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nord_528_4 | Related disorders of Glycogen Storage Disease Type VI | Symptoms of the following disorders can be similar to those of GSD6. Comparisons may be useful for a differential diagnosis: Glycogen storage disease type IX (GSD-IX) is a group of at least four disorders characterized by the accumulation of glycogen in the liver and muscles. This is due to a lack of the enzyme phosphorylase kinase. Common symptoms of the form with liver involvement include enlargement of the liver (hepatomegaly), unusually low levels of blood glucose (hypoglycemia), increase in blood ketones, which are byproducts generated when the body burns fats for energy (hyperketosis) during fasting and growth delays. GSD-IX can be inherited in an autosomal recessive or X-linked pattern, depending on the type. (For more information on this disorder, choose “GSD-IX” as your search term in the Rare Disease Database.) Glycogen storage disease type III (GSD3 or Forbes disease) is characterized by excess amounts of glycogen storage in the liver, muscles, and in some cases, the heart. Symptoms are caused by a lack of the enzyme amylo-1,6 glucosidase. They include growth delays, low blood sugar (hypoglycemia), an elevated level of fatty substances in the blood (hyperlipemia), a protruding abdomen and an enlarged liver. Forbes disease is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “GSD-III” as your search term in the Rare Disease Database.) Glycogen storage disease type I (GSDI or von Gierke disease) is characterized by the build-up of glycogen and fat in the liver and kidneys that can result in enlargement of the liver and kidneys and growth delay leading to short stature. GSDI is associated with mutations in the G6PC gene or SLC37A4 gene that result in lack of the related enzyme and causes excess amounts of glycogen to be stored in the body tissues and low levels of glucose in the blood. GSD1 is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “GSDI” as your search term in the Rare Disease Database.) | Related disorders of Glycogen Storage Disease Type VI. Symptoms of the following disorders can be similar to those of GSD6. Comparisons may be useful for a differential diagnosis: Glycogen storage disease type IX (GSD-IX) is a group of at least four disorders characterized by the accumulation of glycogen in the liver and muscles. This is due to a lack of the enzyme phosphorylase kinase. Common symptoms of the form with liver involvement include enlargement of the liver (hepatomegaly), unusually low levels of blood glucose (hypoglycemia), increase in blood ketones, which are byproducts generated when the body burns fats for energy (hyperketosis) during fasting and growth delays. GSD-IX can be inherited in an autosomal recessive or X-linked pattern, depending on the type. (For more information on this disorder, choose “GSD-IX” as your search term in the Rare Disease Database.) Glycogen storage disease type III (GSD3 or Forbes disease) is characterized by excess amounts of glycogen storage in the liver, muscles, and in some cases, the heart. Symptoms are caused by a lack of the enzyme amylo-1,6 glucosidase. They include growth delays, low blood sugar (hypoglycemia), an elevated level of fatty substances in the blood (hyperlipemia), a protruding abdomen and an enlarged liver. Forbes disease is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “GSD-III” as your search term in the Rare Disease Database.) Glycogen storage disease type I (GSDI or von Gierke disease) is characterized by the build-up of glycogen and fat in the liver and kidneys that can result in enlargement of the liver and kidneys and growth delay leading to short stature. GSDI is associated with mutations in the G6PC gene or SLC37A4 gene that result in lack of the related enzyme and causes excess amounts of glycogen to be stored in the body tissues and low levels of glucose in the blood. GSD1 is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “GSDI” as your search term in the Rare Disease Database.) | 528 | Glycogen Storage Disease Type VI |
nord_528_5 | Diagnosis of Glycogen Storage Disease Type VI | GSD6 is diagnosed based on signs and symptoms of the disease, such as an enlarged liver, growth delay and hypoglycemia. The diagnosis can be confirmed by genetic testing of the PYGL gene. A liver biopsy that tests the function of liver glycogen phosphorylase may be necessary if the results of the genetic testing are not clear. Clinical Testing and Work-Up
Initial workup in patients presenting with hepatomegaly and hypoglycemia include liver ultrasound and biopsy, liver function tests, blood glucose levels and testing for basic metabolic chemistry. Findings of elevated liver transaminases can be seen, in addition to elevated glycogen content and decreased hepatic phosphorylase enzyme activity. Hepatic glycogen phosphorylase enzyme activity can also be performed on blood and liver cells. However, the blood enzyme assay can be normal in affected individuals and should be interpreted with caution. Even in liver tissue, enzyme assay is challenging. Individuals with GSD6 can have very low levels of hepatic enzyme activity. Carriers, individuals with one copy of a PYGL mutation, cannot be detected by evaluating enzyme activity. Because the enzyme results can be non-specific, genetic testing should be used to diagnose GSD6 and determine carrier status. Molecular genetic testing can confirm a diagnosis of GSD6. Molecular genetic testing can detect mutations in PYGL known to cause GSD6. Ideally, testing should be ordered by a medical genetics professional or in a healthcare setting with experience interpreting and counseling families about genetic test results. | Diagnosis of Glycogen Storage Disease Type VI. GSD6 is diagnosed based on signs and symptoms of the disease, such as an enlarged liver, growth delay and hypoglycemia. The diagnosis can be confirmed by genetic testing of the PYGL gene. A liver biopsy that tests the function of liver glycogen phosphorylase may be necessary if the results of the genetic testing are not clear. Clinical Testing and Work-Up
Initial workup in patients presenting with hepatomegaly and hypoglycemia include liver ultrasound and biopsy, liver function tests, blood glucose levels and testing for basic metabolic chemistry. Findings of elevated liver transaminases can be seen, in addition to elevated glycogen content and decreased hepatic phosphorylase enzyme activity. Hepatic glycogen phosphorylase enzyme activity can also be performed on blood and liver cells. However, the blood enzyme assay can be normal in affected individuals and should be interpreted with caution. Even in liver tissue, enzyme assay is challenging. Individuals with GSD6 can have very low levels of hepatic enzyme activity. Carriers, individuals with one copy of a PYGL mutation, cannot be detected by evaluating enzyme activity. Because the enzyme results can be non-specific, genetic testing should be used to diagnose GSD6 and determine carrier status. Molecular genetic testing can confirm a diagnosis of GSD6. Molecular genetic testing can detect mutations in PYGL known to cause GSD6. Ideally, testing should be ordered by a medical genetics professional or in a healthcare setting with experience interpreting and counseling families about genetic test results. | 528 | Glycogen Storage Disease Type VI |
nord_528_6 | Therapies of Glycogen Storage Disease Type VI | Treatment
Because symptoms of GSD6 are generally mild, the disorder usually requires no treatment other than to avoid prolonged periods without eating. Because glycogen is only broken down when stored energy needs to be used, eating frequent meals can prevent the need to break down glycogen. Levels of blood glucose should be monitored to make sure that the diet is working correctly. This will minimize the symptoms of the disease. In some patients, no other treatment is necessary. Frequent, small meals supplemented with uncooked cornstarch are recommended to avoid hypoglycemia. Some individuals may require a bedtime snack and/or cornstarch to prevent nighttime development of hypoglycemia. Even for children and adults with little to no hypoglycemic episodes, a bedtime dose of cornstarch is suggested. Uncooked cornstarch is a complex carbohydrate that is difficult for the body to digest; therefore, it maintains healthy blood sugar levels for a more extended period than most carbohydrates in food. Cornstarch therapy has been noted to improve energy, growth, bone density, well-being and liver size. Routine monitoring of blood glucose and ketone levels periodically as well as during periods of increased activity and illness is necessary. Due to the growth delays associated with GSD6, height, and weight should be measured annually to monitor growth. Bone density examinations are recommended after growth is complete. The outlook for individuals with GSD6 is generally considered very good. However, it has been noted that there is a small increased risk with age for development of liver cancer (hepatic adenocarcinoma). Annual liver ultrasound examinations are recommended beginning at age five years to screen for pre-cancerous tumor formation. Further research is needed to completely understand the risk for liver cancer in adulthood. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Glycogen Storage Disease Type VI. Treatment
Because symptoms of GSD6 are generally mild, the disorder usually requires no treatment other than to avoid prolonged periods without eating. Because glycogen is only broken down when stored energy needs to be used, eating frequent meals can prevent the need to break down glycogen. Levels of blood glucose should be monitored to make sure that the diet is working correctly. This will minimize the symptoms of the disease. In some patients, no other treatment is necessary. Frequent, small meals supplemented with uncooked cornstarch are recommended to avoid hypoglycemia. Some individuals may require a bedtime snack and/or cornstarch to prevent nighttime development of hypoglycemia. Even for children and adults with little to no hypoglycemic episodes, a bedtime dose of cornstarch is suggested. Uncooked cornstarch is a complex carbohydrate that is difficult for the body to digest; therefore, it maintains healthy blood sugar levels for a more extended period than most carbohydrates in food. Cornstarch therapy has been noted to improve energy, growth, bone density, well-being and liver size. Routine monitoring of blood glucose and ketone levels periodically as well as during periods of increased activity and illness is necessary. Due to the growth delays associated with GSD6, height, and weight should be measured annually to monitor growth. Bone density examinations are recommended after growth is complete. The outlook for individuals with GSD6 is generally considered very good. However, it has been noted that there is a small increased risk with age for development of liver cancer (hepatic adenocarcinoma). Annual liver ultrasound examinations are recommended beginning at age five years to screen for pre-cancerous tumor formation. Further research is needed to completely understand the risk for liver cancer in adulthood. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 528 | Glycogen Storage Disease Type VI |
nord_529_0 | Overview of GNE Myopathy | SummaryGNE myopathy, also known as HIBM, Nonaka myopathy, IBM2 and distal myopathy with rimmed vacuoles, is a genetic disorder that affects primarily the skeletal muscles (muscles that the body uses to perform daily physical activity). First signs of the disease appear between 20 and 40 years of age and affect males and females at the same rate. This condition is characterized by progressive muscle weakness which typically worsens over time, decreased grip strength and frequent loss of balance. 1,2GNE myopathy is caused by changes (mutations) in the GNE gene, which encodes for an enzyme known as glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase. The enzyme is responsible for the production of sialic acid (SA), a sugar required by all cells including muscle to produce energy as well as an important component of cell membranes. The condition is inherited in an autosomal recessive manner.3Currently, there is no cure for the disease and treatment is focused on managing the symptoms. However, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies.IntroductionThe term GNE myopathy refers to a group of diseases described worldwide by different investigators and physicians over the last few decades. In 1984, Nonaka et al. were the first to describe a rare muscle disorder predominantly affecting the anterior tibialis muscles and characterized by mild serum creatine kinase (CK) elevation and muscle atrophy. Under a microscope, muscle biopsies often showed characteristic histopathological changes including rimmed vacuoles, lack of inflammation, and no evidence of regeneration. 4,5 As such, they initially termed the disease distal myopathy with rimmed vacuoles (DMRV) to describe a familial myopathy with onset in early adulthood. Reports followed by from Argov and Yarom describing a similar pathology found in Iranian Jewish families and characterized by autosomal recessive inheritance. In addition to showing the typical presence of rimmed vacuoles in muscle biopsies, these studies also suggested that the disease spared the quadriceps.3 This led the group to name the condition hereditary inclusion body myopathy (HIBM).6 Other historical names include Nonaka myopathy, inclusion body myopathy 2 (IBM2) and quadriceps sparing myopathy (QSM). Finally, the identification in the early 2000’s of GNE gene mutations being responsible for these diseases has led to a grouping of the disorders under the same name now known and commonly referred to as GNE myopathy.7-9 | Overview of GNE Myopathy. SummaryGNE myopathy, also known as HIBM, Nonaka myopathy, IBM2 and distal myopathy with rimmed vacuoles, is a genetic disorder that affects primarily the skeletal muscles (muscles that the body uses to perform daily physical activity). First signs of the disease appear between 20 and 40 years of age and affect males and females at the same rate. This condition is characterized by progressive muscle weakness which typically worsens over time, decreased grip strength and frequent loss of balance. 1,2GNE myopathy is caused by changes (mutations) in the GNE gene, which encodes for an enzyme known as glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase. The enzyme is responsible for the production of sialic acid (SA), a sugar required by all cells including muscle to produce energy as well as an important component of cell membranes. The condition is inherited in an autosomal recessive manner.3Currently, there is no cure for the disease and treatment is focused on managing the symptoms. However, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies.IntroductionThe term GNE myopathy refers to a group of diseases described worldwide by different investigators and physicians over the last few decades. In 1984, Nonaka et al. were the first to describe a rare muscle disorder predominantly affecting the anterior tibialis muscles and characterized by mild serum creatine kinase (CK) elevation and muscle atrophy. Under a microscope, muscle biopsies often showed characteristic histopathological changes including rimmed vacuoles, lack of inflammation, and no evidence of regeneration. 4,5 As such, they initially termed the disease distal myopathy with rimmed vacuoles (DMRV) to describe a familial myopathy with onset in early adulthood. Reports followed by from Argov and Yarom describing a similar pathology found in Iranian Jewish families and characterized by autosomal recessive inheritance. In addition to showing the typical presence of rimmed vacuoles in muscle biopsies, these studies also suggested that the disease spared the quadriceps.3 This led the group to name the condition hereditary inclusion body myopathy (HIBM).6 Other historical names include Nonaka myopathy, inclusion body myopathy 2 (IBM2) and quadriceps sparing myopathy (QSM). Finally, the identification in the early 2000’s of GNE gene mutations being responsible for these diseases has led to a grouping of the disorders under the same name now known and commonly referred to as GNE myopathy.7-9 | 529 | GNE Myopathy |
nord_529_1 | Symptoms of GNE Myopathy | GNE myopathy manifests between the second and third decade of life and is characterized by progressive muscle wasting often accompanied by severe incapacitation within 10 to 20 years after onset. Even at early stages of the disease, GNE myopathy patients exhibit a characteristic bilateral foot drop which is caused by weakness of the tibialis anterior muscle (one of the frontal muscles that is connected to the knee and the foot). Early stage muscle weakness in GNE myopathy patients can include disturbed gait and decreased stability, frequent falls, difficulty in climbing stairs, running and getting up from a seated position. Most patients end up wheelchair-bound within 10-20 years of disease onset. Lower limb muscles are affected first with the exception of the quadriceps which appears to be relatively spared. As the disease progresses, 5 to 10 years after the onset of symptoms, the majority of patients experience progressive weakness and loss of the upper limb muscles. In advanced stages of the disease, neck muscles can also be affected. 1, 10, 11 Ultimately, disease progression may result in complete loss of skeletal muscle function and dependence on caregivers 1, 12, 13 | Symptoms of GNE Myopathy. GNE myopathy manifests between the second and third decade of life and is characterized by progressive muscle wasting often accompanied by severe incapacitation within 10 to 20 years after onset. Even at early stages of the disease, GNE myopathy patients exhibit a characteristic bilateral foot drop which is caused by weakness of the tibialis anterior muscle (one of the frontal muscles that is connected to the knee and the foot). Early stage muscle weakness in GNE myopathy patients can include disturbed gait and decreased stability, frequent falls, difficulty in climbing stairs, running and getting up from a seated position. Most patients end up wheelchair-bound within 10-20 years of disease onset. Lower limb muscles are affected first with the exception of the quadriceps which appears to be relatively spared. As the disease progresses, 5 to 10 years after the onset of symptoms, the majority of patients experience progressive weakness and loss of the upper limb muscles. In advanced stages of the disease, neck muscles can also be affected. 1, 10, 11 Ultimately, disease progression may result in complete loss of skeletal muscle function and dependence on caregivers 1, 12, 13 | 529 | GNE Myopathy |
nord_529_2 | Causes of GNE Myopathy | GNE myopathy is caused by mutations in the GNE gene. This gene is responsible for the production of an enzyme needed to make SA. Patients consistently express lower levels of SA as clearly demonstrated by analyses performed on muscle biopsies. It is believed that the loss of SA is one of the main contributors in the typical muscle wasting observed in patients, although further studies are required to determine the specific mechanisms of action of the GNE enzyme in muscle. Mutations in GNE can occur anywhere along the sequence of the gene. The majority of mutations reported are so-called missense mutations. These are alterations of the genetic code that only produce a small change in the genetic sequence but affect the function of the GNE enzyme. GNE myopathy is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. If one parent is a carrier and the other parent has GNE myopathy, the risk to have an affected child is 50% with each pregnancy. The risk is the same for males and females. | Causes of GNE Myopathy. GNE myopathy is caused by mutations in the GNE gene. This gene is responsible for the production of an enzyme needed to make SA. Patients consistently express lower levels of SA as clearly demonstrated by analyses performed on muscle biopsies. It is believed that the loss of SA is one of the main contributors in the typical muscle wasting observed in patients, although further studies are required to determine the specific mechanisms of action of the GNE enzyme in muscle. Mutations in GNE can occur anywhere along the sequence of the gene. The majority of mutations reported are so-called missense mutations. These are alterations of the genetic code that only produce a small change in the genetic sequence but affect the function of the GNE enzyme. GNE myopathy is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. If one parent is a carrier and the other parent has GNE myopathy, the risk to have an affected child is 50% with each pregnancy. The risk is the same for males and females. | 529 | GNE Myopathy |
nord_529_3 | Affects of GNE Myopathy | Mutations in the GNE gene have been reported worldwide in approximately 4,000 patients although the incidence of the disease has been estimated to be 1-9/100,000 individuals (Orphanet; http://www.orpha.net/). This suggests that the vast majority (approximately 40,000) of GNE myopathy patients still remain undiagnosed. 1 GNE myopathy patients have been identified worldwide including Asia, Europe, Middle East, Australia and North America. Clusters of specific mutations among different ethnicities are prevalent in Japanese and Persian Jewish descendants, suggesting an ancestral origin of these specific mutations. The incidence of the disease is similar in males and females. 14 | Affects of GNE Myopathy. Mutations in the GNE gene have been reported worldwide in approximately 4,000 patients although the incidence of the disease has been estimated to be 1-9/100,000 individuals (Orphanet; http://www.orpha.net/). This suggests that the vast majority (approximately 40,000) of GNE myopathy patients still remain undiagnosed. 1 GNE myopathy patients have been identified worldwide including Asia, Europe, Middle East, Australia and North America. Clusters of specific mutations among different ethnicities are prevalent in Japanese and Persian Jewish descendants, suggesting an ancestral origin of these specific mutations. The incidence of the disease is similar in males and females. 14 | 529 | GNE Myopathy |
nord_529_4 | Related disorders of GNE Myopathy | Clinically, the diagnosis may be confused with other conditions, such as other distal myopathies, limb girdle muscular dystrophy, spinal muscular atrophy or Charcot-Marie-Tooth disease. As such, referral to a neuromuscular specialist is highly recommended. | Related disorders of GNE Myopathy. Clinically, the diagnosis may be confused with other conditions, such as other distal myopathies, limb girdle muscular dystrophy, spinal muscular atrophy or Charcot-Marie-Tooth disease. As such, referral to a neuromuscular specialist is highly recommended. | 529 | GNE Myopathy |
nord_529_5 | Diagnosis of GNE Myopathy | Patients presenting with foot drop (young adults) and distal extremity muscle weakness (in individuals at more advance stages of the disease) are good candidates for GNE myopathy testing. Genetic testing represents an ideal first option to assess GNE myopathy in patients. This involves the use of minimal or no invasive procedures, only requires a blood or a saliva sample and results can be obtained in a matter of hours or days. However, because missense mutations don’t necessarily imply defects in enzyme function, the genetic testing alone cannot be considered definitive to provide a diagnosis or to rule out other neuromuscular disorders. Additional testing is needed to confirm GNE myopathy, to rule out the presence of other pathologies as well as to determine the stage of the disease. Tests include a muscle biopsy, which necessitates taking a small sample of muscle using a needle. A magnetic resonance imaging (MRI) will help determine the extent of the damage to lower and upper limb muscles. Echocardiogram and pulmonary function tests are also recommended in non-ambulatory individuals. | Diagnosis of GNE Myopathy. Patients presenting with foot drop (young adults) and distal extremity muscle weakness (in individuals at more advance stages of the disease) are good candidates for GNE myopathy testing. Genetic testing represents an ideal first option to assess GNE myopathy in patients. This involves the use of minimal or no invasive procedures, only requires a blood or a saliva sample and results can be obtained in a matter of hours or days. However, because missense mutations don’t necessarily imply defects in enzyme function, the genetic testing alone cannot be considered definitive to provide a diagnosis or to rule out other neuromuscular disorders. Additional testing is needed to confirm GNE myopathy, to rule out the presence of other pathologies as well as to determine the stage of the disease. Tests include a muscle biopsy, which necessitates taking a small sample of muscle using a needle. A magnetic resonance imaging (MRI) will help determine the extent of the damage to lower and upper limb muscles. Echocardiogram and pulmonary function tests are also recommended in non-ambulatory individuals. | 529 | GNE Myopathy |
nord_529_6 | Therapies of GNE Myopathy | Treatment Currently, there is no effective cure for GNE myopathy and treatment is limited to managing the symptoms. Early diagnosis ensures that patients receive the best optimal care which could ultimately play an important role in slowing down disease progression. Muscle overuse through strenuous activity or underuse due to prolonged inactivity could significantly accelerate the rate of progression. Patients should be followed by a neuromuscular specialist. Periodic physical therapy sessions along with a balanced physical activity have shown to slow down progressive muscle wasting. Physical and occupational therapists as well as physiatrists, specialized doctors trained to treat patients with physical impairments or disabilities, are often helpful in addressing issues due to muscle weakness. Their involvement can have a significant impact on functional ability and quality of life of people affected by the disease. Annual follow up visits with the neuromuscular specialist are usually sufficient to evaluate disease progression and address muscle strength, mobility, function, and activities of daily living.14, 15 Genetic counseling and carrier testing are strongly encouraged for family members of affected individuals. | Therapies of GNE Myopathy. Treatment Currently, there is no effective cure for GNE myopathy and treatment is limited to managing the symptoms. Early diagnosis ensures that patients receive the best optimal care which could ultimately play an important role in slowing down disease progression. Muscle overuse through strenuous activity or underuse due to prolonged inactivity could significantly accelerate the rate of progression. Patients should be followed by a neuromuscular specialist. Periodic physical therapy sessions along with a balanced physical activity have shown to slow down progressive muscle wasting. Physical and occupational therapists as well as physiatrists, specialized doctors trained to treat patients with physical impairments or disabilities, are often helpful in addressing issues due to muscle weakness. Their involvement can have a significant impact on functional ability and quality of life of people affected by the disease. Annual follow up visits with the neuromuscular specialist are usually sufficient to evaluate disease progression and address muscle strength, mobility, function, and activities of daily living.14, 15 Genetic counseling and carrier testing are strongly encouraged for family members of affected individuals. | 529 | GNE Myopathy |
nord_530_0 | Overview of Goblet Cell Adenocarcinoma | SummaryGoblet cell adenocarcinomas (GCA) of the appendix are a subtype of appendiceal cancer. GCA are defined by a unique combination of two types of cancer cells – neuroendocrine (carcinoid) and epithelial (adenocarcinoma). These tumors are more aggressive than neuroendocrine tumors and are now treated and staged like appendiceal adenocarcinomas. They are extremely rare with an estimated incidence of 1 per 2 million individuals. The average age of onset is between 50 and 60 years, most patients are Caucasian (>80%) and they affect males and females equally. They most typically present either as appendicitis or with abdominal pain and a mass. In females, they often spread to the ovaries and can be easily confused with ovarian cancer. Making the diagnosis of GCA requires the examination of a tumor specimen. While GCA tend not to spread to other parts of the body outside the abdomen, they frequently spread inside the abdominal cavity. This condition is referred to as peritoneal carcinomatosis. Treatment for GCA often requires surgery to remove the right side of the colon where the appendix originates, and intravenous chemotherapy. If the GCA has spread in the abdomen, additional surgery to remove the cancer and heated chemotherapy delivered directly into the abdomen may be considered.Introduction
In addition to being quite rare, cancers and tumors of the appendix come in a wide variety of types. The most common type of tumor or cancer of the appendix is a neuroendocrine or carcinoid tumor. Neuroendocrine tumors (NETs) are derived from specialized cells that reside in the wall of the appendix called enterochromaffin (EC) cells. These cells make chemicals that help facilitate gastrointestinal motility and digestion. The next most common type of cancer of the appendix is adenocarcinoma. These are derived from the most abundant cells lining the inside of the appendix called epithelial cells. One of the functions of epithelial cells is to make mucin – a jelly-like substance that helps protect the lining of the intestine. Cells that make mucin are often referred to as goblet cells. Goblet cell adenocarcinomas (GCAs) are an extremely rare subtype of cancer of the appendix that can have characteristics of both adenocarcinomas and NETs. These tumors have had several names in the past, including goblet cell carcinoid, to try to reflect that these tumors often have aspects of adenocarcinoma (goblet cell), and NETs (carcinoid). Previously these tumors have been treated and staged more like NETs but we now know that these tumors are more aggressive than NETs and only rarely associated with hormone secretion. Although GCAs are distinct from appendiceal adenocarcinomas, they are now treated and staged like appendiceal adenocarcinomas. | Overview of Goblet Cell Adenocarcinoma. SummaryGoblet cell adenocarcinomas (GCA) of the appendix are a subtype of appendiceal cancer. GCA are defined by a unique combination of two types of cancer cells – neuroendocrine (carcinoid) and epithelial (adenocarcinoma). These tumors are more aggressive than neuroendocrine tumors and are now treated and staged like appendiceal adenocarcinomas. They are extremely rare with an estimated incidence of 1 per 2 million individuals. The average age of onset is between 50 and 60 years, most patients are Caucasian (>80%) and they affect males and females equally. They most typically present either as appendicitis or with abdominal pain and a mass. In females, they often spread to the ovaries and can be easily confused with ovarian cancer. Making the diagnosis of GCA requires the examination of a tumor specimen. While GCA tend not to spread to other parts of the body outside the abdomen, they frequently spread inside the abdominal cavity. This condition is referred to as peritoneal carcinomatosis. Treatment for GCA often requires surgery to remove the right side of the colon where the appendix originates, and intravenous chemotherapy. If the GCA has spread in the abdomen, additional surgery to remove the cancer and heated chemotherapy delivered directly into the abdomen may be considered.Introduction
In addition to being quite rare, cancers and tumors of the appendix come in a wide variety of types. The most common type of tumor or cancer of the appendix is a neuroendocrine or carcinoid tumor. Neuroendocrine tumors (NETs) are derived from specialized cells that reside in the wall of the appendix called enterochromaffin (EC) cells. These cells make chemicals that help facilitate gastrointestinal motility and digestion. The next most common type of cancer of the appendix is adenocarcinoma. These are derived from the most abundant cells lining the inside of the appendix called epithelial cells. One of the functions of epithelial cells is to make mucin – a jelly-like substance that helps protect the lining of the intestine. Cells that make mucin are often referred to as goblet cells. Goblet cell adenocarcinomas (GCAs) are an extremely rare subtype of cancer of the appendix that can have characteristics of both adenocarcinomas and NETs. These tumors have had several names in the past, including goblet cell carcinoid, to try to reflect that these tumors often have aspects of adenocarcinoma (goblet cell), and NETs (carcinoid). Previously these tumors have been treated and staged more like NETs but we now know that these tumors are more aggressive than NETs and only rarely associated with hormone secretion. Although GCAs are distinct from appendiceal adenocarcinomas, they are now treated and staged like appendiceal adenocarcinomas. | 530 | Goblet Cell Adenocarcinoma |
nord_530_1 | Symptoms of Goblet Cell Adenocarcinoma | At the time of diagnosis, GCAs can be either localized to the appendix or have spread to other parts of the body – particularly the abdomen. For GCAs that are localized, the most common signs and symptoms are those of acute appendicitis – namely right lower abdominal pain. For GCAs that have already spread away from the appendix, the most common presenting signs and symptoms are abdominal pain and a mass. Finding GCAs that have already spread at the time of diagnosis is more common in females and 15-30% are initially diagnosed as having an ovarian cancer. There is a clear attraction of GCAs to the ovary for a reason that is not yet known but it is under investigation.GCAs rarely spread outside the abdominal cavity. However, once the cancer cells escape from the appendix, they can continue to grow in the abdominal cavity and on the surface of other organs, such as the omentum, intestines, ovaries, uterus, liver, spleen and peritoneum (lining of the abdominal cavity). This condition is called peritoneal carcinomatosis (see Related Disorders) – which means growth of cancer cells within the abdominal cavity. Over time, without treatment, this condition can result in blockage of the intestines or loss of intestinal function.Goblet cell carcinoids have been classified in several different ways as indicated below:Tang Classification
Group A (typical GCA)
Group B (signet ring cell)
Group C (poorly differentiated carcinoma)Taggart Classification
Group 1 (GCA with <25% adenocarcinoma)
Group 2 (GCA with 25-50% adenocarcinoma)
Group 3 (GCA with >50% adenocarcinoma)Lee Stratification
Low-grade
High-grade | Symptoms of Goblet Cell Adenocarcinoma. At the time of diagnosis, GCAs can be either localized to the appendix or have spread to other parts of the body – particularly the abdomen. For GCAs that are localized, the most common signs and symptoms are those of acute appendicitis – namely right lower abdominal pain. For GCAs that have already spread away from the appendix, the most common presenting signs and symptoms are abdominal pain and a mass. Finding GCAs that have already spread at the time of diagnosis is more common in females and 15-30% are initially diagnosed as having an ovarian cancer. There is a clear attraction of GCAs to the ovary for a reason that is not yet known but it is under investigation.GCAs rarely spread outside the abdominal cavity. However, once the cancer cells escape from the appendix, they can continue to grow in the abdominal cavity and on the surface of other organs, such as the omentum, intestines, ovaries, uterus, liver, spleen and peritoneum (lining of the abdominal cavity). This condition is called peritoneal carcinomatosis (see Related Disorders) – which means growth of cancer cells within the abdominal cavity. Over time, without treatment, this condition can result in blockage of the intestines or loss of intestinal function.Goblet cell carcinoids have been classified in several different ways as indicated below:Tang Classification
Group A (typical GCA)
Group B (signet ring cell)
Group C (poorly differentiated carcinoma)Taggart Classification
Group 1 (GCA with <25% adenocarcinoma)
Group 2 (GCA with 25-50% adenocarcinoma)
Group 3 (GCA with >50% adenocarcinoma)Lee Stratification
Low-grade
High-grade | 530 | Goblet Cell Adenocarcinoma |
nord_530_2 | Causes of Goblet Cell Adenocarcinoma | The exact cause of GCAs are unknown. One study has suggested a possible connection between schistosomiasis (a parasitic infection found in certain tropical and subtropical countries) and GCAs, however a causal relationship has not been established and the vast majority of GCAs occur in the absence of schistosomiasis. Recent studies have shown that GCAs do have a unique genomic profile distinct from adenocarcinomas and neuroendocrine tumors of the appendix, which may offer future targetable pathways for treatment. There are no genetic, familial or environmental factors known to cause this disorder. It does not run in families. | Causes of Goblet Cell Adenocarcinoma. The exact cause of GCAs are unknown. One study has suggested a possible connection between schistosomiasis (a parasitic infection found in certain tropical and subtropical countries) and GCAs, however a causal relationship has not been established and the vast majority of GCAs occur in the absence of schistosomiasis. Recent studies have shown that GCAs do have a unique genomic profile distinct from adenocarcinomas and neuroendocrine tumors of the appendix, which may offer future targetable pathways for treatment. There are no genetic, familial or environmental factors known to cause this disorder. It does not run in families. | 530 | Goblet Cell Adenocarcinoma |
nord_530_3 | Affects of Goblet Cell Adenocarcinoma | GCAs are very rare with approximately 1 case per 2 million individuals. The average age at the time of diagnosis is most frequently reported between 50-60. While most studies have reported that males and females are affected in equal numbers, a few have suggested a slightly increased frequency in females (2-3:1). Advanced GCAs tend to present more frequently in females and 15-30% of females are initially diagnosed with an ovarian cancer. Less than 1% of GCAs are accurately diagnosed prior to surgery. | Affects of Goblet Cell Adenocarcinoma. GCAs are very rare with approximately 1 case per 2 million individuals. The average age at the time of diagnosis is most frequently reported between 50-60. While most studies have reported that males and females are affected in equal numbers, a few have suggested a slightly increased frequency in females (2-3:1). Advanced GCAs tend to present more frequently in females and 15-30% of females are initially diagnosed with an ovarian cancer. Less than 1% of GCAs are accurately diagnosed prior to surgery. | 530 | Goblet Cell Adenocarcinoma |
nord_530_4 | Related disorders of Goblet Cell Adenocarcinoma | GCAs are a subtype of neoplasms (cancers and tumors) that can occur in the appendix. The general topic of appendiceal cancer and tumors is discussed in a separate Rare Disease Report.Due to the structure of the appendix (a long, thin-walled, finger-like projection off the right colon), it is easy for tumor or cancer cells to break through the wall and spread in the abdominal cavity. Consequently, most appendiceal cancers, even the less aggressive ones, tend to present at an advanced stage with peritoneal carcinomatosis. Once the cancer cells have spread, they continue to grow and may cause abdominal discomfort, distention, a fluid build-up called ascites or pseudomyoma peritonei (mucinous ascites) and intestinal blockage or dysfunction. Over time this can lead to decreased appetite, early satiety (feeling full after eating only a small amount), nausea and vomiting. The different types of appendiceal tumors and cancers can be distinguished by the appearance of the cells under the microscope and by staining them for specific markers.Peritoneal carcinomatosis is the spread and growth of cancer cells in the abdominal cavity. Cancers that are most frequently associated with peritoneal carcinomatosis include the gastrointestinal (colon, rectal, appendiceal, gastric, pancreas, small bowel and gallbladder) and the gynecologic (ovarian, primary peritoneal and uterine) cancers. Other cancers that can spread to the abdominal cavity include breast, esophagus and melanoma. Gastrointestinal stromal tumors (GISTs) are a subtype of sarcoma of the intestine that can also present with multiple cancer tumors in the abdomen. Peritoneal mesothelioma is a cancer that originates in the lining of the abdominal cavity (peritoneum) and presents with signs and symptoms of carcinomatosis. | Related disorders of Goblet Cell Adenocarcinoma. GCAs are a subtype of neoplasms (cancers and tumors) that can occur in the appendix. The general topic of appendiceal cancer and tumors is discussed in a separate Rare Disease Report.Due to the structure of the appendix (a long, thin-walled, finger-like projection off the right colon), it is easy for tumor or cancer cells to break through the wall and spread in the abdominal cavity. Consequently, most appendiceal cancers, even the less aggressive ones, tend to present at an advanced stage with peritoneal carcinomatosis. Once the cancer cells have spread, they continue to grow and may cause abdominal discomfort, distention, a fluid build-up called ascites or pseudomyoma peritonei (mucinous ascites) and intestinal blockage or dysfunction. Over time this can lead to decreased appetite, early satiety (feeling full after eating only a small amount), nausea and vomiting. The different types of appendiceal tumors and cancers can be distinguished by the appearance of the cells under the microscope and by staining them for specific markers.Peritoneal carcinomatosis is the spread and growth of cancer cells in the abdominal cavity. Cancers that are most frequently associated with peritoneal carcinomatosis include the gastrointestinal (colon, rectal, appendiceal, gastric, pancreas, small bowel and gallbladder) and the gynecologic (ovarian, primary peritoneal and uterine) cancers. Other cancers that can spread to the abdominal cavity include breast, esophagus and melanoma. Gastrointestinal stromal tumors (GISTs) are a subtype of sarcoma of the intestine that can also present with multiple cancer tumors in the abdomen. Peritoneal mesothelioma is a cancer that originates in the lining of the abdominal cavity (peritoneum) and presents with signs and symptoms of carcinomatosis. | 530 | Goblet Cell Adenocarcinoma |
nord_530_5 | Diagnosis of Goblet Cell Adenocarcinoma | Because there are no unique features of GCAs on imaging studies such as ultrasound, CT scan, PET scan or MRI, the diagnosis of GCA cannot be made until a tumor specimen is examined by a pathologist. This is frequently accomplished at the time of appendectomy for appendicitis, surgery for an intestinal blockage or presumed ovarian cancer. It can also be diagnosed during a tumor biopsy performed for an abnormal clinical or radiographic finding, such as a palpable tumor or tumors seen on an imaging study. GCAs tend to be easier to identify because of the unique combination of neuroendocrine and epithelial cells, although the presence of neuroendocrine cells is not required. | Diagnosis of Goblet Cell Adenocarcinoma. Because there are no unique features of GCAs on imaging studies such as ultrasound, CT scan, PET scan or MRI, the diagnosis of GCA cannot be made until a tumor specimen is examined by a pathologist. This is frequently accomplished at the time of appendectomy for appendicitis, surgery for an intestinal blockage or presumed ovarian cancer. It can also be diagnosed during a tumor biopsy performed for an abnormal clinical or radiographic finding, such as a palpable tumor or tumors seen on an imaging study. GCAs tend to be easier to identify because of the unique combination of neuroendocrine and epithelial cells, although the presence of neuroendocrine cells is not required. | 530 | Goblet Cell Adenocarcinoma |
nord_530_6 | Therapies of Goblet Cell Adenocarcinoma | Once the diagnosis is established, a staging work-up including imaging studies (most commonly a CT scan of the chest, abdomen and pelvis) and tumor marker blood tests (CEA, CA 19-9 and CA 125) should be performed. (Tumor markers are proteins related to the cancer cells that can be measured in the blood.) Treatment recommendations depend on both the histology of the GCAs (the microscopic structure of the tumor cells) and whether it is localized or disseminated. Most of the larger and more recent studies of GCAs recommend surgical removal of the right side of the colon (right hemicolectomy) to ensure that all the disease has been removed and to test the regional lymph nodes for any cancer cells. Some also recommend removal of the ovaries in post-menopausal females given the affinity of these tumors for the ovaries. In very rare instances, when the tumor is localized to the appendix, low grade, and removed completely with an appendectomy, some may consider appendectomy alone, but this remains controversial. If the cancer has spread to regional lymph nodes or other organs outside the abdominal cavity, the usual recommendation is for systemic (intravenous) chemotherapy. 5-flourouracil-based chemotherapy regimens (the same that are used to treat colon cancer) are typically recommended. If the cancer has spread in the abdominal cavity, cytoreductive surgery to remove the cancer and abdominal perfusion with hyperthermic (heated) chemotherapy (a procedure known as HIPEC) to prevent cancer recurrence may be considered as part of the treatment regimen along with systemic chemotherapy. This should be performed at an experienced HIPEC center. Surveillance for cancer recurrence should include a history and physical exam, imaging studies of the chest, abdomen and pelvis and tumor markers (CEA, CA 19-9 and CA 125) every 6 months for the first two years and then yearly for at least 3 more years, with consideration of continued follow-up thereafter. | Therapies of Goblet Cell Adenocarcinoma. Once the diagnosis is established, a staging work-up including imaging studies (most commonly a CT scan of the chest, abdomen and pelvis) and tumor marker blood tests (CEA, CA 19-9 and CA 125) should be performed. (Tumor markers are proteins related to the cancer cells that can be measured in the blood.) Treatment recommendations depend on both the histology of the GCAs (the microscopic structure of the tumor cells) and whether it is localized or disseminated. Most of the larger and more recent studies of GCAs recommend surgical removal of the right side of the colon (right hemicolectomy) to ensure that all the disease has been removed and to test the regional lymph nodes for any cancer cells. Some also recommend removal of the ovaries in post-menopausal females given the affinity of these tumors for the ovaries. In very rare instances, when the tumor is localized to the appendix, low grade, and removed completely with an appendectomy, some may consider appendectomy alone, but this remains controversial. If the cancer has spread to regional lymph nodes or other organs outside the abdominal cavity, the usual recommendation is for systemic (intravenous) chemotherapy. 5-flourouracil-based chemotherapy regimens (the same that are used to treat colon cancer) are typically recommended. If the cancer has spread in the abdominal cavity, cytoreductive surgery to remove the cancer and abdominal perfusion with hyperthermic (heated) chemotherapy (a procedure known as HIPEC) to prevent cancer recurrence may be considered as part of the treatment regimen along with systemic chemotherapy. This should be performed at an experienced HIPEC center. Surveillance for cancer recurrence should include a history and physical exam, imaging studies of the chest, abdomen and pelvis and tumor markers (CEA, CA 19-9 and CA 125) every 6 months for the first two years and then yearly for at least 3 more years, with consideration of continued follow-up thereafter. | 530 | Goblet Cell Adenocarcinoma |
nord_531_0 | Overview of Goodpasture Syndrome | Goodpasture syndrome is a rare autoimmune disorder characterized by inflammation of the filtering structures (glomeruli) of the kidneys (glomerulonephritis) and excessive bleeding into the lungs (pulmonary hemorrhaging). Autoimmune syndromes occur when the body's natural defenses (antibodies) against invading or “foreign” organisms begin to attack the body's own tissue, often for unknown reasons. Symptoms of Goodpasture syndrome include recurrent episodes of coughing up of blood (hemoptysis), difficulty breathing (dyspnea), fatigue, chest pain, and/or abnormally low levels of circulating red blood cells (anemia). In many cases, Goodpasture syndrome may result in an inability of the kidneys to process waste products from the blood and excrete them in the urine (acute renal failure). In some cases of Goodpasture syndrome, affected individuals have had an upper respiratory tract infection before the development of the disorder. The exact cause of Goodpasture syndrome is not known. | Overview of Goodpasture Syndrome. Goodpasture syndrome is a rare autoimmune disorder characterized by inflammation of the filtering structures (glomeruli) of the kidneys (glomerulonephritis) and excessive bleeding into the lungs (pulmonary hemorrhaging). Autoimmune syndromes occur when the body's natural defenses (antibodies) against invading or “foreign” organisms begin to attack the body's own tissue, often for unknown reasons. Symptoms of Goodpasture syndrome include recurrent episodes of coughing up of blood (hemoptysis), difficulty breathing (dyspnea), fatigue, chest pain, and/or abnormally low levels of circulating red blood cells (anemia). In many cases, Goodpasture syndrome may result in an inability of the kidneys to process waste products from the blood and excrete them in the urine (acute renal failure). In some cases of Goodpasture syndrome, affected individuals have had an upper respiratory tract infection before the development of the disorder. The exact cause of Goodpasture syndrome is not known. | 531 | Goodpasture Syndrome |
nord_531_1 | Symptoms of Goodpasture Syndrome | The major symptoms of Goodpasture syndrome are excessive bleeding into the lungs (pulmonary hemorrhaging) and inflammation of the filtering structures (glomeruli) or the kidneys (glomerulonephritis). In some cases, an upper respiratory tract infection may precede the development of the disorder. General symptoms associated with Goodpasture syndrome may include fever, nausea, and fatigue.Pulmonary hemorrhaging may lead to episodes where affected individuals cough up blood (hemoptysis). The severity of this finding may range from a few flecks to excessive amounts of blood. Affected individuals may also exhibit difficult breathing (dyspnea), fatigue, chest pain, a dry rasping sound from the throat (rhoncus), and/or frequent coughing. In rare cases, affected individuals may exhibit abnormal accumulation of fluid (edema) in the tissue of the lungs. Pulmonary abnormalities are usually noted before or simultaneous to kidney (renal) abnormalities in approximately 70 percent of the cases.Inflammation of the filtering structures (glomeruli) of the kidneys (glomerulonephritis) may lead to an inability of the kidneys to process waste products from the blood and excrete them in the urine (acute renal failure). Renal failure usually leads to a decrease in the amount of urine the body produces. Additional symptoms associated with renal failure may include abnormally pale skin (pallor), drowsiness, nausea, and/or vomiting. Severe complications of renal failure include bleeding into the stomach and/or a decrease in the amount of circulating red blood cells (anemia). In rare cases, affected individuals may exhibit high blood pressure (hypertension) and/or pain and swelling of the joints (arthritis). In some cases, symptoms of Goodpasture syndrome may recur after treatment. | Symptoms of Goodpasture Syndrome. The major symptoms of Goodpasture syndrome are excessive bleeding into the lungs (pulmonary hemorrhaging) and inflammation of the filtering structures (glomeruli) or the kidneys (glomerulonephritis). In some cases, an upper respiratory tract infection may precede the development of the disorder. General symptoms associated with Goodpasture syndrome may include fever, nausea, and fatigue.Pulmonary hemorrhaging may lead to episodes where affected individuals cough up blood (hemoptysis). The severity of this finding may range from a few flecks to excessive amounts of blood. Affected individuals may also exhibit difficult breathing (dyspnea), fatigue, chest pain, a dry rasping sound from the throat (rhoncus), and/or frequent coughing. In rare cases, affected individuals may exhibit abnormal accumulation of fluid (edema) in the tissue of the lungs. Pulmonary abnormalities are usually noted before or simultaneous to kidney (renal) abnormalities in approximately 70 percent of the cases.Inflammation of the filtering structures (glomeruli) of the kidneys (glomerulonephritis) may lead to an inability of the kidneys to process waste products from the blood and excrete them in the urine (acute renal failure). Renal failure usually leads to a decrease in the amount of urine the body produces. Additional symptoms associated with renal failure may include abnormally pale skin (pallor), drowsiness, nausea, and/or vomiting. Severe complications of renal failure include bleeding into the stomach and/or a decrease in the amount of circulating red blood cells (anemia). In rare cases, affected individuals may exhibit high blood pressure (hypertension) and/or pain and swelling of the joints (arthritis). In some cases, symptoms of Goodpasture syndrome may recur after treatment. | 531 | Goodpasture Syndrome |
nord_531_2 | Causes of Goodpasture Syndrome | Goodpasture syndrome develops due to unknown causes. Environmental factors such as hydrocarbon chemical exposure, cigarette smoke, or infections such as influenza may play a role in the development of the disorder. It is not known why simple infections can progress to Goodpasture syndrome in some people. When infection occurs, the body's natural defenses (antibodies) fight the invading organisms (e.g., viruses or bacteria). In autoimmune disorders, antibodies attack healthy tissue for no apparent reason. Pulmonary hemorrhage has been frequently associated with smoking in individuals with Goodpasture syndrome.In Goodpasture syndrome, certain antibodies (anti-glomerular basement membrane [anti-GBM] antibodies) may be produced and circulate throughout the blood. These antibodies may damage the delicate membranes that line the lungs and kidneys or the tiny blood vessels (capillaries) within the lungs and kidneys.In some cases, individuals with Goodpasture syndrome may have an association with human leukocyte antigens (HLAs). HLAs are proteins that play an important role in the body's immune system; they influence the outcome of transplantation and appear to affect an individual's predisposition to certain diseases. However, the implications of such findings are not fully understood.Goodpasture syndrome has been reported in more than one family member (e.g., siblings) in a few cases, supporting the possibility of genetic susceptibility as a factor in some cases. 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 (multifactorial inheritance). | Causes of Goodpasture Syndrome. Goodpasture syndrome develops due to unknown causes. Environmental factors such as hydrocarbon chemical exposure, cigarette smoke, or infections such as influenza may play a role in the development of the disorder. It is not known why simple infections can progress to Goodpasture syndrome in some people. When infection occurs, the body's natural defenses (antibodies) fight the invading organisms (e.g., viruses or bacteria). In autoimmune disorders, antibodies attack healthy tissue for no apparent reason. Pulmonary hemorrhage has been frequently associated with smoking in individuals with Goodpasture syndrome.In Goodpasture syndrome, certain antibodies (anti-glomerular basement membrane [anti-GBM] antibodies) may be produced and circulate throughout the blood. These antibodies may damage the delicate membranes that line the lungs and kidneys or the tiny blood vessels (capillaries) within the lungs and kidneys.In some cases, individuals with Goodpasture syndrome may have an association with human leukocyte antigens (HLAs). HLAs are proteins that play an important role in the body's immune system; they influence the outcome of transplantation and appear to affect an individual's predisposition to certain diseases. However, the implications of such findings are not fully understood.Goodpasture syndrome has been reported in more than one family member (e.g., siblings) in a few cases, supporting the possibility of genetic susceptibility as a factor in some cases. 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 (multifactorial inheritance). | 531 | Goodpasture Syndrome |
nord_531_3 | Affects of Goodpasture Syndrome | Goodpasture syndrome is a rare autoimmune disorder that appears to affect males more frequently than females. Age of onset is usually between 20 and 30, but individuals at any age may be affected. Goodpasture syndrome was first identified in 1919. Since that time approximately 600 cases have been noted in the medical literature. In the US the Anti-GBM disease is an uncommon disorder; approximately 1-2% of all cases of rapidly progressive glomerulonephritis are secondary to this disorder. | Affects of Goodpasture Syndrome. Goodpasture syndrome is a rare autoimmune disorder that appears to affect males more frequently than females. Age of onset is usually between 20 and 30, but individuals at any age may be affected. Goodpasture syndrome was first identified in 1919. Since that time approximately 600 cases have been noted in the medical literature. In the US the Anti-GBM disease is an uncommon disorder; approximately 1-2% of all cases of rapidly progressive glomerulonephritis are secondary to this disorder. | 531 | Goodpasture Syndrome |
nord_531_4 | Related disorders of Goodpasture Syndrome | Symptoms of the following disorders can be similar to those of Goodpasture syndrome. Comparisons may be useful for a differential diagnosis:Wegener's granulomatosis is an uncommon disorder characterized by inflammation of blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some cases, kidney abnormalities may progress to kidney failure, a serious complication. If the lungs are affected, a cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the lung may be present. The exact cause of Wegener's granulomatosis is not known. (For more information on this disorder, choose “Wegener's” as your search term in the Rare Disease Database.)Idiopathic pulmonary hemosiderosis is a lung disorder similar to Goodpasture syndrome. Affected individuals may also have secondary iron-deficiency anemia. It seems to occur mostly in young children, and does not have the antibody reaction found in Goodpasture syndrome. The exact cause of this disorder is unknown (idiopathic).Bacterial endocarditis is a lung and kidney disorder that has some clinical similarities to Goodpasture syndrome, but also involves the heart. Bacterial endocarditis is caused by bacterial infection. Affected individuals may develop heart murmurs as well as artery blockage (embolisms). Skin lesions, spleen enlargement, and intermittent high fever are other symptoms associated with this disorder. | Related disorders of Goodpasture Syndrome. Symptoms of the following disorders can be similar to those of Goodpasture syndrome. Comparisons may be useful for a differential diagnosis:Wegener's granulomatosis is an uncommon disorder characterized by inflammation of blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some cases, kidney abnormalities may progress to kidney failure, a serious complication. If the lungs are affected, a cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the lung may be present. The exact cause of Wegener's granulomatosis is not known. (For more information on this disorder, choose “Wegener's” as your search term in the Rare Disease Database.)Idiopathic pulmonary hemosiderosis is a lung disorder similar to Goodpasture syndrome. Affected individuals may also have secondary iron-deficiency anemia. It seems to occur mostly in young children, and does not have the antibody reaction found in Goodpasture syndrome. The exact cause of this disorder is unknown (idiopathic).Bacterial endocarditis is a lung and kidney disorder that has some clinical similarities to Goodpasture syndrome, but also involves the heart. Bacterial endocarditis is caused by bacterial infection. Affected individuals may develop heart murmurs as well as artery blockage (embolisms). Skin lesions, spleen enlargement, and intermittent high fever are other symptoms associated with this disorder. | 531 | Goodpasture Syndrome |
nord_531_5 | Diagnosis of Goodpasture Syndrome | A diagnosis of Goodpasture syndrome may be suspected based upon the identification of characteristic physical findings (e.g., pulmonary hemorrhaging and glomerulonephritis). The diagnosis may be confirmed by the identification of the presence of anti-glomerular basement membranes antibodies in the body. In some cases, affected individuals may exhibit blood (hematuria) and/or protein (proteinuria) in the urine. | Diagnosis of Goodpasture Syndrome. A diagnosis of Goodpasture syndrome may be suspected based upon the identification of characteristic physical findings (e.g., pulmonary hemorrhaging and glomerulonephritis). The diagnosis may be confirmed by the identification of the presence of anti-glomerular basement membranes antibodies in the body. In some cases, affected individuals may exhibit blood (hematuria) and/or protein (proteinuria) in the urine. | 531 | Goodpasture Syndrome |
nord_531_6 | Therapies of Goodpasture Syndrome | TreatmentMild forms of Goodpasture syndrome may be treated with the use of drugs that suppress or hinder the effectiveness of the body's immune system (immunosuppressive drugs). Corticosteroids such as prednisone may be administered to control bleeding in the lungs (pulmonary hemorrhaging).Many affected individuals may be treated with plasmapheresis. This procedure is a method for removing unwanted substances (toxins, damaging antibodies, and metabolic substances) from the blood. Blood is removed from the patient and blood cells are separated from plasma. The patient's plasma is then replaced with other human plasma and the blood is transfused into the patient. This therapy is still under investigation to analyze side effects and effectiveness. Plasmapheresis is often administered in conjunction with corticosteroid treatment.In severe and repeated cases of Goodpasture syndrome affected individuals may be treated with a procedure where waste products are removed from the blood (dialysis). In the most severe cases, a kidney transplant may be needed. | Therapies of Goodpasture Syndrome. TreatmentMild forms of Goodpasture syndrome may be treated with the use of drugs that suppress or hinder the effectiveness of the body's immune system (immunosuppressive drugs). Corticosteroids such as prednisone may be administered to control bleeding in the lungs (pulmonary hemorrhaging).Many affected individuals may be treated with plasmapheresis. This procedure is a method for removing unwanted substances (toxins, damaging antibodies, and metabolic substances) from the blood. Blood is removed from the patient and blood cells are separated from plasma. The patient's plasma is then replaced with other human plasma and the blood is transfused into the patient. This therapy is still under investigation to analyze side effects and effectiveness. Plasmapheresis is often administered in conjunction with corticosteroid treatment.In severe and repeated cases of Goodpasture syndrome affected individuals may be treated with a procedure where waste products are removed from the blood (dialysis). In the most severe cases, a kidney transplant may be needed. | 531 | Goodpasture Syndrome |
nord_532_0 | Overview of Gordon Syndrome | SummaryGordon syndrome is an extremely rare disorder that belongs to a group of genetic disorders known as the distal arthrogryposes. These disorders typically involve stiffness and impaired mobility of certain joints of the lower arms and legs (distal extremities) including the knees, elbows, wrists, and/or ankles. These joints tend to be permanently fixed in a bent (flexed) or straightened (extended) position (contractures). Gordon syndrome is characterized by the permanent fixation of several fingers in a bent position (camptodactyly), abnormal bending inward of the foot (clubfoot or talipes), and, less frequently, incomplete closure of the roof of the mouth (cleft palate). In some individuals, additional abnormalities may also be present. The range and severity of symptoms may vary from one person to another. Intelligence is not affected. Gordon syndrome is caused by alterations (mutations) in the PIEZO2 gene and is inherited as an autosomal dominant trait. | Overview of Gordon Syndrome. SummaryGordon syndrome is an extremely rare disorder that belongs to a group of genetic disorders known as the distal arthrogryposes. These disorders typically involve stiffness and impaired mobility of certain joints of the lower arms and legs (distal extremities) including the knees, elbows, wrists, and/or ankles. These joints tend to be permanently fixed in a bent (flexed) or straightened (extended) position (contractures). Gordon syndrome is characterized by the permanent fixation of several fingers in a bent position (camptodactyly), abnormal bending inward of the foot (clubfoot or talipes), and, less frequently, incomplete closure of the roof of the mouth (cleft palate). In some individuals, additional abnormalities may also be present. The range and severity of symptoms may vary from one person to another. Intelligence is not affected. Gordon syndrome is caused by alterations (mutations) in the PIEZO2 gene and is inherited as an autosomal dominant trait. | 532 | Gordon Syndrome |
nord_532_1 | Symptoms of Gordon Syndrome | Gordon syndrome is characterized by stiffness and impaired mobility of certain joints of the arms and legs (distal arthrogryposis) including the knees, elbows, wrists, and/or ankles. In most infants with this disorder, several fingers may be permanently fixed in a flexed position (camptodactyly), which may result in limitations in range of motion and manual dexterity. In addition, affected infants may exhibit abnormal bending inward of the foot (clubfoot or talipes). In severe instances, infants with Gordon syndrome may experience delays in walking. Approximately 20-30 percent of affected infants also exhibit incomplete closure of the roof of the mouth (cleft palate). Severe malformation of the palate may lead to difficulty in speaking. In addition, in some people, a soft-tissue structure at the back of the throat (uvula) may be abnormally split (bifid). In some affected individuals, additional findings have occurred in association with Gordon syndrome and may, in fact, be part of the syndrome. Such additional findings may include short stature, dislocation of the hip, abnormal backward curvature of the upper spine (lordosis), and/or abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis). In addition, some affected individuals may exhibit drooping of the eyelids (ptosis); an extra fold of skin on either side of the nose that may cover the eyes’ inner corners (epicanthal folds); mild webbing of the fingers and/or toes (syndactyly); abnormal skin ridge patterns on the hands and feet (dermatoglyphics); and/or a short, webbed neck (pterygium colli). In some males, one or both of the testes may fail to descend into the scrotum (cryptorchidism). Cognitive development of affected individuals is normal. | Symptoms of Gordon Syndrome. Gordon syndrome is characterized by stiffness and impaired mobility of certain joints of the arms and legs (distal arthrogryposis) including the knees, elbows, wrists, and/or ankles. In most infants with this disorder, several fingers may be permanently fixed in a flexed position (camptodactyly), which may result in limitations in range of motion and manual dexterity. In addition, affected infants may exhibit abnormal bending inward of the foot (clubfoot or talipes). In severe instances, infants with Gordon syndrome may experience delays in walking. Approximately 20-30 percent of affected infants also exhibit incomplete closure of the roof of the mouth (cleft palate). Severe malformation of the palate may lead to difficulty in speaking. In addition, in some people, a soft-tissue structure at the back of the throat (uvula) may be abnormally split (bifid). In some affected individuals, additional findings have occurred in association with Gordon syndrome and may, in fact, be part of the syndrome. Such additional findings may include short stature, dislocation of the hip, abnormal backward curvature of the upper spine (lordosis), and/or abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis). In addition, some affected individuals may exhibit drooping of the eyelids (ptosis); an extra fold of skin on either side of the nose that may cover the eyes’ inner corners (epicanthal folds); mild webbing of the fingers and/or toes (syndactyly); abnormal skin ridge patterns on the hands and feet (dermatoglyphics); and/or a short, webbed neck (pterygium colli). In some males, one or both of the testes may fail to descend into the scrotum (cryptorchidism). Cognitive development of affected individuals is normal. | 532 | Gordon Syndrome |
nord_532_2 | Causes of Gordon Syndrome | Gordon syndrome is caused by an alteration (mutation) in the PIEZO2 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.Gordon syndrome is inherited as an autosomal dominant 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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The symptoms associated with Gordon syndrome may vary greatly among affected individuals (variable expressivity). Females seem to be more likely to have a less severe form of the disorder (incomplete penetrance) or to exhibit no symptoms associated with the disorder (asymptomatic) although they carry the disease gene. Two other disorders, Marden-Walker syndrome and distal arthrogryposis 5, are caused by alterations in the PIEZO2 gene. | Causes of Gordon Syndrome. Gordon syndrome is caused by an alteration (mutation) in the PIEZO2 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.Gordon syndrome is inherited as an autosomal dominant 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. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The symptoms associated with Gordon syndrome may vary greatly among affected individuals (variable expressivity). Females seem to be more likely to have a less severe form of the disorder (incomplete penetrance) or to exhibit no symptoms associated with the disorder (asymptomatic) although they carry the disease gene. Two other disorders, Marden-Walker syndrome and distal arthrogryposis 5, are caused by alterations in the PIEZO2 gene. | 532 | Gordon Syndrome |
nord_532_3 | Affects of Gordon Syndrome | Gordon syndrome affects males and females in equal numbers. More than 40 people in five families (kindreds) have been reported in the medical literature. In most people, physical features associated with Gordon syndrome are obvious at birth (congenital). | Affects of Gordon Syndrome. Gordon syndrome affects males and females in equal numbers. More than 40 people in five families (kindreds) have been reported in the medical literature. In most people, physical features associated with Gordon syndrome are obvious at birth (congenital). | 532 | Gordon Syndrome |
nord_532_4 | Related disorders of Gordon Syndrome | Symptoms of the following disorders can be similar to those of Gordon syndrome. Comparisons may be useful for a differential diagnosis: Marden-Walker syndrome and distal arthrogryposis 5 are rare disorders that are caused by alterations in the PIEZO2 gene, the same gene that causes Gordon syndrome. Some researchers believe that these three disorders represent different expressions of one disorder. NORD has a separate report on Marden-Walker syndrome, choose the disorder name as your search term in the Rare Disease Database. Distal arthrogryposis multiplex congenita, type II is a very rare inherited disorder that is apparent at birth and is characterized by stiffness and/or impaired mobility of certain joints (contractures) and deformities of bones of the hands and/or feet. Symptoms may include permanent fixation of the fingers in a flexed position (camptodactyly); abnormal positioning of the fingers and/or toes; abnormal inward positioning of the feet (clubfoot or talipes); and/or other malformations of the arms and/or legs. Other features of this disorder may include an impaired ability to completely open the mouth (trismus); underdevelopment of the jaw bone (micrognathia); a receding jaw (retrognathia); an abnormal groove in the upper lip (cleft lip) and/or incomplete closure of the roof of the mouth (cleft palate); droopy eyelids (ptosis); and/or a webbed neck. Affected individuals may also exhibit abnormalities of the bones of the spine (vertebrae) as well as short stature. Distal arthrogryposis multiplex congenita, type II is thought to be inherited as an autosomal dominant genetic trait. Aase-Smith syndrome, also known as Aase-Smith syndrome type I, is a rare genetic disorder characterized by joint contractures and cleft palate. Affected infants may also have drooping of the eyelids (ptosis), malformed ears, and thin fingers with no knuckles. Some individuals may experience accumulation of excessive cerebrospinal fluid (CSF) in the skull (hydrocephalus) causing increased pressure on the tissues of the brain (hydrocephalus). Because of the overlap of symptoms associated with Aase-Smith and Gordon syndromes some researchers have speculated that the two disorders are actually one entity. Aase-Smith syndrome is inherited as an autosomal dominant trait. Congenital contractural arachnodactyly (CCA), also known as Beals syndrome, is an extremely rare genetic disorder characterized by a Marfan-like body habitus (tall, slender), the permanent fixation of certain joints (e.g., fingers, elbows, knees, and hips) in a flexed position (contractures); abnormally long, slender fingers and toes (arachnodactyly); permanently flexed fingers (camptodactyly); and/or abnormally shaped ears resulting in a “crumpled” appearance. In addition, affected individuals may exhibit front-to-back and side-to-side curvature of the spine (kyphoscoliosis); feet that are abnormally positioned (talipes equinovarus or clubfoot); outward displacement of the fingers (ulnar deviation of the fingers); an abnormally short neck; and/or. Rarely, affected individuals may have a slight deformity of the valve on the left side of the heart (mitral valve prolapse). CCA is inherited as an autosomal dominant trait. (For more information on this disorder, choose “congenital contractural arachnodactyly” as your search term in the Rare Disease Database.) There are other congenital disorders that may be characterized by physical features and symptoms similar to those associated with Gordon syndrome. These may include other disorders associated with stiffness and impaired mobility involving certain joints (e.g., knees, elbows, wrists, and ankles) of the lower arms and/or legs (distal arthrogryposes). (For more information on these disorders, choose the exact disorder name in question as your search term in the Rare Disease Database.) | Related disorders of Gordon Syndrome. Symptoms of the following disorders can be similar to those of Gordon syndrome. Comparisons may be useful for a differential diagnosis: Marden-Walker syndrome and distal arthrogryposis 5 are rare disorders that are caused by alterations in the PIEZO2 gene, the same gene that causes Gordon syndrome. Some researchers believe that these three disorders represent different expressions of one disorder. NORD has a separate report on Marden-Walker syndrome, choose the disorder name as your search term in the Rare Disease Database. Distal arthrogryposis multiplex congenita, type II is a very rare inherited disorder that is apparent at birth and is characterized by stiffness and/or impaired mobility of certain joints (contractures) and deformities of bones of the hands and/or feet. Symptoms may include permanent fixation of the fingers in a flexed position (camptodactyly); abnormal positioning of the fingers and/or toes; abnormal inward positioning of the feet (clubfoot or talipes); and/or other malformations of the arms and/or legs. Other features of this disorder may include an impaired ability to completely open the mouth (trismus); underdevelopment of the jaw bone (micrognathia); a receding jaw (retrognathia); an abnormal groove in the upper lip (cleft lip) and/or incomplete closure of the roof of the mouth (cleft palate); droopy eyelids (ptosis); and/or a webbed neck. Affected individuals may also exhibit abnormalities of the bones of the spine (vertebrae) as well as short stature. Distal arthrogryposis multiplex congenita, type II is thought to be inherited as an autosomal dominant genetic trait. Aase-Smith syndrome, also known as Aase-Smith syndrome type I, is a rare genetic disorder characterized by joint contractures and cleft palate. Affected infants may also have drooping of the eyelids (ptosis), malformed ears, and thin fingers with no knuckles. Some individuals may experience accumulation of excessive cerebrospinal fluid (CSF) in the skull (hydrocephalus) causing increased pressure on the tissues of the brain (hydrocephalus). Because of the overlap of symptoms associated with Aase-Smith and Gordon syndromes some researchers have speculated that the two disorders are actually one entity. Aase-Smith syndrome is inherited as an autosomal dominant trait. Congenital contractural arachnodactyly (CCA), also known as Beals syndrome, is an extremely rare genetic disorder characterized by a Marfan-like body habitus (tall, slender), the permanent fixation of certain joints (e.g., fingers, elbows, knees, and hips) in a flexed position (contractures); abnormally long, slender fingers and toes (arachnodactyly); permanently flexed fingers (camptodactyly); and/or abnormally shaped ears resulting in a “crumpled” appearance. In addition, affected individuals may exhibit front-to-back and side-to-side curvature of the spine (kyphoscoliosis); feet that are abnormally positioned (talipes equinovarus or clubfoot); outward displacement of the fingers (ulnar deviation of the fingers); an abnormally short neck; and/or. Rarely, affected individuals may have a slight deformity of the valve on the left side of the heart (mitral valve prolapse). CCA is inherited as an autosomal dominant trait. (For more information on this disorder, choose “congenital contractural arachnodactyly” as your search term in the Rare Disease Database.) There are other congenital disorders that may be characterized by physical features and symptoms similar to those associated with Gordon syndrome. These may include other disorders associated with stiffness and impaired mobility involving certain joints (e.g., knees, elbows, wrists, and ankles) of the lower arms and/or legs (distal arthrogryposes). (For more information on these disorders, choose the exact disorder name in question as your search term in the Rare Disease Database.) | 532 | Gordon Syndrome |
nord_532_5 | Diagnosis of Gordon Syndrome | In most people, Gordon syndrome is diagnosed at birth by a thorough clinical evaluation and the identification of characteristic physical findings. Many of the physical features associated with Gordon syndrome (e.g., camptodactyly, clubfoot, and/or cleft palate) are obvious at birth (congenital). | Diagnosis of Gordon Syndrome. In most people, Gordon syndrome is diagnosed at birth by a thorough clinical evaluation and the identification of characteristic physical findings. Many of the physical features associated with Gordon syndrome (e.g., camptodactyly, clubfoot, and/or cleft palate) are obvious at birth (congenital). | 532 | Gordon Syndrome |
nord_532_6 | Therapies of Gordon Syndrome | The treatment of Gordon syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, speech pathologists, physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Surgery may be performed to help correct certain physical abnormalities such as clubfoot and camptodactyly. In addition, reconstructive surgery can help correct facial deformities such as cleft palate. Physical therapy may help to increase the range of motion in the elbows, forearms, wrists, fingers, as well as the legs. Braces or splints may be used to improve range of motion. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Gordon Syndrome. The treatment of Gordon syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, speech pathologists, physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.Surgery may be performed to help correct certain physical abnormalities such as clubfoot and camptodactyly. In addition, reconstructive surgery can help correct facial deformities such as cleft palate. Physical therapy may help to increase the range of motion in the elbows, forearms, wrists, fingers, as well as the legs. Braces or splints may be used to improve range of motion. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 532 | Gordon Syndrome |
nord_533_0 | Overview of Gorham-Stout Disease | SummaryGorham-Stout disease (GSD), which is also known as vanishing bone disease, disappearing bone disease, massive osteolysis, and more than a half-dozen other terms in the medical literature, is a rare bone disorder characterized by progressive bone loss (osteolysis) and the overgrowth (proliferation) of lymphatic vessels. Affected individuals experience progressive destruction and resorption of bone. Multiple bones may become involved. Areas commonly affected by GSD include the ribs, spine, pelvis, skull, collarbone (clavicle), and jaw. Pain and swelling in the affected area may occur. Bones affected by GSD are prone to reduced bone mass (osteopenia) and fracture. The severity of GSD can vary from one person to another and the disorder can potentially cause disfigurement and functional disability of affected areas. The exact cause of GSD is unknown.IntroductionThe lymphatic system consists of a network of tubular channels (lymph vessels) that transport lymph back into the bloodstream. Lymph is fluid that contains proteins, fats, and lymphocytes. As lymph moves through the lymphatic system, it passes through a network of lymph nodes that help the body to deactivate sources of infection (e.g., viruses, bacteria, etc.) and other potentially injurious substances and toxins. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. The lymphatic system also includes the spleen, which filters worn-out red blood cells and produces lymphocytes; and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. GSD is a rare disease that is thought to be caused by an error in the development of the lymphatic system. In individuals with GSD, bones become infiltrated with lymphatic vessels and are broken down and replaced by a fibrous band of connective tissue. | Overview of Gorham-Stout Disease. SummaryGorham-Stout disease (GSD), which is also known as vanishing bone disease, disappearing bone disease, massive osteolysis, and more than a half-dozen other terms in the medical literature, is a rare bone disorder characterized by progressive bone loss (osteolysis) and the overgrowth (proliferation) of lymphatic vessels. Affected individuals experience progressive destruction and resorption of bone. Multiple bones may become involved. Areas commonly affected by GSD include the ribs, spine, pelvis, skull, collarbone (clavicle), and jaw. Pain and swelling in the affected area may occur. Bones affected by GSD are prone to reduced bone mass (osteopenia) and fracture. The severity of GSD can vary from one person to another and the disorder can potentially cause disfigurement and functional disability of affected areas. The exact cause of GSD is unknown.IntroductionThe lymphatic system consists of a network of tubular channels (lymph vessels) that transport lymph back into the bloodstream. Lymph is fluid that contains proteins, fats, and lymphocytes. As lymph moves through the lymphatic system, it passes through a network of lymph nodes that help the body to deactivate sources of infection (e.g., viruses, bacteria, etc.) and other potentially injurious substances and toxins. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. The lymphatic system also includes the spleen, which filters worn-out red blood cells and produces lymphocytes; and bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. GSD is a rare disease that is thought to be caused by an error in the development of the lymphatic system. In individuals with GSD, bones become infiltrated with lymphatic vessels and are broken down and replaced by a fibrous band of connective tissue. | 533 | Gorham-Stout Disease |
nord_533_1 | Symptoms of Gorham-Stout Disease | The symptoms of GSD depend upon the specific bones involved. The ribs, spine, pelvis, skull, collarbone (clavicle), and jaw are the most commonly affect bones in GSD. In some cases, affected individuals may rapidly develop pain and swelling in the affected area. In other cases, affected individuals may experience a dull pain or ache or generalized weakness that builds over time. Trauma is often a trigger of the initial presentation of the disease. Bones affected by GSD are prone to pathological fractures. When GSD affects the maxillofacial area, pain, loose teeth, fractures and facial deformity may develop. Involvement of the spine or skull base can be associated with neurological complications. Involvement of the spine can also potentially result in chronic or acute pain or paralysis (paraplegia). Some medical references have reported an association with meningitis in such cases. Meningitis is inflammation of the membranes (meninges) covering the brain and spinal cord, usually due to infection.Involvement of the thoracic cage can lead to chylothorax, which is the accumulation of chyle in the space between the membranes (pleura) that line the lungs and chest cavity. Chyle is a milky fluid that consists of lymph and fat. Chylothorax can cause difficulty breathing (dyspnea), rapid breathing (tachypnea), chest pain or respiratory compromise. Chylothorax can eventually progress to cause life-threatening respiratory complications. Chylous ascites (accumulation of chyle in the abdominal cavity) can also occur in patients with GSD. Some individuals with GSD may develop abnormal fluid accumulation around the heart (pericardial effusion). Specifically, the fluid accumulates in the pericardium, the sac-like structure that surrounds the heart.Clinical Course – Outcomes
The prognosis for GSD patients is uncertain and variable and depends on the extent of the disease, the part of the body involved, and underlying proliferative progressiveness of the disease. Pulmonary involvement with chylothorax or spinal involvement may confer a poor prognosis, sometimes leading to death. In other cases, lesions may remain stable for long periods of time. | Symptoms of Gorham-Stout Disease. The symptoms of GSD depend upon the specific bones involved. The ribs, spine, pelvis, skull, collarbone (clavicle), and jaw are the most commonly affect bones in GSD. In some cases, affected individuals may rapidly develop pain and swelling in the affected area. In other cases, affected individuals may experience a dull pain or ache or generalized weakness that builds over time. Trauma is often a trigger of the initial presentation of the disease. Bones affected by GSD are prone to pathological fractures. When GSD affects the maxillofacial area, pain, loose teeth, fractures and facial deformity may develop. Involvement of the spine or skull base can be associated with neurological complications. Involvement of the spine can also potentially result in chronic or acute pain or paralysis (paraplegia). Some medical references have reported an association with meningitis in such cases. Meningitis is inflammation of the membranes (meninges) covering the brain and spinal cord, usually due to infection.Involvement of the thoracic cage can lead to chylothorax, which is the accumulation of chyle in the space between the membranes (pleura) that line the lungs and chest cavity. Chyle is a milky fluid that consists of lymph and fat. Chylothorax can cause difficulty breathing (dyspnea), rapid breathing (tachypnea), chest pain or respiratory compromise. Chylothorax can eventually progress to cause life-threatening respiratory complications. Chylous ascites (accumulation of chyle in the abdominal cavity) can also occur in patients with GSD. Some individuals with GSD may develop abnormal fluid accumulation around the heart (pericardial effusion). Specifically, the fluid accumulates in the pericardium, the sac-like structure that surrounds the heart.Clinical Course – Outcomes
The prognosis for GSD patients is uncertain and variable and depends on the extent of the disease, the part of the body involved, and underlying proliferative progressiveness of the disease. Pulmonary involvement with chylothorax or spinal involvement may confer a poor prognosis, sometimes leading to death. In other cases, lesions may remain stable for long periods of time. | 533 | Gorham-Stout Disease |
nord_533_2 | Causes of Gorham-Stout Disease | The exact cause of GSD is unknown. No environmental, immunological or genetic risk factors have been identified. Most cases occur randomly for no known reason (sporadically).Bone loss in GSD is accompanied by the uncontrolled growth (proliferation) of lymphatic tissue. The signal that stimulates this abnormal proliferation of vascular and lymphatic tissue is unknown. However, laboratory research has implicated specific growth factors (e.g. vascular endothelial growth factor [VEGF]) in modulating lymphatic vessel growth and bone development and destruction. Future investigations will reveal the role these growth factors serve in promoting GSD.Some investigators have speculated that circulation issues lead to a deficiency of oxygen being delivered to affected areas, which, in turn, causes changes in pH and promotes the activity of specific enzymes that ultimately cause the destruction of bone. Osteoclasts are large cells that degrade bone. Several reports suggest that osteoclasts play a role in the resorption of bone in GSD. Active osteoclasts have been observed in histological samples from some patients with GSD. Additionally, CTX-1 (a circulating marker of osteoclast activity) has been reported to be elevated in several GSD patients. It has been suggested that osteoclast precursors in GSD patients are more sensitive to osteoclast-inducing factors than osteoclasts precursors in unaffected individuals. Also, interleukin-6 (a factor that induces osteoclast formation) has been reported to be elevated in some patients with GSD. More recently, a basic science study revealed that lymphatic endothelial cells (LECs) express a high level of macrophage colony stimulating factor (M-CSF), a factor that induces the development of osteoclasts. Interestingly, LECs were found to induce osteoclast formation and activity in an M-CSF dependent manner. More work is required to elucidate the role of osteoclasts in GSD. Taken together, the specific reason that GSD develops is simply not well understood. More research is necessary to determine the exact cause and underlying mechanisms that ultimately result in GSD. | Causes of Gorham-Stout Disease. The exact cause of GSD is unknown. No environmental, immunological or genetic risk factors have been identified. Most cases occur randomly for no known reason (sporadically).Bone loss in GSD is accompanied by the uncontrolled growth (proliferation) of lymphatic tissue. The signal that stimulates this abnormal proliferation of vascular and lymphatic tissue is unknown. However, laboratory research has implicated specific growth factors (e.g. vascular endothelial growth factor [VEGF]) in modulating lymphatic vessel growth and bone development and destruction. Future investigations will reveal the role these growth factors serve in promoting GSD.Some investigators have speculated that circulation issues lead to a deficiency of oxygen being delivered to affected areas, which, in turn, causes changes in pH and promotes the activity of specific enzymes that ultimately cause the destruction of bone. Osteoclasts are large cells that degrade bone. Several reports suggest that osteoclasts play a role in the resorption of bone in GSD. Active osteoclasts have been observed in histological samples from some patients with GSD. Additionally, CTX-1 (a circulating marker of osteoclast activity) has been reported to be elevated in several GSD patients. It has been suggested that osteoclast precursors in GSD patients are more sensitive to osteoclast-inducing factors than osteoclasts precursors in unaffected individuals. Also, interleukin-6 (a factor that induces osteoclast formation) has been reported to be elevated in some patients with GSD. More recently, a basic science study revealed that lymphatic endothelial cells (LECs) express a high level of macrophage colony stimulating factor (M-CSF), a factor that induces the development of osteoclasts. Interestingly, LECs were found to induce osteoclast formation and activity in an M-CSF dependent manner. More work is required to elucidate the role of osteoclasts in GSD. Taken together, the specific reason that GSD develops is simply not well understood. More research is necessary to determine the exact cause and underlying mechanisms that ultimately result in GSD. | 533 | Gorham-Stout Disease |
nord_533_3 | Affects of Gorham-Stout Disease | GSD usually affects children and young adults under the age of 40. However, the disorder has been reported in an infant less than one month old and an adult more than 70, suggesting GSD can potentially affect individuals of any age. Some medical sources state that males are affected more often than females. Other medical sources state that the ratio is even (1:1). More than 300 affected individuals have been reported in the medical literature. Because GSD is so rare, many cases go undiagnosed or misdiagnosed making it difficult to determine the disorder’s true frequency in the general population. | Affects of Gorham-Stout Disease. GSD usually affects children and young adults under the age of 40. However, the disorder has been reported in an infant less than one month old and an adult more than 70, suggesting GSD can potentially affect individuals of any age. Some medical sources state that males are affected more often than females. Other medical sources state that the ratio is even (1:1). More than 300 affected individuals have been reported in the medical literature. Because GSD is so rare, many cases go undiagnosed or misdiagnosed making it difficult to determine the disorder’s true frequency in the general population. | 533 | Gorham-Stout Disease |
nord_533_4 | Related disorders of Gorham-Stout Disease | Symptoms of the following disorders can be similar to those of GSD. Comparisons may be useful for a differential diagnosis.Bone loss (osteolysis) can be caused by several different conditions including infection, inflammation, cancer and certain endocrine disorders. Several different disorders have been noted in the differential diagnosis of GSD including Hajdu-Cheney syndrome, Paget’s disease, rheumatoid arthritis, fibrous dysplasia, Langerhans cell histiocytosis, Winchester syndrome, carpal tarsal osteolysis, idiopathic multicentric osteolysis, multicentric osteolysis with nephropathy, and eosinophilic granulomatosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Generalized lymphatic anomaly (GLA, formerly known as lymphangiomatosis) is closely related to GSD. Patients with GLA have multifocal lymphatic malformations. These malformations can be present in bone, but do not cause the loss of cortical bone, as observed in GSD. | Related disorders of Gorham-Stout Disease. Symptoms of the following disorders can be similar to those of GSD. Comparisons may be useful for a differential diagnosis.Bone loss (osteolysis) can be caused by several different conditions including infection, inflammation, cancer and certain endocrine disorders. Several different disorders have been noted in the differential diagnosis of GSD including Hajdu-Cheney syndrome, Paget’s disease, rheumatoid arthritis, fibrous dysplasia, Langerhans cell histiocytosis, Winchester syndrome, carpal tarsal osteolysis, idiopathic multicentric osteolysis, multicentric osteolysis with nephropathy, and eosinophilic granulomatosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Generalized lymphatic anomaly (GLA, formerly known as lymphangiomatosis) is closely related to GSD. Patients with GLA have multifocal lymphatic malformations. These malformations can be present in bone, but do not cause the loss of cortical bone, as observed in GSD. | 533 | Gorham-Stout Disease |
nord_533_5 | Diagnosis of Gorham-Stout Disease | There is no specific test or procedure that definitively diagnoses GSD, which is partly a diagnosis of exclusion. A diagnosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including biopsies and specialized imaging techniques.Clinical Testing and Work-Up
A biopsy, which is the surgical removal and microscopic study of affected tissue, can reveal the presence of abnormal lymphatic tissue and characteristic bony changes. There is a caution reported in taking biopsies of rib lesions whenever possible since these biopsies may lead to chronic pleural effusions.Imaging techniques including plain x-rays, ultrasound, radioisotope bone scans, computerized tomography (CT) scanning, and magnetic resonance imaging (MRI) may be used to aid in obtaining a diagnosis. The findings for these exams may be variable, but can show dissolution, fragmentation and fracture of bones. These tests can also be useful in showing the extent of the disease and in detecting soft tissue involvement. In the finding of the presence of bone loss, full-body skeletal scans are useful in the differential diagnosis – especially related to the closely related, multifocal GLA disorder. Newer imaging techniques provide anatomic clarity, such as non-contrast magnetic resonance (MR) lymphangiogram, dynamic contrast MR lymphangiography and intranodal lymphangiogram are available at some institutions. | Diagnosis of Gorham-Stout Disease. There is no specific test or procedure that definitively diagnoses GSD, which is partly a diagnosis of exclusion. A diagnosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including biopsies and specialized imaging techniques.Clinical Testing and Work-Up
A biopsy, which is the surgical removal and microscopic study of affected tissue, can reveal the presence of abnormal lymphatic tissue and characteristic bony changes. There is a caution reported in taking biopsies of rib lesions whenever possible since these biopsies may lead to chronic pleural effusions.Imaging techniques including plain x-rays, ultrasound, radioisotope bone scans, computerized tomography (CT) scanning, and magnetic resonance imaging (MRI) may be used to aid in obtaining a diagnosis. The findings for these exams may be variable, but can show dissolution, fragmentation and fracture of bones. These tests can also be useful in showing the extent of the disease and in detecting soft tissue involvement. In the finding of the presence of bone loss, full-body skeletal scans are useful in the differential diagnosis – especially related to the closely related, multifocal GLA disorder. Newer imaging techniques provide anatomic clarity, such as non-contrast magnetic resonance (MR) lymphangiogram, dynamic contrast MR lymphangiography and intranodal lymphangiogram are available at some institutions. | 533 | Gorham-Stout Disease |
nord_533_6 | Therapies of Gorham-Stout Disease | TreatmentGSD (and GLA) can present at any age. Diagnosis, treatment, and care generally require a multidisciplinary team. Access to care is available through the worldwide Vascular Anomalies Clinical Network. For more information on expertise and consult, contact the Lymphangiomatosis & Gorham’s Disease Alliance. There is no consensus in the medical literature as to what is the most effective treatment for GSD. Treatment is usually directed toward the specific symptoms that are apparent in each individual. Surgery to remove the affect areas of bone has been performed to treat individuals with GSD. In some cases, a bone graft, which stimulates or augments the formation of new bone, may be used in conjunction with the surgical removal of affected bone. However, bone grafts can only be used after stabilization of the osteolytic process. Consequently, some physicians prefer the use of artificial (prosthetic) bone to replace bone removed by surgery.Radiation therapy, sometimes in conjunction with surgery, has also been used to treat individuals with GSD. Radiation therapy has proven effective in treating some affected individuals, achieving pain relief and arresting the spread of osteolysis. Radiation therapy has also been effective in treating chylothorax, which is sometimes associated with GSD.According to cases reported in the medical literature, positive results have been achieved with a total dose of 30 to 45 Gy. In one reported case, positive results were achieved using a total dose of 15 Gy in an individual with GSD affecting the upper extremity. | Therapies of Gorham-Stout Disease. TreatmentGSD (and GLA) can present at any age. Diagnosis, treatment, and care generally require a multidisciplinary team. Access to care is available through the worldwide Vascular Anomalies Clinical Network. For more information on expertise and consult, contact the Lymphangiomatosis & Gorham’s Disease Alliance. There is no consensus in the medical literature as to what is the most effective treatment for GSD. Treatment is usually directed toward the specific symptoms that are apparent in each individual. Surgery to remove the affect areas of bone has been performed to treat individuals with GSD. In some cases, a bone graft, which stimulates or augments the formation of new bone, may be used in conjunction with the surgical removal of affected bone. However, bone grafts can only be used after stabilization of the osteolytic process. Consequently, some physicians prefer the use of artificial (prosthetic) bone to replace bone removed by surgery.Radiation therapy, sometimes in conjunction with surgery, has also been used to treat individuals with GSD. Radiation therapy has proven effective in treating some affected individuals, achieving pain relief and arresting the spread of osteolysis. Radiation therapy has also been effective in treating chylothorax, which is sometimes associated with GSD.According to cases reported in the medical literature, positive results have been achieved with a total dose of 30 to 45 Gy. In one reported case, positive results were achieved using a total dose of 15 Gy in an individual with GSD affecting the upper extremity. | 533 | Gorham-Stout Disease |
nord_534_0 | Overview of Gorlin-Chaudhry-Moss Syndrome | Gorlin-Chaudhry-Moss syndrome is an extremely rare inherited disorder characterized by premature closure of the fibrous joints (sutures) between certain bones in the skull (craniosynostosis), unusually small eyes (microphthalmia), absence of some teeth (hypodontia), and/or excessive amounts of hair (hypertrichosis) on most areas of the body. Affected individuals may also exhibit a mild delay in physical development (growth retardation); short fingers and/or toes; and/or underdevelopment (hypoplasia) of the two long folds of skin on either side of the vaginal opening (labia majora) in females. In addition, there may be an abnormal opening between the two large blood vessels that carry blood away from the heart (pulmonary artery and aorta), causing inappropriate recirculation of some blood through the lungs, rather than throughout the rest of the body (patent ductus arteriosus). In some cases, mild mental retardation may also be present. It is believed that Gorlin-Chaudhry-Moss syndrome may be inherited as an autosomal recessive trait. | Overview of Gorlin-Chaudhry-Moss Syndrome. Gorlin-Chaudhry-Moss syndrome is an extremely rare inherited disorder characterized by premature closure of the fibrous joints (sutures) between certain bones in the skull (craniosynostosis), unusually small eyes (microphthalmia), absence of some teeth (hypodontia), and/or excessive amounts of hair (hypertrichosis) on most areas of the body. Affected individuals may also exhibit a mild delay in physical development (growth retardation); short fingers and/or toes; and/or underdevelopment (hypoplasia) of the two long folds of skin on either side of the vaginal opening (labia majora) in females. In addition, there may be an abnormal opening between the two large blood vessels that carry blood away from the heart (pulmonary artery and aorta), causing inappropriate recirculation of some blood through the lungs, rather than throughout the rest of the body (patent ductus arteriosus). In some cases, mild mental retardation may also be present. It is believed that Gorlin-Chaudhry-Moss syndrome may be inherited as an autosomal recessive trait. | 534 | Gorlin-Chaudhry-Moss Syndrome |
nord_534_1 | Symptoms of Gorlin-Chaudhry-Moss Syndrome | Gorlin-Chaudhry-Moss syndrome is characterized by a mild delay in physical development (growth retardation), short stature, mild mental retardation, and several physical abnormalities. In Gorlin-Chaudhry-Moss syndrome, premature closure of the fibrous joints (coronal sutures) between bones in the front (frontal bone) and sides (parietal bones) of the skull (craniosynostosis) may cause the head to appear abnormally short (brachycephaly). In addition, the middle portion of the face may be underdeveloped (midface hypoplasia), causing these areas (e.g., forehead, nose, and/or chin) to appear flat. Additional abnormalities of the head and facial (craniofacial) area may also be present, such as unusually small eyes (microphthalmia); downwardly slanting eyelid folds (palpebral fissures); incomplete development of the bones in the jaw (maxillary hypoplasia); and/or an abnormally narrow, highly arched roof of the mouth (palate). Individuals with Gorlin-Chaudhry-Moss syndrome may also have several abnormalities of the teeth. Some teeth may be absent (hypodontia), unusually small (microdontia), and/or abnormally shaped. Teeth may also be improperly positioned (malocclusion), causing difficulties in chewing (mastication). With time, some affected individuals may exhibit a thickening or coarsening of facial features. Infants with Gorlin-Chaudhry-Moss syndrome often exhibit several abnormalities involving the hair. The hairline may be abnormally low on the scalp (low frontal hairline) and the hair may be unusually coarse. In addition, affected infants may have excessive amounts of hair (hypertrichosis) on most areas of the body including the face, scalp, hands, feet, arms, and/or legs. Affected individuals often have numerous skeletal abnormalities such as underdevelopment (hypoplasia) of the bones at the end of the fingers and toes (distal phalanges) and/or the bones between the wrist and the fingers (metacarpals). As a result, the hands, fingers, and toes may appear abnormally short. Many individuals with Gorlin-Chaudhry-Moss syndrome also exhibit additional malformations. In affected females, the two long folds of skin on either side of the vaginal opening may be underdeveloped (labia majora hypoplasia). In addition, in some cases, there may be an abnormal opening between two large blood vessels that carry blood away from the heart (pulmonary artery and aorta); as a result, some blood may recirculate through the lungs, rather than throughout the rest of the body (patent ductus arteriosus). If a large amount of blood is misdirected to the lungs, the heart may become strained as it works to pump sufficient amounts of blood to the rest of the body. Affected infants may therefore exhibit an increased heart rate (tachycardia), enlargement of the heart (cardiomegaly), shortness of breath, and/or a failure to gain weight. They may also have an increased susceptibility to respiratory infections and/or bacterial infections causing inflammation of the heart's lining (bacterial endocarditis), and in some cases, a reduction in the heart's ability to pump blood efficiently (congestive heart failure). In some infants with Gorlin-Chaudhry-Moss syndrome, portions of the intestine may protrude through an abnormal opening in the abdominal wall where the umbilical cord joined the fetus' abdomen (umbilical hernia). In addition, in some affected individuals, sound may be inappropriately conducted through the external or middle ear to the inner ear; as a result, there may be a decreased sensitivity to sound (conductive hearing loss). | Symptoms of Gorlin-Chaudhry-Moss Syndrome. Gorlin-Chaudhry-Moss syndrome is characterized by a mild delay in physical development (growth retardation), short stature, mild mental retardation, and several physical abnormalities. In Gorlin-Chaudhry-Moss syndrome, premature closure of the fibrous joints (coronal sutures) between bones in the front (frontal bone) and sides (parietal bones) of the skull (craniosynostosis) may cause the head to appear abnormally short (brachycephaly). In addition, the middle portion of the face may be underdeveloped (midface hypoplasia), causing these areas (e.g., forehead, nose, and/or chin) to appear flat. Additional abnormalities of the head and facial (craniofacial) area may also be present, such as unusually small eyes (microphthalmia); downwardly slanting eyelid folds (palpebral fissures); incomplete development of the bones in the jaw (maxillary hypoplasia); and/or an abnormally narrow, highly arched roof of the mouth (palate). Individuals with Gorlin-Chaudhry-Moss syndrome may also have several abnormalities of the teeth. Some teeth may be absent (hypodontia), unusually small (microdontia), and/or abnormally shaped. Teeth may also be improperly positioned (malocclusion), causing difficulties in chewing (mastication). With time, some affected individuals may exhibit a thickening or coarsening of facial features. Infants with Gorlin-Chaudhry-Moss syndrome often exhibit several abnormalities involving the hair. The hairline may be abnormally low on the scalp (low frontal hairline) and the hair may be unusually coarse. In addition, affected infants may have excessive amounts of hair (hypertrichosis) on most areas of the body including the face, scalp, hands, feet, arms, and/or legs. Affected individuals often have numerous skeletal abnormalities such as underdevelopment (hypoplasia) of the bones at the end of the fingers and toes (distal phalanges) and/or the bones between the wrist and the fingers (metacarpals). As a result, the hands, fingers, and toes may appear abnormally short. Many individuals with Gorlin-Chaudhry-Moss syndrome also exhibit additional malformations. In affected females, the two long folds of skin on either side of the vaginal opening may be underdeveloped (labia majora hypoplasia). In addition, in some cases, there may be an abnormal opening between two large blood vessels that carry blood away from the heart (pulmonary artery and aorta); as a result, some blood may recirculate through the lungs, rather than throughout the rest of the body (patent ductus arteriosus). If a large amount of blood is misdirected to the lungs, the heart may become strained as it works to pump sufficient amounts of blood to the rest of the body. Affected infants may therefore exhibit an increased heart rate (tachycardia), enlargement of the heart (cardiomegaly), shortness of breath, and/or a failure to gain weight. They may also have an increased susceptibility to respiratory infections and/or bacterial infections causing inflammation of the heart's lining (bacterial endocarditis), and in some cases, a reduction in the heart's ability to pump blood efficiently (congestive heart failure). In some infants with Gorlin-Chaudhry-Moss syndrome, portions of the intestine may protrude through an abnormal opening in the abdominal wall where the umbilical cord joined the fetus' abdomen (umbilical hernia). In addition, in some affected individuals, sound may be inappropriately conducted through the external or middle ear to the inner ear; as a result, there may be a decreased sensitivity to sound (conductive hearing loss). | 534 | Gorlin-Chaudhry-Moss Syndrome |
nord_534_2 | Causes of Gorlin-Chaudhry-Moss Syndrome | It is believed that Gorlin-Chaudhry-Moss syndrome may be inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. | Causes of Gorlin-Chaudhry-Moss Syndrome. It is believed that Gorlin-Chaudhry-Moss syndrome may be inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. | 534 | Gorlin-Chaudhry-Moss Syndrome |
nord_534_3 | Affects of Gorlin-Chaudhry-Moss Syndrome | Gorlin-Chaudhry-Moss syndrome is an extremely rare inherited disorder that is apparent at birth (congenital). Approximately four cases have been reported in the medical literature. Although all reported cases have involved females, the true ratio of affected females to males is not known. The first case of Gorlin-Chaudhry-Moss syndrome was reported in the medical literature in 1960. | Affects of Gorlin-Chaudhry-Moss Syndrome. Gorlin-Chaudhry-Moss syndrome is an extremely rare inherited disorder that is apparent at birth (congenital). Approximately four cases have been reported in the medical literature. Although all reported cases have involved females, the true ratio of affected females to males is not known. The first case of Gorlin-Chaudhry-Moss syndrome was reported in the medical literature in 1960. | 534 | Gorlin-Chaudhry-Moss Syndrome |
nord_534_4 | Related disorders of Gorlin-Chaudhry-Moss Syndrome | Symptoms of the following disorders can be similar to those of Gorlin-Chaudhry-Moss syndrome. Comparisons may be useful for a differential diagnosis:Weill-Marchesani syndrome is a rare inherited disorder of the connective tissue. It is characterized by an abnormally short head (brachycephaly), round face, and pug nose; short fingers (brachydactyly); joint stiffness with limited extension; and short stature with a muscular, stocky build. In most cases, several eye abnormalities are present, including abnormally small, round lenses (microspherophakia) that tend to dislocate (ectopia lentis); loss of transparency of the lenses (cataracts); nearsightedness (myopia); and/or abnormally increased pressure in the fluid of the eye (glaucoma). It is believed that Weill-Marchesani syndrome may be inherited as an autosomal dominant or recessive genetic trait. (For more information on this disorder, choose “Weill-Marchesani” as your search term in the Rare Disease Database.) Saethre-Chotzen syndrome (also known as acrocephalosyndactyly type III) is a rare inherited disorder characterized by premature closure of the fibrous joints (sutures) between certain bones in the skull (craniosynostosis), causing the head to appear asymmetrical (plagiocephaly) and/or short and broad (brachycephaly). Additional abnormalities of the head and facial (craniofacial) area may include a beaked nose; underdevelopment of the middle portion of the face (midface hypoplasia), causing these areas (e.g., forehead, nasal bridge, and/or chin) to appear flat; and/or low-set and/or malformed ears. Other craniofacial abnormalities may also be present, including downwardly slanting eyelid folds (palpebral fissures), a highly arched palate, underdevelopment of the upper jaw bone (maxillary hypoplasia), and/or extra, missing, or peg-shaped teeth. Many affected individuals also exhibit abnormally short fingers and/or toes (brachydactyly) that may be mildly fused or webbed (syndactyly), short stature, mild hearing loss, and mild to moderate mental retardation. The syndrome is believed to be inherited as an autosomal dominant trait. (For more information on this disorder, choose “Saethre-Chotzen” as your search term in the Rare Disease Database.) There are several other rare inherited craniofacial disorders that are characterized by craniosynostosis; malformations of the eyes, nose, mouth, and/or teeth; abnormalities of the fingers and/or toes; short stature; and other malformations similar to those of Gorlin-Chaudhry-Moss syndrome. (For more information on these disorders, choose “Craniofacial” or “Craniosynostosis” as your search term in the Rare Disease Database.) | Related disorders of Gorlin-Chaudhry-Moss Syndrome. Symptoms of the following disorders can be similar to those of Gorlin-Chaudhry-Moss syndrome. Comparisons may be useful for a differential diagnosis:Weill-Marchesani syndrome is a rare inherited disorder of the connective tissue. It is characterized by an abnormally short head (brachycephaly), round face, and pug nose; short fingers (brachydactyly); joint stiffness with limited extension; and short stature with a muscular, stocky build. In most cases, several eye abnormalities are present, including abnormally small, round lenses (microspherophakia) that tend to dislocate (ectopia lentis); loss of transparency of the lenses (cataracts); nearsightedness (myopia); and/or abnormally increased pressure in the fluid of the eye (glaucoma). It is believed that Weill-Marchesani syndrome may be inherited as an autosomal dominant or recessive genetic trait. (For more information on this disorder, choose “Weill-Marchesani” as your search term in the Rare Disease Database.) Saethre-Chotzen syndrome (also known as acrocephalosyndactyly type III) is a rare inherited disorder characterized by premature closure of the fibrous joints (sutures) between certain bones in the skull (craniosynostosis), causing the head to appear asymmetrical (plagiocephaly) and/or short and broad (brachycephaly). Additional abnormalities of the head and facial (craniofacial) area may include a beaked nose; underdevelopment of the middle portion of the face (midface hypoplasia), causing these areas (e.g., forehead, nasal bridge, and/or chin) to appear flat; and/or low-set and/or malformed ears. Other craniofacial abnormalities may also be present, including downwardly slanting eyelid folds (palpebral fissures), a highly arched palate, underdevelopment of the upper jaw bone (maxillary hypoplasia), and/or extra, missing, or peg-shaped teeth. Many affected individuals also exhibit abnormally short fingers and/or toes (brachydactyly) that may be mildly fused or webbed (syndactyly), short stature, mild hearing loss, and mild to moderate mental retardation. The syndrome is believed to be inherited as an autosomal dominant trait. (For more information on this disorder, choose “Saethre-Chotzen” as your search term in the Rare Disease Database.) There are several other rare inherited craniofacial disorders that are characterized by craniosynostosis; malformations of the eyes, nose, mouth, and/or teeth; abnormalities of the fingers and/or toes; short stature; and other malformations similar to those of Gorlin-Chaudhry-Moss syndrome. (For more information on these disorders, choose “Craniofacial” or “Craniosynostosis” as your search term in the Rare Disease Database.) | 534 | Gorlin-Chaudhry-Moss Syndrome |
nord_534_5 | Diagnosis of Gorlin-Chaudhry-Moss Syndrome | Gorlin-Chaudhry-Moss syndrome may be diagnosed at birth, based upon a thorough clinical evaluation and characteristic physical findings. The presence of patent ductus arteriosus occurring in association with Gorlin-Chaudhry-Moss syndrome may be determined by a variety of tests. When an abnormal heart murmur is detected, chest X-rays may be ordered along with an electrocardiogram (ECG), a test that measures the heart muscle's electrical activity. Structural and functional abnormalities of the heart and its blood vessels can be analyzed through the reflection of sound waves (echocardiogram). Conductive hearing loss occurring in association with Gorlin-Chaudhry-Moss syndrome can be diagnosed by a battery of tests that measures the functioning of the middle ear (conductive loss battery). | Diagnosis of Gorlin-Chaudhry-Moss Syndrome. Gorlin-Chaudhry-Moss syndrome may be diagnosed at birth, based upon a thorough clinical evaluation and characteristic physical findings. The presence of patent ductus arteriosus occurring in association with Gorlin-Chaudhry-Moss syndrome may be determined by a variety of tests. When an abnormal heart murmur is detected, chest X-rays may be ordered along with an electrocardiogram (ECG), a test that measures the heart muscle's electrical activity. Structural and functional abnormalities of the heart and its blood vessels can be analyzed through the reflection of sound waves (echocardiogram). Conductive hearing loss occurring in association with Gorlin-Chaudhry-Moss syndrome can be diagnosed by a battery of tests that measures the functioning of the middle ear (conductive loss battery). | 534 | Gorlin-Chaudhry-Moss Syndrome |
nord_534_6 | Therapies of Gorlin-Chaudhry-Moss Syndrome | TreatmentThe treatment of Gorlin-Chaudhry-Moss syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, dental specialists, speech pathologists, specialists who assess and treat hearing problems (audiologists), eye specialists, and others may need to systematically and comprehensively plan an affected child's treatment.Surgery may be performed in some cases to correct craniofacial abnormalities. Partial or complete dentures, oral surgery, and/or other steps may be used to correct, restore, and/or replace absent tooth structure or oral tissues (dental restoration). In affected individuals who exhibit conductive hearing loss, treatment may consist of surgery and/or the use of certain hearing aid devices, depending upon the specific middle ear abnormality causing the hearing loss. In those with microphthalmia, physicians who diagnose and treat diseases of the eye (ophthalmologists) may use a variety of methods to treat, prevent, and/or correct any visual abnormalities potentially associated with this condition.In affected infants with patent ductus arteriosus who are born prematurely, the abnormal heart opening may close on its own. If the opening does not close spontaneously, therapy with the drug indomethacin may facilitate such closure. If such drug therapy is not effective, surgery may be performed.Individuals with patent ductus arteriosus may be susceptible to bacterial endocarditis, an infection that causes inflammation of the heart's lining. Preventive steps should be taken to avoid such episodes of infection. For example, antibiotic drug therapy may be given prior to any procedure that could allow bacteria to enter the bloodstream (e.g., dental procedures, invasive diagnostic procedures, surgery). If bacterial endocarditis occurs, antibiotic therapy must be given immediately.In affected infants who have an umbilical hernia, the abnormal opening in the abdominal wall often closes on its own within the 1st or 2nd year of life. However, if the hernia is large, it may need to be closed surgically.Early intervention is also important in ensuring that children with Gorlin-Chaudhry-Moss syndrome reach their potential. Special services that may be beneficial to affected children may include physical therapy, special remedial education, speech therapy, and other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected families. Other treatment is symptomatic and supportive. | Therapies of Gorlin-Chaudhry-Moss Syndrome. TreatmentThe treatment of Gorlin-Chaudhry-Moss syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, dental specialists, speech pathologists, specialists who assess and treat hearing problems (audiologists), eye specialists, and others may need to systematically and comprehensively plan an affected child's treatment.Surgery may be performed in some cases to correct craniofacial abnormalities. Partial or complete dentures, oral surgery, and/or other steps may be used to correct, restore, and/or replace absent tooth structure or oral tissues (dental restoration). In affected individuals who exhibit conductive hearing loss, treatment may consist of surgery and/or the use of certain hearing aid devices, depending upon the specific middle ear abnormality causing the hearing loss. In those with microphthalmia, physicians who diagnose and treat diseases of the eye (ophthalmologists) may use a variety of methods to treat, prevent, and/or correct any visual abnormalities potentially associated with this condition.In affected infants with patent ductus arteriosus who are born prematurely, the abnormal heart opening may close on its own. If the opening does not close spontaneously, therapy with the drug indomethacin may facilitate such closure. If such drug therapy is not effective, surgery may be performed.Individuals with patent ductus arteriosus may be susceptible to bacterial endocarditis, an infection that causes inflammation of the heart's lining. Preventive steps should be taken to avoid such episodes of infection. For example, antibiotic drug therapy may be given prior to any procedure that could allow bacteria to enter the bloodstream (e.g., dental procedures, invasive diagnostic procedures, surgery). If bacterial endocarditis occurs, antibiotic therapy must be given immediately.In affected infants who have an umbilical hernia, the abnormal opening in the abdominal wall often closes on its own within the 1st or 2nd year of life. However, if the hernia is large, it may need to be closed surgically.Early intervention is also important in ensuring that children with Gorlin-Chaudhry-Moss syndrome reach their potential. Special services that may be beneficial to affected children may include physical therapy, special remedial education, speech therapy, and other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected families. Other treatment is symptomatic and supportive. | 534 | Gorlin-Chaudhry-Moss Syndrome |
nord_535_0 | Overview of Gottron Syndrome | SummaryGottron syndrome is an extremely rare inherited disorder characterized by a premature aged appearance (progeroid), especially in the form of unusually fragile, thin skin on the hands and feet (distal extremities). Although the disorder is most typically recognized in early childhood, these characteristic skin findings are present from birth.Gottron syndrome is described as a mild, nonprogressive, congenital form of skin atrophy due to the loss of the fatty tissue directly under the skin (subcutaneous atrophy). This causes the skin to have a dry and transparent appearance. The affected individual is often noted to have hollow cheeks, a beaked nose, and owl-like eyes. Other findings may include abnormally small hands and feet with unusually prominent veins on the chest; irregular hyperpigmentation of the skin (poikiloderma); thinned hair (alopecia); small stature; and/or abnormally small jaw (micrognathia).Characteristics that develop later in life may include premature senility, endocrine disturbances and cataracts. Gottron syndrome may either be inherited in an autosomal dominant or autosomal recessive pattern. Approximately 50 patients have been reported in medical literature.IntroductionGottron syndrome was first described by Heinrich Gottron in 1940. There is some debate in the literature regarding a possible relationship between Gottron syndrome and vascular type Ehlers-Danlos syndrome (formerly type IV). Some clinicians believe the terms are synonymous. Others disagree. | Overview of Gottron Syndrome. SummaryGottron syndrome is an extremely rare inherited disorder characterized by a premature aged appearance (progeroid), especially in the form of unusually fragile, thin skin on the hands and feet (distal extremities). Although the disorder is most typically recognized in early childhood, these characteristic skin findings are present from birth.Gottron syndrome is described as a mild, nonprogressive, congenital form of skin atrophy due to the loss of the fatty tissue directly under the skin (subcutaneous atrophy). This causes the skin to have a dry and transparent appearance. The affected individual is often noted to have hollow cheeks, a beaked nose, and owl-like eyes. Other findings may include abnormally small hands and feet with unusually prominent veins on the chest; irregular hyperpigmentation of the skin (poikiloderma); thinned hair (alopecia); small stature; and/or abnormally small jaw (micrognathia).Characteristics that develop later in life may include premature senility, endocrine disturbances and cataracts. Gottron syndrome may either be inherited in an autosomal dominant or autosomal recessive pattern. Approximately 50 patients have been reported in medical literature.IntroductionGottron syndrome was first described by Heinrich Gottron in 1940. There is some debate in the literature regarding a possible relationship between Gottron syndrome and vascular type Ehlers-Danlos syndrome (formerly type IV). Some clinicians believe the terms are synonymous. Others disagree. | 535 | Gottron Syndrome |
nord_535_1 | Symptoms of Gottron Syndrome | The signs and symptoms of Gottron syndrome vary somewhat from one person to another. Because this condition is so rare, it is difficult to get a complete picture of the core features that define the syndrome. Generally, from birth-onwards, children with Gottron syndrome appear older than their actual age. The skin is unusually thin, taut, and parchment-like on the hands and feet (distal extremities) and may even involve the face. The hands and feet remain abnormally small into adulthood. Those affected by Gottron syndrome are said to have a characteristic face defined by a pinched looking face, hollow cheeks, an owl-eyed appearance, a beaked nose and thin lips.The veins on the chest are very visible and prominent (telangiectasia) due to diminished amounts of fat under the skin (subcutaneous fat). There may also be discoloration of the skin (poikiloderma) or easy bruising especially on the legs and the chest. However, while mostly it is reported that nails appear normal, there have been some reports of a thickened appearance (dystrophic). The affected individual may also have fine or thinning hair (alopecia).Certain skeletal defects may be evident as well. These may include delayed cranial suture closure. The newborn’s skull is comprised of separate bony plates which are separated by sutures. This allows for transient distortion during birth and permits for growth of the brain in the first two years of life. Normally these bony plates will end up fusing by the age of two. Other skeletal defects include bone reabsorption of the ends of the fingers and toes (acro-osteolysis) as well as recurrent fractures.Gottron syndrome is a non-progressive disorder, so the symptoms do not tend to get worse over time. The prognosis is generally quite good and affected individuals have average intelligence as well as a normal life expectancy. Although some patients develop heart disease similar to other premature aging diseases (progeria), people with Gottron syndrome do not usually have the associated premature heart disease. | Symptoms of Gottron Syndrome. The signs and symptoms of Gottron syndrome vary somewhat from one person to another. Because this condition is so rare, it is difficult to get a complete picture of the core features that define the syndrome. Generally, from birth-onwards, children with Gottron syndrome appear older than their actual age. The skin is unusually thin, taut, and parchment-like on the hands and feet (distal extremities) and may even involve the face. The hands and feet remain abnormally small into adulthood. Those affected by Gottron syndrome are said to have a characteristic face defined by a pinched looking face, hollow cheeks, an owl-eyed appearance, a beaked nose and thin lips.The veins on the chest are very visible and prominent (telangiectasia) due to diminished amounts of fat under the skin (subcutaneous fat). There may also be discoloration of the skin (poikiloderma) or easy bruising especially on the legs and the chest. However, while mostly it is reported that nails appear normal, there have been some reports of a thickened appearance (dystrophic). The affected individual may also have fine or thinning hair (alopecia).Certain skeletal defects may be evident as well. These may include delayed cranial suture closure. The newborn’s skull is comprised of separate bony plates which are separated by sutures. This allows for transient distortion during birth and permits for growth of the brain in the first two years of life. Normally these bony plates will end up fusing by the age of two. Other skeletal defects include bone reabsorption of the ends of the fingers and toes (acro-osteolysis) as well as recurrent fractures.Gottron syndrome is a non-progressive disorder, so the symptoms do not tend to get worse over time. The prognosis is generally quite good and affected individuals have average intelligence as well as a normal life expectancy. Although some patients develop heart disease similar to other premature aging diseases (progeria), people with Gottron syndrome do not usually have the associated premature heart disease. | 535 | Gottron Syndrome |
nord_535_2 | Causes of Gottron Syndrome | Gottron syndrome is a rare disorder that for which the mode of inheritance is still not well understood. There is evidence for both autosomal recessive and autosomal dominant inheritance patterns. Most often, a child with Gottron syndrome is the only affected person in the family.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 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.While not yet well understood, there have been reports that Gottron syndrome may arise due to changes (mutations) in the LMNA, ZMPSTE24, or COL3A1 genes. | Causes of Gottron Syndrome. Gottron syndrome is a rare disorder that for which the mode of inheritance is still not well understood. There is evidence for both autosomal recessive and autosomal dominant inheritance patterns. Most often, a child with Gottron syndrome is the only affected person in the family.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 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.While not yet well understood, there have been reports that Gottron syndrome may arise due to changes (mutations) in the LMNA, ZMPSTE24, or COL3A1 genes. | 535 | Gottron Syndrome |
nord_535_3 | Affects of Gottron Syndrome | It is believed that Gottron syndrome may affect more females than males. While about 50 affected individuals have been reported in the medical literature, the exact number of people with this condition is unknown. | Affects of Gottron Syndrome. It is believed that Gottron syndrome may affect more females than males. While about 50 affected individuals have been reported in the medical literature, the exact number of people with this condition is unknown. | 535 | Gottron Syndrome |
nord_535_4 | Related disorders of Gottron Syndrome | Symptoms of the following disorders can be similar to those of Gottron syndrome. Comparisons may be useful for a differential diagnosis:De Barsy syndrome is a rare genetic disorder characterized by a prematurely-aged appearance (progeroid) as well as skin that is loose and lacking elasticity (cutis laxa).The appearance of the infant appears prematurely aged-due to the underdevelopment of the skin and structures of the face (facial hypoplasia) which is further enhanced by wrinkled and saggy skin. Other notable facial features include a prominent forehead, thin lips, and large ears. This is often accompanied by eye abnormalities, intellectual disability as well as growth delays. Affected infants may also have diminished muscle tone (hypotonia). Signs and symptoms of de Barsy syndrome are usually evident in early infancy if not at birth. (For more information on this disorder, choose “De Barsy syndrome” as your search term in the Rare Disease Database.)Hutchinson-Gilford progeria syndrome is a severe form of premature aging (progeria). In early infancy, children with progeria most often have a normal appearance. However, beyond the age of nine months affected children appear as though they are rapidly aging and experience growth delays resulting in very short stature. They may further develop characteristic facial features such as a relatively large head, small face, beak-like nose, a small jaw (micrognathia) and a receding chin. By the age of two, often scalp hair, eyebrows and eyelashes are either lost completely or replaced by pale hairs. Children with Hutchinson-Gilford syndrome usually have normal intelligence, but their life span is shortened due to heart disease (atherosclerosis). (For more information on this disorder, choose “Hutchinson-Gilford Progeria as your search term in the Rare Disease Database.)Werner syndrome is a rare progressive disorder that is characterized by the appearance of unusually accelerated aging (progeria). Although the disorder is typically recognized by the third or fourth decades of life, certain characteristic findings are present in childhood, adolescence, and early adulthood and the condition is most often diagnosed before puberty. Children with Werner syndrome have an abnormally slow growth rate, and growth ends at puberty. As a result, affected individuals have unusually short stature and low weight even relative to height. By age 25, those with the disorder typically experience early graying and premature loss of scalp hair (alopecia). As the disease progresses, additional abnormalities include loss of the layer of fat beneath the skin (subcutaneous adipose tissue); severe wasting (atrophy) of muscle tissue in certain areas of the body; and degenerative skin changes, particularly in the facial area, the upper arms and hands, and the lower legs and feet. Due to degenerative changes affecting the facial area, individuals with Werner syndrome may have unusually prominent eyes, a beaked or pinched nose, and/or other characteristic facial abnormalities. (For more information on this disorder, choose “Werner syndrome” as your search term in the Rare Disease Database.) | Related disorders of Gottron Syndrome. Symptoms of the following disorders can be similar to those of Gottron syndrome. Comparisons may be useful for a differential diagnosis:De Barsy syndrome is a rare genetic disorder characterized by a prematurely-aged appearance (progeroid) as well as skin that is loose and lacking elasticity (cutis laxa).The appearance of the infant appears prematurely aged-due to the underdevelopment of the skin and structures of the face (facial hypoplasia) which is further enhanced by wrinkled and saggy skin. Other notable facial features include a prominent forehead, thin lips, and large ears. This is often accompanied by eye abnormalities, intellectual disability as well as growth delays. Affected infants may also have diminished muscle tone (hypotonia). Signs and symptoms of de Barsy syndrome are usually evident in early infancy if not at birth. (For more information on this disorder, choose “De Barsy syndrome” as your search term in the Rare Disease Database.)Hutchinson-Gilford progeria syndrome is a severe form of premature aging (progeria). In early infancy, children with progeria most often have a normal appearance. However, beyond the age of nine months affected children appear as though they are rapidly aging and experience growth delays resulting in very short stature. They may further develop characteristic facial features such as a relatively large head, small face, beak-like nose, a small jaw (micrognathia) and a receding chin. By the age of two, often scalp hair, eyebrows and eyelashes are either lost completely or replaced by pale hairs. Children with Hutchinson-Gilford syndrome usually have normal intelligence, but their life span is shortened due to heart disease (atherosclerosis). (For more information on this disorder, choose “Hutchinson-Gilford Progeria as your search term in the Rare Disease Database.)Werner syndrome is a rare progressive disorder that is characterized by the appearance of unusually accelerated aging (progeria). Although the disorder is typically recognized by the third or fourth decades of life, certain characteristic findings are present in childhood, adolescence, and early adulthood and the condition is most often diagnosed before puberty. Children with Werner syndrome have an abnormally slow growth rate, and growth ends at puberty. As a result, affected individuals have unusually short stature and low weight even relative to height. By age 25, those with the disorder typically experience early graying and premature loss of scalp hair (alopecia). As the disease progresses, additional abnormalities include loss of the layer of fat beneath the skin (subcutaneous adipose tissue); severe wasting (atrophy) of muscle tissue in certain areas of the body; and degenerative skin changes, particularly in the facial area, the upper arms and hands, and the lower legs and feet. Due to degenerative changes affecting the facial area, individuals with Werner syndrome may have unusually prominent eyes, a beaked or pinched nose, and/or other characteristic facial abnormalities. (For more information on this disorder, choose “Werner syndrome” as your search term in the Rare Disease Database.) | 535 | Gottron Syndrome |
nord_535_5 | Diagnosis of Gottron Syndrome | Typically, Gottron syndrome is diagnosed through a clinical examination once other more common conditions have been initially excluded. Genetic testing may further aid in the diagnosis process. | Diagnosis of Gottron Syndrome. Typically, Gottron syndrome is diagnosed through a clinical examination once other more common conditions have been initially excluded. Genetic testing may further aid in the diagnosis process. | 535 | Gottron Syndrome |
nord_535_6 | Therapies of Gottron Syndrome | Treatment
Treatment for Gottron syndrome is symptomatic and supportive. The management team involved in the care of someone with Gottron syndrome may include a dermatologist, orthopedist and/or a medical geneticist. | Therapies of Gottron Syndrome. Treatment
Treatment for Gottron syndrome is symptomatic and supportive. The management team involved in the care of someone with Gottron syndrome may include a dermatologist, orthopedist and/or a medical geneticist. | 535 | Gottron Syndrome |
nord_536_0 | Overview of GPT2 Deficiency | GPT2 deficiency (glutamate pyruvate transaminase 2 deficiency) is a genetic, neurological and metabolic disorder that results in intellectual disability and progressive motor dysfunction. This deficiency disrupts important biological processes necessary for proper brain growth. The developing brain relies on the creation and reinforcement of synapses, or connections, between neurons. This disease compromises those connections, resulting in fewer synapses and weaker brain circuits. GPT2 deficiency ultimately hinders brain development, causes metabolic abnormalities including deficiencies in metabolites that protect the nervous system, so patients tend to become more severely affected over time (neurodegenerative course). | Overview of GPT2 Deficiency. GPT2 deficiency (glutamate pyruvate transaminase 2 deficiency) is a genetic, neurological and metabolic disorder that results in intellectual disability and progressive motor dysfunction. This deficiency disrupts important biological processes necessary for proper brain growth. The developing brain relies on the creation and reinforcement of synapses, or connections, between neurons. This disease compromises those connections, resulting in fewer synapses and weaker brain circuits. GPT2 deficiency ultimately hinders brain development, causes metabolic abnormalities including deficiencies in metabolites that protect the nervous system, so patients tend to become more severely affected over time (neurodegenerative course). | 536 | GPT2 Deficiency |
nord_536_1 | Symptoms of GPT2 Deficiency | Individuals with GPT2 deficiency have been reported to have varying levels of intellectual disability. Most affected infants have low muscle tone (hypotonia) at birth and too much muscle tone (hypertonia) later in childhood. Most individuals experience progressive coordination and movement problems, including spastic paraplegia or diplegia around 8-10 years of age. Below is a list of reported and researched symptoms:• mild, moderate or severe intellectual disability
• global developmental delay
• postnatal microcephaly (small head)
• failure to thrive
• low percentiles for weight and height
• poor feeding, including frequent vomiting
• ataxia (poor muscle control causing clumsy movements)
• apraxia (difficulty performing learned skills or movements)
• dysarthria (muscle disorder causing difficulty speaking)
• hyperreflexia (overactive reflexes)
• oral-motor dysfunction (muscle disorder causing difficulty speaking and eating)
• hypotonia during infancy
• hypertonia later in childhood
• progressive spastic diplegia or paraplegia (weakness or paralysis of legs or lower half of body)
• seizures | Symptoms of GPT2 Deficiency. Individuals with GPT2 deficiency have been reported to have varying levels of intellectual disability. Most affected infants have low muscle tone (hypotonia) at birth and too much muscle tone (hypertonia) later in childhood. Most individuals experience progressive coordination and movement problems, including spastic paraplegia or diplegia around 8-10 years of age. Below is a list of reported and researched symptoms:• mild, moderate or severe intellectual disability
• global developmental delay
• postnatal microcephaly (small head)
• failure to thrive
• low percentiles for weight and height
• poor feeding, including frequent vomiting
• ataxia (poor muscle control causing clumsy movements)
• apraxia (difficulty performing learned skills or movements)
• dysarthria (muscle disorder causing difficulty speaking)
• hyperreflexia (overactive reflexes)
• oral-motor dysfunction (muscle disorder causing difficulty speaking and eating)
• hypotonia during infancy
• hypertonia later in childhood
• progressive spastic diplegia or paraplegia (weakness or paralysis of legs or lower half of body)
• seizures | 536 | GPT2 Deficiency |
nord_536_2 | Causes of GPT2 Deficiency | GPT2 deficiency is caused by loss-of-function variants (mutations) in the GPT2 gene. This gene codes for the important mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). Loss-of-function mutations reduce the capacity of important enzymes and proteins to carry out normal operation, sometimes with total inactivation. The GPT2 gene is expressed in the brain and helps regulate levels of metabolites central to proper development. Metabolites are tiny molecules that are responsible for proper cell growth, defense and function. The GPT2 enzyme, which is localized to the mitochondria, is responsible for the regulation of important metabolic processes, such as amino acid metabolism and the TCA (tricarboxylic acid) cycle, and is also responsible for encoding a mitochondrial alanine transaminase. Glutamate is a particularly important neurotransmitter as it helps brain cells connect and interact, thereby ensuring proper neuronal development and health. GPT2 deficiency undermines all of these processes, resulting in reduced postnatal brain development as well as cognitive and motor disability.It is important that intermediates of this cycle are replenished and that the cycle is rebuilt through a process called anaplerosis. When the cycle-building process of anaplerosis is disrupted due to GPT2 deficiency, subsequent metabolic pathways are disrupted as well. There is a chain reaction effect resulting first in altered alanine, reduced TCA cycle intermediates and reduced pyruvate, followed by elevations in glycolytic intermediates and amino acids. These disruptions severely compromise neuronal growth and survival – causing various levels of intellectual disability and developmental delays – and seem to lead to neurodegeneration expressed as progressive spastic paraplegia or diplegia. GPT2 deficiency is inherited in an autosomal recessive manner. 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 GPT2 Deficiency. GPT2 deficiency is caused by loss-of-function variants (mutations) in the GPT2 gene. This gene codes for the important mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). Loss-of-function mutations reduce the capacity of important enzymes and proteins to carry out normal operation, sometimes with total inactivation. The GPT2 gene is expressed in the brain and helps regulate levels of metabolites central to proper development. Metabolites are tiny molecules that are responsible for proper cell growth, defense and function. The GPT2 enzyme, which is localized to the mitochondria, is responsible for the regulation of important metabolic processes, such as amino acid metabolism and the TCA (tricarboxylic acid) cycle, and is also responsible for encoding a mitochondrial alanine transaminase. Glutamate is a particularly important neurotransmitter as it helps brain cells connect and interact, thereby ensuring proper neuronal development and health. GPT2 deficiency undermines all of these processes, resulting in reduced postnatal brain development as well as cognitive and motor disability.It is important that intermediates of this cycle are replenished and that the cycle is rebuilt through a process called anaplerosis. When the cycle-building process of anaplerosis is disrupted due to GPT2 deficiency, subsequent metabolic pathways are disrupted as well. There is a chain reaction effect resulting first in altered alanine, reduced TCA cycle intermediates and reduced pyruvate, followed by elevations in glycolytic intermediates and amino acids. These disruptions severely compromise neuronal growth and survival – causing various levels of intellectual disability and developmental delays – and seem to lead to neurodegeneration expressed as progressive spastic paraplegia or diplegia. GPT2 deficiency is inherited in an autosomal recessive manner. 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. | 536 | GPT2 Deficiency |
nord_536_3 | Affects of GPT2 Deficiency | GPT2 deficiency seems to affect males and females equally. Individuals with this condition are from a variety of countries across the globe and from many different ethnic backgrounds. GPT2 deficiency is currently considered an ultra-rare disease with a very small number of individuals reported with the mutations and it is often unrecognized or misdiagnosed. As genetic testing, specifically whole exome sequencing (WES), becomes more accessible, it will be possible to gain more information about affected populations. | Affects of GPT2 Deficiency. GPT2 deficiency seems to affect males and females equally. Individuals with this condition are from a variety of countries across the globe and from many different ethnic backgrounds. GPT2 deficiency is currently considered an ultra-rare disease with a very small number of individuals reported with the mutations and it is often unrecognized or misdiagnosed. As genetic testing, specifically whole exome sequencing (WES), becomes more accessible, it will be possible to gain more information about affected populations. | 536 | GPT2 Deficiency |
nord_536_4 | Related disorders of GPT2 Deficiency | GPT2 deficiency may appear in a differential diagnosis with other disorders that may be defined by intellectual and developmental disability, postnatal microcephaly and spastic paraplegia. This includes several different genetic forms of intellectual disability or complex spastic paraplegias. | Related disorders of GPT2 Deficiency. GPT2 deficiency may appear in a differential diagnosis with other disorders that may be defined by intellectual and developmental disability, postnatal microcephaly and spastic paraplegia. This includes several different genetic forms of intellectual disability or complex spastic paraplegias. | 536 | GPT2 Deficiency |
nord_536_5 | Diagnosis of GPT2 Deficiency | Diagnosis of GPT2 deficiency must be confirmed through genetic testing. The GPT2 gene is included in certain genetic diagnostic panels and whole exome sequencing. | Diagnosis of GPT2 Deficiency. Diagnosis of GPT2 deficiency must be confirmed through genetic testing. The GPT2 gene is included in certain genetic diagnostic panels and whole exome sequencing. | 536 | GPT2 Deficiency |
nord_536_6 | Therapies of GPT2 Deficiency | TreatmentWhile there are no guidelines for the treatment of GPT2 deficiency, standard therapies can address the specific symptoms of this disease. Early intervention is especially important for young children exhibiting symptoms. Ongoing therapies may include but are not limited to physical therapy, occupational therapy, feeding therapy and speech therapy.Comprehensive interdisciplinary care is helpful for managing symptoms and improving patient outcomes. Specialists that may be consulted include geneticists, gastroenterologists, neurologists, ear nose and throat specialists (ENTs), physical therapists, occupational therapists, feeding and speech pathologists as well as developmental pediatricians. It is important to consult with a pediatrician or primary care physician regarding the treatment of any concerning symptoms.
Genetic counseling is recommended for affected individuals and their family members. | Therapies of GPT2 Deficiency. TreatmentWhile there are no guidelines for the treatment of GPT2 deficiency, standard therapies can address the specific symptoms of this disease. Early intervention is especially important for young children exhibiting symptoms. Ongoing therapies may include but are not limited to physical therapy, occupational therapy, feeding therapy and speech therapy.Comprehensive interdisciplinary care is helpful for managing symptoms and improving patient outcomes. Specialists that may be consulted include geneticists, gastroenterologists, neurologists, ear nose and throat specialists (ENTs), physical therapists, occupational therapists, feeding and speech pathologists as well as developmental pediatricians. It is important to consult with a pediatrician or primary care physician regarding the treatment of any concerning symptoms.
Genetic counseling is recommended for affected individuals and their family members. | 536 | GPT2 Deficiency |
nord_537_0 | Overview of Graft versus Host Disease | Graft versus Host Disease (GVHD) is a rare disorder that can strike persons whose immune system is deficient or suppressed and who have received a bone marrow transplant or a nonirradiated blood transfusion. Symptoms may include skin rash, intestinal problems and liver dysfunction. | Overview of Graft versus Host Disease. Graft versus Host Disease (GVHD) is a rare disorder that can strike persons whose immune system is deficient or suppressed and who have received a bone marrow transplant or a nonirradiated blood transfusion. Symptoms may include skin rash, intestinal problems and liver dysfunction. | 537 | Graft versus Host Disease |
nord_537_1 | Symptoms of Graft versus Host Disease | GVHD occurs most frequently after allogeneic bone marrow transplant and initially leads to dermatitis (a skin rash), gastrointestinal problems and liver dysfunction. In its chronic form involvement of mucosa (mouth and eyes) resembling sicca syndrome, lungs (resembling bronchiolitis obliterans) and the muskuloskeletal system (resembling myositis) is observed. GVHD affects about 60% of all bone marrow transplant but usually is limited and mild. GVHD can be acute (sudden) or chronic (long lasting). Acute GVHD occurs in the first 100 days (at earliest 2 to 3 weeks) following bone marrow transplantation. The first symptoms are usually mild skin rash, liver dysfunction and intestinal problems. In some cases the patients may suddenly show very severe skin problems, diarrhea, nausea, abdominal pain and liver failure.Chronic GVHD is used for GVHD lasting beyond 100 days and usually persists long after a bone marrow transplant. The signs and symptoms are similar to those of the acute GVHD, but in addition to the skin, intestinal and liver problems, chronic GVHD may also involve mucosa, lungs and the musculoskeletal system. Long term consequences may be scleroderma-like skin changes and bronchiolitis obliterans. | Symptoms of Graft versus Host Disease. GVHD occurs most frequently after allogeneic bone marrow transplant and initially leads to dermatitis (a skin rash), gastrointestinal problems and liver dysfunction. In its chronic form involvement of mucosa (mouth and eyes) resembling sicca syndrome, lungs (resembling bronchiolitis obliterans) and the muskuloskeletal system (resembling myositis) is observed. GVHD affects about 60% of all bone marrow transplant but usually is limited and mild. GVHD can be acute (sudden) or chronic (long lasting). Acute GVHD occurs in the first 100 days (at earliest 2 to 3 weeks) following bone marrow transplantation. The first symptoms are usually mild skin rash, liver dysfunction and intestinal problems. In some cases the patients may suddenly show very severe skin problems, diarrhea, nausea, abdominal pain and liver failure.Chronic GVHD is used for GVHD lasting beyond 100 days and usually persists long after a bone marrow transplant. The signs and symptoms are similar to those of the acute GVHD, but in addition to the skin, intestinal and liver problems, chronic GVHD may also involve mucosa, lungs and the musculoskeletal system. Long term consequences may be scleroderma-like skin changes and bronchiolitis obliterans. | 537 | Graft versus Host Disease |
nord_537_2 | Causes of Graft versus Host Disease | GVHD is caused by donor T cells recognizing foreign antigens (histocompatibility or human leucocyte antigens) on the recipient's cells and reacting to them. Prior to allogeneic bone marrow transplants recipients usually undergo myeloablative treatment with radiation or chemotherapy to destroy their own diseased bone marrow and weaken their immune system. When receiving the bone marrow or stem cell transplant, immunocompetent donor lymphocytes recognize foreign minor locus histocompatibility antigens on the recipient's cells resulting in GVHD. | Causes of Graft versus Host Disease. GVHD is caused by donor T cells recognizing foreign antigens (histocompatibility or human leucocyte antigens) on the recipient's cells and reacting to them. Prior to allogeneic bone marrow transplants recipients usually undergo myeloablative treatment with radiation or chemotherapy to destroy their own diseased bone marrow and weaken their immune system. When receiving the bone marrow or stem cell transplant, immunocompetent donor lymphocytes recognize foreign minor locus histocompatibility antigens on the recipient's cells resulting in GVHD. | 537 | Graft versus Host Disease |
nord_537_3 | Affects of Graft versus Host Disease | GVHD affects males and females of all ages who have been immunosuppressed before being given a bone marrow transplant or a nonirradiated blood transfusion containing allogeneic lymphocytes. The risk of GVHD usually increases with the recipient's age and with the degree of HLA differences between donor and recipient unless fully T-cell depleted. | Affects of Graft versus Host Disease. GVHD affects males and females of all ages who have been immunosuppressed before being given a bone marrow transplant or a nonirradiated blood transfusion containing allogeneic lymphocytes. The risk of GVHD usually increases with the recipient's age and with the degree of HLA differences between donor and recipient unless fully T-cell depleted. | 537 | Graft versus Host Disease |
nord_537_4 | Related disorders of Graft versus Host Disease | Symptoms of the following disorders can be similar to those of Graft versus Host Disease. Comparisons may be useful for a differential diagnosis.Lichen Planus is a recurrent, itchy, inflammatory eruption of the skin which is characterized by small separate, angular spots that may join together into rough scaly patches. It is often accompanied by oral lesions. The intial attack persists for weeks or months, and intermittent recurrences may be noted for years. Moderate to severe itching may be present, and it often does not respond to treatment.Ulcerative Colitis is an inflammatory disease of the bowel characterized by chronic ulcers in the colon. The chief characteristic of this disorder is bloody diarrhea. Colitis may involve only the left side of the colon or may eventually extend to involve the entire bowel. However, in some cases it may attack most of the large bowel simultaneously. The disease is usually chronic, with repeated periods of exacerbation and remission. | Related disorders of Graft versus Host Disease. Symptoms of the following disorders can be similar to those of Graft versus Host Disease. Comparisons may be useful for a differential diagnosis.Lichen Planus is a recurrent, itchy, inflammatory eruption of the skin which is characterized by small separate, angular spots that may join together into rough scaly patches. It is often accompanied by oral lesions. The intial attack persists for weeks or months, and intermittent recurrences may be noted for years. Moderate to severe itching may be present, and it often does not respond to treatment.Ulcerative Colitis is an inflammatory disease of the bowel characterized by chronic ulcers in the colon. The chief characteristic of this disorder is bloody diarrhea. Colitis may involve only the left side of the colon or may eventually extend to involve the entire bowel. However, in some cases it may attack most of the large bowel simultaneously. The disease is usually chronic, with repeated periods of exacerbation and remission. | 537 | Graft versus Host Disease |
nord_537_5 | Diagnosis of Graft versus Host Disease | Diagnosis of Graft versus Host Disease. | 537 | Graft versus Host Disease |
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nord_537_6 | Therapies of Graft versus Host Disease | Treatment
Treatment of GVHD usually consists of immunosuppressive drugs including glucocorticoid (steroid) drugs and a combination of cyclosporine (Sandimmune) and methotrexate. Instead of cyclosporine other calcineurin inhibitors (tacrolimus) or an mTOR inhibitor (sirolimus) may be chosen. In some cases, where GVHD is resistant to the above treatments antithymocyte globulin (ATG) may be used. Prevention of GVHD consists of prophylactic treatment prior to bone marrow transplant, mostly using cyclosporine and T-cell depletion of the graft. Blood may be treated by radiation before being given to the recipient in order to suppress the donor's lymphocytes. These prophylactic measures often keep GVHD from developing.In 2017, The U.S. Food and Drug Administration (FDA) approval Imbruvica (ibrutinib) for the treatment of adult patients with chronic graft versus host disease (cGVHD) after failure of one or more treatments. Imbruvica is manufactured by Pharmacyclics LLC.In 2021, Orencia (abatacept) was approved for the prevention of acute graft versus host disease (aGVHD). This is the first FDA drug approval for aGVHD prevention. | Therapies of Graft versus Host Disease. Treatment
Treatment of GVHD usually consists of immunosuppressive drugs including glucocorticoid (steroid) drugs and a combination of cyclosporine (Sandimmune) and methotrexate. Instead of cyclosporine other calcineurin inhibitors (tacrolimus) or an mTOR inhibitor (sirolimus) may be chosen. In some cases, where GVHD is resistant to the above treatments antithymocyte globulin (ATG) may be used. Prevention of GVHD consists of prophylactic treatment prior to bone marrow transplant, mostly using cyclosporine and T-cell depletion of the graft. Blood may be treated by radiation before being given to the recipient in order to suppress the donor's lymphocytes. These prophylactic measures often keep GVHD from developing.In 2017, The U.S. Food and Drug Administration (FDA) approval Imbruvica (ibrutinib) for the treatment of adult patients with chronic graft versus host disease (cGVHD) after failure of one or more treatments. Imbruvica is manufactured by Pharmacyclics LLC.In 2021, Orencia (abatacept) was approved for the prevention of acute graft versus host disease (aGVHD). This is the first FDA drug approval for aGVHD prevention. | 537 | Graft versus Host Disease |
nord_538_0 | Overview of Granuloma Annulare | Granuloma annulare is a chronic degenerative skin disorder. The most common form is localized granuloma annulare, which is characterized by the presence of small, firm red or yellow colored bumps (nodules or papules) that appear arranged in a ring on the skin. In most cases, the sizes of the lesions range from one to five centimeters. The most commonly affected sites include the feet, hands, and fingers. In addition to the localized form, there are four less common forms: generalized or disseminated, linear, perforating, and subcutaneous. The lesions associated with granuloma annulare usually disappear without treatment (spontaneous remission). However, the lesions often reappear. The exact cause of granuloma annulare is unknown. | Overview of Granuloma Annulare. Granuloma annulare is a chronic degenerative skin disorder. The most common form is localized granuloma annulare, which is characterized by the presence of small, firm red or yellow colored bumps (nodules or papules) that appear arranged in a ring on the skin. In most cases, the sizes of the lesions range from one to five centimeters. The most commonly affected sites include the feet, hands, and fingers. In addition to the localized form, there are four less common forms: generalized or disseminated, linear, perforating, and subcutaneous. The lesions associated with granuloma annulare usually disappear without treatment (spontaneous remission). However, the lesions often reappear. The exact cause of granuloma annulare is unknown. | 538 | Granuloma Annulare |
nord_538_1 | Symptoms of Granuloma Annulare | Five recognized forms or clinical variants of granuloma annulare have been identified. The most common form is localized granuloma annulare. The four other forms (i.e., generalized or disseminated, linear, perforating, and subcutaneous) occur less often than the localized form. All forms of granuloma annulare are characterized by small, firm bumps (nodules or papules) arranged in a ring on the skin. These bumps are usually skin-colored or slightly red or yellow. Most cases of granuloma annulare clear up without treatment (spontaneous resolution). However, recurrences are common.Granuloma annulare may affect any area of the body. The fingers, hands and feet are the areas most often affected. In most cases both sides of the body are affected (symmetrical). Other commonly affected areas include the forehead, neck and abdomen. Localized granuloma annulare normally affects one specific area of the body.Generalized or disseminated granuloma annulare may affect several areas of the body at one time. The bumps associated with this form of GA are usually smaller and more numerous than those associated with the localized form. These bumps may also be itchy (pruritic).Subcutaneous granuloma annulare may present as a solitary, painless mass or nodule underneath the skin (subcutaneous). The scalp, arms, and legs are most often affected. Children are affected more often than adults.Perforating granuloma annulare is characterized by bumps or pustules that develop a yellow center. These lesions may leak a clear fluid, become crusted and eventually leave a scar. These lesions may come together (coalesce) to form larger plaques.Linear granuloma is an extremely rare form of granuloma annulare that most often affects the fingers. | Symptoms of Granuloma Annulare. Five recognized forms or clinical variants of granuloma annulare have been identified. The most common form is localized granuloma annulare. The four other forms (i.e., generalized or disseminated, linear, perforating, and subcutaneous) occur less often than the localized form. All forms of granuloma annulare are characterized by small, firm bumps (nodules or papules) arranged in a ring on the skin. These bumps are usually skin-colored or slightly red or yellow. Most cases of granuloma annulare clear up without treatment (spontaneous resolution). However, recurrences are common.Granuloma annulare may affect any area of the body. The fingers, hands and feet are the areas most often affected. In most cases both sides of the body are affected (symmetrical). Other commonly affected areas include the forehead, neck and abdomen. Localized granuloma annulare normally affects one specific area of the body.Generalized or disseminated granuloma annulare may affect several areas of the body at one time. The bumps associated with this form of GA are usually smaller and more numerous than those associated with the localized form. These bumps may also be itchy (pruritic).Subcutaneous granuloma annulare may present as a solitary, painless mass or nodule underneath the skin (subcutaneous). The scalp, arms, and legs are most often affected. Children are affected more often than adults.Perforating granuloma annulare is characterized by bumps or pustules that develop a yellow center. These lesions may leak a clear fluid, become crusted and eventually leave a scar. These lesions may come together (coalesce) to form larger plaques.Linear granuloma is an extremely rare form of granuloma annulare that most often affects the fingers. | 538 | Granuloma Annulare |
nord_538_2 | Causes of Granuloma Annulare | The exact cause of granuloma annulare is unknown (idiopathic). Numerous theories exist linking the cause to trauma, sun exposure, thyroid disease, tuberculosis, and various viral infections. However, no definitive proof has been shown for any of these theories.The disseminated type of the disorder, which affects large areas of the body, may be associated with diabetes mellitus. Granuloma annulare may also be a complication of pseudorheumatoid nodules or shingles (herpes zoster). Some forms of GA tend to run in families (familial), but the exact mode of inheritance has not yet been determined. (For more information on the above disorders, chooses “Diabetes Mellitus” and “Herpes Zoster” as your search terms in the Rare Disease Database.) | Causes of Granuloma Annulare. The exact cause of granuloma annulare is unknown (idiopathic). Numerous theories exist linking the cause to trauma, sun exposure, thyroid disease, tuberculosis, and various viral infections. However, no definitive proof has been shown for any of these theories.The disseminated type of the disorder, which affects large areas of the body, may be associated with diabetes mellitus. Granuloma annulare may also be a complication of pseudorheumatoid nodules or shingles (herpes zoster). Some forms of GA tend to run in families (familial), but the exact mode of inheritance has not yet been determined. (For more information on the above disorders, chooses “Diabetes Mellitus” and “Herpes Zoster” as your search terms in the Rare Disease Database.) | 538 | Granuloma Annulare |
nord_538_3 | Affects of Granuloma Annulare | Granuloma annulare occurs more often in females than males. The disorder can affect people of any age, but occurs most frequently in children and young adults. The prevalence of granuloma annulare in the general population is unknown. Localized granuloma annulare occurs more often than the others forms. | Affects of Granuloma Annulare. Granuloma annulare occurs more often in females than males. The disorder can affect people of any age, but occurs most frequently in children and young adults. The prevalence of granuloma annulare in the general population is unknown. Localized granuloma annulare occurs more often than the others forms. | 538 | Granuloma Annulare |
nord_538_4 | Related disorders of Granuloma Annulare | Symptoms of the following disorder can resemble those of granuloma annulare. They may be useful for a differential diagnosis:Tinea corporis, also known as body ringworm, is a skin disorder characterized by an itchy skin rash. The arms and legs are the areas of the body most affected. In most cases, the disorder presents as ring-shaped, reddish lesions. Scaling and crusting may also occur. Tinea corporis is caused by a fungal infection of the skin.Eruptive xanthoma is characterized by the development of clusters of elevated bumps (papules) over the entire body. The clusters may be encircled by a red ring and may be skin-colored, yellow or yellowish-brown. This disorder may be distinguished microscopically from granuloma annulare by the different coloring of its histiocyte cells. | Related disorders of Granuloma Annulare. Symptoms of the following disorder can resemble those of granuloma annulare. They may be useful for a differential diagnosis:Tinea corporis, also known as body ringworm, is a skin disorder characterized by an itchy skin rash. The arms and legs are the areas of the body most affected. In most cases, the disorder presents as ring-shaped, reddish lesions. Scaling and crusting may also occur. Tinea corporis is caused by a fungal infection of the skin.Eruptive xanthoma is characterized by the development of clusters of elevated bumps (papules) over the entire body. The clusters may be encircled by a red ring and may be skin-colored, yellow or yellowish-brown. This disorder may be distinguished microscopically from granuloma annulare by the different coloring of its histiocyte cells. | 538 | Granuloma Annulare |
nord_538_5 | Diagnosis of Granuloma Annulare | Diagnosis of Granuloma Annulare. | 538 | Granuloma Annulare |
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nord_538_6 | Therapies of Granuloma Annulare | In many cases, the eruptions of granuloma annulare disappear without treatment (spontaneous remission). Therefore, many affected individuals do not require specific treatment. However, the episodes of the disorder may recur. Treatments for chronic forms of the disorder include corticosteroid drugs such as dapsone and isotretinoin, which is the synthetic form of retinoic acid (related to vitamin A). | Therapies of Granuloma Annulare. In many cases, the eruptions of granuloma annulare disappear without treatment (spontaneous remission). Therefore, many affected individuals do not require specific treatment. However, the episodes of the disorder may recur. Treatments for chronic forms of the disorder include corticosteroid drugs such as dapsone and isotretinoin, which is the synthetic form of retinoic acid (related to vitamin A). | 538 | Granuloma Annulare |
nord_539_0 | Overview of Granulomatosis with Polyangiitis | Granulomatosis with polyangiitis (GPA) is a rare disorder characterized by inflammation of small- and medium-sized blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some individuals, kidney abnormalities may progress to kidney failure, a serious complication that requires dialysis or a kidney transplant. If the lungs are affected, a cough, coughing up of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the tissues inside of the lung may be present. Other symptoms can occur depending on which organ systems are affected in an individual.Granulomatosis with polyangiitis is not an inherited disorder. It is classified as an autoimmune disorder. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue. Environmental, infectious and some genetic factors may play a role in the development of the disorder, including cigarette smoking. The disorder can occur at any age, but most often affects people between 40 and 60 years of age. For many years, granulomatosis with polyangiitis was known as Wegener’s granulomatosis or Wegener granulomatosis. Wegener is the surname of a physician who was one of the first to describe the disorder in detail in the medical literature back in the 1930s. Other doctors before Wegener also described the disease. Surnames don’t characterize diseases and terms which better describe diseases are generally preferred. Granulomatosis with polyangiitis is classified as a form of vasculitis, and further classified as a form of antineutrophil cytoplasmic antibodies-associated (ANCA-associated) vasculitis or ANCA-associated vasculitides (AAV). | Overview of Granulomatosis with Polyangiitis. Granulomatosis with polyangiitis (GPA) is a rare disorder characterized by inflammation of small- and medium-sized blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some individuals, kidney abnormalities may progress to kidney failure, a serious complication that requires dialysis or a kidney transplant. If the lungs are affected, a cough, coughing up of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the tissues inside of the lung may be present. Other symptoms can occur depending on which organ systems are affected in an individual.Granulomatosis with polyangiitis is not an inherited disorder. It is classified as an autoimmune disorder. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue. Environmental, infectious and some genetic factors may play a role in the development of the disorder, including cigarette smoking. The disorder can occur at any age, but most often affects people between 40 and 60 years of age. For many years, granulomatosis with polyangiitis was known as Wegener’s granulomatosis or Wegener granulomatosis. Wegener is the surname of a physician who was one of the first to describe the disorder in detail in the medical literature back in the 1930s. Other doctors before Wegener also described the disease. Surnames don’t characterize diseases and terms which better describe diseases are generally preferred. Granulomatosis with polyangiitis is classified as a form of vasculitis, and further classified as a form of antineutrophil cytoplasmic antibodies-associated (ANCA-associated) vasculitis or ANCA-associated vasculitides (AAV). | 539 | Granulomatosis with Polyangiitis |
nord_539_1 | Symptoms of Granulomatosis with Polyangiitis | The specific symptoms and severity of the symptoms associated with granulomatosis with polyangiitis vary greatly from one person to another. Indeed, granulomatosis with polyangiitis has been described affecting almost all organ systems of the body.In most people, the disorder affects the respiratory tract and the kidneys. Some people may have mild disease, while others develop life-threatening complications. The disorder can develop slowly over many months or it can develop rapidly over several days (acute). Because each person with granulomatosis with polyangiitis is unique, and the symptoms described below may or may not apply to a specific individual.Initial symptoms usually occur in the upper respiratory tract and resemble those associated with a severe common cold, including a persistent runny nose (rhinorrhea), nasal crusting and nasal obstruction or congestion. More serious symptoms include nosebleeds, ulcerations of the mucous membranes in the nose with secondary bacterial infection, sinus pain, inflammation of the sinuses (paranasal sinusitis), and hoarseness. Some affected individuals will develop a hole or tear in the wall (septum) dividing the nostrils, resulting in the collapse of the bridge of the nose, a condition called saddle nose. Affected individuals may also develop recurrent middle ear inflammation (otitis media), which, if untreated, may eventually result in hearing loss.Additional initial symptoms can include fever, general feeling of ill health (malaise), weakness and fatigue, joint pain (arthralgia), loss of appetite, and unintended weight loss. Sometimes, the upper airways are affected for years before other symptoms develop and, sometimes, granulomatosis with polyangiitis remains isolated in the upper airways and the rest of the body remains unaffected. This may be called localized or limited granulomatosis with polyangiitis.Many affected individuals will develop symptoms affecting the lungs (pulmonary). These symptoms include a persistent cough, episodes of coughing up of blood (hemoptysis), difficulty breathing (dyspnea), chest pain, inflammation of the thin membrane lining the outside of the lungs and the inside of the lungs (pleuritis), excess buildup of fluid around the lungs (pleural effusion), and inflammation of the lung tissues themselves. There may be substances such as blood, pus or protein (pulmonary infiltrates) in lung tissue that can be detected on x-ray examination. Sometimes, affected individuals experience inflammation and narrowing of the area of the windpipe below the vocal cords (subglottis), a condition known as subglottic stenosis. Inflammation and narrowing of the whole windpipe (tracheal stenosis) can also occur. These conditions can cause difficulty breathing, high-pitched noisy breathing (stridor), wheezing, or voice changes. Bleeding (hemorrhaging) in the lungs is a potential serious complication that requires hospitalization and aggressive treatment. Respiratory symptoms are often the first sign in children with this disorder.Approximately 75% of individuals eventually develop kidney (renal) disease. However, in many people, no symptoms are apparent (asymptomatic). Affected individuals may develop high blood pressure (hypertension) and fluid retention in the legs. These symptoms are caused by inflammation of the cluster of blood vessels and nerve fibers of the kidney called the glomeruli, which filter the blood. Glomeruli become swollen and misshapen and cannot perform their proper function, a condition known as glomerulonephritis. This can lead to small amounts of blood but great loss of protein in the urine. Without treatment, progressive kidney damage can occur, eventually causing life-threatening kidney (renal) failure.Most individuals experience symptoms affecting the muscles and skeleton, including pain in various joints (polyarthralgia), inflammation and swelling of the joints (arthritis), inflammation of muscles (myositis), and muscle pain (myalgia).More than half of individuals with granulomatosis with polyangiitis experience eye (ocular) abnormalities, including inflammation of the delicate membrane that lines the eyes (conjunctivitis), corneal ulcerations, inflammation of the white, outer-covering (sclera) of the eyeball (scleritis), and inflammation of the membrane covering the sclera (episcleritis). Affected individuals may also develop an abnormal mass or sore behind the eye (orbital mass lesion or ‘pseudotumor’). Eye abnormalities may result in eye pain, redness, bulging or protrusion of the eyeballs (proptosis), double vision (diplopia), and vision loss. Additional findings can occur in some people. Sometimes, problems with the eyes are the first symptom of granulomatosis with polyangiitis.Approximately half of affected individuals develop skin abnormalities including small raised bumps (papules), slightly larger, deeper bumps just below the surface of the skin (subcutaneous nodules), skin ulcers, bleeding (hemorrhage) within skin layers, causing the appearance of small purplish spots on the skin (petechiae), and/or areas of purple discoloration caused by bleeding vessels near the surface of the skin (purpura). Skin lesions may or may not be painful. Some affected individuals may have painfully cold fingers and toes in response to cold (Raynaud’s phenomenon) caused by lack of blood flow to these areas. Sometimes, this is severe enough to cause tissue death (gangrene) of the tips of the fingers and toes.In rare instances, individuals may also develop neurological abnormalities including inflammation and degeneration of nerve fibers outside of the brain and spinal cord (peripheral neuropathy), injury to a few peripheral nerves in different areas simultaneously (mononeuritis multiplex), and inflammation of cranial nerves (cranial neuritis). Peripheral neuropathy can cause a sensation of numbness, burning or tingling in the hands or feet. Mononeuritis multiplex can cause pain, weakness and abnormal sensations in the affected areas. The specific symptoms depend on which areas of the body are affected. Symptoms of cranial nerve involvement depend on which cranial nerves are affected. Headaches, seizures, and paralysis on one side of the body (hemiplegia) have also been reported.Other rare symptoms include abnormalities of the heart (cardiac) including inflammation of the membranous sac that surrounds the heart (pericarditis), inflammation of the endocardium (endocarditis), which is the inner membrane lining of the heart, inflammation of the arteries that supply blood to the heart muscles (coronary arteritis), and disease of the heart muscle (cardiomyopathy). Some affected individuals may be at an increased risk of having a stroke or heart attack (myocardial infarction). | Symptoms of Granulomatosis with Polyangiitis. The specific symptoms and severity of the symptoms associated with granulomatosis with polyangiitis vary greatly from one person to another. Indeed, granulomatosis with polyangiitis has been described affecting almost all organ systems of the body.In most people, the disorder affects the respiratory tract and the kidneys. Some people may have mild disease, while others develop life-threatening complications. The disorder can develop slowly over many months or it can develop rapidly over several days (acute). Because each person with granulomatosis with polyangiitis is unique, and the symptoms described below may or may not apply to a specific individual.Initial symptoms usually occur in the upper respiratory tract and resemble those associated with a severe common cold, including a persistent runny nose (rhinorrhea), nasal crusting and nasal obstruction or congestion. More serious symptoms include nosebleeds, ulcerations of the mucous membranes in the nose with secondary bacterial infection, sinus pain, inflammation of the sinuses (paranasal sinusitis), and hoarseness. Some affected individuals will develop a hole or tear in the wall (septum) dividing the nostrils, resulting in the collapse of the bridge of the nose, a condition called saddle nose. Affected individuals may also develop recurrent middle ear inflammation (otitis media), which, if untreated, may eventually result in hearing loss.Additional initial symptoms can include fever, general feeling of ill health (malaise), weakness and fatigue, joint pain (arthralgia), loss of appetite, and unintended weight loss. Sometimes, the upper airways are affected for years before other symptoms develop and, sometimes, granulomatosis with polyangiitis remains isolated in the upper airways and the rest of the body remains unaffected. This may be called localized or limited granulomatosis with polyangiitis.Many affected individuals will develop symptoms affecting the lungs (pulmonary). These symptoms include a persistent cough, episodes of coughing up of blood (hemoptysis), difficulty breathing (dyspnea), chest pain, inflammation of the thin membrane lining the outside of the lungs and the inside of the lungs (pleuritis), excess buildup of fluid around the lungs (pleural effusion), and inflammation of the lung tissues themselves. There may be substances such as blood, pus or protein (pulmonary infiltrates) in lung tissue that can be detected on x-ray examination. Sometimes, affected individuals experience inflammation and narrowing of the area of the windpipe below the vocal cords (subglottis), a condition known as subglottic stenosis. Inflammation and narrowing of the whole windpipe (tracheal stenosis) can also occur. These conditions can cause difficulty breathing, high-pitched noisy breathing (stridor), wheezing, or voice changes. Bleeding (hemorrhaging) in the lungs is a potential serious complication that requires hospitalization and aggressive treatment. Respiratory symptoms are often the first sign in children with this disorder.Approximately 75% of individuals eventually develop kidney (renal) disease. However, in many people, no symptoms are apparent (asymptomatic). Affected individuals may develop high blood pressure (hypertension) and fluid retention in the legs. These symptoms are caused by inflammation of the cluster of blood vessels and nerve fibers of the kidney called the glomeruli, which filter the blood. Glomeruli become swollen and misshapen and cannot perform their proper function, a condition known as glomerulonephritis. This can lead to small amounts of blood but great loss of protein in the urine. Without treatment, progressive kidney damage can occur, eventually causing life-threatening kidney (renal) failure.Most individuals experience symptoms affecting the muscles and skeleton, including pain in various joints (polyarthralgia), inflammation and swelling of the joints (arthritis), inflammation of muscles (myositis), and muscle pain (myalgia).More than half of individuals with granulomatosis with polyangiitis experience eye (ocular) abnormalities, including inflammation of the delicate membrane that lines the eyes (conjunctivitis), corneal ulcerations, inflammation of the white, outer-covering (sclera) of the eyeball (scleritis), and inflammation of the membrane covering the sclera (episcleritis). Affected individuals may also develop an abnormal mass or sore behind the eye (orbital mass lesion or ‘pseudotumor’). Eye abnormalities may result in eye pain, redness, bulging or protrusion of the eyeballs (proptosis), double vision (diplopia), and vision loss. Additional findings can occur in some people. Sometimes, problems with the eyes are the first symptom of granulomatosis with polyangiitis.Approximately half of affected individuals develop skin abnormalities including small raised bumps (papules), slightly larger, deeper bumps just below the surface of the skin (subcutaneous nodules), skin ulcers, bleeding (hemorrhage) within skin layers, causing the appearance of small purplish spots on the skin (petechiae), and/or areas of purple discoloration caused by bleeding vessels near the surface of the skin (purpura). Skin lesions may or may not be painful. Some affected individuals may have painfully cold fingers and toes in response to cold (Raynaud’s phenomenon) caused by lack of blood flow to these areas. Sometimes, this is severe enough to cause tissue death (gangrene) of the tips of the fingers and toes.In rare instances, individuals may also develop neurological abnormalities including inflammation and degeneration of nerve fibers outside of the brain and spinal cord (peripheral neuropathy), injury to a few peripheral nerves in different areas simultaneously (mononeuritis multiplex), and inflammation of cranial nerves (cranial neuritis). Peripheral neuropathy can cause a sensation of numbness, burning or tingling in the hands or feet. Mononeuritis multiplex can cause pain, weakness and abnormal sensations in the affected areas. The specific symptoms depend on which areas of the body are affected. Symptoms of cranial nerve involvement depend on which cranial nerves are affected. Headaches, seizures, and paralysis on one side of the body (hemiplegia) have also been reported.Other rare symptoms include abnormalities of the heart (cardiac) including inflammation of the membranous sac that surrounds the heart (pericarditis), inflammation of the endocardium (endocarditis), which is the inner membrane lining of the heart, inflammation of the arteries that supply blood to the heart muscles (coronary arteritis), and disease of the heart muscle (cardiomyopathy). Some affected individuals may be at an increased risk of having a stroke or heart attack (myocardial infarction). | 539 | Granulomatosis with Polyangiitis |
nord_539_2 | Causes of Granulomatosis with Polyangiitis | The exact cause of granulomatosis with polyangiitis is not fully understood. Because of the characteristic tissue changes seen in affected tissues, and increased immune response of the body, an abnormal immune reaction has been suggested as a possible basis for the disorder. Many researchers consider the disorder an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons.In granulomatosis with polyangiitis, white blood cells called neutrophils release abnormal immune proteins that can damage the body. Normally, neutrophils are instrumental in fighting off infection by surrounding and destroying bacteria that enter the body. About 85%-90% of have antineutrophil cytoplasmic antibodies (ANCA). Of these people, about 80% have what is called cytoplasmic-ANCA, or c-ANCA. About 20% of those people have perinuclear-ANCA, or p-ANCA. Antibodies, or immunoglobulins, are specialized proteins that bind to invading or foreign substances in the body and bring about their destruction. Autoantibodies are antibodies that mistakenly attack healthy tissue. The exact role these autoantibodies play in the development of granulomatosis with polyangiitis is not fully understood.Many researchers believe that an infection ‘sets off’ the immune system causing it to malfunction. While many researchers believe that an infection contributes to the development of the disorder, it is unlikely that an infection alone can explain a disorder as complex as granulomatosis with polyangiitis. There are likely additional factors including environmental and genetic ones that also play a role in the development of the disorder, including cigarette smoking. Research into this question is ongoing, but so far, no specific infectious, genetic, or environmental factor has been conclusively identified as the cause of this disease.The symptoms of granulomatosis with polyangiitis occur because of inflammation of the blood vessels (vasculitis). This inflammation leads to narrowing of the vessels and results in reduced blood flow to, and loss of tissue in, various organ systems of the body. The disorder is marked by the abnormal clumping or massing immune system cells that are produced to fight infection or inflammation. These clumps of cells are called granulomas and can be found within various organ tissues and blood vessels of the body (granulomatosis). | Causes of Granulomatosis with Polyangiitis. The exact cause of granulomatosis with polyangiitis is not fully understood. Because of the characteristic tissue changes seen in affected tissues, and increased immune response of the body, an abnormal immune reaction has been suggested as a possible basis for the disorder. Many researchers consider the disorder an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons.In granulomatosis with polyangiitis, white blood cells called neutrophils release abnormal immune proteins that can damage the body. Normally, neutrophils are instrumental in fighting off infection by surrounding and destroying bacteria that enter the body. About 85%-90% of have antineutrophil cytoplasmic antibodies (ANCA). Of these people, about 80% have what is called cytoplasmic-ANCA, or c-ANCA. About 20% of those people have perinuclear-ANCA, or p-ANCA. Antibodies, or immunoglobulins, are specialized proteins that bind to invading or foreign substances in the body and bring about their destruction. Autoantibodies are antibodies that mistakenly attack healthy tissue. The exact role these autoantibodies play in the development of granulomatosis with polyangiitis is not fully understood.Many researchers believe that an infection ‘sets off’ the immune system causing it to malfunction. While many researchers believe that an infection contributes to the development of the disorder, it is unlikely that an infection alone can explain a disorder as complex as granulomatosis with polyangiitis. There are likely additional factors including environmental and genetic ones that also play a role in the development of the disorder, including cigarette smoking. Research into this question is ongoing, but so far, no specific infectious, genetic, or environmental factor has been conclusively identified as the cause of this disease.The symptoms of granulomatosis with polyangiitis occur because of inflammation of the blood vessels (vasculitis). This inflammation leads to narrowing of the vessels and results in reduced blood flow to, and loss of tissue in, various organ systems of the body. The disorder is marked by the abnormal clumping or massing immune system cells that are produced to fight infection or inflammation. These clumps of cells are called granulomas and can be found within various organ tissues and blood vessels of the body (granulomatosis). | 539 | Granulomatosis with Polyangiitis |
nord_539_3 | Affects of Granulomatosis with Polyangiitis | Granulomatosis with polyangiitis is a rare disorder that affects males and females in equal numbers. In most people, onset is after the fourth or fifth decade of life; however, the disorder can occur at any age. There are some studies that suggest that girls are affected more often than boys when the disorder occurs in childhood. There are also studies that suggest that males are more likely to have severe disease, while females are more likely to have localized disease.Estimates of the frequency of granulomatosis with polyangiitis vary greatly depending upon the specific population being studied. Because the disorder often goes unrecognized, researchers believe that it is under-diagnosed, making it difficult to determine the true frequency in the general population. Granulomatosis with polyangiitis affects Caucasians most often, but can affect people of any race or ethnic background anywhere in the world. | Affects of Granulomatosis with Polyangiitis. Granulomatosis with polyangiitis is a rare disorder that affects males and females in equal numbers. In most people, onset is after the fourth or fifth decade of life; however, the disorder can occur at any age. There are some studies that suggest that girls are affected more often than boys when the disorder occurs in childhood. There are also studies that suggest that males are more likely to have severe disease, while females are more likely to have localized disease.Estimates of the frequency of granulomatosis with polyangiitis vary greatly depending upon the specific population being studied. Because the disorder often goes unrecognized, researchers believe that it is under-diagnosed, making it difficult to determine the true frequency in the general population. Granulomatosis with polyangiitis affects Caucasians most often, but can affect people of any race or ethnic background anywhere in the world. | 539 | Granulomatosis with Polyangiitis |
nord_539_4 | Related disorders of Granulomatosis with Polyangiitis | Symptoms of the following disorders can be similar to those of granulomatosis with polyangiitis. Comparisons may be useful for a differential diagnosis:Microscopic polyangiitis (MPA), formerly known as microscopic polyarteritis, is another form of antineutrophil cytoplasmic antibodies-associated (ANCA-associated) vasculitis. MPA overlaps with granulomatosis with polyangiitis and the two disorders are often discussed together in the medical literature. Individuals with MPA have inflammation of small blood vessels in various organs of the body.MPA can be very different in one person when compared to another person. The most common symptoms are kidney inflammation, unintended weight loss, skin lesions especially on the feet and lower legs, nerve damage, and fevers. Kidney inflammation can lead to fatigue, shortness of breath and swelling in the legs due to the accumulation of fluid (edema). Affected individuals often have nonspecific symptoms, which are common to many conditions. These symptoms include fevers, fatigue, weight loss, and a general feeling of poor health (malaise). Nerve damage often occurs in the nerves outside of the central nervous system called the peripheral nervous system. Abnormal sensations including tingling, burning or numbness in the hands and feet may occur. There may be muscle wasting and tissue death (gangrene) of the tips of the fingers and toes. Additional symptoms can also be present.MPA can affect individuals of any ethnic background and can occur at any age, although most times it occurs during middle-age. Different names for this condition have been used in the medical literature, which has led to confusion for patients and physicians. The disorder was sometimes called microscopic polyarteritis nodosa. MPA is an autoimmune disorder and the exact cause is not fully understood.Eosinophilic granulomatosis with polyangiitis, also known as Churg-Strauss syndrome, is a rare disorder that may affect multiple organ systems, especially the lungs. It is also sometimes associated with antineutrophil cytoplasmic antibodies (ANCA) vasculitis. The disorder is characterized by the formation and accumulation of an unusually large number of antibodies, abnormal clustering of certain white blood cells (eosinophilia), inflammation of blood vessels (vasculitis), and the development of inflammatory nodular lesions (granulomatosis).Many individuals with Churg-Strauss syndrome have a history of allergy. In addition, asthma and other associated lung (pulmonary) abnormalities (i.e., pulmonary infiltrates) often precede the development of the generalized (systemic) symptoms and findings seen in Churg-Strauss syndrome by one or more years. Nonspecific findings typically include flu-like symptoms such as fever, a general feeling of weakness and fatigue (malaise), loss of appetite (anorexia), unintended weight loss, and muscle pain (myalgia). Additional symptoms and findings will vary from one person to another, depending upon the specific organ systems involved. Without appropriate treatment, serious organ damage and potentially life-threatening complications may result. Although the exact cause of Churg-Strauss syndrome is unknown, research has shown that abnormal immunologic and autoimmune factors play an important role. (For more information on this disorder, choose “Churg Strauss” as your search term in the Rare Disease Database.)Goodpasture syndrome is a rare autoimmune disorder characterized by inflammation of the filtering structures (glomeruli) of the kidneys (glomerulonephritis) and excessive bleeding into the lungs (pulmonary hemorrhaging). Autoimmune syndromes occur when the body’s natural defenses (antibodies) against invading or “foreign” organisms begin to attack the body’s own tissue, often for unknown reasons. Symptoms include recurrent episodes of coughing up of blood (hemoptysis), difficulty breathing (dyspnea), fatigue, chest pain, and/or abnormally low levels of circulating red blood cells (anemia). In many people, the disorder may result in an inability of the kidneys to process waste products from the blood and excrete them in the urine (acute renal failure). Sometimes, affected individuals have had an upper respiratory tract infection before the development of the disorder. Goodpasture syndrome is associated with anti-GBM antibodies, which mistakenly attack the glomerular basement membrane of the kidneys and the alveolar basement membrane in the lungs. The exact reason why the immune system malfunctions in Goodpasture syndrome is not known. (For more information on this disorder, choose “Goodpasture” as your search term in the Rare Disease Database.)Polyarteritis nodosa, a rare multisystem disorder that usually becomes apparent between the ages of 40 to 50 years, is characterized by widespread inflammation, weakening, and degeneration of small- and medium-sized arteries. Blood vessels in any organ or organ system may be affected, including arteries supplying the kidneys, heart, intestine, nervous system, and/or skeletal muscles. Damage to affected arteries may result in abnormally increased blood pressure (hypertension), “ballooning” (aneurysm) of an arterial wall, the formation of blood clots (thrombosis), obstruction of blood supply to certain tissues, and/or tissue damage and loss (necrosis) in certain affected areas. In many cases, affected individuals experience weight loss, fever, a general feeling of ill health (malaise), fatigue, weakness, headache, muscle aches or pain (myalgias), and/or abdominal pain. Additional symptoms and findings are often present and depend upon which areas of the body are affected. Although the exact cause of polyarteritis nodosa is not known, many researchers suspect that the disorder is due to disturbances of the body’s immune system. (For more information on this disorder, choose “polyarteritis nodosa” as your search term in the Rare Disease Database.)Lymphomatous granulomatosis is a rare, progressive, disease of the lymph nodes and blood vessels characterized by infiltration and destruction of the veins and arteries by nodular lesions created by accumulations of various cells. These lesions can affect various parts of the body, especially the lungs. However, the condition may start by affecting the small arteries and eventually the lungs, skin, kidneys and nervous system. Affected individuals may have a cough with or without blood, fever, weight loss, diarrhea, joint (arthralgias) and muscle (myalgias) pain, shortness of breath (dyspnea), chest pain and a generalized feeling of discomfort (malaise). If the skin is involved, flat and red lesions (macules), nodules and sometimes ulcerations can appear. Lymphomatoid granulomatosis may lead to breathing difficulties and eventually failure of the respiratory system. (For more information on this disorder, choose “lymphomatoid granulomatosis” as your search term in the Rare Disease Database.)There are additional systemic rheumatological disorders and conditions that can present in a similar fashion to granulomatosis with polyangiitis. These include bacteremia, deep fungal infections, anti-glomerular basement membrane antibody disease, systemic lupus erythematosus, sarcoidosis, tuberculosis, and Henoch-Schönlein purpura. Certain malignancies of the lungs can have symptoms that resemble lung involvement in granulomatosis with polyangiitis. ANCA-associated vasculitis can also develop because of the use of certain drugs, including a drug called levamisole that is often a contaminant in cocaine. | Related disorders of Granulomatosis with Polyangiitis. Symptoms of the following disorders can be similar to those of granulomatosis with polyangiitis. Comparisons may be useful for a differential diagnosis:Microscopic polyangiitis (MPA), formerly known as microscopic polyarteritis, is another form of antineutrophil cytoplasmic antibodies-associated (ANCA-associated) vasculitis. MPA overlaps with granulomatosis with polyangiitis and the two disorders are often discussed together in the medical literature. Individuals with MPA have inflammation of small blood vessels in various organs of the body.MPA can be very different in one person when compared to another person. The most common symptoms are kidney inflammation, unintended weight loss, skin lesions especially on the feet and lower legs, nerve damage, and fevers. Kidney inflammation can lead to fatigue, shortness of breath and swelling in the legs due to the accumulation of fluid (edema). Affected individuals often have nonspecific symptoms, which are common to many conditions. These symptoms include fevers, fatigue, weight loss, and a general feeling of poor health (malaise). Nerve damage often occurs in the nerves outside of the central nervous system called the peripheral nervous system. Abnormal sensations including tingling, burning or numbness in the hands and feet may occur. There may be muscle wasting and tissue death (gangrene) of the tips of the fingers and toes. Additional symptoms can also be present.MPA can affect individuals of any ethnic background and can occur at any age, although most times it occurs during middle-age. Different names for this condition have been used in the medical literature, which has led to confusion for patients and physicians. The disorder was sometimes called microscopic polyarteritis nodosa. MPA is an autoimmune disorder and the exact cause is not fully understood.Eosinophilic granulomatosis with polyangiitis, also known as Churg-Strauss syndrome, is a rare disorder that may affect multiple organ systems, especially the lungs. It is also sometimes associated with antineutrophil cytoplasmic antibodies (ANCA) vasculitis. The disorder is characterized by the formation and accumulation of an unusually large number of antibodies, abnormal clustering of certain white blood cells (eosinophilia), inflammation of blood vessels (vasculitis), and the development of inflammatory nodular lesions (granulomatosis).Many individuals with Churg-Strauss syndrome have a history of allergy. In addition, asthma and other associated lung (pulmonary) abnormalities (i.e., pulmonary infiltrates) often precede the development of the generalized (systemic) symptoms and findings seen in Churg-Strauss syndrome by one or more years. Nonspecific findings typically include flu-like symptoms such as fever, a general feeling of weakness and fatigue (malaise), loss of appetite (anorexia), unintended weight loss, and muscle pain (myalgia). Additional symptoms and findings will vary from one person to another, depending upon the specific organ systems involved. Without appropriate treatment, serious organ damage and potentially life-threatening complications may result. Although the exact cause of Churg-Strauss syndrome is unknown, research has shown that abnormal immunologic and autoimmune factors play an important role. (For more information on this disorder, choose “Churg Strauss” as your search term in the Rare Disease Database.)Goodpasture syndrome is a rare autoimmune disorder characterized by inflammation of the filtering structures (glomeruli) of the kidneys (glomerulonephritis) and excessive bleeding into the lungs (pulmonary hemorrhaging). Autoimmune syndromes occur when the body’s natural defenses (antibodies) against invading or “foreign” organisms begin to attack the body’s own tissue, often for unknown reasons. Symptoms include recurrent episodes of coughing up of blood (hemoptysis), difficulty breathing (dyspnea), fatigue, chest pain, and/or abnormally low levels of circulating red blood cells (anemia). In many people, the disorder may result in an inability of the kidneys to process waste products from the blood and excrete them in the urine (acute renal failure). Sometimes, affected individuals have had an upper respiratory tract infection before the development of the disorder. Goodpasture syndrome is associated with anti-GBM antibodies, which mistakenly attack the glomerular basement membrane of the kidneys and the alveolar basement membrane in the lungs. The exact reason why the immune system malfunctions in Goodpasture syndrome is not known. (For more information on this disorder, choose “Goodpasture” as your search term in the Rare Disease Database.)Polyarteritis nodosa, a rare multisystem disorder that usually becomes apparent between the ages of 40 to 50 years, is characterized by widespread inflammation, weakening, and degeneration of small- and medium-sized arteries. Blood vessels in any organ or organ system may be affected, including arteries supplying the kidneys, heart, intestine, nervous system, and/or skeletal muscles. Damage to affected arteries may result in abnormally increased blood pressure (hypertension), “ballooning” (aneurysm) of an arterial wall, the formation of blood clots (thrombosis), obstruction of blood supply to certain tissues, and/or tissue damage and loss (necrosis) in certain affected areas. In many cases, affected individuals experience weight loss, fever, a general feeling of ill health (malaise), fatigue, weakness, headache, muscle aches or pain (myalgias), and/or abdominal pain. Additional symptoms and findings are often present and depend upon which areas of the body are affected. Although the exact cause of polyarteritis nodosa is not known, many researchers suspect that the disorder is due to disturbances of the body’s immune system. (For more information on this disorder, choose “polyarteritis nodosa” as your search term in the Rare Disease Database.)Lymphomatous granulomatosis is a rare, progressive, disease of the lymph nodes and blood vessels characterized by infiltration and destruction of the veins and arteries by nodular lesions created by accumulations of various cells. These lesions can affect various parts of the body, especially the lungs. However, the condition may start by affecting the small arteries and eventually the lungs, skin, kidneys and nervous system. Affected individuals may have a cough with or without blood, fever, weight loss, diarrhea, joint (arthralgias) and muscle (myalgias) pain, shortness of breath (dyspnea), chest pain and a generalized feeling of discomfort (malaise). If the skin is involved, flat and red lesions (macules), nodules and sometimes ulcerations can appear. Lymphomatoid granulomatosis may lead to breathing difficulties and eventually failure of the respiratory system. (For more information on this disorder, choose “lymphomatoid granulomatosis” as your search term in the Rare Disease Database.)There are additional systemic rheumatological disorders and conditions that can present in a similar fashion to granulomatosis with polyangiitis. These include bacteremia, deep fungal infections, anti-glomerular basement membrane antibody disease, systemic lupus erythematosus, sarcoidosis, tuberculosis, and Henoch-Schönlein purpura. Certain malignancies of the lungs can have symptoms that resemble lung involvement in granulomatosis with polyangiitis. ANCA-associated vasculitis can also develop because of the use of certain drugs, including a drug called levamisole that is often a contaminant in cocaine. | 539 | Granulomatosis with Polyangiitis |
nord_539_5 | Diagnosis of Granulomatosis with Polyangiitis | A diagnosis of granulomatosis with polyangiitis is made based upon a thorough clinical evaluation including routine laboratory tests, a detailed patient history, identification of relevant symptoms, and a variety of specialized tests. In many people, surgical removal (biopsy) and microscopic examination of small samples of tissue from an affected organ may reveal characteristic vasculitis or granulomas. Physicians may initially choose to obtain a biopsy sample form the upper respiratory tract. However, sometimes this does not yield enough tissue to a definitive diagnosis. A biopsy of lung tissue or kidney tissue may be done. A lung biopsy may yield the best results.In addition to biopsy, blood tests may be performed to rule out other disorders. A blood test may also reveal the presence of a specific type of antibody known as antineutrophil cytoplasmic antibody (ANCA). Because the test is positive in many individuals with granulomatosis with polyangiitis, the ANCA blood test may help support a suspected diagnosis of the disorder. This test does not differentiate from other forms of ANCA-associated vasculitis like microscopic polyangiitis or Churg-Strauss syndrome. Some people with other conditions may also test positive for ANCA including people with bacterial endocarditis, systemic lupus erythematosus, amebiasis, tuberculosis, and people who abuse cocaine. In addition, in some affected individuals, the test is negative and, especially in such cases, should not be relied upon in place of a biopsy to determine whether someone has granulomatosis with polyangiitis.X-ray and specialized imaging tests are also helpful in supporting a suspected diagnosis of granulomatosis with polyangiitis. X-rays of the lungs or sinuses may reveal characteristic findings associated with the disorder (e.g., thickening of the lining of the sinus), can help to rule out other conditions, and can help to reveal the extent of the disorder. | Diagnosis of Granulomatosis with Polyangiitis. A diagnosis of granulomatosis with polyangiitis is made based upon a thorough clinical evaluation including routine laboratory tests, a detailed patient history, identification of relevant symptoms, and a variety of specialized tests. In many people, surgical removal (biopsy) and microscopic examination of small samples of tissue from an affected organ may reveal characteristic vasculitis or granulomas. Physicians may initially choose to obtain a biopsy sample form the upper respiratory tract. However, sometimes this does not yield enough tissue to a definitive diagnosis. A biopsy of lung tissue or kidney tissue may be done. A lung biopsy may yield the best results.In addition to biopsy, blood tests may be performed to rule out other disorders. A blood test may also reveal the presence of a specific type of antibody known as antineutrophil cytoplasmic antibody (ANCA). Because the test is positive in many individuals with granulomatosis with polyangiitis, the ANCA blood test may help support a suspected diagnosis of the disorder. This test does not differentiate from other forms of ANCA-associated vasculitis like microscopic polyangiitis or Churg-Strauss syndrome. Some people with other conditions may also test positive for ANCA including people with bacterial endocarditis, systemic lupus erythematosus, amebiasis, tuberculosis, and people who abuse cocaine. In addition, in some affected individuals, the test is negative and, especially in such cases, should not be relied upon in place of a biopsy to determine whether someone has granulomatosis with polyangiitis.X-ray and specialized imaging tests are also helpful in supporting a suspected diagnosis of granulomatosis with polyangiitis. X-rays of the lungs or sinuses may reveal characteristic findings associated with the disorder (e.g., thickening of the lining of the sinus), can help to rule out other conditions, and can help to reveal the extent of the disorder. | 539 | Granulomatosis with Polyangiitis |
nord_539_6 | Therapies of Granulomatosis with Polyangiitis | TreatmentThe treatment of granulomatosis with polyangiitis is directed toward the specific symptoms that are apparent in each individual patient. Modern treatment has dramatically improved the life expectancy and reduced organ damage in patients with granulomatosis with polyangiitis. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or primary care physicians; specialists who diagnose and treat lung disorders (pulmonologists); specialists who diagnose and treat disorders of the ear, nose and throat (otolaryngologists); specialists who diagnose and treat disorders of the immune system (immunologists): specialists who diagnose and treat disorders of the musculoskeletal system and autoimmune diseases (rheumatologists); specialists who diagnose and treat the kidneys (nephrologists); specialists who diagnose and treat skin disorders (dermatologists); specialists who diagnose and treat disorders of the central nervous system and the brain (neurologists), specialists who diagnose and treat heart disorders (cardiologists); and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the presence or absence of certain symptoms; specific organs affected, overall severity of the disorder; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. The treatment of granulomatosis with polyangiitis can be broken down into two stages – inducing a remission of symptoms and then maintaining the remission (maintenance therapy). In 2011, the Food and Drug Administration (FDA) approved the use of Rituxan (rituximab) in conjunction with glucocorticoids for the treatment of adults with granulomatosis with polyangiitis. In 2019, Rituxan was FDA-approved for treatment in children 2 years of age and older. Rituximab is classified as a monoclonal antibody or biologic therapy – medications that act like antibodies but are artificially created in a lab. Glucocorticoids are steroid hormones that are important in the regulation of the metabolism of a form of sugar called glucose and the modulation of the body’s response to stress such as reducing inflammation. For many years, affected individuals were treated with a combination of glucocorticoid drugs that reduce inflammation such as prednisone and cytotoxic drugs that impede the abnormal growth (proliferation) of cells. Cytotoxic drugs contain chemicals that are toxic to certain cells in the body. These drugs are used to block the growth or replication of these cells. Cytoxan (cyclophosphamide) is the most common cytotoxic drug used to treat granulomatosis with polyangiitis. When using a combination of a cytotoxic drug with a glucocorticoid, the duration of therapy depends on an affected individual’s response. White blood cell (leukocyte) counts are closely monitored. Dosages are reduced gradually to prevent severe deficiency of white blood cells. Attempts should be made to discontinue cytotoxic therapy if symptoms of the disorder have been absent for three to six months. Cytotoxic therapy can be replaced with another drug such as Imuran (azathioprine) or CellCept (mycophenolate mofetil). The possibility of kidney disease relapse is carefully monitored when reducing (tapering) medication dosage or discontinuing the drug. Otrexup (methotrexate) is another drug used to treat granulomatosis with polyangiitis. Glucocorticoids with methotrexate are sometimes used to treat less severe disease. Generally, methotrexate, mycophenolate mofetil and azathioprine are less toxic than cyclophosphamide. After remission has been achieved, maintenance therapy may be required. This usually involves using azathioprine, methotrexate, or rituximab. Cyclophosphamide is usually not used for maintenance therapy due to toxicity. The dose of glucocorticoids is usually lowered in stages (tapered) as well. Regardless of which therapy is used to achieve remission and for maintenance therapy, affected individuals can experience a recurrence (relapse) of the disorder, which can be called a “flare”. Sometimes, a relapse may be triggered by an infection. Some affected individuals may have progressive kidney damage, and the kidneys may no longer be able to perform their normal functions. Kidney dialysis and eventually a kidney transplant may be needed. Dialysis is a procedure in which a machine is used to perform the kidney’s basic functions of fluid and waste removal. Kidney transplantation has been successful for kidney failure resulting from granulomatosis with polyangiitis. Antibiotics have been used to treat secondary bacterial infections sometimes associated with granulomatosis with polyangiitis. Bactrim (trimethoprim-sulfamethoxazole) is an antibiotic that has been effective in treating affected individuals, particularly those with only upper airway involvement. It is often used to reduce the possibility of a lung infection called Pneumocystis jiroveci pneumonia, especially when intensive immune suppressive therapy is needed to control the vasculitis. Surgical intervention for subglottic stenosis or tracheal stenosis to maintain the airways may be necessary in some people. Surgery can fix a saddle nose if the underlying vasculitis is not active. | Therapies of Granulomatosis with Polyangiitis. TreatmentThe treatment of granulomatosis with polyangiitis is directed toward the specific symptoms that are apparent in each individual patient. Modern treatment has dramatically improved the life expectancy and reduced organ damage in patients with granulomatosis with polyangiitis. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or primary care physicians; specialists who diagnose and treat lung disorders (pulmonologists); specialists who diagnose and treat disorders of the ear, nose and throat (otolaryngologists); specialists who diagnose and treat disorders of the immune system (immunologists): specialists who diagnose and treat disorders of the musculoskeletal system and autoimmune diseases (rheumatologists); specialists who diagnose and treat the kidneys (nephrologists); specialists who diagnose and treat skin disorders (dermatologists); specialists who diagnose and treat disorders of the central nervous system and the brain (neurologists), specialists who diagnose and treat heart disorders (cardiologists); and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the presence or absence of certain symptoms; specific organs affected, overall severity of the disorder; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. The treatment of granulomatosis with polyangiitis can be broken down into two stages – inducing a remission of symptoms and then maintaining the remission (maintenance therapy). In 2011, the Food and Drug Administration (FDA) approved the use of Rituxan (rituximab) in conjunction with glucocorticoids for the treatment of adults with granulomatosis with polyangiitis. In 2019, Rituxan was FDA-approved for treatment in children 2 years of age and older. Rituximab is classified as a monoclonal antibody or biologic therapy – medications that act like antibodies but are artificially created in a lab. Glucocorticoids are steroid hormones that are important in the regulation of the metabolism of a form of sugar called glucose and the modulation of the body’s response to stress such as reducing inflammation. For many years, affected individuals were treated with a combination of glucocorticoid drugs that reduce inflammation such as prednisone and cytotoxic drugs that impede the abnormal growth (proliferation) of cells. Cytotoxic drugs contain chemicals that are toxic to certain cells in the body. These drugs are used to block the growth or replication of these cells. Cytoxan (cyclophosphamide) is the most common cytotoxic drug used to treat granulomatosis with polyangiitis. When using a combination of a cytotoxic drug with a glucocorticoid, the duration of therapy depends on an affected individual’s response. White blood cell (leukocyte) counts are closely monitored. Dosages are reduced gradually to prevent severe deficiency of white blood cells. Attempts should be made to discontinue cytotoxic therapy if symptoms of the disorder have been absent for three to six months. Cytotoxic therapy can be replaced with another drug such as Imuran (azathioprine) or CellCept (mycophenolate mofetil). The possibility of kidney disease relapse is carefully monitored when reducing (tapering) medication dosage or discontinuing the drug. Otrexup (methotrexate) is another drug used to treat granulomatosis with polyangiitis. Glucocorticoids with methotrexate are sometimes used to treat less severe disease. Generally, methotrexate, mycophenolate mofetil and azathioprine are less toxic than cyclophosphamide. After remission has been achieved, maintenance therapy may be required. This usually involves using azathioprine, methotrexate, or rituximab. Cyclophosphamide is usually not used for maintenance therapy due to toxicity. The dose of glucocorticoids is usually lowered in stages (tapered) as well. Regardless of which therapy is used to achieve remission and for maintenance therapy, affected individuals can experience a recurrence (relapse) of the disorder, which can be called a “flare”. Sometimes, a relapse may be triggered by an infection. Some affected individuals may have progressive kidney damage, and the kidneys may no longer be able to perform their normal functions. Kidney dialysis and eventually a kidney transplant may be needed. Dialysis is a procedure in which a machine is used to perform the kidney’s basic functions of fluid and waste removal. Kidney transplantation has been successful for kidney failure resulting from granulomatosis with polyangiitis. Antibiotics have been used to treat secondary bacterial infections sometimes associated with granulomatosis with polyangiitis. Bactrim (trimethoprim-sulfamethoxazole) is an antibiotic that has been effective in treating affected individuals, particularly those with only upper airway involvement. It is often used to reduce the possibility of a lung infection called Pneumocystis jiroveci pneumonia, especially when intensive immune suppressive therapy is needed to control the vasculitis. Surgical intervention for subglottic stenosis or tracheal stenosis to maintain the airways may be necessary in some people. Surgery can fix a saddle nose if the underlying vasculitis is not active. | 539 | Granulomatosis with Polyangiitis |
nord_540_0 | Overview of Graves’ Disease | Graves’ disease is a disease affecting the thyroid and often the skin and eyes. The thyroid is a gland and is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body’s activities as well as regulating the heart rate, body temperature, and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body. Graves’ disease is characterized by abnormal enlargement of the thyroid (goiter) and increased secretion of thyroid hormone (hyperthyroidism). Thyroid hormones are involved with many different systems of the body and, consequently, the specific symptoms and signs of Graves’ disease can vary widely from one person to another. Common symptoms include unintended weight loss, an abnormal intolerance of heat, muscle weakness, fatigue and protrusion or bulging of the eyeballs from their sockets. Graves’ disease is an autoimmune disease. | Overview of Graves’ Disease. Graves’ disease is a disease affecting the thyroid and often the skin and eyes. The thyroid is a gland and is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body’s activities as well as regulating the heart rate, body temperature, and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body. Graves’ disease is characterized by abnormal enlargement of the thyroid (goiter) and increased secretion of thyroid hormone (hyperthyroidism). Thyroid hormones are involved with many different systems of the body and, consequently, the specific symptoms and signs of Graves’ disease can vary widely from one person to another. Common symptoms include unintended weight loss, an abnormal intolerance of heat, muscle weakness, fatigue and protrusion or bulging of the eyeballs from their sockets. Graves’ disease is an autoimmune disease. | 540 | Graves’ Disease |
nord_540_1 | Symptoms of Graves’ Disease | Onset of the symptoms associated with Graves’ disease is usually gradual, often taking several weeks or months to develop. Symptoms may include behavioral changes such as nervousness, irritability, anxiousness, restlessness and difficulty sleeping (insomnia). Additional symptoms include unintended weight loss, muscle weakness, an abnormal intolerance to heat, increased sweating, a rapid, irregular heartbeat (tachycardia) and fatigueGraves’ disease is often associated with abnormalities affecting the eyes often referred to as Graves’ ophthalmopathy. While mild ophthalmopathy is present in the majority of people who have Graves’ hyperthyroidism at some point in their lives, less than 10% have significant eye involvement that requires therapy. Eye symptoms can develop before, at the same time or after the development of hyperthyroidism. In rare instances, individuals with eye symptoms never develop hyperthyroidism. In some instances, Graves’ ophthalmopathy may first become apparent or may worsen following treatment for Graves’ hyperthyroidism.Graves’ ophthalmopathy is highly variable. In some individuals it may remain the same for many years, while in other individuals it may improve or worsen. It can also follow a pattern of worsening (exacerbations) and then going improving greatly (remission). Most individuals have mild disease with no progression.Common eye abnormalities include swelling of the tissues surrounding the eye that may cause the eye to protrude or bulge out of its protective socket (orbit), a condition referred to as proptosis. Affected individuals may also experience dry eyes, puffy eyelids, eyelid retraction, inflammation, redness, pain, and irritation of the eyes. Some individuals describe a gritty sensation in the eyes. Less often, blurred or double vision, sensitivity to light, and/or diminished vision may also occur.Very rarely, individuals with Graves’ disease develop a skin condition known as pretibial dermopathy or myxedema. This condition is characterized by the development of thickened, reddish skin on the front of shins. It is usually limited to the shins but, sometimes, may also occur on the feet. Rarely, soft-tissue swelling of the hands and clubbing of the fingers and toes (acropachy).Additional symptoms associated with Graves’ disease include heart palpitations, slight tremors of the hands and/or fingers, hair loss, brittle nails, exaggerated reflexes (hyperreflexia), increased appetite, and an increase in the frequency of bowel movements. Females with Graves’ disease may experience an alteration in the menstrual cycle. Males may experience erectile dysfunction. In some instances, Graves’ disease may progress to cause congestive heart failure or abnormal thinning and weakness of the bones (osteoporosis) that leaves them brittle and susceptible to repeated fractures. | Symptoms of Graves’ Disease. Onset of the symptoms associated with Graves’ disease is usually gradual, often taking several weeks or months to develop. Symptoms may include behavioral changes such as nervousness, irritability, anxiousness, restlessness and difficulty sleeping (insomnia). Additional symptoms include unintended weight loss, muscle weakness, an abnormal intolerance to heat, increased sweating, a rapid, irregular heartbeat (tachycardia) and fatigueGraves’ disease is often associated with abnormalities affecting the eyes often referred to as Graves’ ophthalmopathy. While mild ophthalmopathy is present in the majority of people who have Graves’ hyperthyroidism at some point in their lives, less than 10% have significant eye involvement that requires therapy. Eye symptoms can develop before, at the same time or after the development of hyperthyroidism. In rare instances, individuals with eye symptoms never develop hyperthyroidism. In some instances, Graves’ ophthalmopathy may first become apparent or may worsen following treatment for Graves’ hyperthyroidism.Graves’ ophthalmopathy is highly variable. In some individuals it may remain the same for many years, while in other individuals it may improve or worsen. It can also follow a pattern of worsening (exacerbations) and then going improving greatly (remission). Most individuals have mild disease with no progression.Common eye abnormalities include swelling of the tissues surrounding the eye that may cause the eye to protrude or bulge out of its protective socket (orbit), a condition referred to as proptosis. Affected individuals may also experience dry eyes, puffy eyelids, eyelid retraction, inflammation, redness, pain, and irritation of the eyes. Some individuals describe a gritty sensation in the eyes. Less often, blurred or double vision, sensitivity to light, and/or diminished vision may also occur.Very rarely, individuals with Graves’ disease develop a skin condition known as pretibial dermopathy or myxedema. This condition is characterized by the development of thickened, reddish skin on the front of shins. It is usually limited to the shins but, sometimes, may also occur on the feet. Rarely, soft-tissue swelling of the hands and clubbing of the fingers and toes (acropachy).Additional symptoms associated with Graves’ disease include heart palpitations, slight tremors of the hands and/or fingers, hair loss, brittle nails, exaggerated reflexes (hyperreflexia), increased appetite, and an increase in the frequency of bowel movements. Females with Graves’ disease may experience an alteration in the menstrual cycle. Males may experience erectile dysfunction. In some instances, Graves’ disease may progress to cause congestive heart failure or abnormal thinning and weakness of the bones (osteoporosis) that leaves them brittle and susceptible to repeated fractures. | 540 | Graves’ Disease |
nord_540_2 | Causes of Graves’ Disease | Graves’ disease is considered to be an autoimmune disorder, but other factors may contribute to its development, including genetic, environmental, and/or other factors.Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue. The immune system normally produces specialized proteins call antibodies. Antibodies react against foreign materials (e.g. bacteria, viruses, toxins) in the body bringing about their destruction. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells. Specific antibodies are created in response to specific materials or substances. A substance that stimulates an antibody to be produced is called an antigen.In Graves’ disease, the immune system creates an abnormal antibody called thyroid-stimulating immunoglobulin. This antibody mimics the function of normal thyroid-stimulating hormone. It attaches to the surface of thyroid cells and turns on the cells to produce thyroid hormones, leading to overproduction of these hormones (overactive thyroid). In Graves’ ophthalmopathy, these antibodies may also affect the cells surrounding the eyes.Affected individuals may carry genes for, or have a genetic susceptibility to, Graves’ disease. 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 (multifactorial inheritance).Various genes have been identified that are linked to Graves’ disease including genes that weaken or modify the response of the immune system (immunomodulators) such as the CD25, CD40, CD40, CTLA-4, FOXP3, and various HLA genes, particularly HLA-DR3. Genes that are directly linked to thyroid function such as the thyroglobulin (Tg) or the thyroid stimulating hormone receptor (TSHR) genes have also been linked to Graves’ disease. The Tg gene produces thyroglobulin a protein that is found only in thyroid tissue and plays a role in the production of thyroid hormones. The TSHR gene produces a protein that is a receptor and binds to thyroid stimulating hormone. The exact underlying manner that genetic and environmental factors interact to cause Graves’ disease is not fully understood. Additional genetic factors, known as modifier genes, may play a role in the development or expression of Graves’ disease.Environmental factors that may trigger the development of Graves’ disease include extreme emotional or physical stress, infection, or pregnancy. Individuals who smoke are at a greater risk of developing Graves’ disease and Graves’ ophthalmopathy. Individuals who have other disorders caused by malfunction of the immune system such as diabetes type 1 or rheumatoid arthritis are at a greater risk of developing Graves’ disease. | Causes of Graves’ Disease. Graves’ disease is considered to be an autoimmune disorder, but other factors may contribute to its development, including genetic, environmental, and/or other factors.Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue. The immune system normally produces specialized proteins call antibodies. Antibodies react against foreign materials (e.g. bacteria, viruses, toxins) in the body bringing about their destruction. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells. Specific antibodies are created in response to specific materials or substances. A substance that stimulates an antibody to be produced is called an antigen.In Graves’ disease, the immune system creates an abnormal antibody called thyroid-stimulating immunoglobulin. This antibody mimics the function of normal thyroid-stimulating hormone. It attaches to the surface of thyroid cells and turns on the cells to produce thyroid hormones, leading to overproduction of these hormones (overactive thyroid). In Graves’ ophthalmopathy, these antibodies may also affect the cells surrounding the eyes.Affected individuals may carry genes for, or have a genetic susceptibility to, Graves’ disease. 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 (multifactorial inheritance).Various genes have been identified that are linked to Graves’ disease including genes that weaken or modify the response of the immune system (immunomodulators) such as the CD25, CD40, CD40, CTLA-4, FOXP3, and various HLA genes, particularly HLA-DR3. Genes that are directly linked to thyroid function such as the thyroglobulin (Tg) or the thyroid stimulating hormone receptor (TSHR) genes have also been linked to Graves’ disease. The Tg gene produces thyroglobulin a protein that is found only in thyroid tissue and plays a role in the production of thyroid hormones. The TSHR gene produces a protein that is a receptor and binds to thyroid stimulating hormone. The exact underlying manner that genetic and environmental factors interact to cause Graves’ disease is not fully understood. Additional genetic factors, known as modifier genes, may play a role in the development or expression of Graves’ disease.Environmental factors that may trigger the development of Graves’ disease include extreme emotional or physical stress, infection, or pregnancy. Individuals who smoke are at a greater risk of developing Graves’ disease and Graves’ ophthalmopathy. Individuals who have other disorders caused by malfunction of the immune system such as diabetes type 1 or rheumatoid arthritis are at a greater risk of developing Graves’ disease. | 540 | Graves’ Disease |
nord_540_3 | Affects of Graves’ Disease | Graves’ disease affects females more often than males by a ratio of 5-10 to 1. The disorder usually develops during middle age with a peak incidence of 40-60, but can also affect children, adolescents and the elderly. Graves’ disease occurs in almost any part of the world. Graves’ disease is estimated to affect 2%-3% of the general population. Graves’ disease is the most common cause of hyperthyroidism. | Affects of Graves’ Disease. Graves’ disease affects females more often than males by a ratio of 5-10 to 1. The disorder usually develops during middle age with a peak incidence of 40-60, but can also affect children, adolescents and the elderly. Graves’ disease occurs in almost any part of the world. Graves’ disease is estimated to affect 2%-3% of the general population. Graves’ disease is the most common cause of hyperthyroidism. | 540 | Graves’ Disease |
nord_540_4 | Related disorders of Graves’ Disease | Individuals with Graves’ disease often have a history of other family members with thyroid or autoimmune problems. Some relatives may have had hyperthyroidism or an underactive thyroid; others may have other autoimmune diseases including premature graying of the hair (beginning in their 20s). Similarly, there may be a history of related immune problems in the family, including juvenile diabetes, pernicious anemia (due to lack of vitamin B12) or painless white patches on the skin known as vitiligo.Hashimoto’s disease, also known as Hashimoto’s thyroiditis or lymphoid thyroiditis, is an autoimmune disorder like Graves’ disease. However, the antibodies in Hashimoto’s disease either block or destroy the thyroid gland and produce below normal amounts of thyroid hormone secretion (hypothyroidism). Hashimoto’s disease can occur at any age but is most common in the third to fifth decades of life, and is more common in women than men. It is characterized by an enlarged thyroid gland that is infiltrated with lymphocytes. Eventually, the thyroid may be completely destroyed. Treatment consists of replacing the amount of hormone that your own thyroid can no longer make with L-thyroxine, the synthetic form of the major thyroid hormone produced by the thyroid gland.Other causes of hyperthyroidism include a toxic nodular or multinodular goiter, which is characterized by one or more nodules or lumps in the thyroid that gradually grow and increase their activity so that the total output of thyroid hormone into the blood is greater than normal. Also, people may temporarily have symptoms of hyperthyroidism if they have a condition called thyroiditis. This condition is caused by a problem with the immune system or a viral infection that causes the gland to leak stored thyroid hormone. Types of thyroiditis include subacute thyroiditis, silent thyroiditis, infectious thyroiditis, radiation-induced thyroiditis and postpartum thyroiditis. Most of the time, the thyroiditis resolves. Rarely, certain forms of thyroid cancer and certain tumors such as TSH-producing pituitary adenomas can cause symptoms similar to those seen in Graves’ disease. Finally, hyperthyroid symptoms can also be caused by taking too much thyroid hormone in tablet form. | Related disorders of Graves’ Disease. Individuals with Graves’ disease often have a history of other family members with thyroid or autoimmune problems. Some relatives may have had hyperthyroidism or an underactive thyroid; others may have other autoimmune diseases including premature graying of the hair (beginning in their 20s). Similarly, there may be a history of related immune problems in the family, including juvenile diabetes, pernicious anemia (due to lack of vitamin B12) or painless white patches on the skin known as vitiligo.Hashimoto’s disease, also known as Hashimoto’s thyroiditis or lymphoid thyroiditis, is an autoimmune disorder like Graves’ disease. However, the antibodies in Hashimoto’s disease either block or destroy the thyroid gland and produce below normal amounts of thyroid hormone secretion (hypothyroidism). Hashimoto’s disease can occur at any age but is most common in the third to fifth decades of life, and is more common in women than men. It is characterized by an enlarged thyroid gland that is infiltrated with lymphocytes. Eventually, the thyroid may be completely destroyed. Treatment consists of replacing the amount of hormone that your own thyroid can no longer make with L-thyroxine, the synthetic form of the major thyroid hormone produced by the thyroid gland.Other causes of hyperthyroidism include a toxic nodular or multinodular goiter, which is characterized by one or more nodules or lumps in the thyroid that gradually grow and increase their activity so that the total output of thyroid hormone into the blood is greater than normal. Also, people may temporarily have symptoms of hyperthyroidism if they have a condition called thyroiditis. This condition is caused by a problem with the immune system or a viral infection that causes the gland to leak stored thyroid hormone. Types of thyroiditis include subacute thyroiditis, silent thyroiditis, infectious thyroiditis, radiation-induced thyroiditis and postpartum thyroiditis. Most of the time, the thyroiditis resolves. Rarely, certain forms of thyroid cancer and certain tumors such as TSH-producing pituitary adenomas can cause symptoms similar to those seen in Graves’ disease. Finally, hyperthyroid symptoms can also be caused by taking too much thyroid hormone in tablet form. | 540 | Graves’ Disease |
nord_540_5 | Diagnosis of Graves’ Disease | A diagnosis of Graves' disease is made based upon a detailed patient and family history, a thorough clinical evaluation, identification of characteristic findings, and specialized tests such as blood tests that measure the levels of thyroid hormone and thyroid-stimulating hormone. Blood tests to detect the presence of specific antibodies that cause Graves’ disease can be performed to confirm a diagnosis, but are usually not necessary. | Diagnosis of Graves’ Disease. A diagnosis of Graves' disease is made based upon a detailed patient and family history, a thorough clinical evaluation, identification of characteristic findings, and specialized tests such as blood tests that measure the levels of thyroid hormone and thyroid-stimulating hormone. Blood tests to detect the presence of specific antibodies that cause Graves’ disease can be performed to confirm a diagnosis, but are usually not necessary. | 540 | Graves’ Disease |
nord_540_6 | Therapies of Graves’ Disease | TreatmentTreatment of Graves' disease usually involves one of three methods, antithyroid drugs (thionamides), use of radioactive iodine, or surgery. The specific form of treatment recommended may be based upon the age of an affected individual and the degree of the illness.The least invasive method of treating Graves’ disease is the use of drugs that reduce the release of thyroid hormone (antithyroid drugs). These drugs are especially preferred for the treatment of young children and pregnant women, individuals with mild cases of hyperthyroidism, or individuals in whom prompt control of hyperthyroidism is required. The most common antithyroid drug used to treat Graves’ disease is methimazole, which is recommended by the American Thyroid Association and the American Association of Clinical Endocrinologists as the initial treatment of choice for hyperthyroidism in children and adolescents. Propylthiouracil is sometimes used in specific instances, especially when Graves’ disease occurs early in pregnancy.Definitive treatments for Graves’ disease are those that destroy the thyroid, frequently resulting in hypothyroidism. Definitive therapy with radioactive iodine is the most common treatment for Graves’ disease in the United States. Iodine is a chemical element used by the thyroid gland to create (synthesize) thyroid hormones. Nearly all of the iodine in a person’s body is absorbed by thyroid tissue. Affected individuals will swallow a solution containing radioactive iodine, which will travel through the bloodstream and collect in the thyroid gland where it will damage and destroy thyroid tissue. This will shrink the thyroid and reduce the overproduction thyroid hormones. If thyroid hormone levels fall too low, hormone therapy to regain adequate levels of thyroid hormone may be necessary.The other definitive therapy is surgery to remove all or part of the thyroid gland (thyroidectomy). This a method of treatment for Graves’ disease is usually reserved for individuals in whom the other forms of treatment have not been successful or are contraindicated or with large glands or by those interested in the quickest resolution to the hyperthyroidism. Hypothyroidism is common after surgery; indeed, this may be the desired outcome.In addition to the three above-mentioned treatments, drugs that block thyroid hormone that is already circulating in the blood from performing its functions (beta blockers) may be prescribed. Beta blockers such as propranolol, atenolol, or metoprolol can be used. When thyroid hormone levels return to normal, therapy with beta blockers can be stopped.Lifelong follow up and laboratory studies are necessary in many cases. In some cases, lifelong hormone replacement therapy may be necessary.Mild cases of Graves’ ophthalmopathy (eye abnormalities associated with Graves' disease) may be treated with sunglasses, ointments, artificial tears, and/or prisms that are attached to glasses. More serious cases of Graves’ ophthalmopathy may be treated with corticosteroids, such as prednisone, to reduce the swelling of tissues surrounding the eyes.Orbital decompression surgery and orbital radiotherapy may also be necessary in more severe cases. During orbital decompression surgery, a surgeon takes out the bone between the eye socket (orbit) and the sinuses. This allows the eye to fall back into its natural position within the eye socket. This surgery is generally reserved for individuals who are at risk of vision loss due to pressure on the optic nerve or in whom other treatment options have not worked. These therapies require management by ophthalmologists specializing in treatment of Graves’ ophthalmopathy. | Therapies of Graves’ Disease. TreatmentTreatment of Graves' disease usually involves one of three methods, antithyroid drugs (thionamides), use of radioactive iodine, or surgery. The specific form of treatment recommended may be based upon the age of an affected individual and the degree of the illness.The least invasive method of treating Graves’ disease is the use of drugs that reduce the release of thyroid hormone (antithyroid drugs). These drugs are especially preferred for the treatment of young children and pregnant women, individuals with mild cases of hyperthyroidism, or individuals in whom prompt control of hyperthyroidism is required. The most common antithyroid drug used to treat Graves’ disease is methimazole, which is recommended by the American Thyroid Association and the American Association of Clinical Endocrinologists as the initial treatment of choice for hyperthyroidism in children and adolescents. Propylthiouracil is sometimes used in specific instances, especially when Graves’ disease occurs early in pregnancy.Definitive treatments for Graves’ disease are those that destroy the thyroid, frequently resulting in hypothyroidism. Definitive therapy with radioactive iodine is the most common treatment for Graves’ disease in the United States. Iodine is a chemical element used by the thyroid gland to create (synthesize) thyroid hormones. Nearly all of the iodine in a person’s body is absorbed by thyroid tissue. Affected individuals will swallow a solution containing radioactive iodine, which will travel through the bloodstream and collect in the thyroid gland where it will damage and destroy thyroid tissue. This will shrink the thyroid and reduce the overproduction thyroid hormones. If thyroid hormone levels fall too low, hormone therapy to regain adequate levels of thyroid hormone may be necessary.The other definitive therapy is surgery to remove all or part of the thyroid gland (thyroidectomy). This a method of treatment for Graves’ disease is usually reserved for individuals in whom the other forms of treatment have not been successful or are contraindicated or with large glands or by those interested in the quickest resolution to the hyperthyroidism. Hypothyroidism is common after surgery; indeed, this may be the desired outcome.In addition to the three above-mentioned treatments, drugs that block thyroid hormone that is already circulating in the blood from performing its functions (beta blockers) may be prescribed. Beta blockers such as propranolol, atenolol, or metoprolol can be used. When thyroid hormone levels return to normal, therapy with beta blockers can be stopped.Lifelong follow up and laboratory studies are necessary in many cases. In some cases, lifelong hormone replacement therapy may be necessary.Mild cases of Graves’ ophthalmopathy (eye abnormalities associated with Graves' disease) may be treated with sunglasses, ointments, artificial tears, and/or prisms that are attached to glasses. More serious cases of Graves’ ophthalmopathy may be treated with corticosteroids, such as prednisone, to reduce the swelling of tissues surrounding the eyes.Orbital decompression surgery and orbital radiotherapy may also be necessary in more severe cases. During orbital decompression surgery, a surgeon takes out the bone between the eye socket (orbit) and the sinuses. This allows the eye to fall back into its natural position within the eye socket. This surgery is generally reserved for individuals who are at risk of vision loss due to pressure on the optic nerve or in whom other treatment options have not worked. These therapies require management by ophthalmologists specializing in treatment of Graves’ ophthalmopathy. | 540 | Graves’ Disease |
nord_541_0 | Overview of Greig Cephalopolysyndactyly Syndrome | Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. Characteristic digital features may include extra (supernumerary) fingers and/or toes (polydactyly), webbing and/or fusion of the fingers and/or toes (cutaneous or osseous syndactyly), and/or additional abnormalities. Craniofacial malformations associated with this disorder may include a large and/or unusually shaped skull; metopic synostosis; a high, prominent forehead (frontal bossing); an abnormally broad nasal bridge; widely spaced eyes (ocular hypertelorism); and/or other physical abnormalities. The range and severity of symptoms may vary greatly among affected individuals. In most individuals, GCPS is inherited in an autosomal dominant pattern. | Overview of Greig Cephalopolysyndactyly Syndrome. Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. Characteristic digital features may include extra (supernumerary) fingers and/or toes (polydactyly), webbing and/or fusion of the fingers and/or toes (cutaneous or osseous syndactyly), and/or additional abnormalities. Craniofacial malformations associated with this disorder may include a large and/or unusually shaped skull; metopic synostosis; a high, prominent forehead (frontal bossing); an abnormally broad nasal bridge; widely spaced eyes (ocular hypertelorism); and/or other physical abnormalities. The range and severity of symptoms may vary greatly among affected individuals. In most individuals, GCPS is inherited in an autosomal dominant pattern. | 541 | Greig Cephalopolysyndactyly Syndrome |
nord_541_1 | Symptoms of Greig Cephalopolysyndactyly Syndrome | GCPS, a rare genetic disorder that is present at birth (congenital), is characterized by abnormalities of the fingers and toes (digits) and the head and facial (craniofacial) area. The range and severity of symptoms vary from individual to individual, with the facial characteristics, in particular, being quite subtle in some individuals.Infants with this disorder exhibit various digital malformations, including extra (supernumerary) fingers and/or toes (polydactyly); webbing or fusion of the fingers and/or toes (cutaneous or osseous syndactyly); abnormally wide thumbs and/or great toes (halluces); and/or split (bifid) end bones of the thumbs and/or halluces (terminal phalanges). Affected infants with supernumerary digits will usually have the additional digit(s) toward the “pinky finger” side of the hand (postaxial polydactyly) and the “big toe” side of the foot (preaxial polydactyly). The extra digit can be a complete digit or a non-functional incomplete digit. The degree of digital fusion may also vary from the skin only joining part of the distance to the fingertip to the skin being joined all the way to the tip of the finger. In some cases, only the soft tissue is fused, but in others, the bone or boney cartilage may be fused.Affected infants can also have craniofacial malformations including an abnormally large head (macrocephaly); a high, prominent or protruding forehead (frontal bossing); high anterior hairline; a broad nasal bridge; and/or widely spaced eyes (ocular hypertelorism). In some cases, the fibrous joints (sutures) between certain bones in the skull may be abnormally wide and may close unusually late in development; on the other hand, in rare individuals, certain cranial sutures may close prematurely (craniosynostosis). Such irregular closure of the sutures may cause the head to appear unusually shaped (scaphocephaly, trigonencephaly, or plagiocephaly).In many individuals with GCPS, additional abnormalities may be present. These may include permanently flexed fingers (camptodactyly), dislocation of the hip, protrusion of a portion of the large intestine through an abnormal opening in the muscular wall that lines the lower abdominal cavity (inguinal hernia), and/or other physical abnormalities. Rarely (less than 10% of affected individuals), it can include developmental delays, intellectual disability, seizure, build-up of fluid inside the skull (hydrocephalus), and abnormalities affecting the nerve fibers (corpus callosum) that connect the two cerebral hemispheres of the brain may be present. In most individuals with the severe form of the disorder, it is caused by a deletion of the entire GLI3 gene. The larger the deletion, the more likely the individual will show these uncommon symptoms, because larger deletions can affect other genes in addition to GLI3. | Symptoms of Greig Cephalopolysyndactyly Syndrome. GCPS, a rare genetic disorder that is present at birth (congenital), is characterized by abnormalities of the fingers and toes (digits) and the head and facial (craniofacial) area. The range and severity of symptoms vary from individual to individual, with the facial characteristics, in particular, being quite subtle in some individuals.Infants with this disorder exhibit various digital malformations, including extra (supernumerary) fingers and/or toes (polydactyly); webbing or fusion of the fingers and/or toes (cutaneous or osseous syndactyly); abnormally wide thumbs and/or great toes (halluces); and/or split (bifid) end bones of the thumbs and/or halluces (terminal phalanges). Affected infants with supernumerary digits will usually have the additional digit(s) toward the “pinky finger” side of the hand (postaxial polydactyly) and the “big toe” side of the foot (preaxial polydactyly). The extra digit can be a complete digit or a non-functional incomplete digit. The degree of digital fusion may also vary from the skin only joining part of the distance to the fingertip to the skin being joined all the way to the tip of the finger. In some cases, only the soft tissue is fused, but in others, the bone or boney cartilage may be fused.Affected infants can also have craniofacial malformations including an abnormally large head (macrocephaly); a high, prominent or protruding forehead (frontal bossing); high anterior hairline; a broad nasal bridge; and/or widely spaced eyes (ocular hypertelorism). In some cases, the fibrous joints (sutures) between certain bones in the skull may be abnormally wide and may close unusually late in development; on the other hand, in rare individuals, certain cranial sutures may close prematurely (craniosynostosis). Such irregular closure of the sutures may cause the head to appear unusually shaped (scaphocephaly, trigonencephaly, or plagiocephaly).In many individuals with GCPS, additional abnormalities may be present. These may include permanently flexed fingers (camptodactyly), dislocation of the hip, protrusion of a portion of the large intestine through an abnormal opening in the muscular wall that lines the lower abdominal cavity (inguinal hernia), and/or other physical abnormalities. Rarely (less than 10% of affected individuals), it can include developmental delays, intellectual disability, seizure, build-up of fluid inside the skull (hydrocephalus), and abnormalities affecting the nerve fibers (corpus callosum) that connect the two cerebral hemispheres of the brain may be present. In most individuals with the severe form of the disorder, it is caused by a deletion of the entire GLI3 gene. The larger the deletion, the more likely the individual will show these uncommon symptoms, because larger deletions can affect other genes in addition to GLI3. | 541 | Greig Cephalopolysyndactyly Syndrome |
nord_541_2 | Causes of Greig Cephalopolysyndactyly Syndrome | GCPS is caused by abnormal variants in the GLI3 gene. Most of the variants in GLI3 that cause the disorder are single nucleotide changes, deletions or insertions. Less commonly, affected individuals have larger insertions or deletions of the gene. Patients who have very large deletions that include GLI3, and neighboring genes are diagnosed with the “Greig cephalopolysyndactyly contiguous gene syndrome.” A few patients have the disorder because of a balanced chromosomal translocation. Regardless of the specific variant type, it is deletion and/or reduced expression of the GLI3 gene that leads to GCPS.GCPS is inherited in an autosomal dominant pattern. 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. Disorders inherited in a dominant pattern 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 an affected parent to an offspring is 50% for each pregnancy regardless of the gender of the child. | Causes of Greig Cephalopolysyndactyly Syndrome. GCPS is caused by abnormal variants in the GLI3 gene. Most of the variants in GLI3 that cause the disorder are single nucleotide changes, deletions or insertions. Less commonly, affected individuals have larger insertions or deletions of the gene. Patients who have very large deletions that include GLI3, and neighboring genes are diagnosed with the “Greig cephalopolysyndactyly contiguous gene syndrome.” A few patients have the disorder because of a balanced chromosomal translocation. Regardless of the specific variant type, it is deletion and/or reduced expression of the GLI3 gene that leads to GCPS.GCPS is inherited in an autosomal dominant pattern. 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. Disorders inherited in a dominant pattern 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 an affected parent to an offspring is 50% for each pregnancy regardless of the gender of the child. | 541 | Greig Cephalopolysyndactyly Syndrome |
nord_541_3 | Affects of Greig Cephalopolysyndactyly Syndrome | GCPS affects males and females in equal numbers. There have been over 200 patients with this disorder reported in the medical literature. However, because some affected individuals may exhibit few and/or mild symptoms, they may never be diagnosed with the disorder. Therefore, it is difficult to determine the true frequency of GCPS in the general population. | Affects of Greig Cephalopolysyndactyly Syndrome. GCPS affects males and females in equal numbers. There have been over 200 patients with this disorder reported in the medical literature. However, because some affected individuals may exhibit few and/or mild symptoms, they may never be diagnosed with the disorder. Therefore, it is difficult to determine the true frequency of GCPS in the general population. | 541 | Greig Cephalopolysyndactyly Syndrome |
nord_541_4 | Related disorders of Greig Cephalopolysyndactyly Syndrome | Symptoms of the following disorders can be similar to those of Greig cephalopolysyndactyly syndrome. Comparisons may be useful for a differential diagnosis.Acrocallosal syndrome (ACLS) is a rare genetic disorder characterized by multiple craniofacial abnormalities, including an enlarged head (macrocephaly), a protruding forehead (frontal bossing), and/or widely spaced eyes (ocular hypertelorism). Additional symptoms can include absence (agenesis) of the nerve fibers that connects the two halves of the brain (corpus callosum), intellectual disability, and digital abnormalities including extra fingers and toes (polydactyly). In the past, many researchers suspected that ACLS and GCPS may have represented variable expressions of the same disorder. Some individuals with ACLS have abnormal variants of the GLI3 gene or abnormal variants of the KIF7 gene. ACLS is typically inherited in an autosomal recessive pattern. (For more information on this disorder, choose “crocallosal” as your search term in the Rare Disease Database.)Oro-facial-digital syndrome is a group of rare genetic disorders in which there have been many types identified. Symptoms common to many types include split tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue, a broad-based nose, vertical folds of the skin covering the inner angle where the eyelids meet (epicanthic folds), extra fingers and toes (polydactyly), shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose “Oro-Facial-Digital” as your search term in the Rare Disease Database.)Pfeiffer syndrome (acrocephalosyndactyly type V) is generally accepted to be the same condition as Noack syndrome (acrocephalopolysyndactyly type I). It is a rare genetic disorder characterized by craniofacial abnormalities, digital malformations, and/or additional physical abnormalities. Affected individuals may exhibit several bone abnormalities of the face and head (craniofacial dysostosis), including a short, pointed head (acrobrachycephaly) and widely spaced eyes (ocular hypertelorism). Several abnormalities of the jaws and teeth may also be present, including an underdeveloped upper jawbone (maxillary hypoplasia), highly arched palate, prominent lower jaw (prognathism), and improper alignment of the teeth (malocclusion) when the jaws close. Individuals with Pfeiffer syndrome may also have webbed fingers and/or toes (syndactyly); abnormally short, broad thumbs and big toes; and/or malformed, misshapen, and/or absent bones (i.e., proximal and terminal phalanges) within the thumbs and/or great toes. Additional physical abnormalities may be present in some patients. Pfeiffer syndrome is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Pfeiffer” as your search term in the Rare Disease Database.) | Related disorders of Greig Cephalopolysyndactyly Syndrome. Symptoms of the following disorders can be similar to those of Greig cephalopolysyndactyly syndrome. Comparisons may be useful for a differential diagnosis.Acrocallosal syndrome (ACLS) is a rare genetic disorder characterized by multiple craniofacial abnormalities, including an enlarged head (macrocephaly), a protruding forehead (frontal bossing), and/or widely spaced eyes (ocular hypertelorism). Additional symptoms can include absence (agenesis) of the nerve fibers that connects the two halves of the brain (corpus callosum), intellectual disability, and digital abnormalities including extra fingers and toes (polydactyly). In the past, many researchers suspected that ACLS and GCPS may have represented variable expressions of the same disorder. Some individuals with ACLS have abnormal variants of the GLI3 gene or abnormal variants of the KIF7 gene. ACLS is typically inherited in an autosomal recessive pattern. (For more information on this disorder, choose “crocallosal” as your search term in the Rare Disease Database.)Oro-facial-digital syndrome is a group of rare genetic disorders in which there have been many types identified. Symptoms common to many types include split tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue, a broad-based nose, vertical folds of the skin covering the inner angle where the eyelids meet (epicanthic folds), extra fingers and toes (polydactyly), shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose “Oro-Facial-Digital” as your search term in the Rare Disease Database.)Pfeiffer syndrome (acrocephalosyndactyly type V) is generally accepted to be the same condition as Noack syndrome (acrocephalopolysyndactyly type I). It is a rare genetic disorder characterized by craniofacial abnormalities, digital malformations, and/or additional physical abnormalities. Affected individuals may exhibit several bone abnormalities of the face and head (craniofacial dysostosis), including a short, pointed head (acrobrachycephaly) and widely spaced eyes (ocular hypertelorism). Several abnormalities of the jaws and teeth may also be present, including an underdeveloped upper jawbone (maxillary hypoplasia), highly arched palate, prominent lower jaw (prognathism), and improper alignment of the teeth (malocclusion) when the jaws close. Individuals with Pfeiffer syndrome may also have webbed fingers and/or toes (syndactyly); abnormally short, broad thumbs and big toes; and/or malformed, misshapen, and/or absent bones (i.e., proximal and terminal phalanges) within the thumbs and/or great toes. Additional physical abnormalities may be present in some patients. Pfeiffer syndrome is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Pfeiffer” as your search term in the Rare Disease Database.) | 541 | Greig Cephalopolysyndactyly Syndrome |
nord_541_5 | Diagnosis of Greig Cephalopolysyndactyly Syndrome | GCPS is usually diagnosed at birth based upon a thorough clinical evaluation; identification of characteristic physical findings; and specialized imaging procedures, including X-rays and computed tomography (CT) scanning. In pregnancies at 50% risk, GCPS may be detected before birth by observing extra fingers or toes (polydactyly) and an enlarged skull (macrocephaly) during ultrasound imaging. During ultrasonography, reflected sound waves create images of the developing fetus. There are other prenatal testing methods available, such as analyzing the fetal cells.X-rays and CT scanning may be used to detect and reveal the extent of bone fusion in severe occurrences of osseous syndactyly. In some individuals with GCPS, X-ray studies may also reveal advanced bone age.Macrocephaly is defined as a head circumference greater than the 97th centile compared to appropriate age and sex standards. In addition, if the distance between the pupils is greater than the 97th centile compared to appropriate age and sex standards, then the individual has widely spaced eyes that can be considered as GCPS feature.Two conditions must be considered prior to diagnostic testing: the presence of developmental delay or intellectual disability and history of recurrent pregnancy losses in the parent of the individual. Once the clinical features consistent with GCPS are confirmed (through X-rays and CT scans), individuals without significant developmental delay or intellectual disability should have genetic testing through sequence analysis. If the individual does have developmental delay or intellectual disability, he or she should have either comparative genomic hybridization or SNP-array to detect possible copy number changes in the GLI3 gene. If the individual has a history of recurrent pregnancy losses, consideration should be given to chromosome (cytogenetic) testing. A balanced chromosome translocation that interrupts the GLI3 gene can cause pregnancy losses due to an unbalanced chromosome translocation in offspring | Diagnosis of Greig Cephalopolysyndactyly Syndrome. GCPS is usually diagnosed at birth based upon a thorough clinical evaluation; identification of characteristic physical findings; and specialized imaging procedures, including X-rays and computed tomography (CT) scanning. In pregnancies at 50% risk, GCPS may be detected before birth by observing extra fingers or toes (polydactyly) and an enlarged skull (macrocephaly) during ultrasound imaging. During ultrasonography, reflected sound waves create images of the developing fetus. There are other prenatal testing methods available, such as analyzing the fetal cells.X-rays and CT scanning may be used to detect and reveal the extent of bone fusion in severe occurrences of osseous syndactyly. In some individuals with GCPS, X-ray studies may also reveal advanced bone age.Macrocephaly is defined as a head circumference greater than the 97th centile compared to appropriate age and sex standards. In addition, if the distance between the pupils is greater than the 97th centile compared to appropriate age and sex standards, then the individual has widely spaced eyes that can be considered as GCPS feature.Two conditions must be considered prior to diagnostic testing: the presence of developmental delay or intellectual disability and history of recurrent pregnancy losses in the parent of the individual. Once the clinical features consistent with GCPS are confirmed (through X-rays and CT scans), individuals without significant developmental delay or intellectual disability should have genetic testing through sequence analysis. If the individual does have developmental delay or intellectual disability, he or she should have either comparative genomic hybridization or SNP-array to detect possible copy number changes in the GLI3 gene. If the individual has a history of recurrent pregnancy losses, consideration should be given to chromosome (cytogenetic) testing. A balanced chromosome translocation that interrupts the GLI3 gene can cause pregnancy losses due to an unbalanced chromosome translocation in offspring | 541 | Greig Cephalopolysyndactyly Syndrome |
nord_541_6 | Therapies of Greig Cephalopolysyndactyly Syndrome | Treatment
The treatment of GCPS is directed toward the specific symptoms apparent in each individual. Treatment may require the efforts of a team of specialists who may need to systematically and comprehensively plan an affected child’s treatment. Such specialists may include pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), orthopedic and plastic surgeons, physical and occupational therapists, and/or other health care professionals.Craniofacial reconstructive surgery for GCPS is not common since the widely spaced eyes and macrocephaly are not sufficiently severe enough to warrant surgery. Surgery for extra digit at the thumb/big toe is normally prioritized over the extra digit near the pinky because of the importance of grasping and balancing.Specific therapies for the treatment of this disorder are symptomatic and supportive. In some patients, surgery may be performed to correct digital and/or craniofacial abnormalities. Genetic counseling is recommended for affected individuals and their families. | Therapies of Greig Cephalopolysyndactyly Syndrome. Treatment
The treatment of GCPS is directed toward the specific symptoms apparent in each individual. Treatment may require the efforts of a team of specialists who may need to systematically and comprehensively plan an affected child’s treatment. Such specialists may include pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), orthopedic and plastic surgeons, physical and occupational therapists, and/or other health care professionals.Craniofacial reconstructive surgery for GCPS is not common since the widely spaced eyes and macrocephaly are not sufficiently severe enough to warrant surgery. Surgery for extra digit at the thumb/big toe is normally prioritized over the extra digit near the pinky because of the importance of grasping and balancing.Specific therapies for the treatment of this disorder are symptomatic and supportive. In some patients, surgery may be performed to correct digital and/or craniofacial abnormalities. Genetic counseling is recommended for affected individuals and their families. | 541 | Greig Cephalopolysyndactyly Syndrome |
nord_542_0 | Overview of Growth Hormone Deficiency | Growth hormone deficiency (GHD) is a rare disorder characterized by the inadequate secretion of growth hormone (GH) from the anterior pituitary gland, a small gland located at the base of the brain that is responsible for the production of several hormones. GHD can be present from birth (congenital), resulting from genetic mutations or from structural defects in the brain. It can also be acquired later in life as a result of trauma, infection, radiation therapy, or tumor growth within the brain. A third category has no known or diagnosable cause (idiopathic). Childhood-onset GHD may be all three: congenital, acquired, or idiopathic. It results in growth retardation, short stature, and maturation delays reflected by the delay of lengthening of the bones of the extremities that is inappropriate to the chronological age of the child. Adult-onset GHD is most often is acquired from a pituitary tumor or trauma to the brain but may also be idiopathic. It is characterized by a number of variable symptoms including reduced energy levels, altered body composition, osteoporosis (reduced bone mineral density), reduced muscle strength, lipid abnormalities such as increased LDL cholesterol, insulin resistance, and impaired cardiac function. Treatment for GHD requires daily injections of recombinant human growth hormone (rHGH). Patients with GHD that have no known cause are diagnosed as having idiopathic GHD. Genetic tests may reveal a congenital anomaly, but are often considered unnecessary after confirmation of GHD since they will have no effect on treatment. However, it is recommended that children be retested for GHD when they transition from pediatric to adult care since GH levels may normalize upon reaching adulthood. The level of GH considered normal for an adult is much lower than that for a child, especially one undergoing the pubertal growth spurt. | Overview of Growth Hormone Deficiency. Growth hormone deficiency (GHD) is a rare disorder characterized by the inadequate secretion of growth hormone (GH) from the anterior pituitary gland, a small gland located at the base of the brain that is responsible for the production of several hormones. GHD can be present from birth (congenital), resulting from genetic mutations or from structural defects in the brain. It can also be acquired later in life as a result of trauma, infection, radiation therapy, or tumor growth within the brain. A third category has no known or diagnosable cause (idiopathic). Childhood-onset GHD may be all three: congenital, acquired, or idiopathic. It results in growth retardation, short stature, and maturation delays reflected by the delay of lengthening of the bones of the extremities that is inappropriate to the chronological age of the child. Adult-onset GHD is most often is acquired from a pituitary tumor or trauma to the brain but may also be idiopathic. It is characterized by a number of variable symptoms including reduced energy levels, altered body composition, osteoporosis (reduced bone mineral density), reduced muscle strength, lipid abnormalities such as increased LDL cholesterol, insulin resistance, and impaired cardiac function. Treatment for GHD requires daily injections of recombinant human growth hormone (rHGH). Patients with GHD that have no known cause are diagnosed as having idiopathic GHD. Genetic tests may reveal a congenital anomaly, but are often considered unnecessary after confirmation of GHD since they will have no effect on treatment. However, it is recommended that children be retested for GHD when they transition from pediatric to adult care since GH levels may normalize upon reaching adulthood. The level of GH considered normal for an adult is much lower than that for a child, especially one undergoing the pubertal growth spurt. | 542 | Growth Hormone Deficiency |
nord_542_1 | Symptoms of Growth Hormone Deficiency | A child with GHD is usually of normal size at birth. A few children may become hypoglycemic (low blood sugar) during the newborn period. Males may have a small penis (micropenis). Later, children with GHD may present with delayed rates of development of facial bones, slow tooth eruption, delayed lengthening of long bones, fine hair, and poor nail growth. They may also demonstrate truncal obesity, a high pitched voice, and delayed closure of the sutures of the skull, causing delayed closure of the fontanelles.Growth increments are the most important criteria in the diagnosis of GHD in children. Normal levels of growth usually follow a pattern, and if growth during a recorded six to twelve month period is within those levels it is unlikely that a growth disorder exists.Growth in the first six months of life is usually 16 to 17 cm and in the second six months approximately 8 cm. During the second year 10 cm or more is normal. Growth in the third year should equal 8 cm or more and 7 cm in the fourth year. In the years between four and ten, an average of 5 or 6 cm is normal. A 10% decrease in these growth rates can result in an insufficient growth velocity, and thus a noticeable decline on the growth chart. When that is recognized, even before the child has fallen to a significantly low percentile (1.2% = -2 SD), he/she should then be tested for abnormally low levels of growth hormone.An individual who acquires GHD later in life presents more generalized symptoms. They may notice a relative increase in fat mass, especially abdominal and visceral, along with a decrease in muscle mass. Decreased energy levels, anxiety, and/or depression are also common. Lipid levels are also affected, resulting in an increase in LDL-cholesterol and triglyceride levels. | Symptoms of Growth Hormone Deficiency. A child with GHD is usually of normal size at birth. A few children may become hypoglycemic (low blood sugar) during the newborn period. Males may have a small penis (micropenis). Later, children with GHD may present with delayed rates of development of facial bones, slow tooth eruption, delayed lengthening of long bones, fine hair, and poor nail growth. They may also demonstrate truncal obesity, a high pitched voice, and delayed closure of the sutures of the skull, causing delayed closure of the fontanelles.Growth increments are the most important criteria in the diagnosis of GHD in children. Normal levels of growth usually follow a pattern, and if growth during a recorded six to twelve month period is within those levels it is unlikely that a growth disorder exists.Growth in the first six months of life is usually 16 to 17 cm and in the second six months approximately 8 cm. During the second year 10 cm or more is normal. Growth in the third year should equal 8 cm or more and 7 cm in the fourth year. In the years between four and ten, an average of 5 or 6 cm is normal. A 10% decrease in these growth rates can result in an insufficient growth velocity, and thus a noticeable decline on the growth chart. When that is recognized, even before the child has fallen to a significantly low percentile (1.2% = -2 SD), he/she should then be tested for abnormally low levels of growth hormone.An individual who acquires GHD later in life presents more generalized symptoms. They may notice a relative increase in fat mass, especially abdominal and visceral, along with a decrease in muscle mass. Decreased energy levels, anxiety, and/or depression are also common. Lipid levels are also affected, resulting in an increase in LDL-cholesterol and triglyceride levels. | 542 | Growth Hormone Deficiency |
nord_542_2 | Causes of Growth Hormone Deficiency | Congenital GHD results from genetic error, and may be associated with brain structure defects or with midline facial defects such as a cleft palate or single central incisor.Several genetic defects have been identified:Growth hormone deficiency IA is autosomal recessive and is characterized by growth retardation in utero. Affected children are small in relation to their siblings. The infant usually has a normal response to administration of human growth hormone (hGH) at first, but then develops antibodies to the hormone and grows into a very short adult.Growth Hormone Deficiency IB is also autosomal recessive and is similar to IA. However, there is some growth hormone (GH) present in the child at birth and usually the child continues to respond to hGH treatments.Growth Hormone Deficiency IIB and III are similar to IB, but IIB is autosomal dominant and III is X-linked.Classic genetic diseases are the product of the interaction of two genes, one received from the father and one from the mother.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.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 receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with X-linked disorders is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.Acquired GHD can occur as a result of many different causes including brain trauma (perinatal or postnatal), central nervous system infection, tumors of the hypothalamus or pituitary (pituitary adenoma, craniopharyngioma, Rathke’s cleft cyst, glioma, germinoma, metastases), radiation therapy, infiltrative diseases (Langerhans cell histiocytosis, sarcoidosis, tuberculosis), or, if without another diagnosis, it is considered idiopathic. | Causes of Growth Hormone Deficiency. Congenital GHD results from genetic error, and may be associated with brain structure defects or with midline facial defects such as a cleft palate or single central incisor.Several genetic defects have been identified:Growth hormone deficiency IA is autosomal recessive and is characterized by growth retardation in utero. Affected children are small in relation to their siblings. The infant usually has a normal response to administration of human growth hormone (hGH) at first, but then develops antibodies to the hormone and grows into a very short adult.Growth Hormone Deficiency IB is also autosomal recessive and is similar to IA. However, there is some growth hormone (GH) present in the child at birth and usually the child continues to respond to hGH treatments.Growth Hormone Deficiency IIB and III are similar to IB, but IIB is autosomal dominant and III is X-linked.Classic genetic diseases are the product of the interaction of two genes, one received from the father and one from the mother.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.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 receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with X-linked disorders is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.Acquired GHD can occur as a result of many different causes including brain trauma (perinatal or postnatal), central nervous system infection, tumors of the hypothalamus or pituitary (pituitary adenoma, craniopharyngioma, Rathke’s cleft cyst, glioma, germinoma, metastases), radiation therapy, infiltrative diseases (Langerhans cell histiocytosis, sarcoidosis, tuberculosis), or, if without another diagnosis, it is considered idiopathic. | 542 | Growth Hormone Deficiency |
nord_542_3 | Affects of Growth Hormone Deficiency | Prevalence and incidence data vary widely due to the lack of standard diagnostic criteria. While congenital GHD and most cases of idiopathic GHD are thought to be present from birth, diagnosis is often delayed until the patient’s short stature is noticed in relation to their peers. Diagnosis most often occurs during two age ranges. The first is around 5 years of age when children begin school. The second is around 10-13 years old in girls and 12-16 years in boys associated with the delay in the pubertal growth spurt.There is no apparent racial difference in the incidence of GHD. However, the National Cooperative Growth Study (NCGS), Genentech’s now closed large North American database, revealed that 85% of patients receiving GH treatment for idiopathic GHD were white, 6% were black, and 2% were Asian. Similar distributions were seen with patients with other forms of short stature. Patients from other racial groups tend to be shorter than their white counterparts at the time of diagnosis.Growth hormone deficiency affects males and females equally except for GHD III which affects only males. However, given the greater concern for boys with short stature in most societies, diagnosis tends to favor males over females. 73% of patients with idiopathic GHD in the NCGS were male. Additionally, patients with GHD from organic causes such as tumors and radiation, in which no gender bias should be present, were still 62% male. | Affects of Growth Hormone Deficiency. Prevalence and incidence data vary widely due to the lack of standard diagnostic criteria. While congenital GHD and most cases of idiopathic GHD are thought to be present from birth, diagnosis is often delayed until the patient’s short stature is noticed in relation to their peers. Diagnosis most often occurs during two age ranges. The first is around 5 years of age when children begin school. The second is around 10-13 years old in girls and 12-16 years in boys associated with the delay in the pubertal growth spurt.There is no apparent racial difference in the incidence of GHD. However, the National Cooperative Growth Study (NCGS), Genentech’s now closed large North American database, revealed that 85% of patients receiving GH treatment for idiopathic GHD were white, 6% were black, and 2% were Asian. Similar distributions were seen with patients with other forms of short stature. Patients from other racial groups tend to be shorter than their white counterparts at the time of diagnosis.Growth hormone deficiency affects males and females equally except for GHD III which affects only males. However, given the greater concern for boys with short stature in most societies, diagnosis tends to favor males over females. 73% of patients with idiopathic GHD in the NCGS were male. Additionally, patients with GHD from organic causes such as tumors and radiation, in which no gender bias should be present, were still 62% male. | 542 | Growth Hormone Deficiency |
nord_542_4 | Related disorders of Growth Hormone Deficiency | Symptoms of the following disorders can be similar to those of Growth Hormone Deficiency. Comparisons may be useful for a differential diagnosis:Small for gestational age (SGA) generally describes any infant whose birth weight and/or length was less than the 3rd percentile (adjusted for prematurity). Children with SGA are shorter and thinner than his or her peers. Typical characteristics for these children include low birth weight, short birth length, inadequate catch-up growth in first two years, persistently low weight-for-height proportion, and lack of muscle mass and/or poor muscle tone. The FDA has approved growth hormone therapy as long-term treatment of children who were born SGA and who have not achieved catch-up growth by two years of age.Short stature homeobox-containing gene (SHOX) deficiency refers to short stature caused by a mutation in one copy of the SHOX gene and is associated with some cases of Turner syndrome, Leri-Weil syndrome and dyschondrosteosis. Turner syndrome is only seen in females, whereas Leri-Weil syndrome and dychondrosteosis is seen in males and females. Growth hormone therapy is FDA-approved for SHOX deficiency.Idiopathic short stature (ISS) is defined as having a height significantly shorter than the normal population (-2.25 SD, that is shorter than 1.2% of the population of the same age and gender), a poor adult height prediction (generally defined by having less than the calculated mid-parental height or, as a rough guide, less than 5’4″ for males and less than 4’11” for females), and no detectable cause for short stature. Growth hormone therapy is FDA-approved to treat ISS.Turner syndrome is a chromosomal disorder affecting 1 of 2,500 females and is characterized by short stature and the lack of sexual development at puberty. Other physical features may include webbing of the neck, heart defects, kidney abnormalities, and various other anomalies. Among affected females, there is also a heightened incidence of autoimmune disease such as Hashimotos’s hypothyroidism and celiac syndrome. There appears to be great variability in the degree to which girls with Turner syndrome are affected by any of its manifestations since classical Turner, completely lacking one X chromosome, comprises only 60% of the total. The other 40% have a wide variety of genetic abnormalities including deletion of segments of the long or short arm of the X (or Y) and mosaicism with different populations of cells. (For more information on this disorder, choose “Turner” as your search term in the Rare Disease Database.)Noonan syndrome is a genetic disorder that is typically evident at birth (congenital) and is thought to affect approximately one in 1,000 to one in 2,500 people. The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings. Noonan syndrome is an autosomal dominant genetic disorder which may be caused by abnormalities (mutations) in a number of genes, four of which are PTPN11, KRAS, SOS1 and RAF1. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)Prader-Willi syndrome (PWS) is a genetic disorder characterized by low muscle tone, short stature, incomplete sexual development, and a chronic feeling of hunger that, coupled with a metabolism that utilizes fewer calories than normal, can lead to excessive eating and life-threatening obesity. The food compulsion makes constant supervision and food restriction necessary. Average IQ is 70, but even children with normal IQs almost all have learning issues. Social and motor deficits also exist. At birth the infant typically has low birth weight for gestation, hypotonia (weak muscles) with difficulty sucking which can lead to a diagnosis of failure to thrive. The second stage (“thriving too well”), has a typical onset between the ages of two and five, but can be later. The hyperphagia (extreme unsatisfied drive to consume food) lasts throughout the lifetime. Younger children with PWS have sweet and loving personalities, but this phase is also characterized by increased appetite, weight control issues, and motor development delays. As the child becomes older, there are more behavioral problems and medical issues. (For more information on this disorder, choose “Prader-Willi” as your search term in the Rare Disease Database.) Primary growth hormone insensitivity (GHI), also known as Laron syndrome, is a group of extremely rare genetic disorders in which the body is unable to use the growth hormone that it produces. GHI can be caused by mutations in the growth hormone receptor gene or mutations in genes involved in the signaling pathway within the cell after growth hormone binds to its receptor, preventing production of insulin-like growth factor (IGF-1), the intermediary hormone responsible for the growth effects of growth hormone. Children with GHI who are treated with IGF-1 before puberty have improved growth, but, unlike children with growth hormone deficiency given growth hormone treatment, they do not have normal growth restored.GHI is characterized by normal or high levels of circulating growth hormone, delayed bone age and onset of puberty, prominent forehead, low blood sugar and obesity in adulthood. Except for an extremely rare form of GHI, where the gene for IGF-I is defective, brain development is normal but some may have mild intellectual impairment. (For more information on this disorder, choose “primary growth hormone insensitivity” as your search term in the Rare Disease Database.) | Related disorders of Growth Hormone Deficiency. Symptoms of the following disorders can be similar to those of Growth Hormone Deficiency. Comparisons may be useful for a differential diagnosis:Small for gestational age (SGA) generally describes any infant whose birth weight and/or length was less than the 3rd percentile (adjusted for prematurity). Children with SGA are shorter and thinner than his or her peers. Typical characteristics for these children include low birth weight, short birth length, inadequate catch-up growth in first two years, persistently low weight-for-height proportion, and lack of muscle mass and/or poor muscle tone. The FDA has approved growth hormone therapy as long-term treatment of children who were born SGA and who have not achieved catch-up growth by two years of age.Short stature homeobox-containing gene (SHOX) deficiency refers to short stature caused by a mutation in one copy of the SHOX gene and is associated with some cases of Turner syndrome, Leri-Weil syndrome and dyschondrosteosis. Turner syndrome is only seen in females, whereas Leri-Weil syndrome and dychondrosteosis is seen in males and females. Growth hormone therapy is FDA-approved for SHOX deficiency.Idiopathic short stature (ISS) is defined as having a height significantly shorter than the normal population (-2.25 SD, that is shorter than 1.2% of the population of the same age and gender), a poor adult height prediction (generally defined by having less than the calculated mid-parental height or, as a rough guide, less than 5’4″ for males and less than 4’11” for females), and no detectable cause for short stature. Growth hormone therapy is FDA-approved to treat ISS.Turner syndrome is a chromosomal disorder affecting 1 of 2,500 females and is characterized by short stature and the lack of sexual development at puberty. Other physical features may include webbing of the neck, heart defects, kidney abnormalities, and various other anomalies. Among affected females, there is also a heightened incidence of autoimmune disease such as Hashimotos’s hypothyroidism and celiac syndrome. There appears to be great variability in the degree to which girls with Turner syndrome are affected by any of its manifestations since classical Turner, completely lacking one X chromosome, comprises only 60% of the total. The other 40% have a wide variety of genetic abnormalities including deletion of segments of the long or short arm of the X (or Y) and mosaicism with different populations of cells. (For more information on this disorder, choose “Turner” as your search term in the Rare Disease Database.)Noonan syndrome is a genetic disorder that is typically evident at birth (congenital) and is thought to affect approximately one in 1,000 to one in 2,500 people. The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic abnormalities of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings. Noonan syndrome is an autosomal dominant genetic disorder which may be caused by abnormalities (mutations) in a number of genes, four of which are PTPN11, KRAS, SOS1 and RAF1. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)Prader-Willi syndrome (PWS) is a genetic disorder characterized by low muscle tone, short stature, incomplete sexual development, and a chronic feeling of hunger that, coupled with a metabolism that utilizes fewer calories than normal, can lead to excessive eating and life-threatening obesity. The food compulsion makes constant supervision and food restriction necessary. Average IQ is 70, but even children with normal IQs almost all have learning issues. Social and motor deficits also exist. At birth the infant typically has low birth weight for gestation, hypotonia (weak muscles) with difficulty sucking which can lead to a diagnosis of failure to thrive. The second stage (“thriving too well”), has a typical onset between the ages of two and five, but can be later. The hyperphagia (extreme unsatisfied drive to consume food) lasts throughout the lifetime. Younger children with PWS have sweet and loving personalities, but this phase is also characterized by increased appetite, weight control issues, and motor development delays. As the child becomes older, there are more behavioral problems and medical issues. (For more information on this disorder, choose “Prader-Willi” as your search term in the Rare Disease Database.) Primary growth hormone insensitivity (GHI), also known as Laron syndrome, is a group of extremely rare genetic disorders in which the body is unable to use the growth hormone that it produces. GHI can be caused by mutations in the growth hormone receptor gene or mutations in genes involved in the signaling pathway within the cell after growth hormone binds to its receptor, preventing production of insulin-like growth factor (IGF-1), the intermediary hormone responsible for the growth effects of growth hormone. Children with GHI who are treated with IGF-1 before puberty have improved growth, but, unlike children with growth hormone deficiency given growth hormone treatment, they do not have normal growth restored.GHI is characterized by normal or high levels of circulating growth hormone, delayed bone age and onset of puberty, prominent forehead, low blood sugar and obesity in adulthood. Except for an extremely rare form of GHI, where the gene for IGF-I is defective, brain development is normal but some may have mild intellectual impairment. (For more information on this disorder, choose “primary growth hormone insensitivity” as your search term in the Rare Disease Database.) | 542 | Growth Hormone Deficiency |
nord_542_5 | Diagnosis of Growth Hormone Deficiency | Testing is very important in determining whether the child with growth retardation does indeed have growth hormone deficiency. Various agents may be used including insulin, arginine, clonidine and l-dopa. These tests are meant to stimulate the pituitary to secrete GH allowing for the testing of blood samples for the levels of GH at timed intervals.Physicians often test for other hormone deficiencies that may be the underlying cause of short stature. FreeT4, TSH, cortisol, celiac antibodies, etc. are measured to rule out underlying organic causes of short stature.IGF-1, a protein produced primarily by the liver but present in all tissues in response to GH stimulation, can be measured to screen for GHD and later to titrate GH therapy.Children with severe GHD should be re-tested after completing growth to see if they meet the requirements for GH therapy as an adult. | Diagnosis of Growth Hormone Deficiency. Testing is very important in determining whether the child with growth retardation does indeed have growth hormone deficiency. Various agents may be used including insulin, arginine, clonidine and l-dopa. These tests are meant to stimulate the pituitary to secrete GH allowing for the testing of blood samples for the levels of GH at timed intervals.Physicians often test for other hormone deficiencies that may be the underlying cause of short stature. FreeT4, TSH, cortisol, celiac antibodies, etc. are measured to rule out underlying organic causes of short stature.IGF-1, a protein produced primarily by the liver but present in all tissues in response to GH stimulation, can be measured to screen for GHD and later to titrate GH therapy.Children with severe GHD should be re-tested after completing growth to see if they meet the requirements for GH therapy as an adult. | 542 | Growth Hormone Deficiency |
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