingers or toes. Craniosynostosis is rare in Greig syndrome, but when present this disorder may easily be mistaken for Carpenter syndrome, particularly when there is evidence of learning disabilities associated with a large deletion involving the GLI3 gene. (For more information on this disorder, choose “Greig cephalopolysyndactyly” as your search term in the Rare Disease Database.)Additional congenital disorders may be characterized by various forms of craniosynostosis, additional craniofacial abnormalities, webbing or fusion (syndactyly) of the fingers or toes, more than the normal number of digits (polydactyly), and/or other symptoms and findings similar to those potentially associated with Carpenter syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | Related disorders of Carpenter Syndrome. Symptoms of the following disorders may be similar to those of Carpenter syndrome. Comparisons may be useful for a differential diagnosis:Pfeiffer syndrome is a rare genetic disorder characterized by abnormalities of the skull and facial (craniofacial) region and distinctive malformations of the fingers and toes (digits). Also known as acrocephalosyndactyly (ACS) type V, Pfeiffer syndrome is generally accepted to be the same disease entity as Noack syndrome (acrocephalopolysyndactyly [ACPS] type I). Researchers have described three major subtypes of Pfeiffer syndrome: i.e., Pfeiffer syndrome types I, II, and III. Findings that may be associated with all subtypes include premature closure of the fibrous joints between particular bones of the skull (craniosynostosis); unusually broad, deviating thumbs and great toes; and webbing or fusion (syndactyly) of certain fingers and toes. Pfeiffer syndrome may result from new (sporadic) genetic changes (mutations) or be inherited as an autosomal dominant trait. Evidence suggests that the disorder may be caused by specific mutations in a gene known as fibroblast growth factor receptor-2 (FGFR2) or another gene called fibroblast growth factor receptor-1 (FGFR1). Individuals with FGFR1 mutations usually have milder craniofacial features compared to those with FGFR2 mutations.In the classic form of Pfeiffer syndrome (type I), craniosynostosis causes the head to appear short and unusually pointed at the top (turribrachycephaly). Additional craniofacial malformations often include a high, full forehead; unusually flat, underdeveloped midfacial regions (midface hypoplasia); widely spaced eyes (ocular hypertelorism); a small upper jaw (hypoplastic maxilla); a prominent lower jaw; and dental abnormalities. Intelligence is typically normal. Pfeiffer syndrome type I may result from spontaneous genetic mutations or be inherited as an autosomal dominant trait.In Pfeiffer syndrome type II, early closure of multiple cranial sutures (Kleeblattschadel type craniosynostosis) causes the skull to be abnormally divided into three lobes (cloverleaf skull deformity). Additional physical malformations may include severe protrusion of the eyes (proptosis); abnormal fixation and restricted movement of the elbow joints; malformations of internal organs in the abdominal area (visceral anomalies); and progressive hydrocephalus. The latter is a condition characterized by impaired flow or absorption of the fluid that circulates through cavities (ventricles) of the brain and the spinal canal (cerebrospinal fluid [CSF]), potentially leading to increasing fluid pressure in the brain and other associated findings. Infants with Pfeiffer syndrome type II often experience impaired mental development and neurological problems due to severe involvement of the brain. Pfeiffer syndrome type II appears to be caused by new genetic mutations that occur spontaneously. Certain mutations in the FGFR2 gene have been implicated in some instances of Pfeiffer syndrome type II.Pfeiffer syndrome type III is characterized by symptoms similar to those associated with type II, with the exception of the cloverleaf skull deformity. Additional abnormalities may include a shortened base of the skull; severe protrusion of the eyes (proptosis) due to shallowness of the eye cavities (orbits); and/or various malformations of internal organs in the abdominal area. As seen with type II, infants with type III often have impaired mental development and neurological problems due to severe brain involvement. Pfeiffer syndrome type III is thought to result from new (sporadic) genetic mutations. (For further information on Pfeiffer syndrome types I, II, or III, choose “Pfeiffer” as your search term in the Rare Disease Database.)Sakati syndrome, also known as acrocephalopolysyndactyly (ACPS) type III, is a rare genetic disorder characterized by early closure of certain cranial sutures (craniosynostosis), causing the head to appear unusually pointed at the top (acrocephaly). Affected individuals may also have additional craniofacial malformations, such as a prominent forehead; an elongated, “beak-like” nose; protrusion of the eyes (proptosis) due to unusually shallow eye cavities; a small upper jaw (maxillary hypoplasia); crowding of the upper teeth; and malformed, low-set ears. The disorder may also be characterized by more than the normal number of fingers and toes (polydactyly); unusually short, broad hands; webbing or fusion of certain toes; short arms; and leg deformities. These may include bowed thigh bones (femurs); malformed, displaced calf bones (fibulas); and underdeveloped shin bones (hypoplastic tibias). Additional physical abnormalities may also be present, including congenital heart disease. Intelligence is usually normal. Sakati syndrome appears to result from new (sporadic) genetic mutations. (For further information, choose “Sakati” as your search term in the Rare Disease Database.)Goodman syndrome (ACPS type IV) and Summitt syndromes are extremely rare genetic disorders that are apparent at birth (congenital). Due to premature closure of certain cranial sutures, the head appears pointed at the top (acrocephaly). Additional craniofacial malformations and skeletal abnormalities may also occur. Only a handful of cases of each one of these two disorders have been described in the medical literature. Many researchers suggest that Goodman syndrome and Summitt syndromes are actually variants of Carpenter syndrome rather than distinct disease entities. The acrocephalosyndactyly (ACS) disorders are a group of rare genetic disorders including Apert syndrome (type I), Apert-Crouzon disease (type II), and Saethre-Chotzen syndrome (type III). All are characterized by premature closure of the fibrous joints (cranial sutures) between certain bones of the skull (craniosynostosis), causing the top of the head to appear pointed (acrocephaly), and/or webbing or fusion (syndactyly) of certain fingers or toes (digits). Such disorders may result from new (sporadic) genetic mutations or be transmitted as autosomal dominant traits. (For further information on these disorders, choose “Apert,” “Apert Crouzon,” “Saethre Chotzen,” or “acrocephalosyndactyly” as your search term in the Rare Disease Database.)Greig cephalopolysyndactyly syndrome, caused by mutations in the GLI3 gene, is characterized by a combination of craniofacial and limb features. The facial appearance may include large head (macrocephaly), prominent or broad forehead with frontal bossing, a broad base to the nose and a wide nasal bridge, associated with limb malformations including both pre-axial and post-axial polydactyly with broad or duplicated thumbs, broad or duplicated big toes, post-axial polydactyly of hands and feet and cutaneous syndactyly of the fingers or toes. Craniosynostosis is rare in Greig syndrome, but when present this disorder may easily be mistaken for Carpenter syndrome, particularly when there is evidence of learning disabilities associated with a large deletion involving the GLI3 gene. (For more information on this disorder, choose “Greig cephalopolysyndactyly” as your search term in the Rare Disease Database.)Additional congenital disorders may be characterized by various forms of craniosynostosis, additional craniofacial abnormalities, webbing or fusion (syndactyly) of the fingers or toes, more than the normal number of digits (polydactyly), and/or other symptoms and findings similar to those potentially associated with Carpenter syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.) | 203 | Carpenter Syndrome |
nord_203_5 | Diagnosis of Carpenter Syndrome | A diagnosis of Carpenter syndrome may sometimes be suggested before birth (prenatally) based upon certain specialized tests, such as fetoscopy or ultrasound. During fetoscopy, a flexible viewing instrument (endoscope) may be introduced into the uterus through the abdominal wall to directly observe the fetus and, in some cases, to obtain fetal blood or tissue samples. Fetal ultrasonography is a noninvasive diagnostic procedure in which reflected sound waves create an image of the developing fetus. Prenatal molecular genetic testing to confirm a suspected diagnosis of Carpenter syndrome is available using samples derived from fetal tissues, obtained for example, by chorionic villus biopsy or amniocentesis.In most cases, the diagnosis is made or confirmed at or shortly after birth based upon a thorough clinical examination, identification of characteristic physical findings, and a variety of specialized tests. Such testing may include advanced imaging techniques, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI), or other diagnostic tests to help detect or characterize certain abnormalities that may be associated with the disorder (e.g., craniosynostosis, polysyndactyly, other skeletal abnormalities, hearing impairment, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves create detailed cross-sectional images of certain organs and tissues.Molecular genetic testing of RAB23 and MEGF8 can confirm a suspected clinical diagnosis of Carpenter syndrome. Molecular genetic testing can detect mutations in the specific genes known to cause the disorder, but is available only on a clinical basis. Array comparative genomic hybridization, to look for chromosome rearrangements including deletion of the GLI3 gene, may be appropriate in some clinical circumstances. A thorough cardiac evaluation may also be recommended to detect any heart abnormalities that may be associated with the disorder. Such evaluation may include a through clinical examination, during which heart and lung sounds are evaluated through use of a stethoscope, and specialized tests that enable physicians to evaluate the structure and function of the heart (e.g., x-ray studies, electrocardiography [EKG]), echocardiography, cardiac catheterization). | Diagnosis of Carpenter Syndrome. A diagnosis of Carpenter syndrome may sometimes be suggested before birth (prenatally) based upon certain specialized tests, such as fetoscopy or ultrasound. During fetoscopy, a flexible viewing instrument (endoscope) may be introduced into the uterus through the abdominal wall to directly observe the fetus and, in some cases, to obtain fetal blood or tissue samples. Fetal ultrasonography is a noninvasive diagnostic procedure in which reflected sound waves create an image of the developing fetus. Prenatal molecular genetic testing to confirm a suspected diagnosis of Carpenter syndrome is available using samples derived from fetal tissues, obtained for example, by chorionic villus biopsy or amniocentesis.In most cases, the diagnosis is made or confirmed at or shortly after birth based upon a thorough clinical examination, identification of characteristic physical findings, and a variety of specialized tests. Such testing may include advanced imaging techniques, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI), or other diagnostic tests to help detect or characterize certain abnormalities that may be associated with the disorder (e.g., craniosynostosis, polysyndactyly, other skeletal abnormalities, hearing impairment, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves create detailed cross-sectional images of certain organs and tissues.Molecular genetic testing of RAB23 and MEGF8 can confirm a suspected clinical diagnosis of Carpenter syndrome. Molecular genetic testing can detect mutations in the specific genes known to cause the disorder, but is available only on a clinical basis. Array comparative genomic hybridization, to look for chromosome rearrangements including deletion of the GLI3 gene, may be appropriate in some clinical circumstances. A thorough cardiac evaluation may also be recommended to detect any heart abnormalities that may be associated with the disorder. Such evaluation may include a through clinical examination, during which heart and lung sounds are evaluated through use of a stethoscope, and specialized tests that enable physicians to evaluate the structure and function of the heart (e.g., x-ray studies, electrocardiography [EKG]), echocardiography, cardiac catheterization). | 203 | Carpenter Syndrome |
nord_203_6 | Therapies of Carpenter Syndrome | TreatmentThe treatment of Carpenter syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in heart disease (cardiologists); physicians who diagnose and treat neurological disorders (neurologists); hearing specialists; and/or other health care professionals.Specific therapies for individuals with Carpenter syndrome are symptomatic and supportive. Because craniosynostosis may sometimes result in abnormally increased pressure within the skull (intracranial pressure) and on the brain, early surgery may be advised to help prevent or correct premature closure of cranial sutures. Some reports suggest that early surgical intervention may help to prevent intellectual disability in some instances. However, intellectual disability has occurred in some individuals with Carpenter syndrome despite early surgical correction of craniosynostosis. In addition, normal intelligence has been present in some without such surgical intervention.In some instances, corrective and reconstructive surgery may also be recommended to help correct additional craniofacial malformations, polydactyly and syndactyly, other skeletal defects, or other physical abnormalities potentially associated with the disorder. In addition, for those with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. The surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.For some individuals with hearing impairment, hearing aids may be beneficial. Appropriate use of hearing aids, other supportive techniques, and/or speech therapy may help to prevent or improve speech problems that may occur in some individuals with the disorder.Early intervention may be important to ensure that children with Carpenter syndrome reach their potential. Special services that may be beneficial to affected children include special education, physical therapy, and/or other medical, social, or vocational services.Genetic counseling is recommended for affected individuals and their families. Diagnostic evaluations are also important for family members of individuals with the disorder to detect any symptoms and physical characteristics that may be associated with Carpenter syndrome. Psychosocial support for the entire family is essential as well. | Therapies of Carpenter Syndrome. TreatmentThe treatment of Carpenter syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in heart disease (cardiologists); physicians who diagnose and treat neurological disorders (neurologists); hearing specialists; and/or other health care professionals.Specific therapies for individuals with Carpenter syndrome are symptomatic and supportive. Because craniosynostosis may sometimes result in abnormally increased pressure within the skull (intracranial pressure) and on the brain, early surgery may be advised to help prevent or correct premature closure of cranial sutures. Some reports suggest that early surgical intervention may help to prevent intellectual disability in some instances. However, intellectual disability has occurred in some individuals with Carpenter syndrome despite early surgical correction of craniosynostosis. In addition, normal intelligence has been present in some without such surgical intervention.In some instances, corrective and reconstructive surgery may also be recommended to help correct additional craniofacial malformations, polydactyly and syndactyly, other skeletal defects, or other physical abnormalities potentially associated with the disorder. In addition, for those with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. The surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.For some individuals with hearing impairment, hearing aids may be beneficial. Appropriate use of hearing aids, other supportive techniques, and/or speech therapy may help to prevent or improve speech problems that may occur in some individuals with the disorder.Early intervention may be important to ensure that children with Carpenter syndrome reach their potential. Special services that may be beneficial to affected children include special education, physical therapy, and/or other medical, social, or vocational services.Genetic counseling is recommended for affected individuals and their families. Diagnostic evaluations are also important for family members of individuals with the disorder to detect any symptoms and physical characteristics that may be associated with Carpenter syndrome. Psychosocial support for the entire family is essential as well. | 203 | Carpenter Syndrome |
nord_204_0 | Overview of Castleman Disease | Castleman disease describes a group of rare disorders with a wide range of symptoms. People with these conditions have enlarged lymph nodes that have a similar appearance when reviewed under the microscope. Castleman disease is first classified based on the number of regions of enlarged lymph nodes that have these abnormal features. Unicentric Castleman disease (UCD) involves a single enlarged lymph node or single region of enlarged lymph nodes whereas multicentric Castleman disease (MCD) involves multiple regions of enlarged lymph nodes. There are two subtypes of MCD. One subtype is caused by human herpesvirus-8 (HHV-8; also known as Kaposi sarcoma–associated herpesvirus). These cases are called HHV-8-associated MCD. The other subtype includes MCD patients who are negative for the HHV-8 virus, and the cause is unknown. These cases are called HHV-8 negative or “idiopathic” MCD (iMCD).Castleman disease can also be described as hyaline-vascular, plasmacytic, or mixed histopathologic variant based on the microscopic appearance. The usefulness of these additional descriptions is unclear. | Overview of Castleman Disease. Castleman disease describes a group of rare disorders with a wide range of symptoms. People with these conditions have enlarged lymph nodes that have a similar appearance when reviewed under the microscope. Castleman disease is first classified based on the number of regions of enlarged lymph nodes that have these abnormal features. Unicentric Castleman disease (UCD) involves a single enlarged lymph node or single region of enlarged lymph nodes whereas multicentric Castleman disease (MCD) involves multiple regions of enlarged lymph nodes. There are two subtypes of MCD. One subtype is caused by human herpesvirus-8 (HHV-8; also known as Kaposi sarcoma–associated herpesvirus). These cases are called HHV-8-associated MCD. The other subtype includes MCD patients who are negative for the HHV-8 virus, and the cause is unknown. These cases are called HHV-8 negative or “idiopathic” MCD (iMCD).Castleman disease can also be described as hyaline-vascular, plasmacytic, or mixed histopathologic variant based on the microscopic appearance. The usefulness of these additional descriptions is unclear. | 204 | Castleman Disease |
nord_204_1 | Symptoms of Castleman Disease | The spectrum of disease symptoms and severity is very broad, ranging from gradual enlargement of lymph nodes with mild symptoms to sudden, intense onset of symptoms due to life-threatening organ dysfunction caused by elevated cytokines such as interleukin-6 (IL-6). Symptoms of Castleman disease often overlap with symptoms of other more common illnesses. A Castleman disease diagnosis can therefore only be made with a lymph node biopsy that shows characteristic Castleman disease features and when other illnesses have been evaluated and excluded.Unicentric Castleman Disease (UCD) UCD is characterized by a single enlarged lymph node or multiple enlarged lymph nodes in a single region of the body, such as the chest, abdomen or neck. Most patients with UCD have no symptoms (asymptomatic). UCD symptoms tend to be mild and occur secondary to compression of surrounding structures by rapidly enlarging lymph nodes. Occasionally, patients experience symptoms due to the size and location of the growth. For example, a growth may form next to a vein, resulting in a bulge and possible obstruction in the involved blood vessel. Less commonly, some UCD patients experience systemic inflammatory symptoms such as fever, fatigue, excessive sweating, weight loss and skin rash as well as laboratory abnormalities such as low hemoglobin and elevated C-reactive protein. These symptoms are typically seen in MCD. These symptoms usually disappear after surgical excision of the UCD lymph node.Multicentric Castleman Disease (MCD) Patients with multicentric Castleman disease (MCD) have enlarged lymph nodes in multiple regions and more severe symptoms than UCD. Some patients are HHV-8 positive (HHV-8 MCD) whereas other patients are HHV-8-negative/idiopathic (iMCD). Signs and symptoms of iMCD include:• Flu-like symptoms: fever, fatigue, weight loss, night sweats, loss of appetite, nausea and vomiting
• Abnormally large lymph nodes, typically in the neck, armpit, collarbone and groin
• Enlarged spleen or liver
• Eruptive cherry hemangiomas
• Edema (swelling), ascites (fluid accumulation in the abdomen) and/or other symptoms of fluid accumulation
• Peripheral neuropathy (numbness in the hands and feet)
• Elevated inflammatory markers (C-reactive protein, erythrocyte sedimentation rate)
• Kidney dysfunction
• Low albumin
• Anemia (low amount of red blood cells)
• Low or high platelet counts
• Elevated immunoglobulins or gamma globulinsiMCD patients can be further subdivided into iMCD-TAFRO or iMCD-NOS. iMCD-TAFRO is characterized by thrombocytopenia (low platelet count), anasarca (ascites, swelling), fever or elevated C-reactive protein (inflammation marker), reticulin fibrosis (evaluated in bone marrow biopsy) and organomegaly (hepatomegaly/splenomegaly). iMCD-NOS typically involves thrombocytosis (elevated platelet count) and elevated immunoglobulins with a less intense disease course. Patients with HHV-8-associated MCD (HHV-8 MCD) also have multiple regions of enlarged lymph nodes and episodic inflammatory symptoms. HHV-8 MCD is most commonly diagnosed in HIV-infected or otherwise immunocompromised individuals so these patients may experience additional symptoms related to their HIV infection or other conditions.The following disorders may be associated with Castleman disease as secondary characteristics:iMCD has been diagnosed in some patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes) syndrome. (For more information on this disorder, choose “POEMS” as your search term in the Rare Disease Database.)There is an increased rate of cancer diagnosed in patients with iMCD and HHV-8-associated MCD.Patients with UCD are at increased risk of developing paraneoplastic pemphigus (PNP), which is a rare autoimmune condition that can be life threatening. PNP involves blisters in the mouth and on the skin that are often misdiagnosed as occurring for another reason. Though the risk of developing PNP is low (<5%) among patients with UCD, it is the deadliest potential complication of UCD and should be evaluated in all UCD patients.
Patients with HHV-8-associated MCD are at increased risk of developing Kaposi’s sarcoma, which is a malignant skin tumor that may spread to other parts of the body. Affected individuals may have skin lesions (e.g., papules, plaques, etc.) that may grow and come together (coalesce). In some patients, the lesions may reduce in size and number (regress). On rare occasions these lesions may be painful.
| Symptoms of Castleman Disease. The spectrum of disease symptoms and severity is very broad, ranging from gradual enlargement of lymph nodes with mild symptoms to sudden, intense onset of symptoms due to life-threatening organ dysfunction caused by elevated cytokines such as interleukin-6 (IL-6). Symptoms of Castleman disease often overlap with symptoms of other more common illnesses. A Castleman disease diagnosis can therefore only be made with a lymph node biopsy that shows characteristic Castleman disease features and when other illnesses have been evaluated and excluded.Unicentric Castleman Disease (UCD) UCD is characterized by a single enlarged lymph node or multiple enlarged lymph nodes in a single region of the body, such as the chest, abdomen or neck. Most patients with UCD have no symptoms (asymptomatic). UCD symptoms tend to be mild and occur secondary to compression of surrounding structures by rapidly enlarging lymph nodes. Occasionally, patients experience symptoms due to the size and location of the growth. For example, a growth may form next to a vein, resulting in a bulge and possible obstruction in the involved blood vessel. Less commonly, some UCD patients experience systemic inflammatory symptoms such as fever, fatigue, excessive sweating, weight loss and skin rash as well as laboratory abnormalities such as low hemoglobin and elevated C-reactive protein. These symptoms are typically seen in MCD. These symptoms usually disappear after surgical excision of the UCD lymph node.Multicentric Castleman Disease (MCD) Patients with multicentric Castleman disease (MCD) have enlarged lymph nodes in multiple regions and more severe symptoms than UCD. Some patients are HHV-8 positive (HHV-8 MCD) whereas other patients are HHV-8-negative/idiopathic (iMCD). Signs and symptoms of iMCD include:• Flu-like symptoms: fever, fatigue, weight loss, night sweats, loss of appetite, nausea and vomiting
• Abnormally large lymph nodes, typically in the neck, armpit, collarbone and groin
• Enlarged spleen or liver
• Eruptive cherry hemangiomas
• Edema (swelling), ascites (fluid accumulation in the abdomen) and/or other symptoms of fluid accumulation
• Peripheral neuropathy (numbness in the hands and feet)
• Elevated inflammatory markers (C-reactive protein, erythrocyte sedimentation rate)
• Kidney dysfunction
• Low albumin
• Anemia (low amount of red blood cells)
• Low or high platelet counts
• Elevated immunoglobulins or gamma globulinsiMCD patients can be further subdivided into iMCD-TAFRO or iMCD-NOS. iMCD-TAFRO is characterized by thrombocytopenia (low platelet count), anasarca (ascites, swelling), fever or elevated C-reactive protein (inflammation marker), reticulin fibrosis (evaluated in bone marrow biopsy) and organomegaly (hepatomegaly/splenomegaly). iMCD-NOS typically involves thrombocytosis (elevated platelet count) and elevated immunoglobulins with a less intense disease course. Patients with HHV-8-associated MCD (HHV-8 MCD) also have multiple regions of enlarged lymph nodes and episodic inflammatory symptoms. HHV-8 MCD is most commonly diagnosed in HIV-infected or otherwise immunocompromised individuals so these patients may experience additional symptoms related to their HIV infection or other conditions.The following disorders may be associated with Castleman disease as secondary characteristics:iMCD has been diagnosed in some patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes) syndrome. (For more information on this disorder, choose “POEMS” as your search term in the Rare Disease Database.)There is an increased rate of cancer diagnosed in patients with iMCD and HHV-8-associated MCD.Patients with UCD are at increased risk of developing paraneoplastic pemphigus (PNP), which is a rare autoimmune condition that can be life threatening. PNP involves blisters in the mouth and on the skin that are often misdiagnosed as occurring for another reason. Though the risk of developing PNP is low (<5%) among patients with UCD, it is the deadliest potential complication of UCD and should be evaluated in all UCD patients.
Patients with HHV-8-associated MCD are at increased risk of developing Kaposi’s sarcoma, which is a malignant skin tumor that may spread to other parts of the body. Affected individuals may have skin lesions (e.g., papules, plaques, etc.) that may grow and come together (coalesce). In some patients, the lesions may reduce in size and number (regress). On rare occasions these lesions may be painful.
| 204 | Castleman Disease |
nord_204_2 | Causes of Castleman Disease | The exact cause of UCD and iMCD is not known. There are no known risk factors; there is no evidence of any food, lifestyle or environmental exposure associated with these diseases. There is no known report of a patient developing UCD or iMCD from contact with another individual with UCD or iMCD. Viruses, genetic mutations acquired over the course of life and inflammation have all been proposed as possible causes of UCD. Recent research suggests that acquired genetic mutations are the likely cause of UCD.HHV-8 is the well-established cause of HHV-8-associated MCD, which accounts for approximately 25-50% of all cases of MCD. HHV-8-associated MCD often occurs in individuals infected with human immunodeficiency virus (HIV). The HIV weakens the ability of the immune system to control the HHV-8 infection. The HHV-8 virus causes MCD by making its own IL-6 and causing cells to rapidly multiply.Approximately 50-75% of MCD cases are negative for HHV-8 and the cause is unknown or “idiopathic.” Recently, four possible causes have been hypothesized: a virus, genetic mutation acquired over the course of life, an inherited genetic mutation or autoimmunity. Some researchers speculate that increased production of interleukin-6 (IL-6) due to one of the above causes may be involved in the development of iMCD. IL-6 is a substance normally produced by cells within the lymph nodes (plasma cells) and in healthy individuals coordinates the immune response to infection. However, IL-6 is not elevated in all patients, and neutralizing IL-6 is not effective for the treatment of all patients. | Causes of Castleman Disease. The exact cause of UCD and iMCD is not known. There are no known risk factors; there is no evidence of any food, lifestyle or environmental exposure associated with these diseases. There is no known report of a patient developing UCD or iMCD from contact with another individual with UCD or iMCD. Viruses, genetic mutations acquired over the course of life and inflammation have all been proposed as possible causes of UCD. Recent research suggests that acquired genetic mutations are the likely cause of UCD.HHV-8 is the well-established cause of HHV-8-associated MCD, which accounts for approximately 25-50% of all cases of MCD. HHV-8-associated MCD often occurs in individuals infected with human immunodeficiency virus (HIV). The HIV weakens the ability of the immune system to control the HHV-8 infection. The HHV-8 virus causes MCD by making its own IL-6 and causing cells to rapidly multiply.Approximately 50-75% of MCD cases are negative for HHV-8 and the cause is unknown or “idiopathic.” Recently, four possible causes have been hypothesized: a virus, genetic mutation acquired over the course of life, an inherited genetic mutation or autoimmunity. Some researchers speculate that increased production of interleukin-6 (IL-6) due to one of the above causes may be involved in the development of iMCD. IL-6 is a substance normally produced by cells within the lymph nodes (plasma cells) and in healthy individuals coordinates the immune response to infection. However, IL-6 is not elevated in all patients, and neutralizing IL-6 is not effective for the treatment of all patients. | 204 | Castleman Disease |
nord_204_3 | Affects of Castleman Disease | UCD and iMCD affect males and females in equal numbers and there are no known factors that increase the risk of UCD or iMCD. HHV-8-associated MCD affects males at an increased rate compared to females. All types of Castleman disease may affect individuals of any age. Persons with HIV are at increased risk of developing HHV-8-associated MCD. It is estimated that there are approximately 4,300-5,200 cases of CD diagnosed each year in the United States. | Affects of Castleman Disease. UCD and iMCD affect males and females in equal numbers and there are no known factors that increase the risk of UCD or iMCD. HHV-8-associated MCD affects males at an increased rate compared to females. All types of Castleman disease may affect individuals of any age. Persons with HIV are at increased risk of developing HHV-8-associated MCD. It is estimated that there are approximately 4,300-5,200 cases of CD diagnosed each year in the United States. | 204 | Castleman Disease |
nord_204_4 | Related disorders of Castleman Disease | Symptoms of the following disorder can be similar to those of Castleman disease. Comparisons may be useful for a differential diagnosis:Hodgkin lymphoma is a form of cancer of the lymphatic system. Tumors occur in the lymph nodes and/or the areas around the nodes. Symptoms associated with this disorder may include fever, night sweats, weight loss and/or enlarged or swollen lymph nodes. The tumors occur most often in the chest, stomach or spleen. Hodgkin lymphoma is usually progressive and may spread to lymph nodes located in other areas of the body. The exact cause of Hodgkin lymphoma is not known. (For more information on this disorder, choose “Hodgkin” as your search term in the Rare Disease Database.) | Related disorders of Castleman Disease. Symptoms of the following disorder can be similar to those of Castleman disease. Comparisons may be useful for a differential diagnosis:Hodgkin lymphoma is a form of cancer of the lymphatic system. Tumors occur in the lymph nodes and/or the areas around the nodes. Symptoms associated with this disorder may include fever, night sweats, weight loss and/or enlarged or swollen lymph nodes. The tumors occur most often in the chest, stomach or spleen. Hodgkin lymphoma is usually progressive and may spread to lymph nodes located in other areas of the body. The exact cause of Hodgkin lymphoma is not known. (For more information on this disorder, choose “Hodgkin” as your search term in the Rare Disease Database.) | 204 | Castleman Disease |
nord_204_5 | Diagnosis of Castleman Disease | Castleman disease can be difficult to diagnose because it is a rare disease and an imitator of many other diseases. Patients can have the same symptoms as other conditions, including common illnesses such as influenza (flu), autoimmune diseases and lymphomas. Due to the complexity of the disease, physicians often need to rule out many other diseases before Castleman disease is suspected. The clinical history and several tests are used to rule out other conditions and confirm a diagnosis of Castleman disease. According to international, evidence-based guidelines for UCD and iMCD from the Castleman Disease Collaborative Network, these tests should include:• Lymph node biopsy: a sample of tissue from a lymph node is examined under a microscope to identify features of Castleman disease
• Laboratory tests: complete blood count, inflammation markers (CRP/ESR) and markers of organ function such as liver function tests, albumin, creatinine as well as HIV/HHV8 testing for HHV-8-associated MCD
• Imaging tests: X-rays and PET-CT scans can be used to locate enlarged lymph nodes and activity of those lymph nodes in the bodyA diagnostic criterion was recently established for UCD. Most UCD patients do not experience systemic symptoms. Typically, the enlarged lymph node will be discovered inadvertently during care for another condition or because it is impeding on nearby organs. UCD is diagnosed by histopathological examination of the excised lymph node. It is important that a complete excisional lymph node biopsy be performed rather than a fine-needle aspirate or core biopsy.There are no official diagnostic criteria for HHV-8-associated MCD. It is generally diagnosed when a patient has multiple regions of enlarged lymph nodes, inflammatory symptoms, biopsy of the lymph node demonstrates “Castleman-like” features under the microscope and HHV-8 testing is positive. Characteristic “Castleman-like” microscopic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization and polytypic plasmacytosis.Diagnostic criteria for iMCD were recently established. The criteria require both major criteria (characteristic lymph node features on biopsy and multiple regions of enlarged lymph nodes), at least 2 of 11 minor criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant and autoimmune disorders that can mimic iMCD. Laboratory and clinical minor criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules and lymphocytic interstitial pneumonitis. | Diagnosis of Castleman Disease. Castleman disease can be difficult to diagnose because it is a rare disease and an imitator of many other diseases. Patients can have the same symptoms as other conditions, including common illnesses such as influenza (flu), autoimmune diseases and lymphomas. Due to the complexity of the disease, physicians often need to rule out many other diseases before Castleman disease is suspected. The clinical history and several tests are used to rule out other conditions and confirm a diagnosis of Castleman disease. According to international, evidence-based guidelines for UCD and iMCD from the Castleman Disease Collaborative Network, these tests should include:• Lymph node biopsy: a sample of tissue from a lymph node is examined under a microscope to identify features of Castleman disease
• Laboratory tests: complete blood count, inflammation markers (CRP/ESR) and markers of organ function such as liver function tests, albumin, creatinine as well as HIV/HHV8 testing for HHV-8-associated MCD
• Imaging tests: X-rays and PET-CT scans can be used to locate enlarged lymph nodes and activity of those lymph nodes in the bodyA diagnostic criterion was recently established for UCD. Most UCD patients do not experience systemic symptoms. Typically, the enlarged lymph node will be discovered inadvertently during care for another condition or because it is impeding on nearby organs. UCD is diagnosed by histopathological examination of the excised lymph node. It is important that a complete excisional lymph node biopsy be performed rather than a fine-needle aspirate or core biopsy.There are no official diagnostic criteria for HHV-8-associated MCD. It is generally diagnosed when a patient has multiple regions of enlarged lymph nodes, inflammatory symptoms, biopsy of the lymph node demonstrates “Castleman-like” features under the microscope and HHV-8 testing is positive. Characteristic “Castleman-like” microscopic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization and polytypic plasmacytosis.Diagnostic criteria for iMCD were recently established. The criteria require both major criteria (characteristic lymph node features on biopsy and multiple regions of enlarged lymph nodes), at least 2 of 11 minor criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant and autoimmune disorders that can mimic iMCD. Laboratory and clinical minor criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules and lymphocytic interstitial pneumonitis. | 204 | Castleman Disease |
nord_204_6 | Therapies of Castleman Disease | Treatment
Treatments for Castleman disease are specific to the subtype. International, evidence-based guidelines have been developed for UCD and iMCD.Unicentric Castleman Disease (UCD)Surgery is considered to be the first-line treatment option for all cases of UCD. Surgical removal of the affected lymph node(s) usually results in cure. However, recurrences of UCD have been reported. Sometimes, removing the enlarged lymph node(s) is not possible. If surgical excision is not possible, treatment is recommended for symptomatic patients. If symptoms are due to compression, rituximab is recommended. If symptoms are due to an inflammatory syndrome, anti-interleukin-6 (IL-6) therapy is recommended. If these treatments are not effective, radiation may be needed.Idiopathic Multicentric Castleman Disease (iMCD) First-line treatment for iMCD is anti-IL-6 therapy with siltuximab (or tocilizumab if siltuximab is not available). Siltuximab is the only FDA-approved treatment for iMCD, and patients who respond to siltuximab tend to have long-term responses. For critically ill patients, chemotherapy and corticosteroids are recommended if the patient’s disease is progressing while on siltuxumab. Approximately half of iMCD patients do not improve with anti-IL-6 therapy, and for these patients, other treatments such as rituximab and sirolimus can be used.HHV-8-Associated Multicentric Castleman Disease (HHV-8 Positive MCD)Rituximab is often used to eliminate a type of immune cell called the B lymphocyte. It is highly effective for HHV-8-associated MCD, but occasionally antivirals and/or cytotoxic chemotherapies are also needed. | Therapies of Castleman Disease. Treatment
Treatments for Castleman disease are specific to the subtype. International, evidence-based guidelines have been developed for UCD and iMCD.Unicentric Castleman Disease (UCD)Surgery is considered to be the first-line treatment option for all cases of UCD. Surgical removal of the affected lymph node(s) usually results in cure. However, recurrences of UCD have been reported. Sometimes, removing the enlarged lymph node(s) is not possible. If surgical excision is not possible, treatment is recommended for symptomatic patients. If symptoms are due to compression, rituximab is recommended. If symptoms are due to an inflammatory syndrome, anti-interleukin-6 (IL-6) therapy is recommended. If these treatments are not effective, radiation may be needed.Idiopathic Multicentric Castleman Disease (iMCD) First-line treatment for iMCD is anti-IL-6 therapy with siltuximab (or tocilizumab if siltuximab is not available). Siltuximab is the only FDA-approved treatment for iMCD, and patients who respond to siltuximab tend to have long-term responses. For critically ill patients, chemotherapy and corticosteroids are recommended if the patient’s disease is progressing while on siltuxumab. Approximately half of iMCD patients do not improve with anti-IL-6 therapy, and for these patients, other treatments such as rituximab and sirolimus can be used.HHV-8-Associated Multicentric Castleman Disease (HHV-8 Positive MCD)Rituximab is often used to eliminate a type of immune cell called the B lymphocyte. It is highly effective for HHV-8-associated MCD, but occasionally antivirals and/or cytotoxic chemotherapies are also needed. | 204 | Castleman Disease |
nord_205_0 | Overview of Cat Eye Syndrome | Cat eye syndrome (CES) is a rare chromosomal disorder that may be evident at birth. Individuals with a normal chromosomal make-up have two 22nd chromosomes, both of which have a short arm, known as 22p, and a long arm, known as 22q. However, in individuals with CES, the short arm and a small region of the long arm of chromosome 22 (i.e., 22pter-22q11) are present four times (partial tetrasomy) rather than twice in cells of the body. In a small number of people with CES, the 22q11 region is present in 3 copies (partial trisomy). The name “cat eye syndrome” is derived from a distinctive eye (ocular) abnormality that is present in a little over half affected individuals. This defect, known as a coloboma, usually appears as a cleft or gap in the iris below the pupil, and the elongated pupil therefore resembles the appearance of a cat’s eye. There are, however, many other features associated with CES involving many organs and systems. These symptoms result from abnormal development during embryo and fetal stages. Associated symptoms vary greatly in presence and severity from one person to another, including among members of the same family. CES may be best thought of as a disorder spectrum. While some people may have few or mild manifestations, others may have multiple severe malformations. | Overview of Cat Eye Syndrome. Cat eye syndrome (CES) is a rare chromosomal disorder that may be evident at birth. Individuals with a normal chromosomal make-up have two 22nd chromosomes, both of which have a short arm, known as 22p, and a long arm, known as 22q. However, in individuals with CES, the short arm and a small region of the long arm of chromosome 22 (i.e., 22pter-22q11) are present four times (partial tetrasomy) rather than twice in cells of the body. In a small number of people with CES, the 22q11 region is present in 3 copies (partial trisomy). The name “cat eye syndrome” is derived from a distinctive eye (ocular) abnormality that is present in a little over half affected individuals. This defect, known as a coloboma, usually appears as a cleft or gap in the iris below the pupil, and the elongated pupil therefore resembles the appearance of a cat’s eye. There are, however, many other features associated with CES involving many organs and systems. These symptoms result from abnormal development during embryo and fetal stages. Associated symptoms vary greatly in presence and severity from one person to another, including among members of the same family. CES may be best thought of as a disorder spectrum. While some people may have few or mild manifestations, others may have multiple severe malformations. | 205 | Cat Eye Syndrome |
nord_205_1 | Symptoms of Cat Eye Syndrome | The classic symptoms associated with CES are ocular coloboma, anal atresia and the minor ear defect preauricular skin tags or pits (see below for explanations). However, the syndrome is extremely variable, and it has been estimated that only 41% of patients with CES have this classic triad of symptoms (Berends et al, 2001). In general the abnormalities associated with CES tend to involve the eyes, ears, anal region, heart, and/or kidneys, but other organs may show involvement and some people show intellectual disability. Below are discussed the most common features of CES. Table 1 gives the estimated incidence of symptoms from two different studies. These estimates are likely to be overestimates. Some affected individuals may manifest no symptoms (asymptomatic) or so few symptoms that they may not be diagnosed with the disorder. Although the CES chromosome is usually new and not inherited from a parent, there are a few inherited cases where the birth of a child with multiple features of CES results in the discovery of a mild case in a parent. The incidence of mild unrecognized cases of CES in the population, while likely rare, is unknown. The presence of the CES chromosome therefore in no way predicts the presence or severity of symptoms. Affected individuals will rarely have all of the symptoms discussed below and every case is different and unique. If a symptom is present in only one case, that may have an independent cause (not part of the syndrome). Parents should talk to their children’s physician and medical team about their child, potential associated symptoms and overall prognosis.1) Coloboma and other eye abnormalities
A coloboma (plural colobomata or colobomas) consists of the partial absence of ocular tissue, often affecting both eyes (bilateral). It results from the failure to close a fissure in the lower part of the eye during early development, resulting in a cleft or gap that persists. Affected ocular tissues may include the colored portion of the eye that controls the amount of light that enters into the eye (iris), the dark-brown, middle layer (choroid), and/or the nerve-rich innermost membrane (retina) of the eye. Iris coloboma may give the iris an unusual “keyhole” appearance. If only the iris is involved, then vision is not affected. However, a more extensive coloboma involving other layers of the eye may result in vision defects and/or blindness. Although coloboma was originally considered a primary feature of the disorder, this abnormality is only present in a little over half of individuals with CES. Some affected individuals have additional eye abnormalities, such crossing of the eyes (strabismus); and/or abnormal smallness of one of the eyes (unilateral microphthalmia). Less frequently, other ocular defects may be present including absence of the iris (aniridia); clouding of the dome-shaped, normally transparent region of the front of the eyeball (cornea); absence of tissue from portions of the eyelid (eyelid coloboma); loss of transparency of the lens of the eye (cataract), and/or Duane syndrome. The latter is a condition characterized by the limitation or absence of certain horizontal eye movements and retraction or “drawing back” of the eyeball into the eye cavity (orbit) upon attempting to look inward. In some cases, depending on the severity and/or combination of eye abnormalities present, varying degrees of visual impairment may result, including blindness. 2) Anal abnormalities
In approximately ¾ of affected individuals, the anal opening may be unusually small or narrow (anal stenosis) or the anal canal may be absent (anal atresia), sometimes with a passage (fistula) from the end portion of the large intestine (rectum) into abnormal locations. In males, fistulae may form between the rectum and the muscular organ that collects urine (bladder), the tube that excretes urine from the bladder (urethra), or the area behind the genitals (perineum). In females, fistulae may be present between the rectum and the bladder or the vagina. Anal atresia and fistulae are corrected surgically.3) Ear Abnormalities
The third classic feature of CES is preauricular skin tags and/or pits. It is the most common feature of CES, seen in over 80% of people. Affected individuals may have small outgrowths of skin (tags) and/or slight depressions (pits) in front of the outer ears (preauricular). In addition, the outer portions of the ears (auricles) may be low set and/or malformed (dysplastic), sometimes with blind-ending or absent external ear canals (microtia). In most cases, absence (atresia) of the external ear canal tends to affect one ear and may cause mild hearing impairment due to inadequate transmission of sound from the external to the inner ear (conductive hearing loss).4) Heart defects
About half of individuals with CES have structural abnormalities of the heart at birth (congenital heart defects), particularly “total anomalous pulmonary venous return” or “tetralogy of Fallot”. Associated symptoms and findings may vary, depending on the size, nature, and/or combination of heart malformations present. In people with severe disease, congenital heart disease may lead to life-threatening complications.Total anomalous pulmonary venous return (TAPVR) is characterized by abnormalities in blood flow to the heart. The pulmonary veins normally return oxygenated blood from both lungs to the left upper chamber (left atrium) of the heart. However, in infants with TAPVR, the pulmonary veins improperly return blood directly to the upper right chamber (right atrium) of the heart or to veins draining into the right atrium. There is also a hole between the two atria (atrial septal defect), leading to mixing of oxygenated and oxygen-deficient blood. Associated symptoms and findings may include bluish discoloration of the skin and mucous membranes due to low blood oxygen (cyanosis), abnormally rapid breathing (tachypnea), rising blood pressure in the lungs (pulmonary hypertension), inability of the heart to pump enough blood to meet the body’s requirements for oxygen (heart failure), and/or other abnormalities. Although TAPVR is a rare heart defect, representing only 1-2% of heart defects in children, it is one of the most common heart defects in CES.Tetralogy of Fallot consists of a combination of cardiac defects. These include an abnormal opening in the partition (septum) separating the two lower chambers of the heart (ventricular septal defect); obstruction of the proper outflow of blood from the right ventricle to the lungs due to narrowing of the opening between the ventricle and the pulmonary artery (pulmonary stenosis), displacement of the aorta, enabling oxygen-depleted blood to flow from the right ventricle to the aorta; and thickening (hypertrophy) of heart muscle of the right ventricle. The pulmonary artery transports oxygen-depleted blood from the right ventricle to the lungs, where the exchange of oxygen and carbon dioxide occurs. The aorta, the major artery of the body, arises from the left ventricle and supplies oxygen-rich blood to most arteries. The symptoms associated tetralogy of Fallot can different in one person compared to another. NORD has a separate report on this disorder. (For more information, choose “tetralogy of Fallot” as your search term in the NORD Rare Disease Database.)Holes between the atria or ventricles (atrial or ventricle septal defects) are also common heart defects associated with CES. A variety of other heart defects have been reported.5) Kidney and genital defects
Collectively defects of the urinary system and the reproductive organs are classified as urogenital defects. These two systems have a common origin in the embryo. Typical kidney defects associated with CES include underdevelopment of one or both kidneys (unilateral or bilateral renal hypoplasia); absence of a kidney (unilateral agenesis); the presence of an additional kidney (supernumerary kidney); abnormal swelling (distention) of and accumulation of urine in the kidneys (hydronephrosis); and/or abnormal development of renal cysts (cystic dysplasia). Typical reproductive tract defects in females include underdevelopment of the uterus, absence of the vagina or abnormal genitalia. In males defects include undescended testes (cryptorchidism) and external genital abnormalities. 6) Intellectual disability
Some individuals with CES have normal intelligence. However, some may have borderline normal to mild intellectual disability, or, less commonly, moderate intellectual disability. Berends et al, 2001 compared the IQ scores of 51 patients and found 47% in the normal range, 22 % borderline normal, 18% with mild intellectual disability and 14% with moderate intellectual disability. Rare cases of severe intellectual disability have also been reported. Individuals with intellectual disability may experience delays in reaching developmental milestones that require the coordination of muscular and mental activity (psychomotor delays). 7) Skeletal defects
Typical skeletal abnormalities may include abnormal sideways curvature of the spine (scoliosis); abnormal fusion of certain bones in the spinal column (vertebral fusions); absence of the bone on the thumb side of the forearm (radial aplasia); absence or abnormal fusion (synostosis) of certain ribs; absence of certain toes and/or duplication of the large toes (hallux); and/or dislocation of the hips.8) Abdominal defects
In some individuals with CES, portions of the intestine may protrude through a defect in the abdominal wall at the navel (umbilical hernia) or into the canal that passes through lower muscular layers of the abdominal wall (inguinal hernia). Additional reported features have included an abnormal saclike protrusion (Meckel diverticulum) from the lower small intestine (ileum), or Hirschsprung disease, which is the incomplete rotation of the upper large intestine (cecum), and/or the absence of groups of nerve fibers (ganglia) in the muscular wall of the large intestine resulting in impairment or absence of the involuntary, rhythmic contractions (peristalsis) that propel waste materials through the lower digestive tract. Associated findings may include an abnormal accumulation of feces within the colon, widening of the colon above the affected segment (megacolon), abdominal bloating, periodic vomiting, loss of appetite (anorexia), and/or other abnormalities. In addition, bile ducts may fail to develop or develop abnormally (biliary atresia). Bile, a liquid secreted by the liver, plays an essential role in carrying waste products from the liver and breaking down fats in the small intestine. The bile ducts are narrow tubes through which bile passes from the liver to the first section of the small intestine (duodenum). Due to such absence or underdevelopment of bile ducts, bile is unable to reach the intestine and abnormally accumulates in the liver. Associated findings may include yellowing of the skin, mucous membranes, and whites of the eyes (jaundice); abnormally dark urine; pale feces; enlargement of the liver; growth failure. Without appropriate treatment, scarring and impaired functioning of the liver may lead to potentially life-threatening complications. 9) Cleft Palate
Cleft palate is the incomplete closure of the roof of the mouth. Varying degrees of this defect may be seen in 14-31% of individuals with CES (Berends et al, 2001, Rosias et al, 2001).10) Short Stature
Short stature has been reported in 15-50% of individuals with CES (Berends et al, 2001, Rosias et al, 2001). However, it is not yet clear that this is associated with a deficiency of growth hormone in most affected individuals. 11) Abnormal facial features
Most individuals with CES show abnormal features of the skull and facial (craniofacial) region. Common features include downwardly slanting eyelid folds (palpebral fissures); eyes that are widely spaced apart (ocular hypertelorism), and vertical skin folds that may cover the inner corners of the eyes (epicanthal folds), an abnormally small lower jaw (mandibular hypoplasia or micrognathia) and a flat nasal bridge.Table 1: Typical features of cat eye syndrome present in over 10% of affected individuals.
Incidences are from two independent review papers from 2001. Incidences likely differ due to variation in the cases examined, the definition of features used and the amount of detail available in the published case reports reviewed. Incidences should be considered overestimates, since mild undiagnosed cases would not be included. Symptom…………………………….Berends et al. (2001)……….Rosias et al. (2001)Coloboma (eye defect)……………………. ……..55% (40/73)…………..61% (54/88)
Anal and rectum defects…………………………. 73% (54/74)…………..81% (71/88)
Preauricular tags or pits (Outer ear defect)……..81% (60/74)……………87% (78/90)
Heart defects………………………………………. 50% (37/74)…………….3% (50/80)
Kidney Defects…………………………………….. 31% (22/72)……………….–…….
Kidney and Genital Defects…………………………… – ………………….71% (55/77)
Intellectual disability……………………………….. 32% (16/50)………….56% (38/68)
Skeletal defects……………………………………. 29% (21/73)…………..73% (46/63)
Abdominal defects…………………………………………– ………………..69% (33/48)
– Hirschsprung disease……………………………………..– ……………..12.5% (6/48)
– Biliary atresia……………………………………………. – …………………8% (4/48)
Cleft Palate………………………………………….. 14% (10/72)…………….. –……..
Cleft palate or absent uvula………………………………. – ………………31% (15/48)
Short stature…………………………………………. 15% (9/62) ………….50% (32/64)
Downslanting palpebral fissures (eye abnormality) ..7% (34/73)…………69% (48/70)
Hypertelorism (wide set eyes)……………………… 38% (28/73)…………70% (48/69)
Microphthalmia (small eye)………………………… 19% (10/54) …………39% (23/59)
Epicanthal folds……………………………………… 26% (19/74) …………64% (29/45)
Hearing loss…………………………………………. 17% (9/54) …………..16% (11/68) | Symptoms of Cat Eye Syndrome. The classic symptoms associated with CES are ocular coloboma, anal atresia and the minor ear defect preauricular skin tags or pits (see below for explanations). However, the syndrome is extremely variable, and it has been estimated that only 41% of patients with CES have this classic triad of symptoms (Berends et al, 2001). In general the abnormalities associated with CES tend to involve the eyes, ears, anal region, heart, and/or kidneys, but other organs may show involvement and some people show intellectual disability. Below are discussed the most common features of CES. Table 1 gives the estimated incidence of symptoms from two different studies. These estimates are likely to be overestimates. Some affected individuals may manifest no symptoms (asymptomatic) or so few symptoms that they may not be diagnosed with the disorder. Although the CES chromosome is usually new and not inherited from a parent, there are a few inherited cases where the birth of a child with multiple features of CES results in the discovery of a mild case in a parent. The incidence of mild unrecognized cases of CES in the population, while likely rare, is unknown. The presence of the CES chromosome therefore in no way predicts the presence or severity of symptoms. Affected individuals will rarely have all of the symptoms discussed below and every case is different and unique. If a symptom is present in only one case, that may have an independent cause (not part of the syndrome). Parents should talk to their children’s physician and medical team about their child, potential associated symptoms and overall prognosis.1) Coloboma and other eye abnormalities
A coloboma (plural colobomata or colobomas) consists of the partial absence of ocular tissue, often affecting both eyes (bilateral). It results from the failure to close a fissure in the lower part of the eye during early development, resulting in a cleft or gap that persists. Affected ocular tissues may include the colored portion of the eye that controls the amount of light that enters into the eye (iris), the dark-brown, middle layer (choroid), and/or the nerve-rich innermost membrane (retina) of the eye. Iris coloboma may give the iris an unusual “keyhole” appearance. If only the iris is involved, then vision is not affected. However, a more extensive coloboma involving other layers of the eye may result in vision defects and/or blindness. Although coloboma was originally considered a primary feature of the disorder, this abnormality is only present in a little over half of individuals with CES. Some affected individuals have additional eye abnormalities, such crossing of the eyes (strabismus); and/or abnormal smallness of one of the eyes (unilateral microphthalmia). Less frequently, other ocular defects may be present including absence of the iris (aniridia); clouding of the dome-shaped, normally transparent region of the front of the eyeball (cornea); absence of tissue from portions of the eyelid (eyelid coloboma); loss of transparency of the lens of the eye (cataract), and/or Duane syndrome. The latter is a condition characterized by the limitation or absence of certain horizontal eye movements and retraction or “drawing back” of the eyeball into the eye cavity (orbit) upon attempting to look inward. In some cases, depending on the severity and/or combination of eye abnormalities present, varying degrees of visual impairment may result, including blindness. 2) Anal abnormalities
In approximately ¾ of affected individuals, the anal opening may be unusually small or narrow (anal stenosis) or the anal canal may be absent (anal atresia), sometimes with a passage (fistula) from the end portion of the large intestine (rectum) into abnormal locations. In males, fistulae may form between the rectum and the muscular organ that collects urine (bladder), the tube that excretes urine from the bladder (urethra), or the area behind the genitals (perineum). In females, fistulae may be present between the rectum and the bladder or the vagina. Anal atresia and fistulae are corrected surgically.3) Ear Abnormalities
The third classic feature of CES is preauricular skin tags and/or pits. It is the most common feature of CES, seen in over 80% of people. Affected individuals may have small outgrowths of skin (tags) and/or slight depressions (pits) in front of the outer ears (preauricular). In addition, the outer portions of the ears (auricles) may be low set and/or malformed (dysplastic), sometimes with blind-ending or absent external ear canals (microtia). In most cases, absence (atresia) of the external ear canal tends to affect one ear and may cause mild hearing impairment due to inadequate transmission of sound from the external to the inner ear (conductive hearing loss).4) Heart defects
About half of individuals with CES have structural abnormalities of the heart at birth (congenital heart defects), particularly “total anomalous pulmonary venous return” or “tetralogy of Fallot”. Associated symptoms and findings may vary, depending on the size, nature, and/or combination of heart malformations present. In people with severe disease, congenital heart disease may lead to life-threatening complications.Total anomalous pulmonary venous return (TAPVR) is characterized by abnormalities in blood flow to the heart. The pulmonary veins normally return oxygenated blood from both lungs to the left upper chamber (left atrium) of the heart. However, in infants with TAPVR, the pulmonary veins improperly return blood directly to the upper right chamber (right atrium) of the heart or to veins draining into the right atrium. There is also a hole between the two atria (atrial septal defect), leading to mixing of oxygenated and oxygen-deficient blood. Associated symptoms and findings may include bluish discoloration of the skin and mucous membranes due to low blood oxygen (cyanosis), abnormally rapid breathing (tachypnea), rising blood pressure in the lungs (pulmonary hypertension), inability of the heart to pump enough blood to meet the body’s requirements for oxygen (heart failure), and/or other abnormalities. Although TAPVR is a rare heart defect, representing only 1-2% of heart defects in children, it is one of the most common heart defects in CES.Tetralogy of Fallot consists of a combination of cardiac defects. These include an abnormal opening in the partition (septum) separating the two lower chambers of the heart (ventricular septal defect); obstruction of the proper outflow of blood from the right ventricle to the lungs due to narrowing of the opening between the ventricle and the pulmonary artery (pulmonary stenosis), displacement of the aorta, enabling oxygen-depleted blood to flow from the right ventricle to the aorta; and thickening (hypertrophy) of heart muscle of the right ventricle. The pulmonary artery transports oxygen-depleted blood from the right ventricle to the lungs, where the exchange of oxygen and carbon dioxide occurs. The aorta, the major artery of the body, arises from the left ventricle and supplies oxygen-rich blood to most arteries. The symptoms associated tetralogy of Fallot can different in one person compared to another. NORD has a separate report on this disorder. (For more information, choose “tetralogy of Fallot” as your search term in the NORD Rare Disease Database.)Holes between the atria or ventricles (atrial or ventricle septal defects) are also common heart defects associated with CES. A variety of other heart defects have been reported.5) Kidney and genital defects
Collectively defects of the urinary system and the reproductive organs are classified as urogenital defects. These two systems have a common origin in the embryo. Typical kidney defects associated with CES include underdevelopment of one or both kidneys (unilateral or bilateral renal hypoplasia); absence of a kidney (unilateral agenesis); the presence of an additional kidney (supernumerary kidney); abnormal swelling (distention) of and accumulation of urine in the kidneys (hydronephrosis); and/or abnormal development of renal cysts (cystic dysplasia). Typical reproductive tract defects in females include underdevelopment of the uterus, absence of the vagina or abnormal genitalia. In males defects include undescended testes (cryptorchidism) and external genital abnormalities. 6) Intellectual disability
Some individuals with CES have normal intelligence. However, some may have borderline normal to mild intellectual disability, or, less commonly, moderate intellectual disability. Berends et al, 2001 compared the IQ scores of 51 patients and found 47% in the normal range, 22 % borderline normal, 18% with mild intellectual disability and 14% with moderate intellectual disability. Rare cases of severe intellectual disability have also been reported. Individuals with intellectual disability may experience delays in reaching developmental milestones that require the coordination of muscular and mental activity (psychomotor delays). 7) Skeletal defects
Typical skeletal abnormalities may include abnormal sideways curvature of the spine (scoliosis); abnormal fusion of certain bones in the spinal column (vertebral fusions); absence of the bone on the thumb side of the forearm (radial aplasia); absence or abnormal fusion (synostosis) of certain ribs; absence of certain toes and/or duplication of the large toes (hallux); and/or dislocation of the hips.8) Abdominal defects
In some individuals with CES, portions of the intestine may protrude through a defect in the abdominal wall at the navel (umbilical hernia) or into the canal that passes through lower muscular layers of the abdominal wall (inguinal hernia). Additional reported features have included an abnormal saclike protrusion (Meckel diverticulum) from the lower small intestine (ileum), or Hirschsprung disease, which is the incomplete rotation of the upper large intestine (cecum), and/or the absence of groups of nerve fibers (ganglia) in the muscular wall of the large intestine resulting in impairment or absence of the involuntary, rhythmic contractions (peristalsis) that propel waste materials through the lower digestive tract. Associated findings may include an abnormal accumulation of feces within the colon, widening of the colon above the affected segment (megacolon), abdominal bloating, periodic vomiting, loss of appetite (anorexia), and/or other abnormalities. In addition, bile ducts may fail to develop or develop abnormally (biliary atresia). Bile, a liquid secreted by the liver, plays an essential role in carrying waste products from the liver and breaking down fats in the small intestine. The bile ducts are narrow tubes through which bile passes from the liver to the first section of the small intestine (duodenum). Due to such absence or underdevelopment of bile ducts, bile is unable to reach the intestine and abnormally accumulates in the liver. Associated findings may include yellowing of the skin, mucous membranes, and whites of the eyes (jaundice); abnormally dark urine; pale feces; enlargement of the liver; growth failure. Without appropriate treatment, scarring and impaired functioning of the liver may lead to potentially life-threatening complications. 9) Cleft Palate
Cleft palate is the incomplete closure of the roof of the mouth. Varying degrees of this defect may be seen in 14-31% of individuals with CES (Berends et al, 2001, Rosias et al, 2001).10) Short Stature
Short stature has been reported in 15-50% of individuals with CES (Berends et al, 2001, Rosias et al, 2001). However, it is not yet clear that this is associated with a deficiency of growth hormone in most affected individuals. 11) Abnormal facial features
Most individuals with CES show abnormal features of the skull and facial (craniofacial) region. Common features include downwardly slanting eyelid folds (palpebral fissures); eyes that are widely spaced apart (ocular hypertelorism), and vertical skin folds that may cover the inner corners of the eyes (epicanthal folds), an abnormally small lower jaw (mandibular hypoplasia or micrognathia) and a flat nasal bridge.Table 1: Typical features of cat eye syndrome present in over 10% of affected individuals.
Incidences are from two independent review papers from 2001. Incidences likely differ due to variation in the cases examined, the definition of features used and the amount of detail available in the published case reports reviewed. Incidences should be considered overestimates, since mild undiagnosed cases would not be included. Symptom…………………………….Berends et al. (2001)……….Rosias et al. (2001)Coloboma (eye defect)……………………. ……..55% (40/73)…………..61% (54/88)
Anal and rectum defects…………………………. 73% (54/74)…………..81% (71/88)
Preauricular tags or pits (Outer ear defect)……..81% (60/74)……………87% (78/90)
Heart defects………………………………………. 50% (37/74)…………….3% (50/80)
Kidney Defects…………………………………….. 31% (22/72)……………….–…….
Kidney and Genital Defects…………………………… – ………………….71% (55/77)
Intellectual disability……………………………….. 32% (16/50)………….56% (38/68)
Skeletal defects……………………………………. 29% (21/73)…………..73% (46/63)
Abdominal defects…………………………………………– ………………..69% (33/48)
– Hirschsprung disease……………………………………..– ……………..12.5% (6/48)
– Biliary atresia……………………………………………. – …………………8% (4/48)
Cleft Palate………………………………………….. 14% (10/72)…………….. –……..
Cleft palate or absent uvula………………………………. – ………………31% (15/48)
Short stature…………………………………………. 15% (9/62) ………….50% (32/64)
Downslanting palpebral fissures (eye abnormality) ..7% (34/73)…………69% (48/70)
Hypertelorism (wide set eyes)……………………… 38% (28/73)…………70% (48/69)
Microphthalmia (small eye)………………………… 19% (10/54) …………39% (23/59)
Epicanthal folds……………………………………… 26% (19/74) …………64% (29/45)
Hearing loss…………………………………………. 17% (9/54) …………..16% (11/68) | 205 | Cat Eye Syndrome |
nord_205_2 | Causes of Cat Eye Syndrome | CES is a rare disorder associated with the presence of an extra chromosome fragment, in which the short arm (p) and a small portion of the long arm (q) of chromosome 22 are usually present in four copies (partial tetrasomy) rather than two copies in cells of the body. The diagnosis of CES is based on the presence of extra chromosomal material derived from chromosome 22, as described below. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, plus two X chromosomes for females and an unequal 23rd pair of X and Y chromosomes for males. Each chromosome has a short arm designated as “p,” a long arm identified by the letter “q,” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, the short arm of chromosome 22 includes bands 22p11.1 to 22p13; the end or “terminal” of the short arm is known as 22pter. The long arm includes bands 22q11.1 to 22q13.Thus, individuals with a normal chromosomal make-up have two 22nd chromosomes, both of which consist of a short arm (22p), a long arm (22q), and a centromere. However, almost all individuals with CES have an unusual extra chromosome (supernumerary bisatellited marker chromosome). This marker chromosome is derived from two segments of chromosome 22, each of which consist of the short arm, the centromere and a piece of the long arm (22q11), both fused together to form a single extra chromosome. Therefore, this chromosomal region (22pter-22q11) is present in cells of the body four times: twice as part of the two normal chromosomes 22, and twice together in the marker chromosome. In addition, in some people, this extra chromosome may be present in only a certain percentage of the body’s cells (mosaicism). Mosaicism seen in the blood cells that are examined does not necessarily predict milder symptoms. There is no way to anticipate the specific symptoms or severity of an infant with a mosaic form of CES.In rare instances, a portion of the chromosomal segment 22 q11 may appear three times: once in a normal chromosome 22 and twice in a chromosome 22 with an internal duplication. A portion of region 22q11 is considered critical for expression of all or most of the features associated with CES. This region is referred to as the CES critical region and contains approximately 12 genes. Research is ongoing to isolate and characterize the gene(s) responsible for features associated with CES.The exact cause of CES is not understood. In most instances, the chromosomal abnormality appears to arise “de novo” or randomly due to an error in the division of a parent’s reproductive cells (meiotic error); in such cases, the parent has normal chromosomes. Formation of the marker chromosome may be a result of specific sequences in the region that predispose to chromosomal rearrangement. It not due to any specific actions taking by the parents during pregnancy.In a small percentage of people, a parent (especially with milder symptoms) will pass the CES chromosome to their offspring. In some of these instances, the parent has the marker chromosome in some body cells while other body cells are unaffected (mosaicism). There have been instances reported where mosaicism for this chromosomal abnormality may be transmitted through several generations in some families; however, as noted above, expression of associated features may be variable. As a result, those with multiple or severe features may be identified while previous generation go unrecognized and undiagnosed. In any case, it is important to note that individuals with CES who have children run a substantial risk of passing the extra marker chromosome to a proportion of their offspring.Further research is necessary to learn more about the complex chromosomal and genetic mechanisms potentially responsible for the expression and transmission of the syndrome. | Causes of Cat Eye Syndrome. CES is a rare disorder associated with the presence of an extra chromosome fragment, in which the short arm (p) and a small portion of the long arm (q) of chromosome 22 are usually present in four copies (partial tetrasomy) rather than two copies in cells of the body. The diagnosis of CES is based on the presence of extra chromosomal material derived from chromosome 22, as described below. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, plus two X chromosomes for females and an unequal 23rd pair of X and Y chromosomes for males. Each chromosome has a short arm designated as “p,” a long arm identified by the letter “q,” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, the short arm of chromosome 22 includes bands 22p11.1 to 22p13; the end or “terminal” of the short arm is known as 22pter. The long arm includes bands 22q11.1 to 22q13.Thus, individuals with a normal chromosomal make-up have two 22nd chromosomes, both of which consist of a short arm (22p), a long arm (22q), and a centromere. However, almost all individuals with CES have an unusual extra chromosome (supernumerary bisatellited marker chromosome). This marker chromosome is derived from two segments of chromosome 22, each of which consist of the short arm, the centromere and a piece of the long arm (22q11), both fused together to form a single extra chromosome. Therefore, this chromosomal region (22pter-22q11) is present in cells of the body four times: twice as part of the two normal chromosomes 22, and twice together in the marker chromosome. In addition, in some people, this extra chromosome may be present in only a certain percentage of the body’s cells (mosaicism). Mosaicism seen in the blood cells that are examined does not necessarily predict milder symptoms. There is no way to anticipate the specific symptoms or severity of an infant with a mosaic form of CES.In rare instances, a portion of the chromosomal segment 22 q11 may appear three times: once in a normal chromosome 22 and twice in a chromosome 22 with an internal duplication. A portion of region 22q11 is considered critical for expression of all or most of the features associated with CES. This region is referred to as the CES critical region and contains approximately 12 genes. Research is ongoing to isolate and characterize the gene(s) responsible for features associated with CES.The exact cause of CES is not understood. In most instances, the chromosomal abnormality appears to arise “de novo” or randomly due to an error in the division of a parent’s reproductive cells (meiotic error); in such cases, the parent has normal chromosomes. Formation of the marker chromosome may be a result of specific sequences in the region that predispose to chromosomal rearrangement. It not due to any specific actions taking by the parents during pregnancy.In a small percentage of people, a parent (especially with milder symptoms) will pass the CES chromosome to their offspring. In some of these instances, the parent has the marker chromosome in some body cells while other body cells are unaffected (mosaicism). There have been instances reported where mosaicism for this chromosomal abnormality may be transmitted through several generations in some families; however, as noted above, expression of associated features may be variable. As a result, those with multiple or severe features may be identified while previous generation go unrecognized and undiagnosed. In any case, it is important to note that individuals with CES who have children run a substantial risk of passing the extra marker chromosome to a proportion of their offspring.Further research is necessary to learn more about the complex chromosomal and genetic mechanisms potentially responsible for the expression and transmission of the syndrome. | 205 | Cat Eye Syndrome |
nord_205_3 | Affects of Cat Eye Syndrome | CES has been recognized for more than a century. More than 100 cases have been described in the medical literature, including apparently sporadic and familial cases. Many more affected individuals exist but have not been described in the medical literature. However, the syndrome is very rare, and currently there are no accurate estimates of the incidence of CES in the population. Schinzel et al (1981) estimated an incidence of approximately one in 50,000 to one in 150,000 individuals in Northeastern Switzerland. Because some affected individuals develop few associated features, however, the disorder may in some people remain unrecognized. There is currently no way to estimate how underdiagnosed this syndrome is. | Affects of Cat Eye Syndrome. CES has been recognized for more than a century. More than 100 cases have been described in the medical literature, including apparently sporadic and familial cases. Many more affected individuals exist but have not been described in the medical literature. However, the syndrome is very rare, and currently there are no accurate estimates of the incidence of CES in the population. Schinzel et al (1981) estimated an incidence of approximately one in 50,000 to one in 150,000 individuals in Northeastern Switzerland. Because some affected individuals develop few associated features, however, the disorder may in some people remain unrecognized. There is currently no way to estimate how underdiagnosed this syndrome is. | 205 | Cat Eye Syndrome |
nord_205_4 | Related disorders of Cat Eye Syndrome | Symptoms of the following disorders may appear similar to those of CES, although the underlying defect would be different. Comparisons may be useful for a differential diagnosis: CHARGE syndrome is a rare pattern of malformations that may affect several organ systems of the body. CHARGE is an acronym that stands for (C)oloboma of the eye; (H)eart defects; (A)tresia of the Choanae, meaning bony or membranous blockage of the passageway between the nose and throat; (R)etardation of growth and development and/or intellectual deficiency; (G)enital anomalies; and (E)ar anomalies and/or deafness. Four or more of these characteristic features must be present for a diagnosis of CHARGE syndrome. Some affected individuals may also have other, variable symptoms and findings, such as a small head, incomplete closure of the roof of the mouth (cleft palate), an abnormal groove in the upper lip (cleft lip), swallowing difficulties, paralysis of facial nerves (facial palsy), an abnormal connection between the windpipe and the tube that carries food from the throat to the stomach (tracheoesophageal fistula), kidney malformations, and/or other features. CHARGE syndrome cases can occur randomly (sporadically) or can be familial. Many patients have a mutation in the CHD7 gene (Lalani et al, 2006).VACTERL association is a rare pattern of malformations. VACTERL is an acronym for (V)ertebral anomalies; (A)nal atresia, with or without fistula; (C)ardiac defects, particularly ventricular septal defect; (T)racheo(E)sophageal fistula; (R)enal abnormalities; and (L)imb anomalies, including abnormal development of the bone on the thumb side of the forearm (radial dysplasia). VACTERL association usually appears to occur randomly for unknown reasons (sporadically). | Related disorders of Cat Eye Syndrome. Symptoms of the following disorders may appear similar to those of CES, although the underlying defect would be different. Comparisons may be useful for a differential diagnosis: CHARGE syndrome is a rare pattern of malformations that may affect several organ systems of the body. CHARGE is an acronym that stands for (C)oloboma of the eye; (H)eart defects; (A)tresia of the Choanae, meaning bony or membranous blockage of the passageway between the nose and throat; (R)etardation of growth and development and/or intellectual deficiency; (G)enital anomalies; and (E)ar anomalies and/or deafness. Four or more of these characteristic features must be present for a diagnosis of CHARGE syndrome. Some affected individuals may also have other, variable symptoms and findings, such as a small head, incomplete closure of the roof of the mouth (cleft palate), an abnormal groove in the upper lip (cleft lip), swallowing difficulties, paralysis of facial nerves (facial palsy), an abnormal connection between the windpipe and the tube that carries food from the throat to the stomach (tracheoesophageal fistula), kidney malformations, and/or other features. CHARGE syndrome cases can occur randomly (sporadically) or can be familial. Many patients have a mutation in the CHD7 gene (Lalani et al, 2006).VACTERL association is a rare pattern of malformations. VACTERL is an acronym for (V)ertebral anomalies; (A)nal atresia, with or without fistula; (C)ardiac defects, particularly ventricular septal defect; (T)racheo(E)sophageal fistula; (R)enal abnormalities; and (L)imb anomalies, including abnormal development of the bone on the thumb side of the forearm (radial dysplasia). VACTERL association usually appears to occur randomly for unknown reasons (sporadically). | 205 | Cat Eye Syndrome |
nord_205_5 | Diagnosis of Cat Eye Syndrome | The diagnosis of CES is based on the presence of extra chromosomal material derived from chromosome 22q11. (see “Causes” above). It is possible that a diagnosis of CES may be suspected before birth (prenatally) based upon specialized tests, such as ultrasound, amniocentesis, and/or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain defects such as a heart defect that might suggest CES. During amniocentesis, a sample of amniotic fluid containing fetal cells is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal studies performed on such cells may reveal the CES chromosome.CES may be recognized after birth (postnatally) by a thorough clinical evaluation, detecting a subset of characteristic physical findings such as coloboma, downslanting eyelid folds (palpebral fissures), preauricular tags and/or pits, malformed ears with absence of the external ear canal, anal atresia, heart defects, and renal malformations. A suspected diagnosis is then confirmed by standard chromosomal studies to identify the CES chromosome or a duplication within the 22q11 region. Once a chromosomal diagnosis is made, various specialized tests may also be performed to determine whether other features of CES are present. In particular, a thorough cardiac evaluation may be advised to detect any heart abnormalities that may be present. Such evaluation may include a thorough clinical examination, evaluation of heart and lung sounds through use of a stethoscope, x-ray studies, electrocardiography (EKG), echocardiography, cardiac catheterization, and/or other cardiac studies. An EKG, which records the electrical activities of heart muscle, may reveal abnormal electrical patterns. During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. When cardiac catheterization is performed, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. This procedure can be used for various purposes, including evaluating the pumping ability of the heart, measuring blood pressure within the heart, and withdrawing blood to measure oxygen content.Additional tests should include thorough eye examination and careful monitoring of hearing. Early recognition of potential visual impairment and/or hearing loss may play an essential role in ensuring prompt intervention and appropriate, early correction or supportive treatment.Specialized imaging techniques and/or other tests may also be used to detect and/or characterize possible gastrointestinal, genitourinary, renal, skeletal, or biliary defects, as well as other physical abnormalities that may occur in association with CES. Investigation of cognitive function may also be appropriate. | Diagnosis of Cat Eye Syndrome. The diagnosis of CES is based on the presence of extra chromosomal material derived from chromosome 22q11. (see “Causes” above). It is possible that a diagnosis of CES may be suspected before birth (prenatally) based upon specialized tests, such as ultrasound, amniocentesis, and/or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain defects such as a heart defect that might suggest CES. During amniocentesis, a sample of amniotic fluid containing fetal cells is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal studies performed on such cells may reveal the CES chromosome.CES may be recognized after birth (postnatally) by a thorough clinical evaluation, detecting a subset of characteristic physical findings such as coloboma, downslanting eyelid folds (palpebral fissures), preauricular tags and/or pits, malformed ears with absence of the external ear canal, anal atresia, heart defects, and renal malformations. A suspected diagnosis is then confirmed by standard chromosomal studies to identify the CES chromosome or a duplication within the 22q11 region. Once a chromosomal diagnosis is made, various specialized tests may also be performed to determine whether other features of CES are present. In particular, a thorough cardiac evaluation may be advised to detect any heart abnormalities that may be present. Such evaluation may include a thorough clinical examination, evaluation of heart and lung sounds through use of a stethoscope, x-ray studies, electrocardiography (EKG), echocardiography, cardiac catheterization, and/or other cardiac studies. An EKG, which records the electrical activities of heart muscle, may reveal abnormal electrical patterns. During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. When cardiac catheterization is performed, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. This procedure can be used for various purposes, including evaluating the pumping ability of the heart, measuring blood pressure within the heart, and withdrawing blood to measure oxygen content.Additional tests should include thorough eye examination and careful monitoring of hearing. Early recognition of potential visual impairment and/or hearing loss may play an essential role in ensuring prompt intervention and appropriate, early correction or supportive treatment.Specialized imaging techniques and/or other tests may also be used to detect and/or characterize possible gastrointestinal, genitourinary, renal, skeletal, or biliary defects, as well as other physical abnormalities that may occur in association with CES. Investigation of cognitive function may also be appropriate. | 205 | Cat Eye Syndrome |
nord_205_6 | Therapies of Cat Eye Syndrome | Treatment
The treatment of CES may require the coordinated efforts of a team of medical professionals, such as pediatricians, surgeons, heart specialists (cardiologists), specialists of the digestive tract, eye specialists; health professionals who detect, evaluate, and help to manage hearing problems; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and related tissues (orthopedists); and/or other health care professionals.Disease management is directed toward the specific symptoms that are apparent in each individual. For those with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be required. In addition, surgical correction is necessary for anal atresia. In some cases, recommended treatment may also include surgical repair, correction, or management of certain ocular defects, skeletal abnormalities, genital defects, hernias, Hirschsprung disease, biliary atresia, and/or other malformations associated with the disorder. The specific surgical procedures performed may depend upon the size, nature, severity, and/or combination of anatomical abnormalities; their associated symptoms; patient age; and other factors.Before and after surgery for certain cardiac defects, individuals may be susceptible to bacterial infection of the heart lining and valves (endocarditis). Therefore, preventive (prophylactic) antibiotic therapy may be prescribed before and after certain surgical procedures and dental visits. In addition, respiratory infections must be treated vigorously and early.For individuals with certain skeletal abnormalities, treatment may include physical therapy and various orthopedic techniques, potentially including surgical measures. In addition, individuals with severe short stature in association with growth hormone deficiency may be candidates for growth hormone therapy.Early intervention is important to ensure that children with CES reach their potential. Special services that may be beneficial include special remedial education, special social support, and/or other medical, social, and/or vocational services.Genetic counseling will also be of benefit for affected individuals and their families. Chromosomal studies may be recommended for parents of affected individuals to determine whether they carry the CES chromosome or exhibit mosaicism for this chromosome, particularly if they manifest any features that may be associated with the disorder. Genetic counseling may also benefit adults with CES who are interested in having children. | Therapies of Cat Eye Syndrome. Treatment
The treatment of CES may require the coordinated efforts of a team of medical professionals, such as pediatricians, surgeons, heart specialists (cardiologists), specialists of the digestive tract, eye specialists; health professionals who detect, evaluate, and help to manage hearing problems; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and related tissues (orthopedists); and/or other health care professionals.Disease management is directed toward the specific symptoms that are apparent in each individual. For those with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be required. In addition, surgical correction is necessary for anal atresia. In some cases, recommended treatment may also include surgical repair, correction, or management of certain ocular defects, skeletal abnormalities, genital defects, hernias, Hirschsprung disease, biliary atresia, and/or other malformations associated with the disorder. The specific surgical procedures performed may depend upon the size, nature, severity, and/or combination of anatomical abnormalities; their associated symptoms; patient age; and other factors.Before and after surgery for certain cardiac defects, individuals may be susceptible to bacterial infection of the heart lining and valves (endocarditis). Therefore, preventive (prophylactic) antibiotic therapy may be prescribed before and after certain surgical procedures and dental visits. In addition, respiratory infections must be treated vigorously and early.For individuals with certain skeletal abnormalities, treatment may include physical therapy and various orthopedic techniques, potentially including surgical measures. In addition, individuals with severe short stature in association with growth hormone deficiency may be candidates for growth hormone therapy.Early intervention is important to ensure that children with CES reach their potential. Special services that may be beneficial include special remedial education, special social support, and/or other medical, social, and/or vocational services.Genetic counseling will also be of benefit for affected individuals and their families. Chromosomal studies may be recommended for parents of affected individuals to determine whether they carry the CES chromosome or exhibit mosaicism for this chromosome, particularly if they manifest any features that may be associated with the disorder. Genetic counseling may also benefit adults with CES who are interested in having children. | 205 | Cat Eye Syndrome |
nord_206_0 | Overview of Catamenial Pneumothorax | Catamenial pneumothorax is an extremely rare condition that affects women. Pneumothorax is the medical term for a collapsed lung, a condition in which air or gas is trapped in the space surrounding the lungs causing the lungs to collapse. Women with catamenial pneumothorax have recurrent episodes of pneumothorax that occur within 72 hours before or after the start of menstruation. The exact cause of catamenial pneumothorax is unknown and several theories have been proposed. Some cases are associated with the abnormal development of endometrial tissue outside of the uterus (endometriosis), although the exact nature of this relationship in these cases is unknown. | Overview of Catamenial Pneumothorax. Catamenial pneumothorax is an extremely rare condition that affects women. Pneumothorax is the medical term for a collapsed lung, a condition in which air or gas is trapped in the space surrounding the lungs causing the lungs to collapse. Women with catamenial pneumothorax have recurrent episodes of pneumothorax that occur within 72 hours before or after the start of menstruation. The exact cause of catamenial pneumothorax is unknown and several theories have been proposed. Some cases are associated with the abnormal development of endometrial tissue outside of the uterus (endometriosis), although the exact nature of this relationship in these cases is unknown. | 206 | Catamenial Pneumothorax |
nord_206_1 | Symptoms of Catamenial Pneumothorax | The symptoms and severity of catamenial pneumothorax can vary from one episode to another and from one person to another. In the majority of affected women, the right lung is affected. Symptoms that may occur with catamenial pneumothorax include monthly episodes of chest pain that can radiate to the shoulder blades, shortness of breath or difficulty breathing (dyspnea), dizziness, fatigue, and a dry cough. Some women have reported a “crackling” sound upon inhaling during an episode. Chest pain associated with a collapsed lung is often severe and the condition often requires prompt medical attention. | Symptoms of Catamenial Pneumothorax. The symptoms and severity of catamenial pneumothorax can vary from one episode to another and from one person to another. In the majority of affected women, the right lung is affected. Symptoms that may occur with catamenial pneumothorax include monthly episodes of chest pain that can radiate to the shoulder blades, shortness of breath or difficulty breathing (dyspnea), dizziness, fatigue, and a dry cough. Some women have reported a “crackling” sound upon inhaling during an episode. Chest pain associated with a collapsed lung is often severe and the condition often requires prompt medical attention. | 206 | Catamenial Pneumothorax |
nord_206_2 | Causes of Catamenial Pneumothorax | The exact cause of catamenial pneumothorax is unknown. Several different theories have been proposed involving metastatic, hormonal and anatomical abnormalities. It is possible that catamenial pneumothorax may have different causes in different cases. In the metastatic model, catamenial pneumothorax is caused by the abnormal migration of endometrial tissue from the lining of the uterus (endometrium) to other areas of the body such as the diaphragm or the space in between the membranes lining the chest cavity wall and the lungs (pleural space). When endometrial tissue is found outside of the uterus, the term endometriosis is used. Many women with catamenial pneumothorax have endometriosis. Endometriosis can cause small holes or openings (fenestrations) in the diaphragm, which would allow air and fluid to pass through into the pleural space. Many women with catamenial pneumothorax have endometrial tissue in the lungs, a condition called thoracic endometriosis. However, some women with catamenial pneumothorax do not have diaphragmatic fenestrations or endometrial tissue in the lungs suggesting that other factors may play a role in the development of the disorder or that other causes of the disorder (apart from endometriosis) exist. In the hormonal model, researchers believe that a hormone known as prostaglandin F2, which is elevated during ovulation, causes narrowing (constriction) of the small tubes within the lungs (bronchioles). Bronchiolar narrowing may cause the small air sacs (alveoli) of the lungs to rupture, allowing air to become trapped in the pleural space. In the anatomical model, researchers believe that the absence of the cervical mucous plug, a normal occurrence during the menstrual cycle, allows air to pass from the genital tract into the pleural space through small holes or openings (fenestrations) in the diaphragm. Another theory that has been proposed as a cause of catamenial pneumothorax is the spontaneous ruptures of blebs. Blebs are small blisters or pustules that may be filled with fluid or air and can develop on the lungs. Some researchers speculate that hormonal changes during the menstrual cycle may cause blebs to rupture, which in turn can result in pneumothorax. | Causes of Catamenial Pneumothorax. The exact cause of catamenial pneumothorax is unknown. Several different theories have been proposed involving metastatic, hormonal and anatomical abnormalities. It is possible that catamenial pneumothorax may have different causes in different cases. In the metastatic model, catamenial pneumothorax is caused by the abnormal migration of endometrial tissue from the lining of the uterus (endometrium) to other areas of the body such as the diaphragm or the space in between the membranes lining the chest cavity wall and the lungs (pleural space). When endometrial tissue is found outside of the uterus, the term endometriosis is used. Many women with catamenial pneumothorax have endometriosis. Endometriosis can cause small holes or openings (fenestrations) in the diaphragm, which would allow air and fluid to pass through into the pleural space. Many women with catamenial pneumothorax have endometrial tissue in the lungs, a condition called thoracic endometriosis. However, some women with catamenial pneumothorax do not have diaphragmatic fenestrations or endometrial tissue in the lungs suggesting that other factors may play a role in the development of the disorder or that other causes of the disorder (apart from endometriosis) exist. In the hormonal model, researchers believe that a hormone known as prostaglandin F2, which is elevated during ovulation, causes narrowing (constriction) of the small tubes within the lungs (bronchioles). Bronchiolar narrowing may cause the small air sacs (alveoli) of the lungs to rupture, allowing air to become trapped in the pleural space. In the anatomical model, researchers believe that the absence of the cervical mucous plug, a normal occurrence during the menstrual cycle, allows air to pass from the genital tract into the pleural space through small holes or openings (fenestrations) in the diaphragm. Another theory that has been proposed as a cause of catamenial pneumothorax is the spontaneous ruptures of blebs. Blebs are small blisters or pustules that may be filled with fluid or air and can develop on the lungs. Some researchers speculate that hormonal changes during the menstrual cycle may cause blebs to rupture, which in turn can result in pneumothorax. | 206 | Catamenial Pneumothorax |
nord_206_3 | Affects of Catamenial Pneumothorax | Catamenial pneumothorax affects women during their reproductive years, most often during their thirties or forties. The exact incidence of the disorder is unknown. Many researchers believe that catamenial pneumothorax often goes undiagnosed or misdiagnosed, making it difficult to determine its true frequency in the general population. The term catamenial is derived from Greek and means “monthly”. The term catamenial pneumothorax was first used in the medical literature in 1972, although the disorder had been reported in the medical literature decades earlier. | Affects of Catamenial Pneumothorax. Catamenial pneumothorax affects women during their reproductive years, most often during their thirties or forties. The exact incidence of the disorder is unknown. Many researchers believe that catamenial pneumothorax often goes undiagnosed or misdiagnosed, making it difficult to determine its true frequency in the general population. The term catamenial is derived from Greek and means “monthly”. The term catamenial pneumothorax was first used in the medical literature in 1972, although the disorder had been reported in the medical literature decades earlier. | 206 | Catamenial Pneumothorax |
nord_206_4 | Related disorders of Catamenial Pneumothorax | Symptoms of the following disorders can be similar to those of catamenial pneumothorax. Comparisons may be useful for a differential diagnosis.Spontaneous pneumothorax is a condition in which gas or air is trapped within the pleural space causing the lung to collapse and that occurs for unknown reasons. Spontaneous pneumothorax can cause sudden chest pain or tightness, difficulty breathing, shortness of breath and a cough. Many women with catamenial pneumothorax are originally diagnosed with spontaneous pneumothorax until a correlation between lung collapse and the menstrual cycle is identified. | Related disorders of Catamenial Pneumothorax. Symptoms of the following disorders can be similar to those of catamenial pneumothorax. Comparisons may be useful for a differential diagnosis.Spontaneous pneumothorax is a condition in which gas or air is trapped within the pleural space causing the lung to collapse and that occurs for unknown reasons. Spontaneous pneumothorax can cause sudden chest pain or tightness, difficulty breathing, shortness of breath and a cough. Many women with catamenial pneumothorax are originally diagnosed with spontaneous pneumothorax until a correlation between lung collapse and the menstrual cycle is identified. | 206 | Catamenial Pneumothorax |
nord_206_5 | Diagnosis of Catamenial Pneumothorax | A diagnosis of catamenial pneumothorax is made based upon a detailed patient history, a thorough clinical evaluation and identification of characteristic symptoms (i.e., repeated episodes of pneumothorax in conjunction with the onset of menses). A variety of tests may be required to rule out other conditions and to identify associated conditions such as thoracic or pelvic endometriosis or damage to the diaphragm. A minimally invasive procedure known as video-assisted thoracoscopy (VATS) may be used as a diagnostic aid. During a VATS procedure, a 1-cm rigid tube (thoracoscope) with a tiny, fiber-optic camera at the end is passed through a small incision in the chest. This allows physicians to examine the lungs, chest cavity and diaphragm. | Diagnosis of Catamenial Pneumothorax. A diagnosis of catamenial pneumothorax is made based upon a detailed patient history, a thorough clinical evaluation and identification of characteristic symptoms (i.e., repeated episodes of pneumothorax in conjunction with the onset of menses). A variety of tests may be required to rule out other conditions and to identify associated conditions such as thoracic or pelvic endometriosis or damage to the diaphragm. A minimally invasive procedure known as video-assisted thoracoscopy (VATS) may be used as a diagnostic aid. During a VATS procedure, a 1-cm rigid tube (thoracoscope) with a tiny, fiber-optic camera at the end is passed through a small incision in the chest. This allows physicians to examine the lungs, chest cavity and diaphragm. | 206 | Catamenial Pneumothorax |
nord_206_6 | Therapies of Catamenial Pneumothorax | TreatmentAn episode of pneumothorax may be treated with oxygen followed by observation and rest if the collapse is small. Serious episodes of pneumothorax may require the insertion of a chest tube to release trapped air and/or blood, thereby allowing the lungs to re-expand.Both surgery and hormonal therapy, either separately or in combination, have been used to treat women with catamenial pneumothorax. No specific guidelines exist for the optimal treatment of catamenial pneumothorax. Specific therapies may depend upon the exact cause of pneumothorax, an individual’s age and general health, personal preference, and/or other factors.Surgery may be performed to remove (excise) all suspected areas of endometrial tissue in the lungs and pleural space and to repair any damage or holes within the diaphragm. Surgery may also be used to remove small blisters located on the top of the lungs (apical blebs).In addition, the artificial destruction of the pleural space (pleurodesis) may also be used to treat women with catamenial pneumothorax. Chemicals or drugs may be used to cause inflammation of the two layers of the pleura (i.e., the membrane lining the lungs and the wall of the chest cavity). This inflammation causes the pleurae to stick together (adhere) eliminating the pleural space. Another procedure, called pleural abrasion, can also be used to cause inflammation and adhesion of the pleurae. During pleural abrasion, the pleurae are inflamed through friction by wearing down or rubbing away (abrading) the pleurae.Another surgical procedure that has been used to treat some affected women involves a mesh made from specialized material. During this procedure, a mesh is placed over the diaphragm in order to block any tiny holes that may have been missed during surgery. The mesh is absorbed over time and the resultant scar tissue eliminates any remaining holes in the diaphragm. This procedure is recommended even in women who have undergone pleurodesis or pleural abrasion.Hormonal therapy may also be used to treat women with catamenial pneumothorax, usually as an adjunct to surgical therapy. Gonadotropin releasing hormone agonists are drugs that suppress ovulation and prevent the release of other hormones including estrogen or progesterone. These drugs are commonly used to treat women with endometriosis, but have been effective in some women with catamenial pneumothorax, even those who do not have signs of endometriosis. | Therapies of Catamenial Pneumothorax. TreatmentAn episode of pneumothorax may be treated with oxygen followed by observation and rest if the collapse is small. Serious episodes of pneumothorax may require the insertion of a chest tube to release trapped air and/or blood, thereby allowing the lungs to re-expand.Both surgery and hormonal therapy, either separately or in combination, have been used to treat women with catamenial pneumothorax. No specific guidelines exist for the optimal treatment of catamenial pneumothorax. Specific therapies may depend upon the exact cause of pneumothorax, an individual’s age and general health, personal preference, and/or other factors.Surgery may be performed to remove (excise) all suspected areas of endometrial tissue in the lungs and pleural space and to repair any damage or holes within the diaphragm. Surgery may also be used to remove small blisters located on the top of the lungs (apical blebs).In addition, the artificial destruction of the pleural space (pleurodesis) may also be used to treat women with catamenial pneumothorax. Chemicals or drugs may be used to cause inflammation of the two layers of the pleura (i.e., the membrane lining the lungs and the wall of the chest cavity). This inflammation causes the pleurae to stick together (adhere) eliminating the pleural space. Another procedure, called pleural abrasion, can also be used to cause inflammation and adhesion of the pleurae. During pleural abrasion, the pleurae are inflamed through friction by wearing down or rubbing away (abrading) the pleurae.Another surgical procedure that has been used to treat some affected women involves a mesh made from specialized material. During this procedure, a mesh is placed over the diaphragm in order to block any tiny holes that may have been missed during surgery. The mesh is absorbed over time and the resultant scar tissue eliminates any remaining holes in the diaphragm. This procedure is recommended even in women who have undergone pleurodesis or pleural abrasion.Hormonal therapy may also be used to treat women with catamenial pneumothorax, usually as an adjunct to surgical therapy. Gonadotropin releasing hormone agonists are drugs that suppress ovulation and prevent the release of other hormones including estrogen or progesterone. These drugs are commonly used to treat women with endometriosis, but have been effective in some women with catamenial pneumothorax, even those who do not have signs of endometriosis. | 206 | Catamenial Pneumothorax |
nord_207_0 | Overview of Catel Manzke Syndrome | SummaryCatel-Manzke syndrome is a rare genetic disorder characterized by distinctive abnormalities of the index fingers and the classic features of Pierre Robin sequence. Affected individuals have an extra bone at the base of the index that causes the index fingers to be locked in a bent position (clinodactyly). Pierre Robin sequence refers to abnormalities that may occur as a distinct syndrome or as part of another underlying disorder. Pierre Robin sequence is characterized by an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate). A variety of additional physical findings can also be present. The specific symptoms can vary from one person to another. Alterations (mutations) in the TGDS gene have been identified in individuals with Catel-Manzke syndrome.IntroductionCatel-Manzke syndrome was first described in the medical literature in 1961 by Dr. Catel and later further evaluated by Dr. Manzke in 1966. The disorder was originally referred to as a palatodigital syndrome, but because cleft palate does not always occur, Dr. Manzke suggested replacing palatodigital syndrome with micrognathia-digital syndrome. | Overview of Catel Manzke Syndrome. SummaryCatel-Manzke syndrome is a rare genetic disorder characterized by distinctive abnormalities of the index fingers and the classic features of Pierre Robin sequence. Affected individuals have an extra bone at the base of the index that causes the index fingers to be locked in a bent position (clinodactyly). Pierre Robin sequence refers to abnormalities that may occur as a distinct syndrome or as part of another underlying disorder. Pierre Robin sequence is characterized by an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate). A variety of additional physical findings can also be present. The specific symptoms can vary from one person to another. Alterations (mutations) in the TGDS gene have been identified in individuals with Catel-Manzke syndrome.IntroductionCatel-Manzke syndrome was first described in the medical literature in 1961 by Dr. Catel and later further evaluated by Dr. Manzke in 1966. The disorder was originally referred to as a palatodigital syndrome, but because cleft palate does not always occur, Dr. Manzke suggested replacing palatodigital syndrome with micrognathia-digital syndrome. | 207 | Catel Manzke Syndrome |
nord_207_1 | Symptoms of Catel Manzke Syndrome | Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Infants with Catel-Manzke syndrome have an extra (supernumerary), irregularly-shaped bone (hyperphalangy) located between the first bone of the index finger (proximal phalanx) and the corresponding bone within the body of the hand (second metacarpal). As a result, the lower part of the index finger may bend toward the thumb and the upper part may bend toward the pinky. Eventually, the extra bone may fuse with the proximal phalanx and second metacarpal. Consequently, the index fingers may be fixed in an abnormally bent position (clinodactyly). These distinctive findings of the index fingers may be known as Manzke dysostosis.In many cases, affected individuals also have the three findings of Pierre-Robin sequence including an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate). However, cleft palate is not always present and a few cases none of the features of Pierre-Robin sequence develop. Individuals with micrognathia and glossoptosis may have feeding and breathing difficulties resulting in growth deficiency and failure to thrive.In addition, some infants with the syndrome may have structural abnormalities of the heart that are present at birth (congenital heart defects), mostly commonly ventricular or atrial septal defects. Better known as “a hole in the heart” these defects occur when there is a hole in the wall (septum) separating the two upper chambers (ventricles) of the heart from each other or in the septum separating the two lower chambers (atria) from each other.Less often, some affected infants may also have additional abnormalities of the hands. Such malformations may include abnormal bending or deviation (clinodactyly) of the “pinkies” or fifth fingers; abnormal division of the first bone of the middle of the hand (bifurcated first metacarpal); adducted thumbs; and/or a single deep crease across the palms of the hands.Affected individuals may also have distinctive facial features including eyes that are spaced apart wider than usual (hypertelorism), full cheeks, low-set ears, thin eyebrows, narrow nostrils, and a cleft or area of missing tissue in the colored portion of the eye (iris coloboma). Additional skeletal abnormalities may occur including abnormal curvature of the spine (scoliosis), an unusually prominent or sunken breastbone (pectus carinatum or pectus excavatum), short big toes (short halluces), clubfoot (talipes equinovarus), looseness (laxity) of certain joints, and dislocation of the joints, such as dislocation of the knees.Some children may experience delays is reaching developmental milestones. Mild-to-moderate intellectual disability and has been reported in few individuals, although in the majority of affected individual intelligence is not affected. | Symptoms of Catel Manzke Syndrome. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Infants with Catel-Manzke syndrome have an extra (supernumerary), irregularly-shaped bone (hyperphalangy) located between the first bone of the index finger (proximal phalanx) and the corresponding bone within the body of the hand (second metacarpal). As a result, the lower part of the index finger may bend toward the thumb and the upper part may bend toward the pinky. Eventually, the extra bone may fuse with the proximal phalanx and second metacarpal. Consequently, the index fingers may be fixed in an abnormally bent position (clinodactyly). These distinctive findings of the index fingers may be known as Manzke dysostosis.In many cases, affected individuals also have the three findings of Pierre-Robin sequence including an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate). However, cleft palate is not always present and a few cases none of the features of Pierre-Robin sequence develop. Individuals with micrognathia and glossoptosis may have feeding and breathing difficulties resulting in growth deficiency and failure to thrive.In addition, some infants with the syndrome may have structural abnormalities of the heart that are present at birth (congenital heart defects), mostly commonly ventricular or atrial septal defects. Better known as “a hole in the heart” these defects occur when there is a hole in the wall (septum) separating the two upper chambers (ventricles) of the heart from each other or in the septum separating the two lower chambers (atria) from each other.Less often, some affected infants may also have additional abnormalities of the hands. Such malformations may include abnormal bending or deviation (clinodactyly) of the “pinkies” or fifth fingers; abnormal division of the first bone of the middle of the hand (bifurcated first metacarpal); adducted thumbs; and/or a single deep crease across the palms of the hands.Affected individuals may also have distinctive facial features including eyes that are spaced apart wider than usual (hypertelorism), full cheeks, low-set ears, thin eyebrows, narrow nostrils, and a cleft or area of missing tissue in the colored portion of the eye (iris coloboma). Additional skeletal abnormalities may occur including abnormal curvature of the spine (scoliosis), an unusually prominent or sunken breastbone (pectus carinatum or pectus excavatum), short big toes (short halluces), clubfoot (talipes equinovarus), looseness (laxity) of certain joints, and dislocation of the joints, such as dislocation of the knees.Some children may experience delays is reaching developmental milestones. Mild-to-moderate intellectual disability and has been reported in few individuals, although in the majority of affected individual intelligence is not affected. | 207 | Catel Manzke Syndrome |
nord_207_2 | Causes of Catel Manzke Syndrome | Alterations (mutations) in the TGDS gene have been identified in individuals with Catel-Manzke syndrome. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The TGDS gene is located on the long arm (q) of chromosome 13 (13q32.1). Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes 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 13q32.1” refers to band 32.1 on the long arm of chromosome 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Researchers believe that, at least in some individuals, Catel-Manzke syndrome may be inherited as an autosomal recessive trait. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. 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 likelihood 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 Catel Manzke Syndrome. Alterations (mutations) in the TGDS gene have been identified in individuals with Catel-Manzke syndrome. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The TGDS gene is located on the long arm (q) of chromosome 13 (13q32.1). Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes 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 13q32.1” refers to band 32.1 on the long arm of chromosome 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Researchers believe that, at least in some individuals, Catel-Manzke syndrome may be inherited as an autosomal recessive trait. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. 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 likelihood 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. | 207 | Catel Manzke Syndrome |
nord_207_3 | Affects of Catel Manzke Syndrome | The incidence and prevalence of Catel-Manzke syndrome is unknown. More than 33 individuals with the disorder have been reported in the medical literature. Since some individuals may go misdiagnosed or undiagnosed, determining the true frequency of Catel-Manzke syndrome in the general population is difficult. More males have been described with the disorder than females, but this may be a coincidence since so few individuals have been reported in the medical literature. | Affects of Catel Manzke Syndrome. The incidence and prevalence of Catel-Manzke syndrome is unknown. More than 33 individuals with the disorder have been reported in the medical literature. Since some individuals may go misdiagnosed or undiagnosed, determining the true frequency of Catel-Manzke syndrome in the general population is difficult. More males have been described with the disorder than females, but this may be a coincidence since so few individuals have been reported in the medical literature. | 207 | Catel Manzke Syndrome |
nord_207_4 | Related disorders of Catel Manzke Syndrome | Symptoms of the following disorders can be similar to those of Catel-Manzke syndrome. Comparisons may be useful for a differential diagnosis.There are other congenital disorders that may be characterized by micrognathia, cleft palate, skeletal malformations, and/or other physical features and symptoms similar to those associated with Catel-Manzke syndrome. However, the unique finger malformations associated with the syndrome may serve to distinguish it from other such congenital disorders. Such disorders include Desbuquois syndrome type I, Temtamy brachydactyly syndrome, GPAPP deficiency (also known as chondrodysplasia with joint dislocations), brachydactyly type C, and the otopalatodigital syndromes. (For more information on these disorders, choose the exact disorder name in question as your search term in the Rare Disease Database.)Pierre Robin sequence, also known as Pierre Robin anomaly, consists of abnormalities that may occur as a distinct syndrome or in association with a number of other underlying disorders, including Catel-Manzke syndrome. (A “sequence” refers to a pattern of malformations derived from a single anomaly.) The primary defect in Pierre Robin syndrome is thought to be underdevelopment (hypoplasia) of the lower jaw (mandibular) region early in fetal development. Pierre Robin sequence is characterized by micrognathia, glossoptosis, and cleft palate. When a distinct syndrome, Pierre Robin syndrome is thought to occur as an autosomal recessive trait. (For more information on this disorder, choose “Pierre Robin” as your search term in the Rare Disease Database.) | Related disorders of Catel Manzke Syndrome. Symptoms of the following disorders can be similar to those of Catel-Manzke syndrome. Comparisons may be useful for a differential diagnosis.There are other congenital disorders that may be characterized by micrognathia, cleft palate, skeletal malformations, and/or other physical features and symptoms similar to those associated with Catel-Manzke syndrome. However, the unique finger malformations associated with the syndrome may serve to distinguish it from other such congenital disorders. Such disorders include Desbuquois syndrome type I, Temtamy brachydactyly syndrome, GPAPP deficiency (also known as chondrodysplasia with joint dislocations), brachydactyly type C, and the otopalatodigital syndromes. (For more information on these disorders, choose the exact disorder name in question as your search term in the Rare Disease Database.)Pierre Robin sequence, also known as Pierre Robin anomaly, consists of abnormalities that may occur as a distinct syndrome or in association with a number of other underlying disorders, including Catel-Manzke syndrome. (A “sequence” refers to a pattern of malformations derived from a single anomaly.) The primary defect in Pierre Robin syndrome is thought to be underdevelopment (hypoplasia) of the lower jaw (mandibular) region early in fetal development. Pierre Robin sequence is characterized by micrognathia, glossoptosis, and cleft palate. When a distinct syndrome, Pierre Robin syndrome is thought to occur as an autosomal recessive trait. (For more information on this disorder, choose “Pierre Robin” as your search term in the Rare Disease Database.) | 207 | Catel Manzke Syndrome |
nord_207_5 | Diagnosis of Catel Manzke Syndrome | In some cases, Catel-Manzke syndrome may be suspected before birth (prenatally) based upon advanced imaging techniques such as ultrasound. In fetal ultrasonography, reflected sound waves may be used to create an image of the developing fetus, potentially revealing certain findings suggestive of Catel-Manzke syndrome (e.g., abnormal smallness of the jaw, malformation of the index fingers, etc.).Clinical Testing and WorkupIn most cases, Catel-Manzke syndrome is diagnosed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings (e.g., micrognathia, cleft palate, abnormalities of the index fingers, etc.), and/or imaging tests. For example, imaging tests may elaborate distinctive abnormalities affecting the fingers, particularly the index fingers. In addition, x-ray studies may also confirm and/or reveal the extent of skeletal malformations and/or additional abnormalities.Congenital heart defects that may occur in association with Catel-Manzke syndrome (e.g., ventricular septal defects) may be detected and/or characterized by a thorough clinical examination, evaluation of heart and lung sounds through use of a stethoscope, and specialized tests that enable physicians to evaluate the structure and function of the heart (e.g., x-ray studies, electrocardiogram [EKG], echocardiogram). An EKG, which records the heart's electrical impulses, may reveal abnormal electrical patterns. During an echocardiogram, reflected high-frequency sound waves are used to obtain an image of the heart, enabling physicians to study cardiac structure and motion. | Diagnosis of Catel Manzke Syndrome. In some cases, Catel-Manzke syndrome may be suspected before birth (prenatally) based upon advanced imaging techniques such as ultrasound. In fetal ultrasonography, reflected sound waves may be used to create an image of the developing fetus, potentially revealing certain findings suggestive of Catel-Manzke syndrome (e.g., abnormal smallness of the jaw, malformation of the index fingers, etc.).Clinical Testing and WorkupIn most cases, Catel-Manzke syndrome is diagnosed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings (e.g., micrognathia, cleft palate, abnormalities of the index fingers, etc.), and/or imaging tests. For example, imaging tests may elaborate distinctive abnormalities affecting the fingers, particularly the index fingers. In addition, x-ray studies may also confirm and/or reveal the extent of skeletal malformations and/or additional abnormalities.Congenital heart defects that may occur in association with Catel-Manzke syndrome (e.g., ventricular septal defects) may be detected and/or characterized by a thorough clinical examination, evaluation of heart and lung sounds through use of a stethoscope, and specialized tests that enable physicians to evaluate the structure and function of the heart (e.g., x-ray studies, electrocardiogram [EKG], echocardiogram). An EKG, which records the heart's electrical impulses, may reveal abnormal electrical patterns. During an echocardiogram, reflected high-frequency sound waves are used to obtain an image of the heart, enabling physicians to study cardiac structure and motion. | 207 | Catel Manzke Syndrome |
nord_207_6 | Therapies of Catel Manzke Syndrome | TreatmentThe treatment of Catel-Manzke syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, craniofacial surgeons, cardiologists, speech therapists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Catel-Manzke syndrome.Specific therapies for the treatment of Catel-Manzke syndrome are symptomatic and supportive. For infants with feeding and respiratory difficulties recommended disease management may include keeping infants on their stomachs (prone positioning) and monitoring of breathing. In some cases, treatment may also require placement of a breathing tube or, if necessary, the performance of certain surgical procedures. Such measures may include a procedure in which the tongue is temporarily joined to the lower lip (tongue-lip adhesion) to keep the tongue from blocking the airway or creation of an opening through the neck into the windpipe into which a tube is inserted (tracheostomy).In addition, surgical measures to correct cleft palate will be advised at the appropriate age during infancy or childhood in order to repair the abnormality and to help improve speech development. Physicians may also recommend surgical correction of additional, associated craniofacial malformations in some cases.In some cases, physicians may advise surgical repair or correction of finger (digital) malformations, additional skeletal defects, and/or other abnormalities associated with the syndrome.For infants and children with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may also be required. The specific surgical procedures performed will depend upon the size, nature, severity, and/or combination of the anatomical abnormalities, their associated symptoms, and other factors.Early intervention may also be important in ensuring that affected children reach their potential. Special services that may be beneficial include special education, speech therapy, physical therapy, and/or other medical, social, and/or vocational services. | Therapies of Catel Manzke Syndrome. TreatmentThe treatment of Catel-Manzke syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, craniofacial surgeons, cardiologists, speech therapists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Catel-Manzke syndrome.Specific therapies for the treatment of Catel-Manzke syndrome are symptomatic and supportive. For infants with feeding and respiratory difficulties recommended disease management may include keeping infants on their stomachs (prone positioning) and monitoring of breathing. In some cases, treatment may also require placement of a breathing tube or, if necessary, the performance of certain surgical procedures. Such measures may include a procedure in which the tongue is temporarily joined to the lower lip (tongue-lip adhesion) to keep the tongue from blocking the airway or creation of an opening through the neck into the windpipe into which a tube is inserted (tracheostomy).In addition, surgical measures to correct cleft palate will be advised at the appropriate age during infancy or childhood in order to repair the abnormality and to help improve speech development. Physicians may also recommend surgical correction of additional, associated craniofacial malformations in some cases.In some cases, physicians may advise surgical repair or correction of finger (digital) malformations, additional skeletal defects, and/or other abnormalities associated with the syndrome.For infants and children with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may also be required. The specific surgical procedures performed will depend upon the size, nature, severity, and/or combination of the anatomical abnormalities, their associated symptoms, and other factors.Early intervention may also be important in ensuring that affected children reach their potential. Special services that may be beneficial include special education, speech therapy, physical therapy, and/or other medical, social, and/or vocational services. | 207 | Catel Manzke Syndrome |
nord_208_0 | Overview of Caudal Regression Syndrome | SummaryCaudal regression syndrome is a broad term for a rare complex disorder characterized by abnormal development of the lower (caudal) end of the spine. The spine consists of many small bones (vertebrae) that collectively form the spinal column. The spinal column is generally broken down into three segments – the cervical spine, consisting of the vertebrae just below the skull; the thoracic spine, consisting of the vertebrae in the chest region; and the lumbar spine, consisting of the vertebrae of the lower back. A triangularly shaped bony structure called the sacrum joins the lumbar portion of spine to the pelvis. The sacrum consists of five vertebrae fused together. At the end of the sacrum is the tailbone (coccyx). A wide range of abnormalities may potentially occur in infants with caudal regression syndrome including abnormal development (agenesis) of the sacrum and coccyx and abnormalities of the lumbar spine. More severe malformations may occur in some people. Abnormalities of the lower spine can cause a variety of additional complications including joint contractures, clubfeet and disruption or damage of the end of the spinal cord may occur, potentially causing urinary incontinence. Additional anomalies of the gastrointestinal tract, kidneys, heart, respiratory system, upper limbs and upper portions of the spine can also occur. The exact cause of caudal regression syndrome is unknown. Both environmental and genetic factors are suspected to play a role in the development of the disorder.IntroductionSome sources in the medical literature classify a condition called sirenomelia as the most severe form of caudal regression syndrome. However, recently many researchers have indicated that sirenomelia is a similar, but distinct, disorder. NORD has a separate report on sirenomelia. | Overview of Caudal Regression Syndrome. SummaryCaudal regression syndrome is a broad term for a rare complex disorder characterized by abnormal development of the lower (caudal) end of the spine. The spine consists of many small bones (vertebrae) that collectively form the spinal column. The spinal column is generally broken down into three segments – the cervical spine, consisting of the vertebrae just below the skull; the thoracic spine, consisting of the vertebrae in the chest region; and the lumbar spine, consisting of the vertebrae of the lower back. A triangularly shaped bony structure called the sacrum joins the lumbar portion of spine to the pelvis. The sacrum consists of five vertebrae fused together. At the end of the sacrum is the tailbone (coccyx). A wide range of abnormalities may potentially occur in infants with caudal regression syndrome including abnormal development (agenesis) of the sacrum and coccyx and abnormalities of the lumbar spine. More severe malformations may occur in some people. Abnormalities of the lower spine can cause a variety of additional complications including joint contractures, clubfeet and disruption or damage of the end of the spinal cord may occur, potentially causing urinary incontinence. Additional anomalies of the gastrointestinal tract, kidneys, heart, respiratory system, upper limbs and upper portions of the spine can also occur. The exact cause of caudal regression syndrome is unknown. Both environmental and genetic factors are suspected to play a role in the development of the disorder.IntroductionSome sources in the medical literature classify a condition called sirenomelia as the most severe form of caudal regression syndrome. However, recently many researchers have indicated that sirenomelia is a similar, but distinct, disorder. NORD has a separate report on sirenomelia. | 208 | Caudal Regression Syndrome |
nord_208_1 | Symptoms of Caudal Regression Syndrome | The specific symptoms and severity of caudal regression syndrome can vary dramatically from one person to another. Caudal regression syndrome most likely represents a spectrum of disease ranging from cases with milder symptoms to cases with severe, disabling or potentially life-threatening complications. It is important to note that affected individuals may not have all of the symptoms discussed below and that one child’s experience will vary (sometimes dramatically) from another child’s. Parents of affected children should talk to their physician and medical team about their child’s specific case, associated symptoms and overall prognosis.Infants with caudal regression syndrome have abnormalities affecting the sacral and lumbar spine. Some affected infants may only have isolated abnormal development of the sacrum (sacral) agenesis. In others, the sacrum may be absent altogether. Sacral agenesis is often associated with narrowing of the hips, underdeveloped of the muscles of the buttock (hypoplastic gluteal muscles), an indentation on the skin of the lower back (sacral dimple) and flattening of the buttocks. In some children, abnormalities of the lumber vertebrae may also occur.The abnormal development of the caudal region of the spine can cause additional abnormalities affecting the spinal cord and lower limbs. In some patients, disruption or damage to the lower portion of the spinal cord may occur causing a variety of neurological abnormalities including defective bladder and bowel control, increased urinary frequency and failure of the bladder to empty completely (neurogenic bladder). The urological abnormalities potentially associated with caudal regression syndrome can be significant.Damage to the nerves can also cause abnormalities of the lower limbs. Such abnormalities may include flexion contractures of the knee and hip. A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. Affected infants may also have reduced muscle mass in the legs, clubfeet or webbed skin on the back of the knees (popliteal ptergyium). When present, the severity of lower limb abnormalities can vary. Some individuals will walk unassisted; others may need an assistance device such as crutches, braces, walkers or in severe cases, a wheelchair.Infants with caudal regression syndrome may have a wide variety of additional physical findings including kidney abnormalities, abnormalities of the upper vertebrae, facial anomalies such as cleft lip, cleft palate, and a condition in which a thin covering blocking the anal opening or the passage that normally connects the anus and lowest part of the large intestine (rectum) fails to develop, which is known as anal atresia or imperforate anus.Kidney abnormalities that occur in caudal regression syndrome may include the absence of one kidney (renal agenesis). Some affected infants may have kidneys that are not located in their normal position (renal ectopia) or fusion of the tubes that force urine from the kidneys to the bladder (fused ureters). Kidney abnormalities can cause urinary obstruction, neurogenic bladder, or the abnormal backflow of urine from the bladder into the ureters (vesicoureteral reflux).Some individuals with caudal regression syndrome may have a meningomyelocele, a condition in which the membranes that cover the spine and, in some patients, the spinal cord itself protrude through a defect in the spinal canal. Congenital heart defects and respiratory complications can also be associated with caudal regression syndrome. | Symptoms of Caudal Regression Syndrome. The specific symptoms and severity of caudal regression syndrome can vary dramatically from one person to another. Caudal regression syndrome most likely represents a spectrum of disease ranging from cases with milder symptoms to cases with severe, disabling or potentially life-threatening complications. It is important to note that affected individuals may not have all of the symptoms discussed below and that one child’s experience will vary (sometimes dramatically) from another child’s. Parents of affected children should talk to their physician and medical team about their child’s specific case, associated symptoms and overall prognosis.Infants with caudal regression syndrome have abnormalities affecting the sacral and lumbar spine. Some affected infants may only have isolated abnormal development of the sacrum (sacral) agenesis. In others, the sacrum may be absent altogether. Sacral agenesis is often associated with narrowing of the hips, underdeveloped of the muscles of the buttock (hypoplastic gluteal muscles), an indentation on the skin of the lower back (sacral dimple) and flattening of the buttocks. In some children, abnormalities of the lumber vertebrae may also occur.The abnormal development of the caudal region of the spine can cause additional abnormalities affecting the spinal cord and lower limbs. In some patients, disruption or damage to the lower portion of the spinal cord may occur causing a variety of neurological abnormalities including defective bladder and bowel control, increased urinary frequency and failure of the bladder to empty completely (neurogenic bladder). The urological abnormalities potentially associated with caudal regression syndrome can be significant.Damage to the nerves can also cause abnormalities of the lower limbs. Such abnormalities may include flexion contractures of the knee and hip. A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. Affected infants may also have reduced muscle mass in the legs, clubfeet or webbed skin on the back of the knees (popliteal ptergyium). When present, the severity of lower limb abnormalities can vary. Some individuals will walk unassisted; others may need an assistance device such as crutches, braces, walkers or in severe cases, a wheelchair.Infants with caudal regression syndrome may have a wide variety of additional physical findings including kidney abnormalities, abnormalities of the upper vertebrae, facial anomalies such as cleft lip, cleft palate, and a condition in which a thin covering blocking the anal opening or the passage that normally connects the anus and lowest part of the large intestine (rectum) fails to develop, which is known as anal atresia or imperforate anus.Kidney abnormalities that occur in caudal regression syndrome may include the absence of one kidney (renal agenesis). Some affected infants may have kidneys that are not located in their normal position (renal ectopia) or fusion of the tubes that force urine from the kidneys to the bladder (fused ureters). Kidney abnormalities can cause urinary obstruction, neurogenic bladder, or the abnormal backflow of urine from the bladder into the ureters (vesicoureteral reflux).Some individuals with caudal regression syndrome may have a meningomyelocele, a condition in which the membranes that cover the spine and, in some patients, the spinal cord itself protrude through a defect in the spinal canal. Congenital heart defects and respiratory complications can also be associated with caudal regression syndrome. | 208 | Caudal Regression Syndrome |
nord_208_2 | Causes of Caudal Regression Syndrome | The exact cause of caudal regression syndrome is unknown. Researchers believe that both environmental and genetic factors may play a role in the development of the disorder. Most cases appear to occur randomly for no apparent reason (sporadically), which suggests environmental factors or a new gene change (mutation). Most likely, caudal regression syndrome is multifactorial, which means that several different factors may play a causative role. In addition, different genetic factors may contribute to the disorder in different people (genetic heterogeneity).One risk factor that has been identified for caudal regression syndrome is maternal diabetes. Caudal regression syndrome occurs with greater frequency in women with diabetes than in the general population. Approximately 16 percent of affected individuals with caudal regression syndrome have occurred in children of women with diabetes. The exact reason why women with diabetes are at a greater risk for having a child with caudal regression syndrome is not fully understood.The environmental factors that play a role in the development of caudal regression syndrome are unknown, although numerous different potential factors have been suggested including alcohol, retinoic acid, lack of oxygen (hypoxia) and amino acid imbalances. More research is necessary to determine what environmental factors play a role in the development of caudal regression syndrome.Some infants with caudal regression syndrome may have a genetic predisposition to developing the disorder.A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors.In some cases, caudal regression syndrome may be associated with changes (pathogenic variants or mutations) in the VANGL1 gene. The exact role this gene variant plays in the development of caudal regression syndrome is unknown. This variant is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new variant in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.A variant in a different gene, HLXB9, is known to cause a rare disorder called Currarino syndrome. This disorder is characterized by partial sacral agenesis, a presacral mass and anorectal malformations. (For more information on this disorder, see the Related Disorders section below.)Environmental or genetic factors associated with caudal regression syndrome have a teratogenic effect on the developing fetus. A teratogen is any substance that can disrupt the development of an embryo or fetus. One theory suggests that environmental or genetic factors impair or block blood flow to the caudal region of the developing fetus (vascular disruption). | Causes of Caudal Regression Syndrome. The exact cause of caudal regression syndrome is unknown. Researchers believe that both environmental and genetic factors may play a role in the development of the disorder. Most cases appear to occur randomly for no apparent reason (sporadically), which suggests environmental factors or a new gene change (mutation). Most likely, caudal regression syndrome is multifactorial, which means that several different factors may play a causative role. In addition, different genetic factors may contribute to the disorder in different people (genetic heterogeneity).One risk factor that has been identified for caudal regression syndrome is maternal diabetes. Caudal regression syndrome occurs with greater frequency in women with diabetes than in the general population. Approximately 16 percent of affected individuals with caudal regression syndrome have occurred in children of women with diabetes. The exact reason why women with diabetes are at a greater risk for having a child with caudal regression syndrome is not fully understood.The environmental factors that play a role in the development of caudal regression syndrome are unknown, although numerous different potential factors have been suggested including alcohol, retinoic acid, lack of oxygen (hypoxia) and amino acid imbalances. More research is necessary to determine what environmental factors play a role in the development of caudal regression syndrome.Some infants with caudal regression syndrome may have a genetic predisposition to developing the disorder.A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors.In some cases, caudal regression syndrome may be associated with changes (pathogenic variants or mutations) in the VANGL1 gene. The exact role this gene variant plays in the development of caudal regression syndrome is unknown. This variant is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new variant in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.A variant in a different gene, HLXB9, is known to cause a rare disorder called Currarino syndrome. This disorder is characterized by partial sacral agenesis, a presacral mass and anorectal malformations. (For more information on this disorder, see the Related Disorders section below.)Environmental or genetic factors associated with caudal regression syndrome have a teratogenic effect on the developing fetus. A teratogen is any substance that can disrupt the development of an embryo or fetus. One theory suggests that environmental or genetic factors impair or block blood flow to the caudal region of the developing fetus (vascular disruption). | 208 | Caudal Regression Syndrome |
nord_208_3 | Affects of Caudal Regression Syndrome | Caudal regression syndrome affects males and females in equal numbers. The incidence of the disorder has been estimated to be 1 in 5 per 100,000 live births. The disorder occurs with greater frequency among women with diabetes. | Affects of Caudal Regression Syndrome. Caudal regression syndrome affects males and females in equal numbers. The incidence of the disorder has been estimated to be 1 in 5 per 100,000 live births. The disorder occurs with greater frequency among women with diabetes. | 208 | Caudal Regression Syndrome |
nord_208_4 | Related disorders of Caudal Regression Syndrome | Symptoms of the following disorders can be similar to those of caudal regression syndrome. Comparisons may be useful for a differential diagnosis.Sirenomelia, which is also known as mermaid syndrome, is a rare congenital disorder characterized by anomalies of the lower spine and the lower limbs. The disorder is characterized by partial or complete fusion of the legs. Additional malformations may also occur including genitourinary abnormalities, gastrointestinal abnormalities, anomalies of the lumbar sacral spine and pelvis and absence or underdeveloped (agenesis) of one or both kidneys. Affected infants may not have one foot, no feet or both feet, which may be rotated externally. The tailbone is usually absent, and the sacrum is partially or completely absent as well. Additional conditions may occur with sirenomelia including anal atresia, spina bifida, and heart (cardiac) malformations. Most cases of sirenomelia occur randomly for no apparent reason (sporadically). (For more information on this disorder, choose “sirenomelia” as your search term in the Rare Disease Database.)VACTERL association is a nonrandom association of birth defects that affects multiple organ systems. The term VACTERL is an acronym with each letter representing the first letter of one of the more common findings seen in affected children: (V) = vertebral abnormalities; (A) = anal atresia; (C) = cardiac (heart) defects; (T) = tracheal anomalies including tracheoesophageal fistula; (E) = esophageal atresia; (R) = renal (kidney) and radial abnormalities; and (L) = (other) limb abnormalities. In addition, to the above-mentioned features, affected children may also exhibit less frequent abnormalities including growth deficiencies and failure to gain weight and grow at the expected rate (failure to thrive). Further low-frequency findings include facial asymmetry (hemifacial microsomia), external ear malformations, lung lobation defects, intestinal malrotation and genital anomalies. VATER/VACTERL features are more common in twinning. In some cases, the acronym VATER association is used. Some researchers have added an (S) to the VACTERL or VATER acronym to represent a single umbilical artery instead of the normal two. Intelligence is usually normal; developmental delay/intellectual disability should suggest an alternative diagnosis. The exact cause of VACTERL association is unknown. Most cases occur randomly, for no apparent reason (sporadic). (For more information on this disorder, choose “VACTERL” as your search term in the Rare Disease Database.)Currarino syndrome is an extremely rare disorder characterized by partial underdevelopment or absence of the sacrum (partial sacral agenesis), a mass in the presacral region and malformations of the anus and/or rectum (anorectal malformations). Specific symptoms may include abnormal stretching or widening of the abdomen (abdominal distention), narrowing (stenosis) of the anus or rectum, an abnormal connection or passage between the anal canal and the skin near the anus or rectum (anal fistula) and a condition in which a thin covering blocking the anal opening or the passage that normally connects the anus and lowest part of the large intestine (rectum) fails to develop, which is known as anal atresia or imperforate anus. Affected infants may also have gastrointestinal obstruction and chronic constipation. Kidney abnormalities may occur including abnormal fusion of the two kidneys into a horseshoe shape. Urinary abnormalities including incontinence, recurrent urinary tract infections, abnormal backflow of urine from the bladder into the ureters (vesicoureteral reflux) and failure of the bladder to empty completely (neurogenic bladder). Some cases of Currarino syndrome are caused by variants in the homeobox-HB9 gene. The disorder is inherited in an autosomal dominant pattern. | Related disorders of Caudal Regression Syndrome. Symptoms of the following disorders can be similar to those of caudal regression syndrome. Comparisons may be useful for a differential diagnosis.Sirenomelia, which is also known as mermaid syndrome, is a rare congenital disorder characterized by anomalies of the lower spine and the lower limbs. The disorder is characterized by partial or complete fusion of the legs. Additional malformations may also occur including genitourinary abnormalities, gastrointestinal abnormalities, anomalies of the lumbar sacral spine and pelvis and absence or underdeveloped (agenesis) of one or both kidneys. Affected infants may not have one foot, no feet or both feet, which may be rotated externally. The tailbone is usually absent, and the sacrum is partially or completely absent as well. Additional conditions may occur with sirenomelia including anal atresia, spina bifida, and heart (cardiac) malformations. Most cases of sirenomelia occur randomly for no apparent reason (sporadically). (For more information on this disorder, choose “sirenomelia” as your search term in the Rare Disease Database.)VACTERL association is a nonrandom association of birth defects that affects multiple organ systems. The term VACTERL is an acronym with each letter representing the first letter of one of the more common findings seen in affected children: (V) = vertebral abnormalities; (A) = anal atresia; (C) = cardiac (heart) defects; (T) = tracheal anomalies including tracheoesophageal fistula; (E) = esophageal atresia; (R) = renal (kidney) and radial abnormalities; and (L) = (other) limb abnormalities. In addition, to the above-mentioned features, affected children may also exhibit less frequent abnormalities including growth deficiencies and failure to gain weight and grow at the expected rate (failure to thrive). Further low-frequency findings include facial asymmetry (hemifacial microsomia), external ear malformations, lung lobation defects, intestinal malrotation and genital anomalies. VATER/VACTERL features are more common in twinning. In some cases, the acronym VATER association is used. Some researchers have added an (S) to the VACTERL or VATER acronym to represent a single umbilical artery instead of the normal two. Intelligence is usually normal; developmental delay/intellectual disability should suggest an alternative diagnosis. The exact cause of VACTERL association is unknown. Most cases occur randomly, for no apparent reason (sporadic). (For more information on this disorder, choose “VACTERL” as your search term in the Rare Disease Database.)Currarino syndrome is an extremely rare disorder characterized by partial underdevelopment or absence of the sacrum (partial sacral agenesis), a mass in the presacral region and malformations of the anus and/or rectum (anorectal malformations). Specific symptoms may include abnormal stretching or widening of the abdomen (abdominal distention), narrowing (stenosis) of the anus or rectum, an abnormal connection or passage between the anal canal and the skin near the anus or rectum (anal fistula) and a condition in which a thin covering blocking the anal opening or the passage that normally connects the anus and lowest part of the large intestine (rectum) fails to develop, which is known as anal atresia or imperforate anus. Affected infants may also have gastrointestinal obstruction and chronic constipation. Kidney abnormalities may occur including abnormal fusion of the two kidneys into a horseshoe shape. Urinary abnormalities including incontinence, recurrent urinary tract infections, abnormal backflow of urine from the bladder into the ureters (vesicoureteral reflux) and failure of the bladder to empty completely (neurogenic bladder). Some cases of Currarino syndrome are caused by variants in the homeobox-HB9 gene. The disorder is inherited in an autosomal dominant pattern. | 208 | Caudal Regression Syndrome |
nord_208_5 | Diagnosis of Caudal Regression Syndrome | A diagnosis of caudal regression syndrome can often be made before birth (prenatally) usually using a fetal ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. A fetal ultrasound can detect some of the defects associated with caudal regression syndrome. Additional tests may be required to detect or assess physical findings potentially associated with the disorder. For example, echocardiography is usually performed to evaluate the extent of the involvement of the heart. Echocardiography is an exam that uses sound waves to produce images of the heart. Magnetic resonance imaging (MRI) may also be performed to assess the degree of certain anomalies such as spinal defects. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. | Diagnosis of Caudal Regression Syndrome. A diagnosis of caudal regression syndrome can often be made before birth (prenatally) usually using a fetal ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. A fetal ultrasound can detect some of the defects associated with caudal regression syndrome. Additional tests may be required to detect or assess physical findings potentially associated with the disorder. For example, echocardiography is usually performed to evaluate the extent of the involvement of the heart. Echocardiography is an exam that uses sound waves to produce images of the heart. Magnetic resonance imaging (MRI) may also be performed to assess the degree of certain anomalies such as spinal defects. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. | 208 | Caudal Regression Syndrome |
nord_208_6 | Therapies of Caudal Regression Syndrome | Treatment
The treatment of caudal regression syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurosurgeons, neurologists, urologists, orthopedists, orthopedist surgeons, cardiologists, kidney specialists (nephrologists) and other health care professionals may need to systematically and comprehensively plan an affect child’s treatment.The specific treatment strategy for infants with caudal regression syndrome will vary from one infant to another based upon various factors. Because caudal regression syndrome is a spectrum of disease with a wide variety of severity, the prognosis can vary greatly as well. Affected infants may require complex medical care and surgical intervention. Multiple surgeries may be necessary to treat various urological, spinal and cardiac abnormalities, anal atresia and certain limb deformities associated with caudal regression syndrome. In addition, anticholingergic drugs may be administered to treat urological abnormalities.Early intervention is important in ensuring that children with caudal regression syndrome reach their highest potential. Services that may be beneficial may include physical therapy, psychological services and other medical, social and/or vocational services. | Therapies of Caudal Regression Syndrome. Treatment
The treatment of caudal regression syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurosurgeons, neurologists, urologists, orthopedists, orthopedist surgeons, cardiologists, kidney specialists (nephrologists) and other health care professionals may need to systematically and comprehensively plan an affect child’s treatment.The specific treatment strategy for infants with caudal regression syndrome will vary from one infant to another based upon various factors. Because caudal regression syndrome is a spectrum of disease with a wide variety of severity, the prognosis can vary greatly as well. Affected infants may require complex medical care and surgical intervention. Multiple surgeries may be necessary to treat various urological, spinal and cardiac abnormalities, anal atresia and certain limb deformities associated with caudal regression syndrome. In addition, anticholingergic drugs may be administered to treat urological abnormalities.Early intervention is important in ensuring that children with caudal regression syndrome reach their highest potential. Services that may be beneficial may include physical therapy, psychological services and other medical, social and/or vocational services. | 208 | Caudal Regression Syndrome |
nord_209_0 | Overview of Cavernous Malformation | Vascular malformations are localized collections of blood vessels that are abnormal in structure or number. Vascular malformations lead to altered blood flow and are not cancerous (nonneoplastic). In the past, researchers believed that most vascular malformations are present at birth (congenital). However, we now know that cavernous malformation lesions display some cancer-like qualities and can develop throughout the lifetime of the affected individual. The four most common types of vascular malformations are capillary telangiectasias, cavernous malformations, venous malformations, and arteriovenous malformations.Cavernous malformations are lesions made of dilated blood vessels and characterized by multiple distended “caverns” of blood-filled vasculature through which the blood flows very slowly. Vessels of a cavernous malformation lesion lack the proper junctions between neighboring cells as well as the necessary structural support from smooth muscle and stretchable material (elastin). These properties cause cavernous malformations to leak. Leakage (bleeding) from these vascular lesions is an underlying cause of clinical symptoms associated with the illness. Most often located in the brain, cavernous malformations can also present in the spinal cord, on the skin, and more rarely in the retina.Cerebral cavernous malformations (CCMs) usually develop in the white matter (cortex) of the brain. CCM lesions lack intervening brain tissue within the malformation. CCMs are dynamic structures, changing in size and number over time, and they can range in size from a few millimeters to several centimeters.CCMs are present in approximately 0.2% of the general population, and they account for a large proportion (8-15%) of all brain and spinal vascular malformations. While the prevalence of individuals with at least one CCM lesion is quite high, a significant number of affected individuals will remain undiagnosed for their entire lives. As many as 40% of affected individuals may never experience symptoms or become diagnosed with cavernous malformation. A majority of these individuals have only a single lesion, no family history of the disease, and no inherited mutation. These cases are termed ‘sporadic.' Individuals with the familial (genetic) form of cavernous malformation typically develop multiple lesions and may be more likely to experience symptoms associated with the disorder. People of all ages may be affected by cavernous malformations. Children represent approximately 25% of all diagnosed individuals.In sporadic cases, it is common for CCM lesions to develop close to an abnormal vein. Developmental venous anomalies (DVA), also called venous malformations or venous angiomas, are a type of vascular malformation that, on its own, do not cause any clinical symptoms. However, when found in combination with a CCM lesion, the DVA complicates the option for surgical intervention, because disturbing the DVA during surgery could cause dangerous bleeding. Association of CCMs with DVAs is uncommon in familial cavernous malformation. With the application of better imaging technologies in recent years, there is consensus among the research and clinical communities that all sporadic lesions form near an abnormal vein or within the vicinity of a DVA. Rarely, multiple sporadic cavernous malformations develop in a cluster near an associated DVA. The significance of DVA in association with sporadic lesions is not entirely understood. | Overview of Cavernous Malformation. Vascular malformations are localized collections of blood vessels that are abnormal in structure or number. Vascular malformations lead to altered blood flow and are not cancerous (nonneoplastic). In the past, researchers believed that most vascular malformations are present at birth (congenital). However, we now know that cavernous malformation lesions display some cancer-like qualities and can develop throughout the lifetime of the affected individual. The four most common types of vascular malformations are capillary telangiectasias, cavernous malformations, venous malformations, and arteriovenous malformations.Cavernous malformations are lesions made of dilated blood vessels and characterized by multiple distended “caverns” of blood-filled vasculature through which the blood flows very slowly. Vessels of a cavernous malformation lesion lack the proper junctions between neighboring cells as well as the necessary structural support from smooth muscle and stretchable material (elastin). These properties cause cavernous malformations to leak. Leakage (bleeding) from these vascular lesions is an underlying cause of clinical symptoms associated with the illness. Most often located in the brain, cavernous malformations can also present in the spinal cord, on the skin, and more rarely in the retina.Cerebral cavernous malformations (CCMs) usually develop in the white matter (cortex) of the brain. CCM lesions lack intervening brain tissue within the malformation. CCMs are dynamic structures, changing in size and number over time, and they can range in size from a few millimeters to several centimeters.CCMs are present in approximately 0.2% of the general population, and they account for a large proportion (8-15%) of all brain and spinal vascular malformations. While the prevalence of individuals with at least one CCM lesion is quite high, a significant number of affected individuals will remain undiagnosed for their entire lives. As many as 40% of affected individuals may never experience symptoms or become diagnosed with cavernous malformation. A majority of these individuals have only a single lesion, no family history of the disease, and no inherited mutation. These cases are termed ‘sporadic.' Individuals with the familial (genetic) form of cavernous malformation typically develop multiple lesions and may be more likely to experience symptoms associated with the disorder. People of all ages may be affected by cavernous malformations. Children represent approximately 25% of all diagnosed individuals.In sporadic cases, it is common for CCM lesions to develop close to an abnormal vein. Developmental venous anomalies (DVA), also called venous malformations or venous angiomas, are a type of vascular malformation that, on its own, do not cause any clinical symptoms. However, when found in combination with a CCM lesion, the DVA complicates the option for surgical intervention, because disturbing the DVA during surgery could cause dangerous bleeding. Association of CCMs with DVAs is uncommon in familial cavernous malformation. With the application of better imaging technologies in recent years, there is consensus among the research and clinical communities that all sporadic lesions form near an abnormal vein or within the vicinity of a DVA. Rarely, multiple sporadic cavernous malformations develop in a cluster near an associated DVA. The significance of DVA in association with sporadic lesions is not entirely understood. | 209 | Cavernous Malformation |
nord_209_1 | Symptoms of Cavernous Malformation | Individuals with cerebral cavernous malformations present with a wide variety of symptoms. Some affected individuals may have no symptoms at all while others may experience headaches or neurological deficits, including weakness in the arms or legs, problems with memory or balance, or difficulties with vision or speech. Hemorrhagic stroke and seizures are the most severe symptoms caused by cavernous malformations. Clinical symptoms vary by individual and are dependent on the location of the lesion(s) and on the propensity to bleed. Spinal cord cavernous malformations can cause numbness, weakness, paralysis, tingling, burning, or itching. Cavernous malformations of the spinal cord can also cause problems with bladder and bowel control. Seizures are one of the most common symptoms of cavernous malformations. A person who experiences more than one seizure is said to have epilepsy. Seizures tend to worsen with age and frequency. Anti-seizure medications control many cases of epilepsy. However, for some individuals for whom medication is ineffective for seizure control, surgical removal of the cavernous malformation may be necessary. Even if seizures are well controlled with medication, surgery may be recommended to avoid a lifetime of exposure to anti-epilepsy medications. If a person has seizures and more than one cavernous malformation, it may be difficult to pinpoint which cavernous malformation is the cause of the seizures. | Symptoms of Cavernous Malformation. Individuals with cerebral cavernous malformations present with a wide variety of symptoms. Some affected individuals may have no symptoms at all while others may experience headaches or neurological deficits, including weakness in the arms or legs, problems with memory or balance, or difficulties with vision or speech. Hemorrhagic stroke and seizures are the most severe symptoms caused by cavernous malformations. Clinical symptoms vary by individual and are dependent on the location of the lesion(s) and on the propensity to bleed. Spinal cord cavernous malformations can cause numbness, weakness, paralysis, tingling, burning, or itching. Cavernous malformations of the spinal cord can also cause problems with bladder and bowel control. Seizures are one of the most common symptoms of cavernous malformations. A person who experiences more than one seizure is said to have epilepsy. Seizures tend to worsen with age and frequency. Anti-seizure medications control many cases of epilepsy. However, for some individuals for whom medication is ineffective for seizure control, surgical removal of the cavernous malformation may be necessary. Even if seizures are well controlled with medication, surgery may be recommended to avoid a lifetime of exposure to anti-epilepsy medications. If a person has seizures and more than one cavernous malformation, it may be difficult to pinpoint which cavernous malformation is the cause of the seizures. | 209 | Cavernous Malformation |
nord_209_2 | Causes of Cavernous Malformation | Individuals with only one CCM and no affected relatives most likely have the sporadic (non-inherited) form of the illness. Those with multiple CCMs and/or a family history of the cavernous malformations are much more likely to have the familial type due to a change (mutation) in one of three genes, CCM1 (KRIT1), CCM2, or CCM3 (PDCD10).Determining the normal function of these CCM genes has been a research focus since each gene was identified in 1999, 2003, and 2005, respectively. Researchers have learned that these genes each have necessary functions related to maintaining structural integrity between blood vessel cells and ensuring that the blood does not leak into the brain. When a genetic mutation is inherited that causes one of these genes not to function correctly, the blood vessels of the brain can become malformed and lead to the onset of cavernous malformation.Familial CCM accounts for at least 20% of all cases. An inherited mutation of the CCM1, CCM2, or CCM3 gene causes familial cavernous malformation. The illness follows autosomal dominant inheritance. It will be present in every generation of a family (does not skip generation like recessive diseases) and is not selective for males or females. Each child of an individual with familial CCM has a 50% chance of inheriting the illness. Families with the genetic form of CCM typically have several affected individuals in more than one consecutive generation. Lesions develop when a second somatic (randomly acquired and not heritable) mutation occurs within brain blood vessel cells that completely destroys the function of one of the CCM genes. Multiple lesions are typical of those with familial CCM. A mutation in any of the three CCM genes will likely result in lesion development. However, CCM3 gene mutations cause the most aggressive form of the illness and lead to distinct features that warrant special consideration. Individuals affected by CCM3 gene mutations are more likely to be diagnosed as children, hemorrhage at an early age, develop high numbers of lesions, and may also experience scoliosis, cognitive disability, benign brain tumors and/or skin lesions. Even considering these unique features of CCM3, as with all familial CCM, the clinical course varies within and between families.In contrast to familial CCM, inherited mutations do not cause the sporadic form of the illness. Therefore, individuals with sporadic CCM do not have a higher chance of having a child with CCM than anyone in the general population, and the illness will not run in their family. Furthermore, experts do not recommend genetic testing for someone with sporadic CCM because mutations will not be detectable in the blood or saliva.Individuals with sporadic CCM typically have only one cavernous malformation lesion and have no family members with CCM. However, from time to time, individuals with sporadic CCM may have multiple lesions in close association with a DVA. Recent evidence suggests that the cause of sporadic CCM lesion development is quite similar to familial CCM lesions. Researchers have found that there are genetic mutations of the CCM genes, but that these mutations occur only with the blood vessels of the sporadic CCM lesion. These mutations are not heritable; they are randomly acquired within brain blood vessels and cause a CCM lesion to form. This data suggests that all forms of CCM lesions develop following a similar mechanism (a complete loss of function of one of the CCM genes within the brain blood vessel cells). Because of this biological similarity, there is optimism that the same therapeutic drug may treat all forms of CCM in the future. | Causes of Cavernous Malformation. Individuals with only one CCM and no affected relatives most likely have the sporadic (non-inherited) form of the illness. Those with multiple CCMs and/or a family history of the cavernous malformations are much more likely to have the familial type due to a change (mutation) in one of three genes, CCM1 (KRIT1), CCM2, or CCM3 (PDCD10).Determining the normal function of these CCM genes has been a research focus since each gene was identified in 1999, 2003, and 2005, respectively. Researchers have learned that these genes each have necessary functions related to maintaining structural integrity between blood vessel cells and ensuring that the blood does not leak into the brain. When a genetic mutation is inherited that causes one of these genes not to function correctly, the blood vessels of the brain can become malformed and lead to the onset of cavernous malformation.Familial CCM accounts for at least 20% of all cases. An inherited mutation of the CCM1, CCM2, or CCM3 gene causes familial cavernous malformation. The illness follows autosomal dominant inheritance. It will be present in every generation of a family (does not skip generation like recessive diseases) and is not selective for males or females. Each child of an individual with familial CCM has a 50% chance of inheriting the illness. Families with the genetic form of CCM typically have several affected individuals in more than one consecutive generation. Lesions develop when a second somatic (randomly acquired and not heritable) mutation occurs within brain blood vessel cells that completely destroys the function of one of the CCM genes. Multiple lesions are typical of those with familial CCM. A mutation in any of the three CCM genes will likely result in lesion development. However, CCM3 gene mutations cause the most aggressive form of the illness and lead to distinct features that warrant special consideration. Individuals affected by CCM3 gene mutations are more likely to be diagnosed as children, hemorrhage at an early age, develop high numbers of lesions, and may also experience scoliosis, cognitive disability, benign brain tumors and/or skin lesions. Even considering these unique features of CCM3, as with all familial CCM, the clinical course varies within and between families.In contrast to familial CCM, inherited mutations do not cause the sporadic form of the illness. Therefore, individuals with sporadic CCM do not have a higher chance of having a child with CCM than anyone in the general population, and the illness will not run in their family. Furthermore, experts do not recommend genetic testing for someone with sporadic CCM because mutations will not be detectable in the blood or saliva.Individuals with sporadic CCM typically have only one cavernous malformation lesion and have no family members with CCM. However, from time to time, individuals with sporadic CCM may have multiple lesions in close association with a DVA. Recent evidence suggests that the cause of sporadic CCM lesion development is quite similar to familial CCM lesions. Researchers have found that there are genetic mutations of the CCM genes, but that these mutations occur only with the blood vessels of the sporadic CCM lesion. These mutations are not heritable; they are randomly acquired within brain blood vessels and cause a CCM lesion to form. This data suggests that all forms of CCM lesions develop following a similar mechanism (a complete loss of function of one of the CCM genes within the brain blood vessel cells). Because of this biological similarity, there is optimism that the same therapeutic drug may treat all forms of CCM in the future. | 209 | Cavernous Malformation |
nord_209_3 | Affects of Cavernous Malformation | In general, cavernous malformations can develop at any age and are present in males and females in equal numbers. Importantly, all ethnic populations are susceptible to the development of a CCM.The highest known density of individuals affected by cavernous malformation is in New Mexico, USA. The disproportionate number of affected individuals is because of a specific genetic mutation in the CCM1 gene, termed the common Hispanic mutation. This mutation is known as a founder mutation; it arose hundreds of years ago and has been passed through at least 14 generations of Americans descended from the original Spanish settlers of the Southwest. Being Hispanic does not predispose individuals to CCM. Instead, the large population affected by the common Hispanic mutation is due to family relatedness and passing the mutation from generation to generation for several hundred years. In recent years, researchers identified two additional CCM2 gene founder mutations. One of the founder mutations runs in the Ashkenazi Jewish population, and another, a large deletion in the CCM2 gene, traces its ancestry to an originating family born in the southern United States in the 1700s. The genealogy for all of the founder mutations is still a work in progress. | Affects of Cavernous Malformation. In general, cavernous malformations can develop at any age and are present in males and females in equal numbers. Importantly, all ethnic populations are susceptible to the development of a CCM.The highest known density of individuals affected by cavernous malformation is in New Mexico, USA. The disproportionate number of affected individuals is because of a specific genetic mutation in the CCM1 gene, termed the common Hispanic mutation. This mutation is known as a founder mutation; it arose hundreds of years ago and has been passed through at least 14 generations of Americans descended from the original Spanish settlers of the Southwest. Being Hispanic does not predispose individuals to CCM. Instead, the large population affected by the common Hispanic mutation is due to family relatedness and passing the mutation from generation to generation for several hundred years. In recent years, researchers identified two additional CCM2 gene founder mutations. One of the founder mutations runs in the Ashkenazi Jewish population, and another, a large deletion in the CCM2 gene, traces its ancestry to an originating family born in the southern United States in the 1700s. The genealogy for all of the founder mutations is still a work in progress. | 209 | Cavernous Malformation |
nord_209_4 | Related disorders of Cavernous Malformation | Symptoms of the following disorders can be similar to those of Parry-Romberg syndrome. Comparisons may be useful for a differential diagnosis.Cerebral arteriovenous malformations (AVMs) are comprised of blood vessels in which arteries and veins meet directly, without the capillaries that are normally found between the veins and arteries. Without capillaries, the high-pressure arteries have no way of reducing pressure before blood reaches the weaker veins, so the vessels get distended with blood and possibly burst. AVMs may cause headaches, seizures, strokes, or bleeding into the brain, similar to CCMs. However, there are several detectable differences between cerebral cavernous malformations and arteriovenous malformations. AVMs are high-flow lesions with rapid blood movement, while CCM lesions are low-flow lesions. The low-flow nature of CCMs makes them angiographically occult and they are only reliably visually detectable using magnetic resonance imaging (MRI). Brain AVMs are a feature of another complex autosomal dominant vascular disorder called hereditary hemorrhagic telangiectasia (HHT). (For more information on these disorders, choose “arteriovenous malformation” and “HHT” as your search term in the Rare Disease Database.)Von Hippel-Lindau disease is an autosomal dominant condition characterized by multiple localized tissue malformations called hemangioblastomas and angiomas. These growths may be found in the retina, brain, kidneys, adrenal glands, and other organs. Symptoms may include headaches, dizziness and difficulty coordinating muscle movement (ataxia). Chronic high blood pressure (hypertension) can also occur. The disorder may begin during young adulthood or may develop during early childhood. Aneurysms (bulges in blood vessels) may develop and form an angioma (nodule) that resembles a balloon. Benign tumors (pheochromocytomas) of the adrenal glands may be present as well, causing chronic high blood pressure, pounding heartbeat, headache, cold hands and feet, and excessive sweating. This condition is found equally in males and females and all ethnic groups. (For more information on this disorder, choose “Von Hippel-Lindau” as your search term in the Rare Disease Database.)Moyamoya disease is a progressive disease-causing constriction of the cerebral blood vessels, particularly the connection of blood vessels called the Circle of Willis and the surrounding arteries that feed it. Moyamoya means “puff of smoke” in Japanese, which is how the angiography appears, due to the constriction of the vessels that usually occur on both sides (bilaterally). No one knows the exact cause of Moyamoya, but it may have both genetic and environmental components. Some infections may lead to the condition (leptospirosis and tuberculosis), and several genetic conditions have Moyamoya disease in association, including Fanconi anemia, sickle cell anemia, Apert syndrome, Down syndrome, Marfan syndrome, tuberous sclerosis, Turner syndrome, and neurofibromatosis. This condition is more common in females (ratio of females to males is 1.8:1) and occurs primarily in Asians (but has been found in Caucasians, African Americans, Haitians, and Hispanics). (For more information on this disorder, choose “moyamoya” as your search term in the Rare Disease Database.)Blue rubber bleb nevus syndrome is a rare disorder, characterized by soft elevated blue, blue-black, or purplish-red swellings on or under the skin and on internal organs. On the skin, they are usually located on the upper arms or trunk, and internally they can be found in many locations, including the lungs, liver, spleen, gallbladder, kidney and skeletal muscles. When found in the gastrointestinal tract, they can cause severe anemia through uncontrolled bleeding. In the brain, hemorrhage or swelling of the brain (increased intracranial pressure) can occur. This condition occurs equally in males and females and is found in all ethnic groups. (For more information on this disorder, choose “blue rubber bleb nevus” as your search term in the Rare Disease Database.) | Related disorders of Cavernous Malformation. Symptoms of the following disorders can be similar to those of Parry-Romberg syndrome. Comparisons may be useful for a differential diagnosis.Cerebral arteriovenous malformations (AVMs) are comprised of blood vessels in which arteries and veins meet directly, without the capillaries that are normally found between the veins and arteries. Without capillaries, the high-pressure arteries have no way of reducing pressure before blood reaches the weaker veins, so the vessels get distended with blood and possibly burst. AVMs may cause headaches, seizures, strokes, or bleeding into the brain, similar to CCMs. However, there are several detectable differences between cerebral cavernous malformations and arteriovenous malformations. AVMs are high-flow lesions with rapid blood movement, while CCM lesions are low-flow lesions. The low-flow nature of CCMs makes them angiographically occult and they are only reliably visually detectable using magnetic resonance imaging (MRI). Brain AVMs are a feature of another complex autosomal dominant vascular disorder called hereditary hemorrhagic telangiectasia (HHT). (For more information on these disorders, choose “arteriovenous malformation” and “HHT” as your search term in the Rare Disease Database.)Von Hippel-Lindau disease is an autosomal dominant condition characterized by multiple localized tissue malformations called hemangioblastomas and angiomas. These growths may be found in the retina, brain, kidneys, adrenal glands, and other organs. Symptoms may include headaches, dizziness and difficulty coordinating muscle movement (ataxia). Chronic high blood pressure (hypertension) can also occur. The disorder may begin during young adulthood or may develop during early childhood. Aneurysms (bulges in blood vessels) may develop and form an angioma (nodule) that resembles a balloon. Benign tumors (pheochromocytomas) of the adrenal glands may be present as well, causing chronic high blood pressure, pounding heartbeat, headache, cold hands and feet, and excessive sweating. This condition is found equally in males and females and all ethnic groups. (For more information on this disorder, choose “Von Hippel-Lindau” as your search term in the Rare Disease Database.)Moyamoya disease is a progressive disease-causing constriction of the cerebral blood vessels, particularly the connection of blood vessels called the Circle of Willis and the surrounding arteries that feed it. Moyamoya means “puff of smoke” in Japanese, which is how the angiography appears, due to the constriction of the vessels that usually occur on both sides (bilaterally). No one knows the exact cause of Moyamoya, but it may have both genetic and environmental components. Some infections may lead to the condition (leptospirosis and tuberculosis), and several genetic conditions have Moyamoya disease in association, including Fanconi anemia, sickle cell anemia, Apert syndrome, Down syndrome, Marfan syndrome, tuberous sclerosis, Turner syndrome, and neurofibromatosis. This condition is more common in females (ratio of females to males is 1.8:1) and occurs primarily in Asians (but has been found in Caucasians, African Americans, Haitians, and Hispanics). (For more information on this disorder, choose “moyamoya” as your search term in the Rare Disease Database.)Blue rubber bleb nevus syndrome is a rare disorder, characterized by soft elevated blue, blue-black, or purplish-red swellings on or under the skin and on internal organs. On the skin, they are usually located on the upper arms or trunk, and internally they can be found in many locations, including the lungs, liver, spleen, gallbladder, kidney and skeletal muscles. When found in the gastrointestinal tract, they can cause severe anemia through uncontrolled bleeding. In the brain, hemorrhage or swelling of the brain (increased intracranial pressure) can occur. This condition occurs equally in males and females and is found in all ethnic groups. (For more information on this disorder, choose “blue rubber bleb nevus” as your search term in the Rare Disease Database.) | 209 | Cavernous Malformation |
nord_209_5 | Diagnosis of Cavernous Malformation | Magnetic resonance imaging (MRI) is now the standard of care for diagnosing cavernous malformations. Unless an individual has had a recent bleed, CT scans or angiography will not detect CCM lesions. For familial cases, molecular genetic testing for mutations in the CCM1, CCM2, and CCM3 genes is commercially available to confirm the diagnosis and is less expensive than MRI. Experts recommend genetic testing for individuals with a family history and/or multiple CCM lesions. By identifying the affected individual's genetic mutation, other family members can undergo targeted genetic testing to see whether or not they also carry the family’s specific disease-causing mutation. Genetic screening of family members can provide them with a definitive diagnosis without the need to undergo a MRI, or with relief if they do not have a mutation. | Diagnosis of Cavernous Malformation. Magnetic resonance imaging (MRI) is now the standard of care for diagnosing cavernous malformations. Unless an individual has had a recent bleed, CT scans or angiography will not detect CCM lesions. For familial cases, molecular genetic testing for mutations in the CCM1, CCM2, and CCM3 genes is commercially available to confirm the diagnosis and is less expensive than MRI. Experts recommend genetic testing for individuals with a family history and/or multiple CCM lesions. By identifying the affected individual's genetic mutation, other family members can undergo targeted genetic testing to see whether or not they also carry the family’s specific disease-causing mutation. Genetic screening of family members can provide them with a definitive diagnosis without the need to undergo a MRI, or with relief if they do not have a mutation. | 209 | Cavernous Malformation |
nord_209_6 | Therapies of Cavernous Malformation | TreatmentCurrently, there is no available drug treatment for CCM. Most cavernous malformations are conservatively managed by observing for change in appearance, recent hemorrhage, or clinical symptoms. Medications are available to treat symptoms like seizures and headaches caused by cavernous malformations. Assessment of the risk and possible benefit of surgery is unique to each patient. Neurosurgeons may recommend lesion removal by craniotomy for cavernous malformations with recent hemorrhage, or those that are causing seizures. Radiosurgery, by gamma knife, linear accelerator, or shaped beam techniques, is a controversial treatment option that has been used on cavernous malformations that are solitary, symptomatic, and too dangerous to reach through traditional surgery. Expert consensus recommends not using radiosurgery for asymptomatic or surgically accessible lesions. Additionally, radiosurgery is not recommended for those individuals with familial CCM, as the radiation may contribute to the development of additional lesions.
In all age groups, management decisions need to weigh the risk of keeping a cavernous malformation versus the risk of surgery. Surgery is often not recommended when a CCM is found unexpectedly (incidental finding). However, clinical and MRI follow-up is recommended to monitor growth and hemorrhage events of all lesions, including those found incidentally. Researchers are working to develop a technique to predict future and diagnose past hemorrhage that does not require imaging. Prognostic and diagnostic biomarkers are tools that measure inflammatory markers in the blood as a surrogate measure of hemorrhage. Validation of these biomarkers is currently underway. The goal is to use these tools in the clinic to estimate future risk of hemorrhage and diagnose past hemorrhage.The therapeutic approach decided upon by the patient and physician should take into account age, location of the lesion, effects on seizures, and risk factors for severe, potentially life-threatening hemorrhage. Risks of any surgery, including cavernous malformation resection, include stroke, paralysis, coma, or death, although these complications are rare with modern surgery performed by expert neurosurgeons. Surgery on cavernous malformation in the brain stem and spinal cord poses an additional risk, but these cavernous malformations are more dangerous if left alone. While recovery is different for everyone, many patients leave the hospital within a few days and resume normal life within a few weeks of surgery. However, people with neurological deficits may require a prolonged period of rehabilitation. | Therapies of Cavernous Malformation. TreatmentCurrently, there is no available drug treatment for CCM. Most cavernous malformations are conservatively managed by observing for change in appearance, recent hemorrhage, or clinical symptoms. Medications are available to treat symptoms like seizures and headaches caused by cavernous malformations. Assessment of the risk and possible benefit of surgery is unique to each patient. Neurosurgeons may recommend lesion removal by craniotomy for cavernous malformations with recent hemorrhage, or those that are causing seizures. Radiosurgery, by gamma knife, linear accelerator, or shaped beam techniques, is a controversial treatment option that has been used on cavernous malformations that are solitary, symptomatic, and too dangerous to reach through traditional surgery. Expert consensus recommends not using radiosurgery for asymptomatic or surgically accessible lesions. Additionally, radiosurgery is not recommended for those individuals with familial CCM, as the radiation may contribute to the development of additional lesions.
In all age groups, management decisions need to weigh the risk of keeping a cavernous malformation versus the risk of surgery. Surgery is often not recommended when a CCM is found unexpectedly (incidental finding). However, clinical and MRI follow-up is recommended to monitor growth and hemorrhage events of all lesions, including those found incidentally. Researchers are working to develop a technique to predict future and diagnose past hemorrhage that does not require imaging. Prognostic and diagnostic biomarkers are tools that measure inflammatory markers in the blood as a surrogate measure of hemorrhage. Validation of these biomarkers is currently underway. The goal is to use these tools in the clinic to estimate future risk of hemorrhage and diagnose past hemorrhage.The therapeutic approach decided upon by the patient and physician should take into account age, location of the lesion, effects on seizures, and risk factors for severe, potentially life-threatening hemorrhage. Risks of any surgery, including cavernous malformation resection, include stroke, paralysis, coma, or death, although these complications are rare with modern surgery performed by expert neurosurgeons. Surgery on cavernous malformation in the brain stem and spinal cord poses an additional risk, but these cavernous malformations are more dangerous if left alone. While recovery is different for everyone, many patients leave the hospital within a few days and resume normal life within a few weeks of surgery. However, people with neurological deficits may require a prolonged period of rehabilitation. | 209 | Cavernous Malformation |
nord_210_0 | Overview of CDKL5 Deficiency Disorder | IntroductionCDKL5 deficiency disorder (CDD) is a rare developmental epileptic encephalopathy (DEE) caused by changes (mutations) in the CDKL5 gene. CDD has been classified as a DEE because the genetic change causes both the epileptic activity as well as the severe impairment of development. The hallmarks of CDD are the onset of seizures at a very early age, (usually about 3 months but can be as early as the first week of life) and severe neurodevelopmental delay impacting cognitive, motor, speech, and visual function.1,2 CDD can manifest in a broad range of clinical severity and is often associated with other symptoms such as gastrointestinal and sleep disturbances.2,3 Although rare, the occurrence could be between ~1:40,000 and 1:60,000 live births,4 although an Australian population-based study suggested a lower incidence.5Previously known as serine/threonine protein kinase 9 (STK9),6 CDKL5 stands for cyclin-dependent kinase-like 5 and mutations in this gene were first identified as disease-causing in 2004.7,8 The letters are an abbreviation of the scientific name of the gene which describes what it does. The CDKL5 gene provides instructions for making proteins that are essential for normal brain and neuron development.The CDKL5 gene is located on the X chromosome. The X chromosome is one of the sex chromosomes; females have two X’s and males have one X and one Y chromosome. Although many identified patients are males, because of the location of the gene, this disorder mainly affects females. Affected males may have more severe symptoms than females. | Overview of CDKL5 Deficiency Disorder. IntroductionCDKL5 deficiency disorder (CDD) is a rare developmental epileptic encephalopathy (DEE) caused by changes (mutations) in the CDKL5 gene. CDD has been classified as a DEE because the genetic change causes both the epileptic activity as well as the severe impairment of development. The hallmarks of CDD are the onset of seizures at a very early age, (usually about 3 months but can be as early as the first week of life) and severe neurodevelopmental delay impacting cognitive, motor, speech, and visual function.1,2 CDD can manifest in a broad range of clinical severity and is often associated with other symptoms such as gastrointestinal and sleep disturbances.2,3 Although rare, the occurrence could be between ~1:40,000 and 1:60,000 live births,4 although an Australian population-based study suggested a lower incidence.5Previously known as serine/threonine protein kinase 9 (STK9),6 CDKL5 stands for cyclin-dependent kinase-like 5 and mutations in this gene were first identified as disease-causing in 2004.7,8 The letters are an abbreviation of the scientific name of the gene which describes what it does. The CDKL5 gene provides instructions for making proteins that are essential for normal brain and neuron development.The CDKL5 gene is located on the X chromosome. The X chromosome is one of the sex chromosomes; females have two X’s and males have one X and one Y chromosome. Although many identified patients are males, because of the location of the gene, this disorder mainly affects females. Affected males may have more severe symptoms than females. | 210 | CDKL5 Deficiency Disorder |
nord_210_1 | Symptoms of CDKL5 Deficiency Disorder | Seizures are a major problem for patients with CDD because they are usually severe and difficult to control with medication.10,11 Multiple different types of seizures occur and include infantile spasms, myoclonic seizures and tonic-clonic seizures. Doctors have described more than 30 different types of seizures, and they are divided into two major categories — focal seizures and generalized seizures although not all seizures fit well into these categories. Some individuals have seizures that begin as focal seizures but then spread to the entire brain. Others may have both types of seizures but with no clear pattern.Everyday functioning has been shown to be severely impaired in about a quarter of affected females and a lesser proportion of males able to walk independently.12 Fine motor skills, such as the ability to pick up small objects, are also impaired; about half of affected individuals have some purposeful use of their hands.12 About three quarters have been found to have cortical visual impairment.13 Most individuals have severe intellectual disability and little or no speech.12Core SymptomsEpileptic seizures starting early in life
Epileptic spasms often occurring without hypsarrhythmia
Multiple different types of seizures
Limited ability to walk
Inability to speak but may use complex gestures/vocalization
Limited hand skills
Lack of eye contact (cortical visual impairment)
Constipation
Sleep difficulties
Purposeless hand movements (stereotypies)
Teeth-grinding (bruxism)
Poor muscle tone (hypotonia)
Intellectual disability Other SymptomsBreathing irregularities (such as hyperventilation)
Respiratory infections
VomitingGastroesophageal reflux
Scoliosis
Characteristics such as a sideways glance and habit of crossing legs
Behavioural symptoms such as anxiety and social avoidance
.The International CDKL5 Disorder Database was established in September 2012 and is continuing to collect data from families with a child with CDD throughout the world. This database provides the capacity to collect important information which will help to better understand this disorder and the associated medical problems.2,3,5,10,12,14-19 The first output from the database examined developmental milestones in 127 children with CDD.14 Overall attainment of milestones was extremely delayed. For example, the median age of independent sitting for girls was 36 months and by five years only three quarters had learned to sit independently. Males generally have more delayed milestones and more impaired development than females. 12,14 Lack of response to anti-epileptic medication 10 often necessitates the need for other therapeutic options such as ketogenic diet19 or vagal nerve stimulation 15 while there is growing interest in a possible role for medical cannabis.2,20 Sleep disturbances which have an impact not only on the child but on the whole family can be extreme2, affecting over 80% of individuals at some point in their life course.3 Gastrointestinal problems such as constipation and reflux are common as is compromised nutrition with nearly a quarter of females and almost half of males having a gastrostomy tube inserted by the age of 7.5 years.3 A proportion of individuals experience frequent respiratory infections often leading to multiple hospital admissions with over a third of families reporting that lower respiratory tract infections were a problem in the first five years of their child’s life.3Relationships with genotype (i.e. type of CDKL5 gene mutation) have also been explored using data from the International CDKL5 Database, but difficult to determine because of the large number of unique mutations. A catalogue of CDKL5 sequence variations, including pathogenic mutations, nonpathogenic polymorphisms, and sequence variations of uncertain significance can be found at the RettBASE website (http://mecp2.chw.edu.au). Further studies are currently underway to understand the characteristics of the small number of mutations that are shared by more than one individual so that at least for those with these mutations, doctors will be able to provide some information to families about the predicted clinical course for their child.The International Foundation for CDKL5 Research (IFCR) CDKL5 Centers of Excellence deliver multidisciplinary clinical care and collect clinical or research data on patients with CDD in the USA. The first site was established in 2013 and the network has grown to eight sites located at world class institutions. These sites have allowed the development of a CDD specific multicenter clinical research network structure to support clinical research goals.2,13,22 | Symptoms of CDKL5 Deficiency Disorder. Seizures are a major problem for patients with CDD because they are usually severe and difficult to control with medication.10,11 Multiple different types of seizures occur and include infantile spasms, myoclonic seizures and tonic-clonic seizures. Doctors have described more than 30 different types of seizures, and they are divided into two major categories — focal seizures and generalized seizures although not all seizures fit well into these categories. Some individuals have seizures that begin as focal seizures but then spread to the entire brain. Others may have both types of seizures but with no clear pattern.Everyday functioning has been shown to be severely impaired in about a quarter of affected females and a lesser proportion of males able to walk independently.12 Fine motor skills, such as the ability to pick up small objects, are also impaired; about half of affected individuals have some purposeful use of their hands.12 About three quarters have been found to have cortical visual impairment.13 Most individuals have severe intellectual disability and little or no speech.12Core SymptomsEpileptic seizures starting early in life
Epileptic spasms often occurring without hypsarrhythmia
Multiple different types of seizures
Limited ability to walk
Inability to speak but may use complex gestures/vocalization
Limited hand skills
Lack of eye contact (cortical visual impairment)
Constipation
Sleep difficulties
Purposeless hand movements (stereotypies)
Teeth-grinding (bruxism)
Poor muscle tone (hypotonia)
Intellectual disability Other SymptomsBreathing irregularities (such as hyperventilation)
Respiratory infections
VomitingGastroesophageal reflux
Scoliosis
Characteristics such as a sideways glance and habit of crossing legs
Behavioural symptoms such as anxiety and social avoidance
.The International CDKL5 Disorder Database was established in September 2012 and is continuing to collect data from families with a child with CDD throughout the world. This database provides the capacity to collect important information which will help to better understand this disorder and the associated medical problems.2,3,5,10,12,14-19 The first output from the database examined developmental milestones in 127 children with CDD.14 Overall attainment of milestones was extremely delayed. For example, the median age of independent sitting for girls was 36 months and by five years only three quarters had learned to sit independently. Males generally have more delayed milestones and more impaired development than females. 12,14 Lack of response to anti-epileptic medication 10 often necessitates the need for other therapeutic options such as ketogenic diet19 or vagal nerve stimulation 15 while there is growing interest in a possible role for medical cannabis.2,20 Sleep disturbances which have an impact not only on the child but on the whole family can be extreme2, affecting over 80% of individuals at some point in their life course.3 Gastrointestinal problems such as constipation and reflux are common as is compromised nutrition with nearly a quarter of females and almost half of males having a gastrostomy tube inserted by the age of 7.5 years.3 A proportion of individuals experience frequent respiratory infections often leading to multiple hospital admissions with over a third of families reporting that lower respiratory tract infections were a problem in the first five years of their child’s life.3Relationships with genotype (i.e. type of CDKL5 gene mutation) have also been explored using data from the International CDKL5 Database, but difficult to determine because of the large number of unique mutations. A catalogue of CDKL5 sequence variations, including pathogenic mutations, nonpathogenic polymorphisms, and sequence variations of uncertain significance can be found at the RettBASE website (http://mecp2.chw.edu.au). Further studies are currently underway to understand the characteristics of the small number of mutations that are shared by more than one individual so that at least for those with these mutations, doctors will be able to provide some information to families about the predicted clinical course for their child.The International Foundation for CDKL5 Research (IFCR) CDKL5 Centers of Excellence deliver multidisciplinary clinical care and collect clinical or research data on patients with CDD in the USA. The first site was established in 2013 and the network has grown to eight sites located at world class institutions. These sites have allowed the development of a CDD specific multicenter clinical research network structure to support clinical research goals.2,13,22 | 210 | CDKL5 Deficiency Disorder |
nord_210_2 | Causes of CDKL5 Deficiency Disorder | The CDKL5 gene provides instructions for making a protein that is essential for normal brain development. Mutations in the CDKL5 gene reduce the amount of functional CDKL5 protein or alter its activity in neurons. A shortage (deficiency) of CDKL5 or impairment of its function disrupts brain development, but it is unclear how these changes cause the specific features of CDD. The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding oxygen and phosphate atoms (a phosphate group) at specific positions. Researchers have not yet determined which proteins are targeted by the CDKL5 protein.CDD is an X-linked dominant disorder. X-linked dominant disorders are caused by a mutation in a gene on the X chromosome and occur mostly in females. Females are affected when they have an X chromosome with the CDKL5 gene mutation. Males with a CDKL5 gene mutation are more severely affected than females. Most of the CDKL5 gene mutations are “de novo”, meaning that they occur spontaneously, and are not passed down through families. However, rare families in which multiple siblings were affected with the same mutation have been reported.8 | Causes of CDKL5 Deficiency Disorder. The CDKL5 gene provides instructions for making a protein that is essential for normal brain development. Mutations in the CDKL5 gene reduce the amount of functional CDKL5 protein or alter its activity in neurons. A shortage (deficiency) of CDKL5 or impairment of its function disrupts brain development, but it is unclear how these changes cause the specific features of CDD. The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding oxygen and phosphate atoms (a phosphate group) at specific positions. Researchers have not yet determined which proteins are targeted by the CDKL5 protein.CDD is an X-linked dominant disorder. X-linked dominant disorders are caused by a mutation in a gene on the X chromosome and occur mostly in females. Females are affected when they have an X chromosome with the CDKL5 gene mutation. Males with a CDKL5 gene mutation are more severely affected than females. Most of the CDKL5 gene mutations are “de novo”, meaning that they occur spontaneously, and are not passed down through families. However, rare families in which multiple siblings were affected with the same mutation have been reported.8 | 210 | CDKL5 Deficiency Disorder |
nord_210_3 | Affects of CDKL5 Deficiency Disorder | CDKL5 mutations have been identified in many ethnic groups, with more females than males being reported with an approximate ratio of 4:1. Affected males appear to be more severely affected than females unless they have evidence of two or more populations of cells with different genotypes (mosaicism).12,14 | Affects of CDKL5 Deficiency Disorder. CDKL5 mutations have been identified in many ethnic groups, with more females than males being reported with an approximate ratio of 4:1. Affected males appear to be more severely affected than females unless they have evidence of two or more populations of cells with different genotypes (mosaicism).12,14 | 210 | CDKL5 Deficiency Disorder |
nord_210_4 | Related disorders of CDKL5 Deficiency Disorder | Symptoms of the following disorders may be similar to those of CDD. Comparisons may be useful for a differential diagnosis:Rett syndrome is a rare neurodevelopmental disorder that appears to occur almost exclusively in females but can occur rarely in males.23 (For more information about this condition, choose “Rett” as your search term in the Rare Disease Database.)Atypical Rett syndrome includes the Hanefeld variant and X-linked infantile spasm syndrome (ISSX). The Hanefeld variant is used to describe females with early-onset epileptic seizures or infantile spasms with Rett-like features.23West syndrome is a type of epilepsy characterized by spasms, abnormal brain wave patterns called hypsarrhythmia and sometimes intellectual disability. (For more information about this condition, choose “West” as your search term in the Rare Disease Database.)Lennox-Gastaut Syndrome is another severe form of epilepsy that typically becomes apparent during infancy or early childhood. (For more information about this condition, choose “Lennox-Gastaut” as your search term in the Rare Disease Database.)Cerebral palsy is group of neurological disorders that can affect the brain and/or spinal cord. Common features include a lack of muscle coordination when performing voluntary movements (ataxia); stiff or tight muscles and exaggerated reflexes (spasticity); walking with one foot or leg dragging; walking on the toes, a crouched gait, or a “scissored” gait; and muscle tone that is either too stiff or too floppy.Autism and autism spectrum disorders (ASDs) are a group of severe neurodevelopmental disorders in which individuals show deficits in social interaction, impaired communication, repetitive behavior and restricted interests and activities. Note that to date CDKL5 mutations have only rarely been found to be associated with autism and intellectual disability in the absence of seizures8,16 and have not been described in patients with classical Rett syndrome. CDD has overlapping symptoms with many of the developmental and epileptic encephalopathies. | Related disorders of CDKL5 Deficiency Disorder. Symptoms of the following disorders may be similar to those of CDD. Comparisons may be useful for a differential diagnosis:Rett syndrome is a rare neurodevelopmental disorder that appears to occur almost exclusively in females but can occur rarely in males.23 (For more information about this condition, choose “Rett” as your search term in the Rare Disease Database.)Atypical Rett syndrome includes the Hanefeld variant and X-linked infantile spasm syndrome (ISSX). The Hanefeld variant is used to describe females with early-onset epileptic seizures or infantile spasms with Rett-like features.23West syndrome is a type of epilepsy characterized by spasms, abnormal brain wave patterns called hypsarrhythmia and sometimes intellectual disability. (For more information about this condition, choose “West” as your search term in the Rare Disease Database.)Lennox-Gastaut Syndrome is another severe form of epilepsy that typically becomes apparent during infancy or early childhood. (For more information about this condition, choose “Lennox-Gastaut” as your search term in the Rare Disease Database.)Cerebral palsy is group of neurological disorders that can affect the brain and/or spinal cord. Common features include a lack of muscle coordination when performing voluntary movements (ataxia); stiff or tight muscles and exaggerated reflexes (spasticity); walking with one foot or leg dragging; walking on the toes, a crouched gait, or a “scissored” gait; and muscle tone that is either too stiff or too floppy.Autism and autism spectrum disorders (ASDs) are a group of severe neurodevelopmental disorders in which individuals show deficits in social interaction, impaired communication, repetitive behavior and restricted interests and activities. Note that to date CDKL5 mutations have only rarely been found to be associated with autism and intellectual disability in the absence of seizures8,16 and have not been described in patients with classical Rett syndrome. CDD has overlapping symptoms with many of the developmental and epileptic encephalopathies. | 210 | CDKL5 Deficiency Disorder |
nord_210_5 | Diagnosis of CDKL5 Deficiency Disorder | Diagnosis is initially suspected based on clinical presentation and confirmed by molecular genetic testing for CDKL5 mutations or multigene panel testing for early onset epilepsy.24 As some CDKL5 mutations/variants are not disease-causing but benign, to confirm a diagnosis the mutation has to be considered disease-causing in accordance with recognized guidelines for assessing pathogenicity.25 | Diagnosis of CDKL5 Deficiency Disorder. Diagnosis is initially suspected based on clinical presentation and confirmed by molecular genetic testing for CDKL5 mutations or multigene panel testing for early onset epilepsy.24 As some CDKL5 mutations/variants are not disease-causing but benign, to confirm a diagnosis the mutation has to be considered disease-causing in accordance with recognized guidelines for assessing pathogenicity.25 | 210 | CDKL5 Deficiency Disorder |
nord_210_6 | Therapies of CDKL5 Deficiency Disorder | Treatment
Medical management for individuals with CDD is mostly symptomatic and supportive. A multidisciplinary team approach is the most effective way to deliver necessary treatments aimed at maximizing the individual’s abilities and facilitating any skills that may be emerging. An emphasis should be placed on early intervention therapies such as physical therapy, occupational therapy, and speech and augmentative communication therapy. Important aspects of management include psychosocial support for the family, development of an appropriate education plan, and assessment of available community resources.It is important to have the involvement of a dietitian with expertise in the management of individuals with severe intellectual disability, so that optimal nutritional status can be maintained. Some affected individuals can feed orally, however many require the assistance of enteral nutritional support.Most individuals with CDD do not develop verbal expressive language, and so other forms of communication should be considered, including communication boards, technical devices and switch activated systems to facilitate choice making and environmental access.Seizure control is challenging and is often the most difficult health issue to manage. No one anticonvulsant has been found to be uniformly effective, and often multiple anticonvulsants are needed. In 2022, ganaxolone (Ztalmy) was approved to treat seizures associated with CDD in patients 2 years of age and older. This is the first treatment for seizures associated with CDD and the first treatment specifically for CDD.Vagal nerve stimulation (VNS) has also been used with improvements in some patients.15 Dietary modifications such as the ketogenic diet have shown variable improvement in some individuals.19 However, these rigid dietary changes must only be implemented under close medical supervision and can be demanding on families.Many affected individuals develop scoliosis, although as with many comorbidities in this disorder,3 there is limited literature on prevalence or natural history. Bracing may be suggested for some, while others will need to have surgical intervention. Guidelines developed for Rett syndrome may be helpful in providing management options in CDD.26 Increased muscle tone may develop, placing the individual at risk of developing foot deformities and shortened heel cords. It is important to maintain ambulation as much as possible in those who have learned to walk, and ankle orthoses may prove beneficial to prevent these orthopedic problems from developing.Physiotherapy/physical therapy is also of benefit in improving overall muscle tone, trunk stability, strengthening, balance, prevention of foot deformities, maintaining foot alignment and keeping heel cords lengthened.Genetic counseling is recommended for families with an affected child. | Therapies of CDKL5 Deficiency Disorder. Treatment
Medical management for individuals with CDD is mostly symptomatic and supportive. A multidisciplinary team approach is the most effective way to deliver necessary treatments aimed at maximizing the individual’s abilities and facilitating any skills that may be emerging. An emphasis should be placed on early intervention therapies such as physical therapy, occupational therapy, and speech and augmentative communication therapy. Important aspects of management include psychosocial support for the family, development of an appropriate education plan, and assessment of available community resources.It is important to have the involvement of a dietitian with expertise in the management of individuals with severe intellectual disability, so that optimal nutritional status can be maintained. Some affected individuals can feed orally, however many require the assistance of enteral nutritional support.Most individuals with CDD do not develop verbal expressive language, and so other forms of communication should be considered, including communication boards, technical devices and switch activated systems to facilitate choice making and environmental access.Seizure control is challenging and is often the most difficult health issue to manage. No one anticonvulsant has been found to be uniformly effective, and often multiple anticonvulsants are needed. In 2022, ganaxolone (Ztalmy) was approved to treat seizures associated with CDD in patients 2 years of age and older. This is the first treatment for seizures associated with CDD and the first treatment specifically for CDD.Vagal nerve stimulation (VNS) has also been used with improvements in some patients.15 Dietary modifications such as the ketogenic diet have shown variable improvement in some individuals.19 However, these rigid dietary changes must only be implemented under close medical supervision and can be demanding on families.Many affected individuals develop scoliosis, although as with many comorbidities in this disorder,3 there is limited literature on prevalence or natural history. Bracing may be suggested for some, while others will need to have surgical intervention. Guidelines developed for Rett syndrome may be helpful in providing management options in CDD.26 Increased muscle tone may develop, placing the individual at risk of developing foot deformities and shortened heel cords. It is important to maintain ambulation as much as possible in those who have learned to walk, and ankle orthoses may prove beneficial to prevent these orthopedic problems from developing.Physiotherapy/physical therapy is also of benefit in improving overall muscle tone, trunk stability, strengthening, balance, prevention of foot deformities, maintaining foot alignment and keeping heel cords lengthened.Genetic counseling is recommended for families with an affected child. | 210 | CDKL5 Deficiency Disorder |
nord_211_0 | Overview of Central Core Disease | Central core disease (CCD) is a rare genetic neuromuscular disorder that is classified as a congenital myopathy, meaning that it is present at birth (congenital) and is a disorder that causes muscle weakness (myopathy). Affected infants have low muscle tone (hypotonia) resulting in abnormal “floppiness”, muscle weakness and a variety of skeletal abnormalities such as side-to-side curvature of the spine (scoliosis). Muscle weakness normally affects the proximal muscles, which are those muscles closest to the center of the body such as the muscles of the shoulder, pelvis and upper arms and legs. Affected infants may experience delays in acquiring motor milestones such as crawling or walking. Some individuals with CCD may be susceptible to developing malignant hyperthermia, a condition in which individuals develop adverse reactions to certain anesthetic drugs during surgical procedures. CCD may be very mild or may cause serious complications. Most cases are inherited in an autosomal dominant pattern and associated with stable or slowly progressive muscle disease and a good prognosis. Some cases are inherited in an autosomal recessive pattern and are more likely to be associated with severe complications.The disorder derives its name from characteristic, abnormal areas within the centers of muscle fibers. These abnormal “central cores” are detected during microscopic examination of small samples of muscle tissue (muscle biopsy). The muscle biopsy may reveal characteristic findings such as a lack of mitochondria, the part of the cell that releases energy, or absence of the sarcoplasmic reticulum, a membrane-bound structure in muscle fibers. | Overview of Central Core Disease. Central core disease (CCD) is a rare genetic neuromuscular disorder that is classified as a congenital myopathy, meaning that it is present at birth (congenital) and is a disorder that causes muscle weakness (myopathy). Affected infants have low muscle tone (hypotonia) resulting in abnormal “floppiness”, muscle weakness and a variety of skeletal abnormalities such as side-to-side curvature of the spine (scoliosis). Muscle weakness normally affects the proximal muscles, which are those muscles closest to the center of the body such as the muscles of the shoulder, pelvis and upper arms and legs. Affected infants may experience delays in acquiring motor milestones such as crawling or walking. Some individuals with CCD may be susceptible to developing malignant hyperthermia, a condition in which individuals develop adverse reactions to certain anesthetic drugs during surgical procedures. CCD may be very mild or may cause serious complications. Most cases are inherited in an autosomal dominant pattern and associated with stable or slowly progressive muscle disease and a good prognosis. Some cases are inherited in an autosomal recessive pattern and are more likely to be associated with severe complications.The disorder derives its name from characteristic, abnormal areas within the centers of muscle fibers. These abnormal “central cores” are detected during microscopic examination of small samples of muscle tissue (muscle biopsy). The muscle biopsy may reveal characteristic findings such as a lack of mitochondria, the part of the cell that releases energy, or absence of the sarcoplasmic reticulum, a membrane-bound structure in muscle fibers. | 211 | Central Core Disease |
nord_211_1 | Symptoms of Central Core Disease | The specific symptoms and severity of CCD vary greatly from person to person. Some individuals may develop very mild muscle disease that may go unnoticed or get a congenital myopathy incidental finding report from a next-generation sequencing (NGS) genetic test; others may develop serious muscle disease that can delay motor milestones or cause serious breathing (respiratory) difficulties. In most patients, muscle weakness in CCD is not progressive or only progresses very slowly.Infants with CCD typically have diminished muscle tone (hypotonia), resulting in abnormal “floppiness”. Weakness of the proximal muscles occurs early during infancy. The proximal muscles are those muscles closest to the center of the body such as the muscles of the shoulder, pelvis and upper arms and legs. In CCD, the hip-girdle area is especially affected by muscle weakness. In some patients, muscle cramps or stiffness may occur especially upon exertion. Muscle weakness may cause delays in reaching milestones that require the coordination and development of muscles (motor milestones) such as crawling, standing and walking. Intelligence is unaffected.Certain facial muscles may be affected in individuals with CCD. Rarely, individuals may develop wasting of facial muscles. Mild facial muscle involvement may not be noticeable, except for the inability to bury the eyelashes resulting from weakness of muscles surrounding the eyes (signe de cils). In classic, autosomal dominant CCD, the muscles around the eyes are not affected, an important finding that distinguishes CCD from other congenital myopathies. In the autosomal recessive form of CCD, these muscles may be affected.A variety of skeletal abnormalities often occur in individuals with CCD including abnormal side-to-side curvature of the spine (scoliosis) and congenital dislocation of the hip, a condition in which the hip joint is too shallow causing the upper bone of the leg (femur) to pop out of the joint. These skeletal findings may be present at birth. Additional skeletal symptoms may occur including front-to-back curvature of the spine (kyphosis), dislocation of the kneecap (patella), clubfoot (talipes equinovarus), flattening of the arch of the foot (flatfoot or pes panus) and an abnormally high arch of the foot (pes cavus). Abnormal tightening of certain joints, resulting in restricted or stiff movements (contractures) occurs rarely. The Achilles tendon is most common site for contracture.Some patients with CCD may present with severe symptoms at birth or early during infancy. Severe symptoms associated with CCD may be caused by a prolonged decrease or absence of movements by the fetus (fetal akinesia sequence). Such symptoms include profoundly low muscle tone (hypotonia or floppiness), reduced mobility of many joints of the body due to the overgrowth (proliferation) of fibrous tissue in the joints (arthrogryposis multiplex congenita) and breathing difficulties that may require a mechanical device to assist breathing. Some severely affected infants may not be able to walk independently. Individuals with CCD have susceptibility to developing malignant hyperthermia, an autosomal dominant genetic disorder in which affected individuals are susceptible to adverse reactions to certain anesthetic drugs. The drugs that trigger malignant hyperthermia are the volatile inhalation gases including sevoflurane, desflurane, isoflurane, halothane, enflurane, methoxyflurane and depolarizing muscle relaxants such a succinylcholine. The characteristics of a malignant hyperthermia episode are variable and include muscle rigidity, high blood pressure (hypertension), increased levels of carbon dioxide in the blood or exhaled gas, a rapid irregular heart rate, rapid deep breathing, bluish skin color (cyanosis), acidity of the blood and muscle damage. Body temperature can rise rapidly (hyperthermia), but sometimes only occurs late in an episode. When an episode is not recognized and treated, internal bleeding, brain damage, skeletal muscle degeneration (rhabdomyolysis) and kidney and heart failure can result. | Symptoms of Central Core Disease. The specific symptoms and severity of CCD vary greatly from person to person. Some individuals may develop very mild muscle disease that may go unnoticed or get a congenital myopathy incidental finding report from a next-generation sequencing (NGS) genetic test; others may develop serious muscle disease that can delay motor milestones or cause serious breathing (respiratory) difficulties. In most patients, muscle weakness in CCD is not progressive or only progresses very slowly.Infants with CCD typically have diminished muscle tone (hypotonia), resulting in abnormal “floppiness”. Weakness of the proximal muscles occurs early during infancy. The proximal muscles are those muscles closest to the center of the body such as the muscles of the shoulder, pelvis and upper arms and legs. In CCD, the hip-girdle area is especially affected by muscle weakness. In some patients, muscle cramps or stiffness may occur especially upon exertion. Muscle weakness may cause delays in reaching milestones that require the coordination and development of muscles (motor milestones) such as crawling, standing and walking. Intelligence is unaffected.Certain facial muscles may be affected in individuals with CCD. Rarely, individuals may develop wasting of facial muscles. Mild facial muscle involvement may not be noticeable, except for the inability to bury the eyelashes resulting from weakness of muscles surrounding the eyes (signe de cils). In classic, autosomal dominant CCD, the muscles around the eyes are not affected, an important finding that distinguishes CCD from other congenital myopathies. In the autosomal recessive form of CCD, these muscles may be affected.A variety of skeletal abnormalities often occur in individuals with CCD including abnormal side-to-side curvature of the spine (scoliosis) and congenital dislocation of the hip, a condition in which the hip joint is too shallow causing the upper bone of the leg (femur) to pop out of the joint. These skeletal findings may be present at birth. Additional skeletal symptoms may occur including front-to-back curvature of the spine (kyphosis), dislocation of the kneecap (patella), clubfoot (talipes equinovarus), flattening of the arch of the foot (flatfoot or pes panus) and an abnormally high arch of the foot (pes cavus). Abnormal tightening of certain joints, resulting in restricted or stiff movements (contractures) occurs rarely. The Achilles tendon is most common site for contracture.Some patients with CCD may present with severe symptoms at birth or early during infancy. Severe symptoms associated with CCD may be caused by a prolonged decrease or absence of movements by the fetus (fetal akinesia sequence). Such symptoms include profoundly low muscle tone (hypotonia or floppiness), reduced mobility of many joints of the body due to the overgrowth (proliferation) of fibrous tissue in the joints (arthrogryposis multiplex congenita) and breathing difficulties that may require a mechanical device to assist breathing. Some severely affected infants may not be able to walk independently. Individuals with CCD have susceptibility to developing malignant hyperthermia, an autosomal dominant genetic disorder in which affected individuals are susceptible to adverse reactions to certain anesthetic drugs. The drugs that trigger malignant hyperthermia are the volatile inhalation gases including sevoflurane, desflurane, isoflurane, halothane, enflurane, methoxyflurane and depolarizing muscle relaxants such a succinylcholine. The characteristics of a malignant hyperthermia episode are variable and include muscle rigidity, high blood pressure (hypertension), increased levels of carbon dioxide in the blood or exhaled gas, a rapid irregular heart rate, rapid deep breathing, bluish skin color (cyanosis), acidity of the blood and muscle damage. Body temperature can rise rapidly (hyperthermia), but sometimes only occurs late in an episode. When an episode is not recognized and treated, internal bleeding, brain damage, skeletal muscle degeneration (rhabdomyolysis) and kidney and heart failure can result. | 211 | Central Core Disease |
nord_211_2 | Causes of Central Core Disease | Most cases of CCD are thought to be caused by specific variants (mutations) in the ryanodine receptor (RYR1) gene. The RYR1 gene regulates production of a protein (known as RyR1 calcium-release channel) that plays an essential role in calcium regulation in skeletal (voluntary) muscle. Certain variants in the RYR1 gene are thought to result in abnormalities in the normal flow of electrically charged particles known as calcium ions through pores in cell membranes (calcium channels), potentially leading to impaired maturation of skeletal muscle, abnormalities in muscle contraction and other symptoms and findings associated with the disorder. Individuals who carry one abnormal RYR1 gene may also be at increased risk for malignant hyperthermia and are advised to avoid exposure to inhaled anesthetics and succinylcholine during invasive or surgical procedures. Changes in the RYR1 gene appear to be responsible for over 50% of the susceptibility to malignant hyperthermia. (For further information on this condition, search for “malignant hyperthermia” in the Rare Disease Database.)InheritanceIn most patients, CCD is inherited in an autosomal dominant pattern. Rarely, CCD can be inherited in an autosomal recessive pattern and associated with more severe symptoms. 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. When CCD occurs in the absence of any apparent family history of the disorder, this may be referred to as “de novo”. The risk of passing the abnormal gene from an affected parent to a child 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. | Causes of Central Core Disease. Most cases of CCD are thought to be caused by specific variants (mutations) in the ryanodine receptor (RYR1) gene. The RYR1 gene regulates production of a protein (known as RyR1 calcium-release channel) that plays an essential role in calcium regulation in skeletal (voluntary) muscle. Certain variants in the RYR1 gene are thought to result in abnormalities in the normal flow of electrically charged particles known as calcium ions through pores in cell membranes (calcium channels), potentially leading to impaired maturation of skeletal muscle, abnormalities in muscle contraction and other symptoms and findings associated with the disorder. Individuals who carry one abnormal RYR1 gene may also be at increased risk for malignant hyperthermia and are advised to avoid exposure to inhaled anesthetics and succinylcholine during invasive or surgical procedures. Changes in the RYR1 gene appear to be responsible for over 50% of the susceptibility to malignant hyperthermia. (For further information on this condition, search for “malignant hyperthermia” in the Rare Disease Database.)InheritanceIn most patients, CCD is inherited in an autosomal dominant pattern. Rarely, CCD can be inherited in an autosomal recessive pattern and associated with more severe symptoms. 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. When CCD occurs in the absence of any apparent family history of the disorder, this may be referred to as “de novo”. The risk of passing the abnormal gene from an affected parent to a child 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. | 211 | Central Core Disease |
nord_211_3 | Affects of Central Core Disease | Central core disease affects males and females in equal numbers. The exact incidence and prevalence of CCD is unknown. CCD is believed to be the most common form of congenital myopathy, which as a group occurs in 6 out of every 100,000 live births.The disorder was originally described in 1956 (Shy GM, Magee KR) in five members in three successive generations of a family. However, the disease was not termed “central core disease” until later. | Affects of Central Core Disease. Central core disease affects males and females in equal numbers. The exact incidence and prevalence of CCD is unknown. CCD is believed to be the most common form of congenital myopathy, which as a group occurs in 6 out of every 100,000 live births.The disorder was originally described in 1956 (Shy GM, Magee KR) in five members in three successive generations of a family. However, the disease was not termed “central core disease” until later. | 211 | Central Core Disease |
nord_211_4 | Related disorders of Central Core Disease | Symptoms of the following disorders can be similar to those of CCD. Comparisons may be useful for a differential diagnosis.Congenital fiber type disproportion (CFTD) is a rare genetic muscle disease that is apparent at birth (congenital myopathy). Major symptoms may include loss of muscle tone (hypotonia) and generalized muscle weakness. Affected infants may also have distinctive facial features. Additional common symptoms that occur include abnormal side-to-side curvature of the spine (scoliosis), delays in motor development, dislocated hips and the permanent fixation of certain joints in a flexed position (contractures). The diagnosis of congenital fiber type disproportion is controversial. The changes to muscle tissue that characterize the disorder can also occur in association with many other disorders or conditions including other congenital muscle disorders, Krabbe disease, Lowe syndrome, myotonic dystrophy, fetal alcohol syndrome and a variety of brain malformations such as cerebellar hypoplasia. CFTD is considered a distinct muscle disease when no underlying cause can be identified. Most cases of CFTD occur randomly (sporadically). Some cases are inherited in an autosomal recessive or dominant pattern. One familial case was inherited in an X-linked recessive pattern. Multiminicore disease, also known as minicore myopathy or multicore myopathy, is a rare genetic muscle disorder. Four subtypes have been identified. The most common form, or classic form, accounts for approximately 75% of patients. Common symptoms include low muscle tone (hypotonia), muscle weakness and delays in reaching developmental milestones. Some individuals may develop breathing or feeding difficulties. Additional findings include side-to-side curvature of the spine (scoliosis) and spinal rigidity. Microscopic examination of small samples of muscle tissue (muscle biopsy) typically reveals multiple variants of central cores, known as “minicores” within muscle fibers. Multiminicore disease is thought to be inherited in an autosomal recessive pattern. The disorder has been linked to multiple genes, with the two main genes being the SELENON (formerly designated as SEPN1) gene and the ryanodine receptor 1 (RYR1) gene.Congenital neuromuscular disease with uniform type 1 fibers (CNMDU1) is a rare form of congenital myopathy which is diagnosed pathologically by the presence of more than 99% of type 1 muscle fiber, with no specific structural changes (no central or peripheral cores). Individuals present with early onset of symptoms including mild proximal weakness, mild facial weakness, poor or no response to stimulation (hyporeflexia or areflexia), delayed motor milestones and normal serum muscle enzyme levels. A common observation in CCD and CNMDU1 is type 1 muscle fiber predominance. Young patients in families with cases of CCD are sometimes initially diagnosed with CNMDU1 and may develop cores at a later stage.Congenital myopathy is a group of muscle disorders (myopathies) that are present at birth (congenital). These disorders are characterized by muscle weakness, loss of muscle tone (hypotonia), diminished reflexes and delays in reaching motor milestones (e.g., walking). In some of these disorders, muscle weakness is progressive and may result in life-threatening complications. This group of disorders includes nemaline rod myopathy, hyaline body myopathy, centronuclear myopathy, congenital fiber type disproportion and multiminicore myopathy. Congenital myopathies are usually apparent in the newborn (neonatal) period but may present much later in childhood or even in adulthood. In most cases, inheritance of these disorders is either autosomal recessive or autosomal dominant. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Central Core Disease. Symptoms of the following disorders can be similar to those of CCD. Comparisons may be useful for a differential diagnosis.Congenital fiber type disproportion (CFTD) is a rare genetic muscle disease that is apparent at birth (congenital myopathy). Major symptoms may include loss of muscle tone (hypotonia) and generalized muscle weakness. Affected infants may also have distinctive facial features. Additional common symptoms that occur include abnormal side-to-side curvature of the spine (scoliosis), delays in motor development, dislocated hips and the permanent fixation of certain joints in a flexed position (contractures). The diagnosis of congenital fiber type disproportion is controversial. The changes to muscle tissue that characterize the disorder can also occur in association with many other disorders or conditions including other congenital muscle disorders, Krabbe disease, Lowe syndrome, myotonic dystrophy, fetal alcohol syndrome and a variety of brain malformations such as cerebellar hypoplasia. CFTD is considered a distinct muscle disease when no underlying cause can be identified. Most cases of CFTD occur randomly (sporadically). Some cases are inherited in an autosomal recessive or dominant pattern. One familial case was inherited in an X-linked recessive pattern. Multiminicore disease, also known as minicore myopathy or multicore myopathy, is a rare genetic muscle disorder. Four subtypes have been identified. The most common form, or classic form, accounts for approximately 75% of patients. Common symptoms include low muscle tone (hypotonia), muscle weakness and delays in reaching developmental milestones. Some individuals may develop breathing or feeding difficulties. Additional findings include side-to-side curvature of the spine (scoliosis) and spinal rigidity. Microscopic examination of small samples of muscle tissue (muscle biopsy) typically reveals multiple variants of central cores, known as “minicores” within muscle fibers. Multiminicore disease is thought to be inherited in an autosomal recessive pattern. The disorder has been linked to multiple genes, with the two main genes being the SELENON (formerly designated as SEPN1) gene and the ryanodine receptor 1 (RYR1) gene.Congenital neuromuscular disease with uniform type 1 fibers (CNMDU1) is a rare form of congenital myopathy which is diagnosed pathologically by the presence of more than 99% of type 1 muscle fiber, with no specific structural changes (no central or peripheral cores). Individuals present with early onset of symptoms including mild proximal weakness, mild facial weakness, poor or no response to stimulation (hyporeflexia or areflexia), delayed motor milestones and normal serum muscle enzyme levels. A common observation in CCD and CNMDU1 is type 1 muscle fiber predominance. Young patients in families with cases of CCD are sometimes initially diagnosed with CNMDU1 and may develop cores at a later stage.Congenital myopathy is a group of muscle disorders (myopathies) that are present at birth (congenital). These disorders are characterized by muscle weakness, loss of muscle tone (hypotonia), diminished reflexes and delays in reaching motor milestones (e.g., walking). In some of these disorders, muscle weakness is progressive and may result in life-threatening complications. This group of disorders includes nemaline rod myopathy, hyaline body myopathy, centronuclear myopathy, congenital fiber type disproportion and multiminicore myopathy. Congenital myopathies are usually apparent in the newborn (neonatal) period but may present much later in childhood or even in adulthood. In most cases, inheritance of these disorders is either autosomal recessive or autosomal dominant. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) | 211 | Central Core Disease |
nord_211_5 | Diagnosis of Central Core Disease | CCD may be diagnosed based upon a thorough clinical evaluation, detection of characteristic physical findings, patient and family history and specialized tests. However, genetic testing is gradually becoming the first step in the diagnostic process, with other evaluations performed to confirm the genetic results. The disorder may sometimes be diagnosed during the first years of life; however, not infrequently, it may not be recognized until later during childhood, adolescence or adulthood following certain associated musculoskeletal abnormalities (see “Symptoms”).Diagnostic studies may include blood tests, electromyography (EMG), nerve conduction velocity studies, muscle biopsies and/or other tests. Blood studies typically reveal normal or slightly increased levels of the enzyme creatine kinase in the fluid portion of the blood (except during a malignant hyperthermic crisis). EMG is a test that records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. Reports indicate that EMG results may be almost normal in people with CCD, particularly in younger children; however, the recorded electrical activity in certain muscle fibers during activity (motor unit action potential) may be of unusually short duration and low amplitude. During a nerve conduction velocity study, motor and sensory nerves are electrically stimulated to assess a nerve's ability and speed to conduct nerve impulses. Evidence indicates that the results of such a study are usually normal in people with CCD.Small samples of muscle tissue are also removed and examined microscopically with the use of special stains (histochemistry). Microscopic evaluation typically reveals dense, ill-defined areas within the central portion of muscle fibers (“central cores”) that contain myofibril material. Muscle fibers are thread-like muscle cells within skeletal muscle, which are comprised of slender, usually highly organized strands known as myofibrils. These altered regions or central cores within muscle fibers may appear to lack enzyme activity, contrasting with normal activities in surrounding fibers. Enzymes are proteins that accelerate particular chemical activities in the body. In addition, absence of certain cellular structures called mitochondria may be confirmed with an electron microscope, which uses electron beams rather than visible light for increased magnification. Mitochondria are the rod-like structures (organelles) outside the nuclei of cells that serve as a primary source of cellular energy due to their complex, continual chemical reactions. As a result, they are important to the proper functioning of muscle cells, including those of skeletal muscle.Additional diagnostic studies may also be recommended to detect and/or characterize particular abnormalities that may be associated with the disorder. For example, advanced imaging techniques may be conducted to characterize certain skeletal abnormalities. | Diagnosis of Central Core Disease. CCD may be diagnosed based upon a thorough clinical evaluation, detection of characteristic physical findings, patient and family history and specialized tests. However, genetic testing is gradually becoming the first step in the diagnostic process, with other evaluations performed to confirm the genetic results. The disorder may sometimes be diagnosed during the first years of life; however, not infrequently, it may not be recognized until later during childhood, adolescence or adulthood following certain associated musculoskeletal abnormalities (see “Symptoms”).Diagnostic studies may include blood tests, electromyography (EMG), nerve conduction velocity studies, muscle biopsies and/or other tests. Blood studies typically reveal normal or slightly increased levels of the enzyme creatine kinase in the fluid portion of the blood (except during a malignant hyperthermic crisis). EMG is a test that records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. Reports indicate that EMG results may be almost normal in people with CCD, particularly in younger children; however, the recorded electrical activity in certain muscle fibers during activity (motor unit action potential) may be of unusually short duration and low amplitude. During a nerve conduction velocity study, motor and sensory nerves are electrically stimulated to assess a nerve's ability and speed to conduct nerve impulses. Evidence indicates that the results of such a study are usually normal in people with CCD.Small samples of muscle tissue are also removed and examined microscopically with the use of special stains (histochemistry). Microscopic evaluation typically reveals dense, ill-defined areas within the central portion of muscle fibers (“central cores”) that contain myofibril material. Muscle fibers are thread-like muscle cells within skeletal muscle, which are comprised of slender, usually highly organized strands known as myofibrils. These altered regions or central cores within muscle fibers may appear to lack enzyme activity, contrasting with normal activities in surrounding fibers. Enzymes are proteins that accelerate particular chemical activities in the body. In addition, absence of certain cellular structures called mitochondria may be confirmed with an electron microscope, which uses electron beams rather than visible light for increased magnification. Mitochondria are the rod-like structures (organelles) outside the nuclei of cells that serve as a primary source of cellular energy due to their complex, continual chemical reactions. As a result, they are important to the proper functioning of muscle cells, including those of skeletal muscle.Additional diagnostic studies may also be recommended to detect and/or characterize particular abnormalities that may be associated with the disorder. For example, advanced imaging techniques may be conducted to characterize certain skeletal abnormalities. | 211 | Central Core Disease |
nord_211_6 | Therapies of Central Core Disease | TreatmentThe treatment of CCD is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; specialists who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues in children (pediatric orthopedists); physicians who specialize in physical medicine and rehabilitation (physiatrists); physical therapists; occupational therapists and/or other health care professionals.Specific therapies for the treatment of CCD are symptomatic and supportive. In cases of “floppiness” during infancy, disease management may require careful attention to posture, the use of appropriate adaptive seating with careful trunk and head support and other measures. In addition, for infants with extremely severe weakness, tube-feeding may be required to ensure proper caloric and nutritional intake.In some patients, various orthopedic techniques, such as the use of special braces, other devices and/or surgical measures, may be recommended to help prevent and/or treat certain musculoskeletal abnormalities potentially associated with the disorder. Family-centered, early intervention services may also be advised, such as physical and occupational therapy, including assistance with seating and mobility devices; instruction for parents on proper handling, exercising and stretching certain muscles; and/or other measures as appropriate.Because individuals with CCD may be at risk for malignant hyperthermia when exposed to certain general anesthetics or muscle relaxants, this risk must be taken into consideration by surgeons, anesthesiologists, dentists and other health care workers when making decisions concerning surgery, the use of certain anesthetics and the administration of certain medications. Any surgical procedure, including dental surgery, must be performed in a setting that is well monitored by anesthesiologists with necessary precautions to help prevent or appropriately manage a possible malignant hyperthermic event.Genetic counseling is recommended for affected individuals and their families. For additional information on treatment and symptom management, please refer to the RYR-1 Foundation clinical care guidelines (https://www.ryr1.org/ccg) and TREAT NMD family guide (https://treat-nmd.org/wp-content/uploads/2021/07/uncategorized-CMFG-11-4-2019_Update.pdf) | Therapies of Central Core Disease. TreatmentThe treatment of CCD is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; specialists who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues in children (pediatric orthopedists); physicians who specialize in physical medicine and rehabilitation (physiatrists); physical therapists; occupational therapists and/or other health care professionals.Specific therapies for the treatment of CCD are symptomatic and supportive. In cases of “floppiness” during infancy, disease management may require careful attention to posture, the use of appropriate adaptive seating with careful trunk and head support and other measures. In addition, for infants with extremely severe weakness, tube-feeding may be required to ensure proper caloric and nutritional intake.In some patients, various orthopedic techniques, such as the use of special braces, other devices and/or surgical measures, may be recommended to help prevent and/or treat certain musculoskeletal abnormalities potentially associated with the disorder. Family-centered, early intervention services may also be advised, such as physical and occupational therapy, including assistance with seating and mobility devices; instruction for parents on proper handling, exercising and stretching certain muscles; and/or other measures as appropriate.Because individuals with CCD may be at risk for malignant hyperthermia when exposed to certain general anesthetics or muscle relaxants, this risk must be taken into consideration by surgeons, anesthesiologists, dentists and other health care workers when making decisions concerning surgery, the use of certain anesthetics and the administration of certain medications. Any surgical procedure, including dental surgery, must be performed in a setting that is well monitored by anesthesiologists with necessary precautions to help prevent or appropriately manage a possible malignant hyperthermic event.Genetic counseling is recommended for affected individuals and their families. For additional information on treatment and symptom management, please refer to the RYR-1 Foundation clinical care guidelines (https://www.ryr1.org/ccg) and TREAT NMD family guide (https://treat-nmd.org/wp-content/uploads/2021/07/uncategorized-CMFG-11-4-2019_Update.pdf) | 211 | Central Core Disease |
nord_212_0 | Overview of Central Diabetes Insipidus | Central diabetes insipidus (CDI) is a rare disorder characterized by excessive thirst (polydipsia) and excessive urination (polyuria). It is not related to the more common diabetes mellitus (sugar diabetes), in which the body does not produce or properly use insulin. CDI is a distinct disorder caused by complete or partial deficiency of the protein, arginine vasopressin (AVP), which is required by the kidneys to manage water balance in the body. If affected individuals do not have access to water, dehydration may occur. Eventually, more serious symptoms can develop including changes in consciousness and confusion associated with dehydration and elevation in serum sodium concentration (hypertonic dehydration). CDI may be caused by any condition that affects the creation, transport or release of vasopressin. CDI may be inherited or acquired. In some cases, no cause can be identified (idiopathic). | Overview of Central Diabetes Insipidus. Central diabetes insipidus (CDI) is a rare disorder characterized by excessive thirst (polydipsia) and excessive urination (polyuria). It is not related to the more common diabetes mellitus (sugar diabetes), in which the body does not produce or properly use insulin. CDI is a distinct disorder caused by complete or partial deficiency of the protein, arginine vasopressin (AVP), which is required by the kidneys to manage water balance in the body. If affected individuals do not have access to water, dehydration may occur. Eventually, more serious symptoms can develop including changes in consciousness and confusion associated with dehydration and elevation in serum sodium concentration (hypertonic dehydration). CDI may be caused by any condition that affects the creation, transport or release of vasopressin. CDI may be inherited or acquired. In some cases, no cause can be identified (idiopathic). | 212 | Central Diabetes Insipidus |
nord_212_1 | Symptoms of Central Diabetes Insipidus | In CDI, symptoms may develop over time or abruptly and may affect individuals of any age. CDI is characterized by excessive thirst (polydipsia) and excessive urination (polyuria), even at night (nocturia). The severity and progression of CDI varies from case to case. Some individuals may have a severe form of the disorder (complete CDI) with little or no vasopressin activity. Others may have a mild form of the disorder (partial CDI) with residual vasopressin activity.Without appropriate AVP secretion, individuals with central diabetes insipidus are unable to concentrate the urine by reabsorbing water in the kidneys. This results in obligatory excessive urine output of dilute urine. Consequently, individuals must drink excessively to prevent dehydration. In response to thirst, affected individuals may drink several gallons of water a day. If affected individuals are deprived of water for an extended period of time, rapid dehydration will occur. Thirst cravings can be strong enough to awaken people from sleep.In infants, additional symptoms may occur including irritability, lethargy, vomiting, constipation and fever. If left untreated, repeated episodes of dehydration can potentially result in seizures, brain damage, developmental delays, and physical and mental retardation. However, with proper diagnosis and prompt treatment intelligence and development is usually normal unless more global problems in development of the brain are associated. Affected children may develop bedwetting (enuresis), fatigue, weight loss, and growth retardation.Individuals with CDI are at risk of developing dehydration and cardiovascular symptoms including irregular heartbeats, fever, dry skin and mucous membranes, confusion, seizures, change in consciousness, and potentially coma. Affected adults may develop orthostatic hypotension, a condition in which there is a dramatic decrease in blood pressure upon standing or sitting. Orthostatic hypotension can result in dizziness or momentary loss of consciousness (syncope). | Symptoms of Central Diabetes Insipidus. In CDI, symptoms may develop over time or abruptly and may affect individuals of any age. CDI is characterized by excessive thirst (polydipsia) and excessive urination (polyuria), even at night (nocturia). The severity and progression of CDI varies from case to case. Some individuals may have a severe form of the disorder (complete CDI) with little or no vasopressin activity. Others may have a mild form of the disorder (partial CDI) with residual vasopressin activity.Without appropriate AVP secretion, individuals with central diabetes insipidus are unable to concentrate the urine by reabsorbing water in the kidneys. This results in obligatory excessive urine output of dilute urine. Consequently, individuals must drink excessively to prevent dehydration. In response to thirst, affected individuals may drink several gallons of water a day. If affected individuals are deprived of water for an extended period of time, rapid dehydration will occur. Thirst cravings can be strong enough to awaken people from sleep.In infants, additional symptoms may occur including irritability, lethargy, vomiting, constipation and fever. If left untreated, repeated episodes of dehydration can potentially result in seizures, brain damage, developmental delays, and physical and mental retardation. However, with proper diagnosis and prompt treatment intelligence and development is usually normal unless more global problems in development of the brain are associated. Affected children may develop bedwetting (enuresis), fatigue, weight loss, and growth retardation.Individuals with CDI are at risk of developing dehydration and cardiovascular symptoms including irregular heartbeats, fever, dry skin and mucous membranes, confusion, seizures, change in consciousness, and potentially coma. Affected adults may develop orthostatic hypotension, a condition in which there is a dramatic decrease in blood pressure upon standing or sitting. Orthostatic hypotension can result in dizziness or momentary loss of consciousness (syncope). | 212 | Central Diabetes Insipidus |
nord_212_2 | Causes of Central Diabetes Insipidus | CDI is caused by partial or complete deficiency of the antidiuretic hormone, arginine vasopressin. This deficiency usually results from damage to the hypothalamus or pituitary gland. In extremely rare cases, vasopressin deficiency is caused by a genetic mutation that is inherited as an autosomal dominant or autosomal recessive trait. In approximately one third of cases, no specific cause can be identified (idiopathic) and may be autoimmune in etiology.The hypothalamus is a portion of the brain that acts as a link between the brain and the endocrine systems. The hypothalamus releases neuro-hormones that influence the secretion of other hormones such as those that aid in the regulation of various metabolic process, growth, reproductive function and autonomic functions of the body. One of the substances secreted by the hypothalamus is vasopressin, which travels via nerve fibers to the posterior pituitary gland.The pituitary is a small gland located near the base of the brain that stores several hormones and releases them into the bloodstream as needed by the body. These hormones regulate many bodily functions. The posterior lobe of the pituitary gland is known as the neurophysis (neurohypophsyeal region), which stores hormones and eventually secretes them into the bloodstream. After the hypothalamus produces vasopressin, the hormone travels to the pituitary gland, and is stored in the neurophysis. Vasopressin is eventually released into the bloodstream as needed by the body. Vasopressin travels to the kidneys where it binds to receptor proteins found on the surface of certain kidney cells, initiating a process through which the kidneys reabsorb water into the body. Without proper levels of vasopressin, water is not reabsorbed and is lost through urination.Damage to the hypothalamus, pituitary gland or the connection between the hypothalamus and pituitary gland (pituitary stalk) may impair the production, transport, storage, or release of vasopressin, which in turn impairs the ability of the body to conserve water. Such damage may occur from trauma due to an accident or surgery (e.g., surgery to remove a tumor in the area), various infections, tumors such as a craniopharyngioma or a germinoma, a rare disease known as Langerhans cell histiocytosis, or a variety of inflammatory, vascular, or granulomatous diseases.In rare cases, CDI may be inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. Even rarer is an autosomal recessive mode of inheritance in which neither parent is affected but each carries an abnormal gene which when combined together in the offspring result in disease.Investigators have determined that some cases of inherited CDI are caused by disruptions or changes (mutations) of the arginine vasopressin (AVP) gene. Mutations of the AVP gene impair the production (synthesis) or secretion of vasopressin.The AVP gene is located on the short arm (p) of chromosome 20 (20p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human 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 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Researchers believe that some cases of idiopathic CDI may be caused by autoimmune factors. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. In CDI, the body produces antibodies or lymphocytes that attack cells that secrete vasopressin.CDI may also occur as part of a larger syndrome or disorder including Wolfram syndrome or septo-optic dysplasia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Causes of Central Diabetes Insipidus. CDI is caused by partial or complete deficiency of the antidiuretic hormone, arginine vasopressin. This deficiency usually results from damage to the hypothalamus or pituitary gland. In extremely rare cases, vasopressin deficiency is caused by a genetic mutation that is inherited as an autosomal dominant or autosomal recessive trait. In approximately one third of cases, no specific cause can be identified (idiopathic) and may be autoimmune in etiology.The hypothalamus is a portion of the brain that acts as a link between the brain and the endocrine systems. The hypothalamus releases neuro-hormones that influence the secretion of other hormones such as those that aid in the regulation of various metabolic process, growth, reproductive function and autonomic functions of the body. One of the substances secreted by the hypothalamus is vasopressin, which travels via nerve fibers to the posterior pituitary gland.The pituitary is a small gland located near the base of the brain that stores several hormones and releases them into the bloodstream as needed by the body. These hormones regulate many bodily functions. The posterior lobe of the pituitary gland is known as the neurophysis (neurohypophsyeal region), which stores hormones and eventually secretes them into the bloodstream. After the hypothalamus produces vasopressin, the hormone travels to the pituitary gland, and is stored in the neurophysis. Vasopressin is eventually released into the bloodstream as needed by the body. Vasopressin travels to the kidneys where it binds to receptor proteins found on the surface of certain kidney cells, initiating a process through which the kidneys reabsorb water into the body. Without proper levels of vasopressin, water is not reabsorbed and is lost through urination.Damage to the hypothalamus, pituitary gland or the connection between the hypothalamus and pituitary gland (pituitary stalk) may impair the production, transport, storage, or release of vasopressin, which in turn impairs the ability of the body to conserve water. Such damage may occur from trauma due to an accident or surgery (e.g., surgery to remove a tumor in the area), various infections, tumors such as a craniopharyngioma or a germinoma, a rare disease known as Langerhans cell histiocytosis, or a variety of inflammatory, vascular, or granulomatous diseases.In rare cases, CDI may be inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. Even rarer is an autosomal recessive mode of inheritance in which neither parent is affected but each carries an abnormal gene which when combined together in the offspring result in disease.Investigators have determined that some cases of inherited CDI are caused by disruptions or changes (mutations) of the arginine vasopressin (AVP) gene. Mutations of the AVP gene impair the production (synthesis) or secretion of vasopressin.The AVP gene is located on the short arm (p) of chromosome 20 (20p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human 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 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Researchers believe that some cases of idiopathic CDI may be caused by autoimmune factors. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. In CDI, the body produces antibodies or lymphocytes that attack cells that secrete vasopressin.CDI may also occur as part of a larger syndrome or disorder including Wolfram syndrome or septo-optic dysplasia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 212 | Central Diabetes Insipidus |
nord_212_3 | Affects of Central Diabetes Insipidus | CDI affects males and females in equal numbers and can occur at any age. Onset is more common between the ages of 10 and 20 years. The inherited form of CDI is extremely rare with fewer than 100 cases reported in the medical literature. CDI is estimated to occur in 1 out of every 25,000 individuals. | Affects of Central Diabetes Insipidus. CDI affects males and females in equal numbers and can occur at any age. Onset is more common between the ages of 10 and 20 years. The inherited form of CDI is extremely rare with fewer than 100 cases reported in the medical literature. CDI is estimated to occur in 1 out of every 25,000 individuals. | 212 | Central Diabetes Insipidus |
nord_212_4 | Related disorders of Central Diabetes Insipidus | Symptoms of the following disorders can be similar to those of CDI. Comparisons may be useful for a differential diagnosis.Nephrogenic diabetes insipidus (NDI) is a rare kidney disorder that may be inherited or acquired. NDI is caused by complete or partial resistance of the kidneys to arginine vasopressin (AVP). In this situation, the problem is not a defect in synthesis or secretion of vasopressin, but rather an inability of the kidney to respond to the vasopressin that is secreted. NDI causes chronic excessive thirst (polydipsia), excessive urine production (polyuria), and potentially dehydration. If left untreated, repeated episodes of severe dehydration may develop, eventually resulting in serious complications. Most cases of hereditary NDI are inherited as an X-linked recessive trait. Rare cases are inherited as an autosomal recessive or dominant trait. Two different genes have been identified that cause hereditary NDI: AVPR2 which codes for the vasopressin receptor and AQP2 which codes for acquaporin that facilitates water transport and reabsorption in the kidney. NDI may also be acquired during life as a result of drug use (e.g.,lithium therapy), kidney disease, obstruction of the tubes that carry urine from the kidneys to the bladder (ureters), and prolonged metabolic imbalances such as low levels of potassium in the blood (hypokalemia) or high levels of calcium in the blood (hypercalcemia). (For more information on this disorder, choose “nephrogenic diabetes insipidus” as your search term in the Rare Disease Database.)Diabetes mellitus (insulin dependent diabetes) is a common disorder in which the body does not produce enough insulin or is unable to properly use available insulin. Therefore, the body is not able to properly transport glucose (a form of suger) into the cells of the body. . The disorder has different etiologies: genetic and environmental. Although the most obvious symptoms are usually excessive thirst and urination, diabetes mellitus is not related to diabetes insipidus and therefore the treatments are different. (For more information on this disorder, choose “Diabetes Mellitus” as your search term in the Rare Disease Database.)Primary psychogenic polydipsia is a rare disorder in which individuals drink excessive amounts of water in the absence of any normal stimulus for thirst. Affected individuals will produce excessive amounts of urine (polyuria) because they drink excessively, not because they are unable to concentrate the urine. In response to the excessive intake of water, their pituitary secretes less vasopressin. Primary psychogenic polydipsia can potentially cause water intoxication – a condition that can cause serious complications. Some cases of primary psychogenic polydispsia occur as part of mental illness. In other cases, the cause is unknown. | Related disorders of Central Diabetes Insipidus. Symptoms of the following disorders can be similar to those of CDI. Comparisons may be useful for a differential diagnosis.Nephrogenic diabetes insipidus (NDI) is a rare kidney disorder that may be inherited or acquired. NDI is caused by complete or partial resistance of the kidneys to arginine vasopressin (AVP). In this situation, the problem is not a defect in synthesis or secretion of vasopressin, but rather an inability of the kidney to respond to the vasopressin that is secreted. NDI causes chronic excessive thirst (polydipsia), excessive urine production (polyuria), and potentially dehydration. If left untreated, repeated episodes of severe dehydration may develop, eventually resulting in serious complications. Most cases of hereditary NDI are inherited as an X-linked recessive trait. Rare cases are inherited as an autosomal recessive or dominant trait. Two different genes have been identified that cause hereditary NDI: AVPR2 which codes for the vasopressin receptor and AQP2 which codes for acquaporin that facilitates water transport and reabsorption in the kidney. NDI may also be acquired during life as a result of drug use (e.g.,lithium therapy), kidney disease, obstruction of the tubes that carry urine from the kidneys to the bladder (ureters), and prolonged metabolic imbalances such as low levels of potassium in the blood (hypokalemia) or high levels of calcium in the blood (hypercalcemia). (For more information on this disorder, choose “nephrogenic diabetes insipidus” as your search term in the Rare Disease Database.)Diabetes mellitus (insulin dependent diabetes) is a common disorder in which the body does not produce enough insulin or is unable to properly use available insulin. Therefore, the body is not able to properly transport glucose (a form of suger) into the cells of the body. . The disorder has different etiologies: genetic and environmental. Although the most obvious symptoms are usually excessive thirst and urination, diabetes mellitus is not related to diabetes insipidus and therefore the treatments are different. (For more information on this disorder, choose “Diabetes Mellitus” as your search term in the Rare Disease Database.)Primary psychogenic polydipsia is a rare disorder in which individuals drink excessive amounts of water in the absence of any normal stimulus for thirst. Affected individuals will produce excessive amounts of urine (polyuria) because they drink excessively, not because they are unable to concentrate the urine. In response to the excessive intake of water, their pituitary secretes less vasopressin. Primary psychogenic polydipsia can potentially cause water intoxication – a condition that can cause serious complications. Some cases of primary psychogenic polydispsia occur as part of mental illness. In other cases, the cause is unknown. | 212 | Central Diabetes Insipidus |
nord_212_5 | Diagnosis of Central Diabetes Insipidus | A diagnosis of CDI may be suspected based upon the identification of characteristic findings, specifically excessive thirst and excessive urination. A thorough clinical evaluation, a detailed patient history, and a variety of specialized tests may be used to confirm a diagnosis. Physicians may take blood and urine samples to determine the concentration of salts, and sugar within those samples. The ratio of these substances to water within the blood or urine is known as osmolality. Individuals with CDI have a high osmolality in their blood and a low osmolality in their urine. The urine osmolality may be estimated by the specific gravity, which is low in untreated diabetes insipidus.Additional tests may be necessary to confirm a diagnosis or rule out other causes of diabetes insipidus. Assay of vasopressin in the circulation is problematic since it is unstable and has a short half-life. Copeptin is cosecreted with vasopressin and is more stable. Therefore, it provides a surrogate marker of vasopressin secretion. Affected individuals may also receive a diagnostic injection of the hormone arginine vasopressin or an analogue of vasopressin such as DDAVP (see below) to determine the kidneys’ response. Individuals with a different form of diabetes insipidus (i.e., nephrogenic diabetes insipidus) do not respond to vasopressin supplementation because in NDI the kidneys are resistant to the effects of vasopressin. Conversely, individuals with CDI respond to supplemental vasopressin treatment.In some individuals an additional test, known as a water deprivation test, may be required to confirm a diagnosis. During this test, affected individuals cannot ingest any fluids and can only eat dry foods for a specific period of time. Blood and urine samples will be taken to measure serum sodium concentration or osmolality and urine output, osmolality or specific gravity. This dehydration provides a stimulus for vasopressin secretion which can be estimated by measuring copeptin concentrations or by the concentration of the urine. Serum vasopressin levels may be measured as well if handled appropriately. Body weight and vital signs are monitored to prevent excessive dehydration. This test may be used to distinguish between the various causes of diabetes insipidus.Some individuals will have x-ray scans including computed tomography (CT scan) or magnetic resonance imaging (MRI) to rule out brain tumors that can affect the pituitary gland, a potential cause of CDI. A common finding on MRI in children with central diabetes insipidus is absence of the “bright spot” in the posterior sella which is normally thought to represent vasopressin containing neurons. | Diagnosis of Central Diabetes Insipidus. A diagnosis of CDI may be suspected based upon the identification of characteristic findings, specifically excessive thirst and excessive urination. A thorough clinical evaluation, a detailed patient history, and a variety of specialized tests may be used to confirm a diagnosis. Physicians may take blood and urine samples to determine the concentration of salts, and sugar within those samples. The ratio of these substances to water within the blood or urine is known as osmolality. Individuals with CDI have a high osmolality in their blood and a low osmolality in their urine. The urine osmolality may be estimated by the specific gravity, which is low in untreated diabetes insipidus.Additional tests may be necessary to confirm a diagnosis or rule out other causes of diabetes insipidus. Assay of vasopressin in the circulation is problematic since it is unstable and has a short half-life. Copeptin is cosecreted with vasopressin and is more stable. Therefore, it provides a surrogate marker of vasopressin secretion. Affected individuals may also receive a diagnostic injection of the hormone arginine vasopressin or an analogue of vasopressin such as DDAVP (see below) to determine the kidneys’ response. Individuals with a different form of diabetes insipidus (i.e., nephrogenic diabetes insipidus) do not respond to vasopressin supplementation because in NDI the kidneys are resistant to the effects of vasopressin. Conversely, individuals with CDI respond to supplemental vasopressin treatment.In some individuals an additional test, known as a water deprivation test, may be required to confirm a diagnosis. During this test, affected individuals cannot ingest any fluids and can only eat dry foods for a specific period of time. Blood and urine samples will be taken to measure serum sodium concentration or osmolality and urine output, osmolality or specific gravity. This dehydration provides a stimulus for vasopressin secretion which can be estimated by measuring copeptin concentrations or by the concentration of the urine. Serum vasopressin levels may be measured as well if handled appropriately. Body weight and vital signs are monitored to prevent excessive dehydration. This test may be used to distinguish between the various causes of diabetes insipidus.Some individuals will have x-ray scans including computed tomography (CT scan) or magnetic resonance imaging (MRI) to rule out brain tumors that can affect the pituitary gland, a potential cause of CDI. A common finding on MRI in children with central diabetes insipidus is absence of the “bright spot” in the posterior sella which is normally thought to represent vasopressin containing neurons. | 212 | Central Diabetes Insipidus |
nord_212_6 | Therapies of Central Diabetes Insipidus | TreatmentEnsuring proper fluid intake and reducing urine output are essential. Specific treatments include the administration of certain drugs. Specific therapy varies depending upon the severity of vasopressin deficiency. Individuals with the severe form of the disorder may receive replacement therapy with a synthetic form of vasopressin known as desmopressin (DDAVP, 1-desamino-8-D-arginine vasopressin). Desmopressin may be taken orally, injected, or used as a nasal spray.Individuals with partial CDI and residual vasopressin activity may be treated with other drugs such as hydrochlorothiazide. Infants with diabetes insipidus are particularly problematic and may be treated by diluting the formula with water and with hydrochlorothiazide. DDAVP must be used with caution in this age group since infants have an obligate liquid intake to provide adequate calories for growth.In cases of hereditary CDI, genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Central Diabetes Insipidus. TreatmentEnsuring proper fluid intake and reducing urine output are essential. Specific treatments include the administration of certain drugs. Specific therapy varies depending upon the severity of vasopressin deficiency. Individuals with the severe form of the disorder may receive replacement therapy with a synthetic form of vasopressin known as desmopressin (DDAVP, 1-desamino-8-D-arginine vasopressin). Desmopressin may be taken orally, injected, or used as a nasal spray.Individuals with partial CDI and residual vasopressin activity may be treated with other drugs such as hydrochlorothiazide. Infants with diabetes insipidus are particularly problematic and may be treated by diluting the formula with water and with hydrochlorothiazide. DDAVP must be used with caution in this age group since infants have an obligate liquid intake to provide adequate calories for growth.In cases of hereditary CDI, genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | 212 | Central Diabetes Insipidus |
nord_213_0 | Overview of Centronuclear Myopathy | SummaryCentronuclear myopathy (CNM) is an umbrella term for a group of rare genetic muscle disorders. These disorders are characterized by muscle weakness that can range from mild to profound. Symptoms are often present at birth in the severe forms, but may first develop at any point during life, although onset in adulthood is unusual. CNMs derive their name based on the central location of the muscle fiber (muscle cell) nucleus, which is an abnormal finding that can be seen in muscle biopsies. Muscle fiber nuclei are normally located at the periphery of the muscle fiber. Centrally placed nuclei can be seen when examining muscle biopsy tissue in the microscope and this feature is an important finding to recognize in making a diagnosis of CNM.There are several genetic forms of CNM including an X-linked form known as myotubular myopathy (XLMTM) and a few autosomal forms, usually referred to as centronuclear myopathy. Autosomal refers to genes that are found on autosomes, or chromosomes other than the X or Y chromosomes (sex chromosomes). Generally, the autosomal forms are less severe than XLMTM, however, in rare cases, individuals with an autosomal form can develop severe complications that are similar to those seen in XLMTM.Common symptoms include mild to profound muscle weakness and diminished muscle tone (hypotonia). In more severe cases, feeding difficulties and potentially severe breathing complications (respiratory distress) may occur. Feeding difficulties and respiratory distress develop because of weakness of the muscles that are involved in swallowing and breathing. Involvement of the muscles controlling eye movements is common in all different forms. The overall severity of the disorder can range from mildly affected individuals to individuals who develop severe, life-threatening complications during infancy and early childhood. Three different genes, DNM2, BIN1, and RYR1, have been identified that cause autosomal forms of CNM. XLMTM is caused by mutations to the myotubularin (MTM1) gene.IntroductionCentronuclear myopathies are a group of muscle diseases that are considered part of a larger family of muscle diseases known as congenital myopathies, a group of genetic muscle disorder that are evident at or around the time of birth. In the medical literature, centronuclear myopathy (CNM) is generally used for the autosomal forms of the disorder and myotubular myopathy is generally used for the X-linked form (XLMTM). Distinguishing between the X-linked myotubular form and the autosomal forms of CNM is essential as the symptoms are usually more severe in the X-linked form. NORD has a separate report on X-linked myotubular myopathy that describes that form in greater detail. This report specifically deals with the autosomal forms of centronuclear myopathy. | Overview of Centronuclear Myopathy. SummaryCentronuclear myopathy (CNM) is an umbrella term for a group of rare genetic muscle disorders. These disorders are characterized by muscle weakness that can range from mild to profound. Symptoms are often present at birth in the severe forms, but may first develop at any point during life, although onset in adulthood is unusual. CNMs derive their name based on the central location of the muscle fiber (muscle cell) nucleus, which is an abnormal finding that can be seen in muscle biopsies. Muscle fiber nuclei are normally located at the periphery of the muscle fiber. Centrally placed nuclei can be seen when examining muscle biopsy tissue in the microscope and this feature is an important finding to recognize in making a diagnosis of CNM.There are several genetic forms of CNM including an X-linked form known as myotubular myopathy (XLMTM) and a few autosomal forms, usually referred to as centronuclear myopathy. Autosomal refers to genes that are found on autosomes, or chromosomes other than the X or Y chromosomes (sex chromosomes). Generally, the autosomal forms are less severe than XLMTM, however, in rare cases, individuals with an autosomal form can develop severe complications that are similar to those seen in XLMTM.Common symptoms include mild to profound muscle weakness and diminished muscle tone (hypotonia). In more severe cases, feeding difficulties and potentially severe breathing complications (respiratory distress) may occur. Feeding difficulties and respiratory distress develop because of weakness of the muscles that are involved in swallowing and breathing. Involvement of the muscles controlling eye movements is common in all different forms. The overall severity of the disorder can range from mildly affected individuals to individuals who develop severe, life-threatening complications during infancy and early childhood. Three different genes, DNM2, BIN1, and RYR1, have been identified that cause autosomal forms of CNM. XLMTM is caused by mutations to the myotubularin (MTM1) gene.IntroductionCentronuclear myopathies are a group of muscle diseases that are considered part of a larger family of muscle diseases known as congenital myopathies, a group of genetic muscle disorder that are evident at or around the time of birth. In the medical literature, centronuclear myopathy (CNM) is generally used for the autosomal forms of the disorder and myotubular myopathy is generally used for the X-linked form (XLMTM). Distinguishing between the X-linked myotubular form and the autosomal forms of CNM is essential as the symptoms are usually more severe in the X-linked form. NORD has a separate report on X-linked myotubular myopathy that describes that form in greater detail. This report specifically deals with the autosomal forms of centronuclear myopathy. | 213 | Centronuclear Myopathy |
nord_213_1 | Symptoms of Centronuclear Myopathy | The specific symptoms and severity of CNMs can vary greatly among the different forms and from one person to another. Some individuals may only develop mild symptoms; others develop serious life-threatening complications. Unlike the X-linked form, the autosomal dominant form of CNM is rarely fatal during childhood. The autosomal recessive forms can be severe or mild. The course of an individual case is often unpredictable. Because of the variable nature of these disorders, parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.DNM2-RELATED CNM
This form of CNM is caused by mutations of the DNM2 gene and is highly variable in presentation and severity. The disorder can be present at birth or develop during childhood or even adulthood. Some individuals will have mild cases that go unnoticed for prolonged periods; others will have symptoms that are present in infancy or early childhood.Many individuals with DNM2-related CNM have a mild form of the disorder and early development is normal. Symptoms may not develop until adolescence when abnormal fatigue, muscle pain (myalgia) and leg cramps may occur especially when exercising. Muscle weakness associated with DNM2-related CNM can be slowly progressive often during the teen-age years or even during adulthood. Often, weakness predominantly affects the upper legs or arms (proximally), but in some cases can start in the lower arms and legs (distally) and slowly progress to affect the upper arms and legs. Some individuals may experience delays in attaining certain developmental milestones such as walking, running or climbing stairs. Some individuals may have slowly progressive difficulty walking as they grow older. Ultimately, some affected individuals have lost the ability to walk, but this usually does not occur before the 6th decade of life.Some affected individuals may develop drooping of the upper eyelid (ptosis) and complete or partial paralysis of the muscles that control the movements of the eyes (ophthalmoplegia).
When DNM2-related CNM occurs during infancy or early childhood common symptoms include hypotonia, generalized weakness, facial muscle weakness, ptosis, and ophthalmoplegia. Affected children may exhibit delays in attaining motor milestones, such as holding their head up. Facial weakness can cause infants to have a weak sucking ability and/or experience difficulties swallowing, potentially resulting in feeding difficulties. Eventually, affected individuals can develop breathing (respiratory) complications.Additional symptoms have been reported in some individuals with DNM2-related CNM including cataracts, an increase in the size of skeletal muscle (muscle hypertrophy), a reduced jaw opening, a mildly high arch of the foot (pes cavus) and abnormal side-to-side curvature of the spine (scoliosis). Contractures of the Achilles tendon can also occur. A contracture is defined as shortening or hardening of muscle or tendon tissue that causes deformity and restricts the movements of affected areas, especially the joints.BIN1-RELATED CNM
This form of CNM is caused by mutations of the BIN1 gene and is inherited as an autosomal recessive condition. The symptoms of this disorder can vary greatly from one person to another and the severity can range from mildly affected individuals to those with severe, life-threatening complications early in life. However, relatively few families with BIN1-related CNM have been reported to date and the full spectrum of manifestations may not be known yet.BIN1-related CNM may be present at birth or during early childhood. Overall, the severity of muscle weakness can vary. Affected individuals have mildly progressive muscle weakness. Facial muscle weakness is usually present and affected infants or children may exhibit ptosis or ophthalmoplegia. The muscles used for chewing (mastication) may be particularly involved in some cases. Weakness predominantly affects the muscles of the upper arms and legs (proximally), but can potentially affect the muscles of the lower arms and legs as well (distally). Loss of muscle tissue mass (atrophy) may also occur. Some individuals will not experience respiratory involvement; others will experience potentially severe respiratory difficulties requiring ventilation. Feeding difficulties can also occur. Some individuals will experience delays in attaining developmental milestones such as sitting up, walking, or climbing stairs. In the severe form of BIN1-related CNM, progressive muscle weakness can result in difficulty walking and some individuals may lose the ability to walk unassisted by their 20s.Individuals with early onset BIN1-related CNM may develop distinctive facial features including a long face and a highly arched palate.Affected individuals may also exhibit skeletal abnormalities including a high arch of the foot (pes cavus), clubfoot, joint contractures, and side-to-side curvature of the spine (scoliosis) or abnormal front-to-back curvature of the spine (kyphosis).Individuals with later onset of BIN1-related CNM typically do not exhibit ophthalmoplegia and may not have distinctive facial features. These individuals usually develop mild, slowly progressive muscle weakness that particularly affects the proximal muscles of the arms and legs. Some individuals may go undiagnosed until adulthood because the symptoms are subtle and cause little difficulty.RYR1-RELATED CNM
Most cases of this form of CNM tend to fall somewhere in between the severe or mild ends of the CNM spectrum. Many affected infants are profoundly hypotonic and weak at birth. However, some of these infants may improve significantly over time. Muscle weakness predominantly affects the proximal and axial muscles. Feeding difficulties and frequent respiratory infections may affect infants with RYR1-related CNM. Delays in attaining developmental milestones such as walking and climbing stairs may also occur.Most affected individuals have distinctive facial features such as a V-shaped mouth. Additional symptoms that have been reported include scoliosis, absent reflexes, ophthalmoplegia, and bilateral ptosis. Some individuals may develop contractures. In some cases, individuals who experience profound difficulties at birth improve and only have mild issues during their teen-aged years.At least one male child with RYR1-related CNM developed a severe form of the disorder and was initially diagnosed with X-linked myotubular myopathy before being identified as having a mutation in the RYR1 gene. | Symptoms of Centronuclear Myopathy. The specific symptoms and severity of CNMs can vary greatly among the different forms and from one person to another. Some individuals may only develop mild symptoms; others develop serious life-threatening complications. Unlike the X-linked form, the autosomal dominant form of CNM is rarely fatal during childhood. The autosomal recessive forms can be severe or mild. The course of an individual case is often unpredictable. Because of the variable nature of these disorders, parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.DNM2-RELATED CNM
This form of CNM is caused by mutations of the DNM2 gene and is highly variable in presentation and severity. The disorder can be present at birth or develop during childhood or even adulthood. Some individuals will have mild cases that go unnoticed for prolonged periods; others will have symptoms that are present in infancy or early childhood.Many individuals with DNM2-related CNM have a mild form of the disorder and early development is normal. Symptoms may not develop until adolescence when abnormal fatigue, muscle pain (myalgia) and leg cramps may occur especially when exercising. Muscle weakness associated with DNM2-related CNM can be slowly progressive often during the teen-age years or even during adulthood. Often, weakness predominantly affects the upper legs or arms (proximally), but in some cases can start in the lower arms and legs (distally) and slowly progress to affect the upper arms and legs. Some individuals may experience delays in attaining certain developmental milestones such as walking, running or climbing stairs. Some individuals may have slowly progressive difficulty walking as they grow older. Ultimately, some affected individuals have lost the ability to walk, but this usually does not occur before the 6th decade of life.Some affected individuals may develop drooping of the upper eyelid (ptosis) and complete or partial paralysis of the muscles that control the movements of the eyes (ophthalmoplegia).
When DNM2-related CNM occurs during infancy or early childhood common symptoms include hypotonia, generalized weakness, facial muscle weakness, ptosis, and ophthalmoplegia. Affected children may exhibit delays in attaining motor milestones, such as holding their head up. Facial weakness can cause infants to have a weak sucking ability and/or experience difficulties swallowing, potentially resulting in feeding difficulties. Eventually, affected individuals can develop breathing (respiratory) complications.Additional symptoms have been reported in some individuals with DNM2-related CNM including cataracts, an increase in the size of skeletal muscle (muscle hypertrophy), a reduced jaw opening, a mildly high arch of the foot (pes cavus) and abnormal side-to-side curvature of the spine (scoliosis). Contractures of the Achilles tendon can also occur. A contracture is defined as shortening or hardening of muscle or tendon tissue that causes deformity and restricts the movements of affected areas, especially the joints.BIN1-RELATED CNM
This form of CNM is caused by mutations of the BIN1 gene and is inherited as an autosomal recessive condition. The symptoms of this disorder can vary greatly from one person to another and the severity can range from mildly affected individuals to those with severe, life-threatening complications early in life. However, relatively few families with BIN1-related CNM have been reported to date and the full spectrum of manifestations may not be known yet.BIN1-related CNM may be present at birth or during early childhood. Overall, the severity of muscle weakness can vary. Affected individuals have mildly progressive muscle weakness. Facial muscle weakness is usually present and affected infants or children may exhibit ptosis or ophthalmoplegia. The muscles used for chewing (mastication) may be particularly involved in some cases. Weakness predominantly affects the muscles of the upper arms and legs (proximally), but can potentially affect the muscles of the lower arms and legs as well (distally). Loss of muscle tissue mass (atrophy) may also occur. Some individuals will not experience respiratory involvement; others will experience potentially severe respiratory difficulties requiring ventilation. Feeding difficulties can also occur. Some individuals will experience delays in attaining developmental milestones such as sitting up, walking, or climbing stairs. In the severe form of BIN1-related CNM, progressive muscle weakness can result in difficulty walking and some individuals may lose the ability to walk unassisted by their 20s.Individuals with early onset BIN1-related CNM may develop distinctive facial features including a long face and a highly arched palate.Affected individuals may also exhibit skeletal abnormalities including a high arch of the foot (pes cavus), clubfoot, joint contractures, and side-to-side curvature of the spine (scoliosis) or abnormal front-to-back curvature of the spine (kyphosis).Individuals with later onset of BIN1-related CNM typically do not exhibit ophthalmoplegia and may not have distinctive facial features. These individuals usually develop mild, slowly progressive muscle weakness that particularly affects the proximal muscles of the arms and legs. Some individuals may go undiagnosed until adulthood because the symptoms are subtle and cause little difficulty.RYR1-RELATED CNM
Most cases of this form of CNM tend to fall somewhere in between the severe or mild ends of the CNM spectrum. Many affected infants are profoundly hypotonic and weak at birth. However, some of these infants may improve significantly over time. Muscle weakness predominantly affects the proximal and axial muscles. Feeding difficulties and frequent respiratory infections may affect infants with RYR1-related CNM. Delays in attaining developmental milestones such as walking and climbing stairs may also occur.Most affected individuals have distinctive facial features such as a V-shaped mouth. Additional symptoms that have been reported include scoliosis, absent reflexes, ophthalmoplegia, and bilateral ptosis. Some individuals may develop contractures. In some cases, individuals who experience profound difficulties at birth improve and only have mild issues during their teen-aged years.At least one male child with RYR1-related CNM developed a severe form of the disorder and was initially diagnosed with X-linked myotubular myopathy before being identified as having a mutation in the RYR1 gene. | 213 | Centronuclear Myopathy |
nord_213_2 | Causes of Centronuclear Myopathy | Centronuclear myopathies are caused by a mutation in a specific gene. The autosomal forms are denoted by their associated gene. DNM2-related myopathy is caused by a mutation in the dynamin 2 (DNM2) gene and is inherited as an autosomal dominant condition. Some cases of DNM2-related CNM may occur spontaneously (sporadically) with no previous family history of the disorder (i.e. new mutations). BIN1-related CNM is caused by mutations to the amphiphysin 2 (BIN1) gene and is inherited as an autosomal recessive condition. RYR1-related CNM is caused by mutations to the skeletal muscle ryanodine receptor (RYR1) gene and is thought to be inherited as an autosomal recessive condition.Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The protein products produced by the genes associated with the various forms of centronuclear myopathy are believed to be critical for the proper development, maintenance, and function of muscle tissue. The exact, specific functions of these proteins are not fully understood.Each individual receives a separate set of genes from each of their parents. 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 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. 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 mutated (changed) 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.Mutations in the genes that cause CNM have also been associated with other disorders (allelic disorders). Mutations in the DNM2 gene are also associated with specific forms of Charcot Marie Tooth disease. Mutations in the RYR1 gene are also associated with other forms of congenital myopathies, namely central core disease, multi-minicore disease, and congenital fiber-type disproportion, and a susceptibility to malignant hyperthermia, a genetically determined adverse reaction to certain anesthetics and muscle relaxants. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Other genes that may be associated with CNM include the gene known as the myotubularin-related protein 14 (hJumpy) gene, the SPEG gene and the TTN gene. Researchers are unsure whether these genes can directly cause CNM or are modifier genes that influences the expression of the disorder in individuals with a different mutation.One person has been identified with a mutation in the myogenic factor 6 (MYF6) gene located on chromosome 12. Mutations in the CCDC78 gene have (August 2012) been reported in one family with a unique form of congenital myopathy with central nuclei. It is important to note that mutations in these genes have been reported in a limited number of patients. Some individuals with a diagnosis of CNM (based upon muscle biopsy results) do not have an identifiable mutation in any of the genes known to be associated with CNM. This may be due to specific mutations that are undetectable by current testing methods, but also suggests that additional, as-yet-unidentified genes may also cause CNM. More research is necessary to fully understand the complex genetics factors associated with CNM. | Causes of Centronuclear Myopathy. Centronuclear myopathies are caused by a mutation in a specific gene. The autosomal forms are denoted by their associated gene. DNM2-related myopathy is caused by a mutation in the dynamin 2 (DNM2) gene and is inherited as an autosomal dominant condition. Some cases of DNM2-related CNM may occur spontaneously (sporadically) with no previous family history of the disorder (i.e. new mutations). BIN1-related CNM is caused by mutations to the amphiphysin 2 (BIN1) gene and is inherited as an autosomal recessive condition. RYR1-related CNM is caused by mutations to the skeletal muscle ryanodine receptor (RYR1) gene and is thought to be inherited as an autosomal recessive condition.Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The protein products produced by the genes associated with the various forms of centronuclear myopathy are believed to be critical for the proper development, maintenance, and function of muscle tissue. The exact, specific functions of these proteins are not fully understood.Each individual receives a separate set of genes from each of their parents. 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 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. 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 mutated (changed) 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.Mutations in the genes that cause CNM have also been associated with other disorders (allelic disorders). Mutations in the DNM2 gene are also associated with specific forms of Charcot Marie Tooth disease. Mutations in the RYR1 gene are also associated with other forms of congenital myopathies, namely central core disease, multi-minicore disease, and congenital fiber-type disproportion, and a susceptibility to malignant hyperthermia, a genetically determined adverse reaction to certain anesthetics and muscle relaxants. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Other genes that may be associated with CNM include the gene known as the myotubularin-related protein 14 (hJumpy) gene, the SPEG gene and the TTN gene. Researchers are unsure whether these genes can directly cause CNM or are modifier genes that influences the expression of the disorder in individuals with a different mutation.One person has been identified with a mutation in the myogenic factor 6 (MYF6) gene located on chromosome 12. Mutations in the CCDC78 gene have (August 2012) been reported in one family with a unique form of congenital myopathy with central nuclei. It is important to note that mutations in these genes have been reported in a limited number of patients. Some individuals with a diagnosis of CNM (based upon muscle biopsy results) do not have an identifiable mutation in any of the genes known to be associated with CNM. This may be due to specific mutations that are undetectable by current testing methods, but also suggests that additional, as-yet-unidentified genes may also cause CNM. More research is necessary to fully understand the complex genetics factors associated with CNM. | 213 | Centronuclear Myopathy |
nord_213_3 | Affects of Centronuclear Myopathy | Autosomal forms of CNM affect males and females in equal numbers. The disorders are often present at birth, but in mild cases may go undiagnosed into adulthood. The exact incidence of these disorders is unknown. More than 100 families have been reported in the medical literature with DNM2-related CNM. Both BIN1-related CNM and RYR1-related CNM have been reported in fewer than 50 individuals respectively. Because these disorders may go undiagnosed or misdiagnosed, it is difficult to determine the true frequency of CNMs in the general population. | Affects of Centronuclear Myopathy. Autosomal forms of CNM affect males and females in equal numbers. The disorders are often present at birth, but in mild cases may go undiagnosed into adulthood. The exact incidence of these disorders is unknown. More than 100 families have been reported in the medical literature with DNM2-related CNM. Both BIN1-related CNM and RYR1-related CNM have been reported in fewer than 50 individuals respectively. Because these disorders may go undiagnosed or misdiagnosed, it is difficult to determine the true frequency of CNMs in the general population. | 213 | Centronuclear Myopathy |
nord_213_4 | Related disorders of Centronuclear Myopathy | Symptoms of the following disorders can be similar to those of CNM. Comparisons may be useful for a differential diagnosis.X-linked myotubular myopathy (XLMTM) is a rare genetic neuromuscular disorder that is characterized by muscle weakness that is often profound. Symptoms are often present at birth, but in rare cases may first develop during infancy or early childhood. Common symptoms include mild to profound muscle weakness, diminished muscle tone (hypotonia), feeding difficulties, and potentially severe breathing complications (respiratory distress) requiring ventilator support. Feeding difficulties and respiratory distress develop because of weakness of the muscles that are involved in swallowing and breathing. Most affected males have a severe form of the disorder and respiratory failure is an almost uniform occurrence, although milder presentations have been recognized. XLMTM is caused by mutations to the myotubularin (MTM1) gene. The disorder is inherited as an X-linked recessive condition. The disorder predominantly affects males, but female carriers can develop mild symptoms. In rare specific cases, females can develop a severe form similar to that seen in males, usually due to the presence of other genetic abnormalities affecting the X-chromosomes. (For more information on this disorder, choose “X-linked myotubular myopathy” as your search term in the Rare Disease Database.)Congenital myopathy is a group of muscle disorders (myopathies) that are present at birth (congenital). These conditions are distinguished from other early-onset muscle disorders (such as the congenital muscular dystrophies) on the pattern of changes seen on a muscle biopsy and, in most cases, normal creatine kinase (CK) blood levels on laboratory investigations. These disorders are characterized by muscle weakness, loss of muscle tone (hypotonia), diminished reflexes, and delays in reaching motor milestones (e.g., walking). In some disorders, muscle weakness is progressive, particularly weakness affecting the respiratory muscles. The severity of these disorders can range from mild cases to those associated with severe, life-threatening complications. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, minimulticore myopathy, and the centronuclear myopathies. Congenital myopathies are usually apparent in the newborn (neonatal) period, but may present much later in life even in adulthood. Inheritance of these disorders is either autosomal recessive or autosomal dominant or X-linked. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Congenital myasthenic syndromes are a group of rare genetic disorders characterized by abnormalities affecting the neuromuscular junction, which is the point where the nerve and muscle cells meet. The underlying defect in these disorders can involve the part of the neuromuscular junction located on the nerve cell, the muscle cells, or the space in between. These disorders are characterized by muscle weakness and fatigue of the skeletal muscle. Onset is usually at birth or during infancy or early childhood. The severity of these disorders is highly variable, ranging from mild symptoms to severe, disabling symptoms. Symptoms that can be associated with these disorders include respiratory insufficiency or distress, feeding difficulties, reduced eye movements (ophthalmoplegia), drooping of the upper eyelids (ptosis), and multiple joint contractures. Affected infants and children may exhibit delays in attaining motor milestones. They may fatigue rapidly from normal activities such as climbing stairs or running. Additional symptoms are usually present as well. Congenital myasthenic syndromes can be inherited as autosomal recessive conditions or, less frequently, as autosomal dominant conditions. | Related disorders of Centronuclear Myopathy. Symptoms of the following disorders can be similar to those of CNM. Comparisons may be useful for a differential diagnosis.X-linked myotubular myopathy (XLMTM) is a rare genetic neuromuscular disorder that is characterized by muscle weakness that is often profound. Symptoms are often present at birth, but in rare cases may first develop during infancy or early childhood. Common symptoms include mild to profound muscle weakness, diminished muscle tone (hypotonia), feeding difficulties, and potentially severe breathing complications (respiratory distress) requiring ventilator support. Feeding difficulties and respiratory distress develop because of weakness of the muscles that are involved in swallowing and breathing. Most affected males have a severe form of the disorder and respiratory failure is an almost uniform occurrence, although milder presentations have been recognized. XLMTM is caused by mutations to the myotubularin (MTM1) gene. The disorder is inherited as an X-linked recessive condition. The disorder predominantly affects males, but female carriers can develop mild symptoms. In rare specific cases, females can develop a severe form similar to that seen in males, usually due to the presence of other genetic abnormalities affecting the X-chromosomes. (For more information on this disorder, choose “X-linked myotubular myopathy” as your search term in the Rare Disease Database.)Congenital myopathy is a group of muscle disorders (myopathies) that are present at birth (congenital). These conditions are distinguished from other early-onset muscle disorders (such as the congenital muscular dystrophies) on the pattern of changes seen on a muscle biopsy and, in most cases, normal creatine kinase (CK) blood levels on laboratory investigations. These disorders are characterized by muscle weakness, loss of muscle tone (hypotonia), diminished reflexes, and delays in reaching motor milestones (e.g., walking). In some disorders, muscle weakness is progressive, particularly weakness affecting the respiratory muscles. The severity of these disorders can range from mild cases to those associated with severe, life-threatening complications. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, minimulticore myopathy, and the centronuclear myopathies. Congenital myopathies are usually apparent in the newborn (neonatal) period, but may present much later in life even in adulthood. Inheritance of these disorders is either autosomal recessive or autosomal dominant or X-linked. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Congenital myasthenic syndromes are a group of rare genetic disorders characterized by abnormalities affecting the neuromuscular junction, which is the point where the nerve and muscle cells meet. The underlying defect in these disorders can involve the part of the neuromuscular junction located on the nerve cell, the muscle cells, or the space in between. These disorders are characterized by muscle weakness and fatigue of the skeletal muscle. Onset is usually at birth or during infancy or early childhood. The severity of these disorders is highly variable, ranging from mild symptoms to severe, disabling symptoms. Symptoms that can be associated with these disorders include respiratory insufficiency or distress, feeding difficulties, reduced eye movements (ophthalmoplegia), drooping of the upper eyelids (ptosis), and multiple joint contractures. Affected infants and children may exhibit delays in attaining motor milestones. They may fatigue rapidly from normal activities such as climbing stairs or running. Additional symptoms are usually present as well. Congenital myasthenic syndromes can be inherited as autosomal recessive conditions or, less frequently, as autosomal dominant conditions. | 213 | Centronuclear Myopathy |
nord_213_5 | Diagnosis of Centronuclear Myopathy | CNM should be suspected in newborns with hypotonia and muscle weakness and older children or adults with weakness in the arms and legs. A diagnosis is based upon identification of additional characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests.Clinical Testing and Workup
A muscle biopsy may be performed to aid in obtaining a diagnosis. A biopsy involves surgical removal of a small sample of affected muscle tissue and examining the sample under a microscope. This allows physicians to note the characteristic, microscopic changes to muscle tissue, specifically the presence of the nucleus in the center of the muscle fiber (muscle cell) rather than toward the edge.Specialized imaging techniques such as a muscle MRI (magnetic resonance imaging) may be used to inform the choice of genetic testing in different forms of CNM, particularly in DNM2– and RYR1-related CNM. An MRI uses a magnetic field to produce cross-sectional images of particular organs and bodily tissues such as skeletal muscle tissue.A diagnosis of CNM can be confirmed through molecular genetic testing, which can detect the characteristic gene mutation that causes specific forms of the disorder. Molecular genetic testing is available as a diagnostic service at specialized laboratories. | Diagnosis of Centronuclear Myopathy. CNM should be suspected in newborns with hypotonia and muscle weakness and older children or adults with weakness in the arms and legs. A diagnosis is based upon identification of additional characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests.Clinical Testing and Workup
A muscle biopsy may be performed to aid in obtaining a diagnosis. A biopsy involves surgical removal of a small sample of affected muscle tissue and examining the sample under a microscope. This allows physicians to note the characteristic, microscopic changes to muscle tissue, specifically the presence of the nucleus in the center of the muscle fiber (muscle cell) rather than toward the edge.Specialized imaging techniques such as a muscle MRI (magnetic resonance imaging) may be used to inform the choice of genetic testing in different forms of CNM, particularly in DNM2– and RYR1-related CNM. An MRI uses a magnetic field to produce cross-sectional images of particular organs and bodily tissues such as skeletal muscle tissue.A diagnosis of CNM can be confirmed through molecular genetic testing, which can detect the characteristic gene mutation that causes specific forms of the disorder. Molecular genetic testing is available as a diagnostic service at specialized laboratories. | 213 | Centronuclear Myopathy |
nord_213_6 | Therapies of Centronuclear Myopathy | Treatment
The treatment of CNM is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists with expertise in treating neuromuscular disorders. Pediatricians, pulmonologists, neurologists, orthopedists, eye specialists, dental specialists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.Some individuals may not require ventilation assistance. Other individuals may only need ventilation-assistance for a specific period of time (e.g. infancy) or at night when asleep. Individuals with severe forms of CNM will require prolonged, constant ventilation support. There are different methods for ventilation including noninvasive and invasive techniques. The decision about the type of ventilation and the duration of respiratory support is best made by the family in careful consultation with the patient’s physicians and other members of the healthcare team based upon the specifics of their case.In some individuals feeding difficulties will require the insertion of a feeding tube (gastrostomy). This procedure involves inserting a tube directly into the stomach through a small surgical opening in the abdominal wall.Physical and occupational therapy is recommended to improve muscle strength and prevent contractures. Special measures may be necessary to allow ventilator-dependent individuals to communicate. Additional therapies are symptomatic and supportive. For example, scoliosis may require surgical intervention.Mutations in the RYR1 gene may be associated with a susceptibility to malignant hyperthermia, a potential life-threatening condition in which individuals experience a fast rise in body temperature and severe muscle contractions when under general anesthesia. Although no individuals with RYR1-related CNM are known to have developed malignant hyperthermia, physicians need to be aware of the potential risk and plan treatment accordingly. Consultation with a specialist center experienced in the diagnosis and management of malignant hyperthermia may also be advisable. | Therapies of Centronuclear Myopathy. Treatment
The treatment of CNM is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists with expertise in treating neuromuscular disorders. Pediatricians, pulmonologists, neurologists, orthopedists, eye specialists, dental specialists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.Some individuals may not require ventilation assistance. Other individuals may only need ventilation-assistance for a specific period of time (e.g. infancy) or at night when asleep. Individuals with severe forms of CNM will require prolonged, constant ventilation support. There are different methods for ventilation including noninvasive and invasive techniques. The decision about the type of ventilation and the duration of respiratory support is best made by the family in careful consultation with the patient’s physicians and other members of the healthcare team based upon the specifics of their case.In some individuals feeding difficulties will require the insertion of a feeding tube (gastrostomy). This procedure involves inserting a tube directly into the stomach through a small surgical opening in the abdominal wall.Physical and occupational therapy is recommended to improve muscle strength and prevent contractures. Special measures may be necessary to allow ventilator-dependent individuals to communicate. Additional therapies are symptomatic and supportive. For example, scoliosis may require surgical intervention.Mutations in the RYR1 gene may be associated with a susceptibility to malignant hyperthermia, a potential life-threatening condition in which individuals experience a fast rise in body temperature and severe muscle contractions when under general anesthesia. Although no individuals with RYR1-related CNM are known to have developed malignant hyperthermia, physicians need to be aware of the potential risk and plan treatment accordingly. Consultation with a specialist center experienced in the diagnosis and management of malignant hyperthermia may also be advisable. | 213 | Centronuclear Myopathy |
nord_214_0 | Overview of Cerebellar Agenesis | Cerebellar agenesis is an extremely rare condition. Cerebellar agenesis is a descriptive term implying complete absence of the cerebellum, irrespective of its underlying cause (etiology). Usually, small remnants of the cerebellum are present; therefore, the term subtotal cerebellar agenesis is also used in the literature. It is now recognized that cerebellar agenesis can represent a primary disturbance of embryonic development (also called malformation), but it can also result from a secondary destruction of normally developed tissue (also called a disruption). (See the Causes section below for additional information). It is now established that the cerebellum is not only responsible for motor coordination (of muscles, trunk and limbs, tongue and the eye muscles), but also plays an important role in many non-motor functions, including learning, memory, language and behavior. Therefore, individuals with congenital as well as acquired cerebellar disorders often have learning disabilities, impaired executive functions and variable degree of cognitive impairments. | Overview of Cerebellar Agenesis. Cerebellar agenesis is an extremely rare condition. Cerebellar agenesis is a descriptive term implying complete absence of the cerebellum, irrespective of its underlying cause (etiology). Usually, small remnants of the cerebellum are present; therefore, the term subtotal cerebellar agenesis is also used in the literature. It is now recognized that cerebellar agenesis can represent a primary disturbance of embryonic development (also called malformation), but it can also result from a secondary destruction of normally developed tissue (also called a disruption). (See the Causes section below for additional information). It is now established that the cerebellum is not only responsible for motor coordination (of muscles, trunk and limbs, tongue and the eye muscles), but also plays an important role in many non-motor functions, including learning, memory, language and behavior. Therefore, individuals with congenital as well as acquired cerebellar disorders often have learning disabilities, impaired executive functions and variable degree of cognitive impairments. | 214 | Cerebellar Agenesis |
nord_214_1 | Symptoms of Cerebellar Agenesis | The signs and symptoms of cerebellar agenesis can vary greatly from one individual to another. According to the medical literature, some individuals with cerebellar agenesis have had only mild symptoms. In fact, in some reported cases, it has been claimed that motor function may be almost normal, perhaps due to partial compensation from other areas of the brain. Reports in the medical literature discuss individuals with cerebellar agenesis who had a normal lifespan, attended regular schools and found employment and lived productive though often “simple” lives.Additional reports have noted individuals with cerebellar agenesis whose mental capacities were unaffected and who did not exhibit any symptoms of cerebellar agenesis (asymptomatic cases). However, other researchers have disputed these claims, stating that in virtually all of cases of cerebellar agenesis there have been observable symptoms including profound abnormalities in motor skills. Most likely, cerebellar agenesis represents a spectrum of disease that may range from those with severe disability to those with milder expressions of the disorder.It is important to note that the symptoms of cerebellar agenesis are extremely variable and that affected individuals may not have all of the symptoms discussed below. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Cerebellar agenesis is most often associated with impairment of motor function, especially an inability to coordinate voluntary movements (ataxia). Affected individuals may be clumsy and there may be delays in the acquisition of motor activities (psychomotor delays). Walking may be delayed until 4-7 years of age. Cerebellar agenesis may also be associated with low muscle tone (hypotonia).Some affected individuals may have difficulty speaking usually due to problems with the muscles that enable speech (dysarthria). The ability to speak is usually delayed, sometimes significantly. Some individuals may exhibit rapid, involuntary movements of the eyes (nystagmus).Intelligence may be unaffected. However, some affected individuals may display mild to moderate cognitive impairment. Some individuals with cerebellar agenesis have exhibited intellectual disability, but normal or near-normal motor skills.In addition to affecting motor skills, damage to the cerebellum has also been associated with abnormalities of non-motor functions. Cerebellar dysfunction may also be associated with abnormalities of visuospatial abilities, expressive language, working memory and affective behavior. | Symptoms of Cerebellar Agenesis. The signs and symptoms of cerebellar agenesis can vary greatly from one individual to another. According to the medical literature, some individuals with cerebellar agenesis have had only mild symptoms. In fact, in some reported cases, it has been claimed that motor function may be almost normal, perhaps due to partial compensation from other areas of the brain. Reports in the medical literature discuss individuals with cerebellar agenesis who had a normal lifespan, attended regular schools and found employment and lived productive though often “simple” lives.Additional reports have noted individuals with cerebellar agenesis whose mental capacities were unaffected and who did not exhibit any symptoms of cerebellar agenesis (asymptomatic cases). However, other researchers have disputed these claims, stating that in virtually all of cases of cerebellar agenesis there have been observable symptoms including profound abnormalities in motor skills. Most likely, cerebellar agenesis represents a spectrum of disease that may range from those with severe disability to those with milder expressions of the disorder.It is important to note that the symptoms of cerebellar agenesis are extremely variable and that affected individuals may not have all of the symptoms discussed below. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Cerebellar agenesis is most often associated with impairment of motor function, especially an inability to coordinate voluntary movements (ataxia). Affected individuals may be clumsy and there may be delays in the acquisition of motor activities (psychomotor delays). Walking may be delayed until 4-7 years of age. Cerebellar agenesis may also be associated with low muscle tone (hypotonia).Some affected individuals may have difficulty speaking usually due to problems with the muscles that enable speech (dysarthria). The ability to speak is usually delayed, sometimes significantly. Some individuals may exhibit rapid, involuntary movements of the eyes (nystagmus).Intelligence may be unaffected. However, some affected individuals may display mild to moderate cognitive impairment. Some individuals with cerebellar agenesis have exhibited intellectual disability, but normal or near-normal motor skills.In addition to affecting motor skills, damage to the cerebellum has also been associated with abnormalities of non-motor functions. Cerebellar dysfunction may also be associated with abnormalities of visuospatial abilities, expressive language, working memory and affective behavior. | 214 | Cerebellar Agenesis |
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