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nord_500_0 | Overview of Gaucher Disease | SummaryGaucher disease is a rare, inherited metabolic disorder in which deficiency of the enzyme glucocerebrosidase results in the accumulation of harmful quantities of certain fats (lipids), specifically the glycolipid glucocerebroside, throughout the body especially within the bone marrow, spleen and liver. The symptoms and physical findings associated with Gaucher disease vary greatly from patient to patient. Some individuals develop few or no symptoms (asymptomatic); others may have serious complications.Common manifestations of Gaucher disease include an abnormally enlarged liver and/or spleen (hepatosplenomegaly), low levels of circulating red blood cells (anemia), low levels of platelets (thrombocytopenia), and skeletal abnormalities. Platelets are blood cells that promote clotting and patients with thrombocytopenia may develop bleeding problems. Three separate forms of Gaucher disease have been identified and are distinguished by the absence of, or the presence and extent of, neurological complications. All three forms of Gaucher disease are inherited in an autosomal recessive pattern.IntroductionGaucher disease is categorized as a lysosomal storage disorder (LSD). Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or “digest” nutrients, including certain complex carbohydrates and fats. In Gaucher disease certain sugar (glucose) containing fat, known as glycolipids, abnormally accumulate in the body because of the lack of the enzyme, glucocerebrosidase. This accumulation or “storage” of lipids leads to the various symptoms or physical findings associated with a lysosomal storage disease. Gaucher disease is the second most common type of lysosomal storage disorder. (Recent publications indicate that Fabry disease is the most prevalent LSD). | Overview of Gaucher Disease. SummaryGaucher disease is a rare, inherited metabolic disorder in which deficiency of the enzyme glucocerebrosidase results in the accumulation of harmful quantities of certain fats (lipids), specifically the glycolipid glucocerebroside, throughout the body especially within the bone marrow, spleen and liver. The symptoms and physical findings associated with Gaucher disease vary greatly from patient to patient. Some individuals develop few or no symptoms (asymptomatic); others may have serious complications.Common manifestations of Gaucher disease include an abnormally enlarged liver and/or spleen (hepatosplenomegaly), low levels of circulating red blood cells (anemia), low levels of platelets (thrombocytopenia), and skeletal abnormalities. Platelets are blood cells that promote clotting and patients with thrombocytopenia may develop bleeding problems. Three separate forms of Gaucher disease have been identified and are distinguished by the absence of, or the presence and extent of, neurological complications. All three forms of Gaucher disease are inherited in an autosomal recessive pattern.IntroductionGaucher disease is categorized as a lysosomal storage disorder (LSD). Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or “digest” nutrients, including certain complex carbohydrates and fats. In Gaucher disease certain sugar (glucose) containing fat, known as glycolipids, abnormally accumulate in the body because of the lack of the enzyme, glucocerebrosidase. This accumulation or “storage” of lipids leads to the various symptoms or physical findings associated with a lysosomal storage disease. Gaucher disease is the second most common type of lysosomal storage disorder. (Recent publications indicate that Fabry disease is the most prevalent LSD). | 500 | Gaucher Disease |
nord_500_1 | Symptoms of Gaucher Disease | Researchers have identified three distinct forms of Gaucher disease separated by the absence (type 1) or presence and extent (type 2 or type 3) of neurological complications. Additional forms of Gaucher disease include perinatal-lethal form and cardiovascular form. The specific symptoms present in individuals with Gaucher disease vary greatly from person to person. Some individuals exhibit few or no symptoms (asymptomatic); others experience chronic, and sometimes severe, complications.Gaucher disease type 1 is also known as non-neuronopathic, because it does not involve the central nervous system (brain and spinal cord). Type 1 Gaucher disease is the most common form of the condition. Most individuals with Gaucher disease type 1 experience easy bruising due to low levels of blood clotting cells known as platelets (thrombocytopenia), chronic fatigue due to low levels of circulating red blood cells (anemia), and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). Affected individuals may also experience lack of blood supply (infarction) to various bones of the body resulting in dull or intense bone pain (bone crises), degeneration (avascular necrosis) and deformity of affected bones, and thinning and weakening of bones (osteoporosis). Such skeletal abnormalities result in an increased susceptibility to fractures. In rare cases, affected individuals may also experience involvement of the lungs and/or kidneys.Gaucher disease type 2, also known as acute neuronopathic Gaucher disease, occurs in newborns and infants and is characterized by neurological complications due to the abnormal accumulation of glucocerebroside in the brain. Enlargement of the spleen (splenomegaly) is often the first symptom and may become apparent before six months of age. Enlargement of the liver (hepatomegaly) is not always evident. Affected infants may lose previously acquired motor skills and exhibit low muscle tone (hypotonia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the arms and legs, and crossed eyes (strabismus). In addition, affected infants may experience difficulty swallowing (dysphagia), which may result in feeding difficulties; abnormal positioning or bending of the neck (retroflexion); and failure to gain weight and grow at the expected rate (failure to thrive) and high-pitched breathing (stridor) due to contraction of the muscles of the voice box (laryngeal spasm). Anemia and thrombocytopenia may also occur. Gaucher disease type 2 often progresses to life-threatening complications such as respiratory distress or the entrance of food into the respiratory passages (aspiration pneumonia). Severely affected newborns may show skin abnormalities (collodion skin or ichthvosiform changes) and generalized swelling (hydrops), with death in the first few weeks of life. Other children with Gaucher disease type 2 have greatly reduced lifespans, with death usually occurring between 1 and 3 years of life.Gaucher disease type 3, also known as chronic neuronopathic Gaucher disease, occurs during the first decade of life. In addition to the blood and bone abnormalities discussed above, affected individuals develop neurological complications that develop and progress slower than in Gaucher disease type 2. Associated neurological complications include mental deterioration; an inability to coordinate voluntary movements (ataxia); and brief, shock-like muscle spasms of the arms, legs or entire body (myoclonic seizures). Some individuals with Gaucher disease type 3 may have difficulty moving their eyes from side-to-side (horizontal gaze palsy). Patients with Type 3 Gaucher disease can also have a vertical gaze palsy that usually occurs later than the horizontal gaze paresis. A significant proportion of patients also develop pulmonary (lung) disease (interstitial lung disease). There can be wide variability in presentation and clinical course among patients with type 3 Gaucher disease. Some affected patients may live into their teens and early 20’s, while others have lived for much longer (30’s and 40’s). With increasing difficulties, affected individuals may require assistance to fulfill the task of daily living (for example, with eating, bathing, and ambulation).The perinatal-lethal form or fetal/neonatal Gaucher disease occurs in less than 5% of patients. This type is very severe and associated with death before 3 months of age or even in the womb. The fetus/newborn may present with widespread swelling of the skin (edema or anasarca) leading to fluid buildup in the heart, skin, or lungs (hydrops fetalis). Other symptoms include bleeding within the skull (intracranial hemorrhage), scaling of the skin (non-bullous ichthyosiform erythrodema) with a reddish appearance, and contraction of the joints in fixed, bent position (arthrogryposis multiplex congenita).The cardiovascular form is characterized by CNS involvement, such as having difficulty initiating eye movement in desired directions (oculomotor apraxia). Other symptoms include calcification of the mitral and aortic valve, corneal opacity, and mild splenomegaly. Calcium deposits on the heart can reduce blood flow to these valves, and can increase blood pressure. Supranuclear ophthalmoplegia can also be present, which causes problems with balance, walking, and thinking. Cardiac-related complications and associated neurologic problems lead to a reduced lifespan, although this can extend into young adulthood in some patients. | Symptoms of Gaucher Disease. Researchers have identified three distinct forms of Gaucher disease separated by the absence (type 1) or presence and extent (type 2 or type 3) of neurological complications. Additional forms of Gaucher disease include perinatal-lethal form and cardiovascular form. The specific symptoms present in individuals with Gaucher disease vary greatly from person to person. Some individuals exhibit few or no symptoms (asymptomatic); others experience chronic, and sometimes severe, complications.Gaucher disease type 1 is also known as non-neuronopathic, because it does not involve the central nervous system (brain and spinal cord). Type 1 Gaucher disease is the most common form of the condition. Most individuals with Gaucher disease type 1 experience easy bruising due to low levels of blood clotting cells known as platelets (thrombocytopenia), chronic fatigue due to low levels of circulating red blood cells (anemia), and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). Affected individuals may also experience lack of blood supply (infarction) to various bones of the body resulting in dull or intense bone pain (bone crises), degeneration (avascular necrosis) and deformity of affected bones, and thinning and weakening of bones (osteoporosis). Such skeletal abnormalities result in an increased susceptibility to fractures. In rare cases, affected individuals may also experience involvement of the lungs and/or kidneys.Gaucher disease type 2, also known as acute neuronopathic Gaucher disease, occurs in newborns and infants and is characterized by neurological complications due to the abnormal accumulation of glucocerebroside in the brain. Enlargement of the spleen (splenomegaly) is often the first symptom and may become apparent before six months of age. Enlargement of the liver (hepatomegaly) is not always evident. Affected infants may lose previously acquired motor skills and exhibit low muscle tone (hypotonia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the arms and legs, and crossed eyes (strabismus). In addition, affected infants may experience difficulty swallowing (dysphagia), which may result in feeding difficulties; abnormal positioning or bending of the neck (retroflexion); and failure to gain weight and grow at the expected rate (failure to thrive) and high-pitched breathing (stridor) due to contraction of the muscles of the voice box (laryngeal spasm). Anemia and thrombocytopenia may also occur. Gaucher disease type 2 often progresses to life-threatening complications such as respiratory distress or the entrance of food into the respiratory passages (aspiration pneumonia). Severely affected newborns may show skin abnormalities (collodion skin or ichthvosiform changes) and generalized swelling (hydrops), with death in the first few weeks of life. Other children with Gaucher disease type 2 have greatly reduced lifespans, with death usually occurring between 1 and 3 years of life.Gaucher disease type 3, also known as chronic neuronopathic Gaucher disease, occurs during the first decade of life. In addition to the blood and bone abnormalities discussed above, affected individuals develop neurological complications that develop and progress slower than in Gaucher disease type 2. Associated neurological complications include mental deterioration; an inability to coordinate voluntary movements (ataxia); and brief, shock-like muscle spasms of the arms, legs or entire body (myoclonic seizures). Some individuals with Gaucher disease type 3 may have difficulty moving their eyes from side-to-side (horizontal gaze palsy). Patients with Type 3 Gaucher disease can also have a vertical gaze palsy that usually occurs later than the horizontal gaze paresis. A significant proportion of patients also develop pulmonary (lung) disease (interstitial lung disease). There can be wide variability in presentation and clinical course among patients with type 3 Gaucher disease. Some affected patients may live into their teens and early 20’s, while others have lived for much longer (30’s and 40’s). With increasing difficulties, affected individuals may require assistance to fulfill the task of daily living (for example, with eating, bathing, and ambulation).The perinatal-lethal form or fetal/neonatal Gaucher disease occurs in less than 5% of patients. This type is very severe and associated with death before 3 months of age or even in the womb. The fetus/newborn may present with widespread swelling of the skin (edema or anasarca) leading to fluid buildup in the heart, skin, or lungs (hydrops fetalis). Other symptoms include bleeding within the skull (intracranial hemorrhage), scaling of the skin (non-bullous ichthyosiform erythrodema) with a reddish appearance, and contraction of the joints in fixed, bent position (arthrogryposis multiplex congenita).The cardiovascular form is characterized by CNS involvement, such as having difficulty initiating eye movement in desired directions (oculomotor apraxia). Other symptoms include calcification of the mitral and aortic valve, corneal opacity, and mild splenomegaly. Calcium deposits on the heart can reduce blood flow to these valves, and can increase blood pressure. Supranuclear ophthalmoplegia can also be present, which causes problems with balance, walking, and thinking. Cardiac-related complications and associated neurologic problems lead to a reduced lifespan, although this can extend into young adulthood in some patients. | 500 | Gaucher Disease |
nord_500_2 | Causes of Gaucher Disease | Gaucher disease is caused by changes (mutations) in the GBA gene.All three forms of Gaucher disease are inherited in an autosomal recessive pattern. 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 an abnormal gene from each parent. If an individual receives from each parent one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | Causes of Gaucher Disease. Gaucher disease is caused by changes (mutations) in the GBA gene.All three forms of Gaucher disease are inherited in an autosomal recessive pattern. 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 an abnormal gene from each parent. If an individual receives from each parent one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | 500 | Gaucher Disease |
nord_500_3 | Affects of Gaucher Disease | All forms of Gaucher disease affect males and females in equal numbers. Gaucher disease type 1 is the most common type, accounting for more than 90 percent of cases among Caucasians. Individuals with Gaucher disease type 1 usually exhibit symptoms during adolescence, but the age of onset ranges from childhood to adulthood. The age of onset for Gaucher disease type 2 is during early infancy. The age of onset of Gaucher disease type 3 varies, but the disorder generally begins during childhood or adolescence. The frequency of neuropathic forms of Gaucher disease, that is, the proportion of such cases, is higher among non-Caucasians.There are approximately 6,000 individuals with Gaucher disease in the United States. Gaucher disease is the most common genetic disorder of persons of Ashkenazic Jewish ancestry, where the incidence may be as high as 1 in 450 births. There is no ethnic prevalence associated with Gaucher disease types 2 or 3. However, there is a subtype of Gaucher disease type 3 that occurs with greater frequency in the Norrbotten region of Sweden (Norrbottnian Gaucher disease). The estimated prevalence in the Swedish Norrbotten population is 1 in 50,000. | Affects of Gaucher Disease. All forms of Gaucher disease affect males and females in equal numbers. Gaucher disease type 1 is the most common type, accounting for more than 90 percent of cases among Caucasians. Individuals with Gaucher disease type 1 usually exhibit symptoms during adolescence, but the age of onset ranges from childhood to adulthood. The age of onset for Gaucher disease type 2 is during early infancy. The age of onset of Gaucher disease type 3 varies, but the disorder generally begins during childhood or adolescence. The frequency of neuropathic forms of Gaucher disease, that is, the proportion of such cases, is higher among non-Caucasians.There are approximately 6,000 individuals with Gaucher disease in the United States. Gaucher disease is the most common genetic disorder of persons of Ashkenazic Jewish ancestry, where the incidence may be as high as 1 in 450 births. There is no ethnic prevalence associated with Gaucher disease types 2 or 3. However, there is a subtype of Gaucher disease type 3 that occurs with greater frequency in the Norrbotten region of Sweden (Norrbottnian Gaucher disease). The estimated prevalence in the Swedish Norrbotten population is 1 in 50,000. | 500 | Gaucher Disease |
nord_500_4 | Related disorders of Gaucher Disease | Symptoms of the following disorders can be similar to those of Gaucher disease. Comparisons may be useful for a differential diagnosis:Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism. At least five types of Niemann-Pick disease have been identified (NPD types A, B, C, D, and E). Symptoms of types A and B occur as a result of a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found in all tissues, especially in the brain and nervous system. This deficiency results in abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body such as the liver, spleen, and brain. Symptoms of type C occur because of an inability to mobilize cholesterol and other substances, which results in excessive amounts of these materials in various organs of the body. Symptoms common to all types of Niemann-Pick disease include yellow discoloration of the skin, eyes, and/or mucous membranes (jaundice), progressive loss of motor skills, feeding difficulties, learning disabilities, and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). The different types of Niemann-Pick disease are inherited as autosomal recessive traits. (For more information on this disorder, choose “Niemann Pick” as your search term in the Rare Disease Database.)Pompe disease is a glycogen storage disease. This inherited metabolic disorder is caused by an inborn lack of the enzyme alpha-1,4 glucosidase (lysosomal glucosidase; acid maltase), which is necessary to break down glycogen, a substance that is a source of energy for the body. This enzyme deficiency causes excess amounts of glycogen to accumulate in lysosomes, which are structures within cells that break down waste products within the cell. The symptoms and physical findings of Pompe disease result from the abnormal accumulation of glycogen in the cells. Three separate forms of Pompe disease have been identified. The infantile form is characterized by severe muscle weakness and abnormally diminished muscle tone (hypotonia) without muscle wasting, and usually manifests within the first few months of life. Additional abnormalities may include enlargement of the heart (cardiomegaly), the liver (hepatomegaly), and/or the tongue (macroglossia). Progressive cardiac failure usually causes life-threatening complications by the age of 12 to 18 months. The childhood form usually begins during late infancy or early childhood. The extent of organ involvement may vary among affected individuals; however, skeletal muscle weakness is usually present with minimal cardiac involvement. In the adult form of Pompe disease, symptoms include muscle weakness such as that found in other chronic muscle disorders. Onset of symptoms usually occurs in the second to fourth decade. This form of the disorder is slowly progressive without cardiac involvement, but can be associated with significant pulmonary complications (respiratory failure). (For more information on this disorder, choose “Pompe” as your search term in the Rare Disease Database.)Hurler syndrome (MPS I) is one of a group of disorders known as the mucopolysaccharidoses (MPS Disorders), which are rare genetic disorders caused by the deficiency of one of ten specific lysosomal enzymes, resulting in an inability to breakdown complex carbohydrates (mucopolysaccharides) into simpler molecules. The accumulation of these large, undegraded mucopolysaccharides (also known as glycosaminoglycans) in the cells of the body causes several physical symptoms and abnormalities. There are three forms of Hurler Syndrome with varying severity. Infants with Hurler Syndrome usually appear normal at birth, but may have inguinal and umbilical hernias, clouding of the cornea, enlarged liver and spleen, a large tongue, skeletal abnormalities, poor growth, and joint stiffness. Hurler Syndrome is caused by a deficiency of the enzyme alpha-L-iduronidase. (For more information on this disorder, choose “Hurler” as your search term in the Rare Disease Database.)Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain. This abnormal accumulation of gangliosides leads to progressive destruction of cells in the central nervous system. Symptoms associated with Tay-Sachs disease may include an exaggerated startle response to sudden noises, listlessness, loss of previously acquired skills (i.e., psychomotor regression), and severely diminished muscle tone (hypotonia). With disease progression, affected infants and children may develop cherry-red spots within the middle layer of the eyes (specifically, retinal ganglion cells), gradual loss of vision, and deafness, increasing muscle stiffness and restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). The classical form of Tay-Sachs disease occurs during infancy and may resemble some cases of Gaucher disease type II. (For more information on this disorder, choose “Tay-Sachs” as your search term in the Rare Disease Database.) | Related disorders of Gaucher Disease. Symptoms of the following disorders can be similar to those of Gaucher disease. Comparisons may be useful for a differential diagnosis:Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism. At least five types of Niemann-Pick disease have been identified (NPD types A, B, C, D, and E). Symptoms of types A and B occur as a result of a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found in all tissues, especially in the brain and nervous system. This deficiency results in abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body such as the liver, spleen, and brain. Symptoms of type C occur because of an inability to mobilize cholesterol and other substances, which results in excessive amounts of these materials in various organs of the body. Symptoms common to all types of Niemann-Pick disease include yellow discoloration of the skin, eyes, and/or mucous membranes (jaundice), progressive loss of motor skills, feeding difficulties, learning disabilities, and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). The different types of Niemann-Pick disease are inherited as autosomal recessive traits. (For more information on this disorder, choose “Niemann Pick” as your search term in the Rare Disease Database.)Pompe disease is a glycogen storage disease. This inherited metabolic disorder is caused by an inborn lack of the enzyme alpha-1,4 glucosidase (lysosomal glucosidase; acid maltase), which is necessary to break down glycogen, a substance that is a source of energy for the body. This enzyme deficiency causes excess amounts of glycogen to accumulate in lysosomes, which are structures within cells that break down waste products within the cell. The symptoms and physical findings of Pompe disease result from the abnormal accumulation of glycogen in the cells. Three separate forms of Pompe disease have been identified. The infantile form is characterized by severe muscle weakness and abnormally diminished muscle tone (hypotonia) without muscle wasting, and usually manifests within the first few months of life. Additional abnormalities may include enlargement of the heart (cardiomegaly), the liver (hepatomegaly), and/or the tongue (macroglossia). Progressive cardiac failure usually causes life-threatening complications by the age of 12 to 18 months. The childhood form usually begins during late infancy or early childhood. The extent of organ involvement may vary among affected individuals; however, skeletal muscle weakness is usually present with minimal cardiac involvement. In the adult form of Pompe disease, symptoms include muscle weakness such as that found in other chronic muscle disorders. Onset of symptoms usually occurs in the second to fourth decade. This form of the disorder is slowly progressive without cardiac involvement, but can be associated with significant pulmonary complications (respiratory failure). (For more information on this disorder, choose “Pompe” as your search term in the Rare Disease Database.)Hurler syndrome (MPS I) is one of a group of disorders known as the mucopolysaccharidoses (MPS Disorders), which are rare genetic disorders caused by the deficiency of one of ten specific lysosomal enzymes, resulting in an inability to breakdown complex carbohydrates (mucopolysaccharides) into simpler molecules. The accumulation of these large, undegraded mucopolysaccharides (also known as glycosaminoglycans) in the cells of the body causes several physical symptoms and abnormalities. There are three forms of Hurler Syndrome with varying severity. Infants with Hurler Syndrome usually appear normal at birth, but may have inguinal and umbilical hernias, clouding of the cornea, enlarged liver and spleen, a large tongue, skeletal abnormalities, poor growth, and joint stiffness. Hurler Syndrome is caused by a deficiency of the enzyme alpha-L-iduronidase. (For more information on this disorder, choose “Hurler” as your search term in the Rare Disease Database.)Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain. This abnormal accumulation of gangliosides leads to progressive destruction of cells in the central nervous system. Symptoms associated with Tay-Sachs disease may include an exaggerated startle response to sudden noises, listlessness, loss of previously acquired skills (i.e., psychomotor regression), and severely diminished muscle tone (hypotonia). With disease progression, affected infants and children may develop cherry-red spots within the middle layer of the eyes (specifically, retinal ganglion cells), gradual loss of vision, and deafness, increasing muscle stiffness and restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). The classical form of Tay-Sachs disease occurs during infancy and may resemble some cases of Gaucher disease type II. (For more information on this disorder, choose “Tay-Sachs” as your search term in the Rare Disease Database.) | 500 | Gaucher Disease |
nord_500_5 | Diagnosis of Gaucher Disease | A diagnosis of Gaucher disease should be considered in individuals with unexplained anemia and easy bruising, particularly if they have enlargement of the spleen and liver and fractures. The diagnosis of Gaucher disease may be confirmed by a thorough clinical evaluation and a variety of specialized tests, particularly tests (i.e., enzyme assay) that measure acid beta-glucosidase activity in white blood cells (leukocytes) or skin cells (fibroblasts) and genetic (DNA) analysis for the causal gene defects (mutations). Note: the enzyme test cannot reliably detect carriers.The enzyme assay test is known as BGL (beta-glucosidase leukocyte) blood test. This is a standard tool used by physicians to diagnose someone who is thought to have Gaucher disease, because usually these patients have low glucocerebrosidase enzyme activity. If the results are slightly low, the individual would be then referred by the physician to undergo genetic testing for mutations in the GBA gene. Genetic testing is done via blood or saliva. Identification of two causal gene defects, in conjunction with enzyme test results, confirms the diagnosis of Gaucher disease. Individuals in whom only a single gene defect is identified may be a carrier or, in the presence of low beta-glucosidase, may be affected with a second gene defect (mutation) not detected. Referral to an appropriate genetic specialist may be indicated in this situation. DNA analysis identifies individuals who carry a mutation in the GBA gene who can pass the mutation to children.Prenatal diagnosis of Gaucher disease is possible if a known GBA gene mutation is present in the family. Testing can be done through amniocentesis or chorionic villus sampling (CVS), but is uncommon unless there is a family history of Gaucher disease type 2. During amniocentesis, a sample of fluid that surrounds the fetus (amniotic fluid) is removed and analyzed, whereas CVS involves the removal of tissue samples from a portion of the placenta. Prenatal diagnosis can confirm a definite diagnosis of Gaucher disease but does not determine the type of disease. | Diagnosis of Gaucher Disease. A diagnosis of Gaucher disease should be considered in individuals with unexplained anemia and easy bruising, particularly if they have enlargement of the spleen and liver and fractures. The diagnosis of Gaucher disease may be confirmed by a thorough clinical evaluation and a variety of specialized tests, particularly tests (i.e., enzyme assay) that measure acid beta-glucosidase activity in white blood cells (leukocytes) or skin cells (fibroblasts) and genetic (DNA) analysis for the causal gene defects (mutations). Note: the enzyme test cannot reliably detect carriers.The enzyme assay test is known as BGL (beta-glucosidase leukocyte) blood test. This is a standard tool used by physicians to diagnose someone who is thought to have Gaucher disease, because usually these patients have low glucocerebrosidase enzyme activity. If the results are slightly low, the individual would be then referred by the physician to undergo genetic testing for mutations in the GBA gene. Genetic testing is done via blood or saliva. Identification of two causal gene defects, in conjunction with enzyme test results, confirms the diagnosis of Gaucher disease. Individuals in whom only a single gene defect is identified may be a carrier or, in the presence of low beta-glucosidase, may be affected with a second gene defect (mutation) not detected. Referral to an appropriate genetic specialist may be indicated in this situation. DNA analysis identifies individuals who carry a mutation in the GBA gene who can pass the mutation to children.Prenatal diagnosis of Gaucher disease is possible if a known GBA gene mutation is present in the family. Testing can be done through amniocentesis or chorionic villus sampling (CVS), but is uncommon unless there is a family history of Gaucher disease type 2. During amniocentesis, a sample of fluid that surrounds the fetus (amniotic fluid) is removed and analyzed, whereas CVS involves the removal of tissue samples from a portion of the placenta. Prenatal diagnosis can confirm a definite diagnosis of Gaucher disease but does not determine the type of disease. | 500 | Gaucher Disease |
nord_500_6 | Therapies of Gaucher Disease | Treatment
The main goal is to improve the patients’ quality of life by allowing them to perform their normal daily activities, such as working without feeling the excess fatigue or walking normally without experiencing joint pain. Other goals include preventing the severity of complications, such as reduced bone density to thinning, weak bones (osteoporosis) and easy fractures or shortness of breath from the reduced lung function. Normalizing the growth for a child for them to reach a normal height can also be a target within a couple of years of treatment and achieving a normal onset of puberty.Treatment is individualized for each patient depending on the type of Gaucher disease. Type 1 Gaucher disease is considered treatable and mild, because it does not involve neurological symptoms since the brain is not affected. Type 2 is not considered to be treatable at this point due to the quick and irreversible brain damage in the infantile years. Type 3 still involves neurological damage, but these symptoms progress more slowly than in type 2. There are current FDA-approved drug therapy options that include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT).Enzyme replacement therapy (ERT) has proven effective for individuals with Gaucher disease type 1. In studies of ERT, anemia and low platelet counts have improved, enlargement of the liver and spleen have been greatly reduced, and skeletal findings have improved. These systemic manifestations also improve in individuals with Gaucher disease types 2 and 3 who receive ERT. However, ERT has not been effective in reducing or reversing certain neurological symptoms associated with Gaucher disease types 2 and 3.ERT is given every 2 weeks via intravenous (IV) infusions either at infusion centers, National Gaucher Disease Treatment Center, or at home by self-administration, assistance from a family member/friend or home care nurse. The three current FDA-approved ERT drugs include imiglucerase (Cerezyme), velaglucerase alfa (VPRIV), and taliglucerase (Elelyso).The orphan drug alglucerase injection (Ceredase), which is a placenta-derived enzyme, was approved by the U.S. Food and Drug Administration (FDA) in 1991 for the treatment of Gaucher disease type 1. It was the first ERT proven effective for the treatment of Gaucher disease type 1.The synthetic form of this drug, imiglucerase (Cerezyme), was approved in 1994. Recombinant DNA technology, or genetic engineering, is used to produce Cerezyme. This was an important step in overcoming limitations of the availability of Ceredase, which is derived from human placentas. Therefore, Ceredase has been withdrawn from the market due to similar drugs being made without having bioavailability issues from human derived cells and the transfer of diseases. Cerezyme, manufactured by Genzyme, replaces the human lysosomal enzyme glucocerebrosidase that is lacking in individuals with Gaucher disease.Another FDA approved preparation of glucocerebrosidase called Velaglucerase alfa (trade name VPRIV) produced in a continuous human cell line is available from Shire.Elelyso (also known as Uplyso or taliglucerase alfa) by Pfizer Inc., under license from Protalix BioTherapeutics Inc., was approved by the FDA in 2012 as a treatment for Gaucher disease type 1. Elelyso is an injected long-term enzyme replacement therapy that should be administered by a health care professional every other week. It uses genetically engineered carrot cells to provide replacement glucocerebrosidase.Substrate reduction therapy may also be utilized in specific patient populations. These work differently than the ERT’s by blocking the production of glucocerebroside (fatty substance) by inhibiting the enzyme glucosylceramide synthase. These come in tablets/capsules and are taken daily. SRT’s are not to be used in children and teenagers, pregnant or breastfeeding women, elderly patients, and people with severe kidney or liver disease. The two current FDA-approved drugs include eliglustat (Cerdelga) and imiglustat (Zavesca).In 2014, Cerdelga (eliglustat), manufactured by Genzyme, was approved by the FDA for the long-term treatment of adult patients with the Gaucher disease type 1.In 2003, the U.S. Food and Drug Administration approved Zavesca, an oral therapy, for the treatment of adult patients with mild to moderate Gaucher disease type 1 for whom enzyme replacement therapy is not a treatment option (as a result of allergy, hypersensitivity, etc.).Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.There is current research at the Medical Genetics Branch of the National Human Genome Research Institute about a possible link or association between Gaucher disease and Parkinson disease. Studies have shown that affected individuals (with two disease-causing GBA gene mutations) and carriers (with a single GBA gene mutation) both have an increased risk of Parkinson disease.Individuals with Gaucher disease are at increased risk for multiple myeloma, and as adults should be monitored carefully. | Therapies of Gaucher Disease. Treatment
The main goal is to improve the patients’ quality of life by allowing them to perform their normal daily activities, such as working without feeling the excess fatigue or walking normally without experiencing joint pain. Other goals include preventing the severity of complications, such as reduced bone density to thinning, weak bones (osteoporosis) and easy fractures or shortness of breath from the reduced lung function. Normalizing the growth for a child for them to reach a normal height can also be a target within a couple of years of treatment and achieving a normal onset of puberty.Treatment is individualized for each patient depending on the type of Gaucher disease. Type 1 Gaucher disease is considered treatable and mild, because it does not involve neurological symptoms since the brain is not affected. Type 2 is not considered to be treatable at this point due to the quick and irreversible brain damage in the infantile years. Type 3 still involves neurological damage, but these symptoms progress more slowly than in type 2. There are current FDA-approved drug therapy options that include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT).Enzyme replacement therapy (ERT) has proven effective for individuals with Gaucher disease type 1. In studies of ERT, anemia and low platelet counts have improved, enlargement of the liver and spleen have been greatly reduced, and skeletal findings have improved. These systemic manifestations also improve in individuals with Gaucher disease types 2 and 3 who receive ERT. However, ERT has not been effective in reducing or reversing certain neurological symptoms associated with Gaucher disease types 2 and 3.ERT is given every 2 weeks via intravenous (IV) infusions either at infusion centers, National Gaucher Disease Treatment Center, or at home by self-administration, assistance from a family member/friend or home care nurse. The three current FDA-approved ERT drugs include imiglucerase (Cerezyme), velaglucerase alfa (VPRIV), and taliglucerase (Elelyso).The orphan drug alglucerase injection (Ceredase), which is a placenta-derived enzyme, was approved by the U.S. Food and Drug Administration (FDA) in 1991 for the treatment of Gaucher disease type 1. It was the first ERT proven effective for the treatment of Gaucher disease type 1.The synthetic form of this drug, imiglucerase (Cerezyme), was approved in 1994. Recombinant DNA technology, or genetic engineering, is used to produce Cerezyme. This was an important step in overcoming limitations of the availability of Ceredase, which is derived from human placentas. Therefore, Ceredase has been withdrawn from the market due to similar drugs being made without having bioavailability issues from human derived cells and the transfer of diseases. Cerezyme, manufactured by Genzyme, replaces the human lysosomal enzyme glucocerebrosidase that is lacking in individuals with Gaucher disease.Another FDA approved preparation of glucocerebrosidase called Velaglucerase alfa (trade name VPRIV) produced in a continuous human cell line is available from Shire.Elelyso (also known as Uplyso or taliglucerase alfa) by Pfizer Inc., under license from Protalix BioTherapeutics Inc., was approved by the FDA in 2012 as a treatment for Gaucher disease type 1. Elelyso is an injected long-term enzyme replacement therapy that should be administered by a health care professional every other week. It uses genetically engineered carrot cells to provide replacement glucocerebrosidase.Substrate reduction therapy may also be utilized in specific patient populations. These work differently than the ERT’s by blocking the production of glucocerebroside (fatty substance) by inhibiting the enzyme glucosylceramide synthase. These come in tablets/capsules and are taken daily. SRT’s are not to be used in children and teenagers, pregnant or breastfeeding women, elderly patients, and people with severe kidney or liver disease. The two current FDA-approved drugs include eliglustat (Cerdelga) and imiglustat (Zavesca).In 2014, Cerdelga (eliglustat), manufactured by Genzyme, was approved by the FDA for the long-term treatment of adult patients with the Gaucher disease type 1.In 2003, the U.S. Food and Drug Administration approved Zavesca, an oral therapy, for the treatment of adult patients with mild to moderate Gaucher disease type 1 for whom enzyme replacement therapy is not a treatment option (as a result of allergy, hypersensitivity, etc.).Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.There is current research at the Medical Genetics Branch of the National Human Genome Research Institute about a possible link or association between Gaucher disease and Parkinson disease. Studies have shown that affected individuals (with two disease-causing GBA gene mutations) and carriers (with a single GBA gene mutation) both have an increased risk of Parkinson disease.Individuals with Gaucher disease are at increased risk for multiple myeloma, and as adults should be monitored carefully. | 500 | Gaucher Disease |
nord_501_0 | Overview of General Myoclonus | Myoclonus is the term used to describe the sudden, involuntary jerking of a muscle or group of muscles caused by muscle contractions (positive myoclonus) or muscle relaxation (negative myoclonus). The twitching or jerking of muscles cannot be controlled by the person experiencing it. Myoclonic jerks may occur infrequently or many times a minute. They sometimes occur in response to an external event or when a person attempts to make a movement. By itself, myoclonus may be seen as a symptom rather than a disease. To some degree, it may occur occasionally to otherwise healthy people. (For instance, hiccups may be considered a type of myoclonus.) In severe cases, it can interfere with movement control and balance, and limit various everyday activities such as eating or talking. | Overview of General Myoclonus. Myoclonus is the term used to describe the sudden, involuntary jerking of a muscle or group of muscles caused by muscle contractions (positive myoclonus) or muscle relaxation (negative myoclonus). The twitching or jerking of muscles cannot be controlled by the person experiencing it. Myoclonic jerks may occur infrequently or many times a minute. They sometimes occur in response to an external event or when a person attempts to make a movement. By itself, myoclonus may be seen as a symptom rather than a disease. To some degree, it may occur occasionally to otherwise healthy people. (For instance, hiccups may be considered a type of myoclonus.) In severe cases, it can interfere with movement control and balance, and limit various everyday activities such as eating or talking. | 501 | General Myoclonus |
nord_501_1 | Symptoms of General Myoclonus | There are different forms of myoclonus and they are classified in different ways. One way of classifying the different forms is by their cause. Some of the types of myoclonus are:Physiologic myoclonus
This occurs in neurologically normal people. The occurrence of myoclonus during sleep and sleep transitions is the most common example.Essential myoclonus
In this type, the myoclonic jerks or twitches are usually the most prominent or only clinical finding. This type of myoclonus usually progresses slowly or not at all. There are hereditary (autosomal dominant) and non-inherited, random (sporadic) forms.Progressive myoclonus epilepsy (PME)
This is a group of diseases characterized by myoclonus, epilepsy, and other symptoms such as trouble walking or speaking. These disorders tend to get worse over time (progressive).Sleep myoclonus
This typically occurs just at the moment of dropping off to sleep. In some cases, the affected individual does not find it particularly troublesome. In other cases, it may interfere with the sleep process. Myoclonus may be a symptom in certain sleep disorders such as restless legs syndrome.Symptomatic (secondary) myoclonus
This is the most common category and usually is found in the setting of an identifiable underlying disorder. Myoclonus may not be the most prominent clinical symptom. Common co-existing problems include ataxia, dementia, and Parkinsonism. Myoclonus may also be a symptom associated with infections, non-neurologic medical illnesses, toxic-metabolic states, and storage diseases. | Symptoms of General Myoclonus. There are different forms of myoclonus and they are classified in different ways. One way of classifying the different forms is by their cause. Some of the types of myoclonus are:Physiologic myoclonus
This occurs in neurologically normal people. The occurrence of myoclonus during sleep and sleep transitions is the most common example.Essential myoclonus
In this type, the myoclonic jerks or twitches are usually the most prominent or only clinical finding. This type of myoclonus usually progresses slowly or not at all. There are hereditary (autosomal dominant) and non-inherited, random (sporadic) forms.Progressive myoclonus epilepsy (PME)
This is a group of diseases characterized by myoclonus, epilepsy, and other symptoms such as trouble walking or speaking. These disorders tend to get worse over time (progressive).Sleep myoclonus
This typically occurs just at the moment of dropping off to sleep. In some cases, the affected individual does not find it particularly troublesome. In other cases, it may interfere with the sleep process. Myoclonus may be a symptom in certain sleep disorders such as restless legs syndrome.Symptomatic (secondary) myoclonus
This is the most common category and usually is found in the setting of an identifiable underlying disorder. Myoclonus may not be the most prominent clinical symptom. Common co-existing problems include ataxia, dementia, and Parkinsonism. Myoclonus may also be a symptom associated with infections, non-neurologic medical illnesses, toxic-metabolic states, and storage diseases. | 501 | General Myoclonus |
nord_501_2 | Causes of General Myoclonus | Myoclonus is caused by an abrupt and brief discharge of motor neurons to affected muscles. In most cases, this results from a disturbance in the central nervous system, although it is believed that in rare cases may be caused by an injury to the nerves outside the central nervous system (peripheral nerves). Several different locations within the brain are thought to be involved in myoclonus. As a result, various types of testing is usually required to define the cause of myoclonus.The locations that cause myoclonus are reflected in the physiological classification of myoclonus:– Cortical (Focal or multifocal source)
– Cortical-Subcortical (e.g. Myoclonic Epilepsy)
– Subcortical/Nonsegmental
– Segmental
– PeripheralChemicals that carry messages from one nerve cell to another (neurotransmitters) may play a role. In some cases, myoclonus may be present because of an imbalance in these chemicals. However, the specific causes are not well understood at this time. | Causes of General Myoclonus. Myoclonus is caused by an abrupt and brief discharge of motor neurons to affected muscles. In most cases, this results from a disturbance in the central nervous system, although it is believed that in rare cases may be caused by an injury to the nerves outside the central nervous system (peripheral nerves). Several different locations within the brain are thought to be involved in myoclonus. As a result, various types of testing is usually required to define the cause of myoclonus.The locations that cause myoclonus are reflected in the physiological classification of myoclonus:– Cortical (Focal or multifocal source)
– Cortical-Subcortical (e.g. Myoclonic Epilepsy)
– Subcortical/Nonsegmental
– Segmental
– PeripheralChemicals that carry messages from one nerve cell to another (neurotransmitters) may play a role. In some cases, myoclonus may be present because of an imbalance in these chemicals. However, the specific causes are not well understood at this time. | 501 | General Myoclonus |
nord_501_3 | Affects of General Myoclonus | Myoclonus affects males and females in equal numbers. Some forms of myoclonus are common and some forms are rare. In general, the incidence of myoclonus is 1.3 cases per 100,000 person-years, and the prevalence is 8.6 cases per 100,000 populations. | Affects of General Myoclonus. Myoclonus affects males and females in equal numbers. Some forms of myoclonus are common and some forms are rare. In general, the incidence of myoclonus is 1.3 cases per 100,000 person-years, and the prevalence is 8.6 cases per 100,000 populations. | 501 | General Myoclonus |
nord_501_4 | Related disorders of General Myoclonus | Symptoms of the following disorders can be similar to those of myoclonus. Comparisons may be useful for a differential diagnosis:Tourette syndrome is a neurologic movement disorder that is characterized by repetitive motor and vocal tics. The first symptoms are usually rapid eye blinking or facial grimaces. Symptoms may also include facial tics and involuntary movements of the extremities, shoulders, and the voluntary muscles. Inarticulate sounds or sometimes inappropriate words may occur. Tourette syndrome is not a progressive or degenerative disorder; rather, symptoms tend to be variable and follow a chronic waxing and waning course. Symptoms usually begin before the age of 16 years. (For more information on this disorder, choose “Tourette” as your search term in the Rare Disease Database.)Jumping Frenchmen of Maine is a very rare disorder characterized by an extreme startle response. The symptoms occur as a response to sudden, unexpected noise or movement. The extreme startle reaction includes jumping, raising the arms, hitting, yelling, unintelligible speech, and/or imitation or repetition of another person's body movements (echopraxia). The intensity of the response increases with fatigue and stress. (For more information on this disorder, choose “Jumping Frenchmen of Maine” as your search term in the Rare Disease Database.)Huntington's disease (Huntington's chorea) is a rare inherited, progressively degenerative neurological disorder characterized by involuntary muscle movements and dementia. Initially there are personality changes and uncontrolled rapid jerky muscle movements. In time, speech and memory become impaired and involuntary muscle movements become more frequent and severe. As Huntington's disease progresses, there is a further loss of cognitive abilities and dementia. The symptoms of this disorder usually begin during adulthood, generally after the age of forty. (For more information on this disorder choose, “Huntington's” as your search term in the Rare Disease Database.)Torsion dystonia is a rare inherited neurological disorder characterized by involuntary contortions of the muscles in the neck, torso, arms, and legs. Occasionally only one or a few muscles are involved. People with torsion dystonia typically have an awkward, sideways gait. Other symptoms may include foot drag, cramps on the hands and feet, difficulty in grasping objects, and unclear speech. The involuntary movements of dystonia are slow writhing movements. (For more information on this disorder, choose “Torsion Dystonia” as your search term in the Rare Disease Database.)Benign essential tremor is a rare neurological disorder characterized by a rhythmical tremor that may be pronounced. This disorder typically affects the upper extremities. The tremors may be aggravated by stress, anxiety, fatigue, and/or cold temperatures. Relief from the tremors may be achieved by rest and sedation. The symptoms of benign essential tremor generally stabilize after a period of progression. (For more information on this disorder, choose “Benign Essential Tremor” as your search term in the Rare Disease Database.) | Related disorders of General Myoclonus. Symptoms of the following disorders can be similar to those of myoclonus. Comparisons may be useful for a differential diagnosis:Tourette syndrome is a neurologic movement disorder that is characterized by repetitive motor and vocal tics. The first symptoms are usually rapid eye blinking or facial grimaces. Symptoms may also include facial tics and involuntary movements of the extremities, shoulders, and the voluntary muscles. Inarticulate sounds or sometimes inappropriate words may occur. Tourette syndrome is not a progressive or degenerative disorder; rather, symptoms tend to be variable and follow a chronic waxing and waning course. Symptoms usually begin before the age of 16 years. (For more information on this disorder, choose “Tourette” as your search term in the Rare Disease Database.)Jumping Frenchmen of Maine is a very rare disorder characterized by an extreme startle response. The symptoms occur as a response to sudden, unexpected noise or movement. The extreme startle reaction includes jumping, raising the arms, hitting, yelling, unintelligible speech, and/or imitation or repetition of another person's body movements (echopraxia). The intensity of the response increases with fatigue and stress. (For more information on this disorder, choose “Jumping Frenchmen of Maine” as your search term in the Rare Disease Database.)Huntington's disease (Huntington's chorea) is a rare inherited, progressively degenerative neurological disorder characterized by involuntary muscle movements and dementia. Initially there are personality changes and uncontrolled rapid jerky muscle movements. In time, speech and memory become impaired and involuntary muscle movements become more frequent and severe. As Huntington's disease progresses, there is a further loss of cognitive abilities and dementia. The symptoms of this disorder usually begin during adulthood, generally after the age of forty. (For more information on this disorder choose, “Huntington's” as your search term in the Rare Disease Database.)Torsion dystonia is a rare inherited neurological disorder characterized by involuntary contortions of the muscles in the neck, torso, arms, and legs. Occasionally only one or a few muscles are involved. People with torsion dystonia typically have an awkward, sideways gait. Other symptoms may include foot drag, cramps on the hands and feet, difficulty in grasping objects, and unclear speech. The involuntary movements of dystonia are slow writhing movements. (For more information on this disorder, choose “Torsion Dystonia” as your search term in the Rare Disease Database.)Benign essential tremor is a rare neurological disorder characterized by a rhythmical tremor that may be pronounced. This disorder typically affects the upper extremities. The tremors may be aggravated by stress, anxiety, fatigue, and/or cold temperatures. Relief from the tremors may be achieved by rest and sedation. The symptoms of benign essential tremor generally stabilize after a period of progression. (For more information on this disorder, choose “Benign Essential Tremor” as your search term in the Rare Disease Database.) | 501 | General Myoclonus |
nord_501_5 | Diagnosis of General Myoclonus | Diagnosis of General Myoclonus. | 501 | General Myoclonus |
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nord_501_6 | Therapies of General Myoclonus | If the cause for the underlying disorder cannot be cured, then the standard treatment for myoclonus is medications that may help reduce symptoms. The first line of therapy depends on where the myoclonus originates within the nervous system (i.e. physiological classification).For cortical myoclonus (most common source), this would include levetiracetam and/or valproic acid, a type of tranquilizer, and other drugs known as benzodiazepine derivatives which include clonazepam. The beneficial effects of certain drugs, including clonazepam, may diminish over time.Many of the drugs used for myoclonus, such as barbiturates, phenytoin, and primidone, are also used to treat epilepsy. Certain of these drugs may have side effects such as sleepiness, unsteady gait (ataxia), or lethargy, and patients and their families should be aware of these beforehand.Newer therapies have been suggested for very specific types of myoclonus. Deep brain stimulation may be considered for the inherited Myoclonus-Dystonia Syndrome, a type of Subcortical/Nonsegmental myoclonus. Botulinum toxin has been tried for palatal myoclonus, a type of segmental myoclonus. Extensive physician consultation is needed before these therapies should be performed.Genetic counseling will be of benefit for patients with the inherited forms of myoclonus and their families. | Therapies of General Myoclonus. If the cause for the underlying disorder cannot be cured, then the standard treatment for myoclonus is medications that may help reduce symptoms. The first line of therapy depends on where the myoclonus originates within the nervous system (i.e. physiological classification).For cortical myoclonus (most common source), this would include levetiracetam and/or valproic acid, a type of tranquilizer, and other drugs known as benzodiazepine derivatives which include clonazepam. The beneficial effects of certain drugs, including clonazepam, may diminish over time.Many of the drugs used for myoclonus, such as barbiturates, phenytoin, and primidone, are also used to treat epilepsy. Certain of these drugs may have side effects such as sleepiness, unsteady gait (ataxia), or lethargy, and patients and their families should be aware of these beforehand.Newer therapies have been suggested for very specific types of myoclonus. Deep brain stimulation may be considered for the inherited Myoclonus-Dystonia Syndrome, a type of Subcortical/Nonsegmental myoclonus. Botulinum toxin has been tried for palatal myoclonus, a type of segmental myoclonus. Extensive physician consultation is needed before these therapies should be performed.Genetic counseling will be of benefit for patients with the inherited forms of myoclonus and their families. | 501 | General Myoclonus |
nord_502_0 | Overview of Generalized Arterial Calcification of Infancy | SummaryGeneralized arterial calcification of infancy (GACI) is a rare genetic disorder that affects the circulatory system in addition to other body systems. It occurs in approximately 1:200,000 pregnancies. GACI affects males and females equally and occurs in populations all around the world. It has an autosomal recessive inheritance pattern and usually affects infants during the first 6 months of life. There have been slightly over 200 cases documented since GACI was first described in medical literature in 1899.Symptoms of GACI include respiratory distress, arterial calcification, gastrointestinal issues, joint calcification, hearing loss, high blood pressure, stroke, reduced or absent pulses, and heart failure. GACI manifests itself differently even within families with the same genetic cause of the disease. No two people with GACI will have identical medical characteristics.GACI type 1 occurs in 75% of patients, is caused by variants in the ENPP1 gene, and is also called ENPP1 deficiency. Patients with ENPP1 deficiency are at risk of developing autosomal recessive hypophosphatemic rickets type 2 (ARHR2). ARHR2 can cause bone pain, bone deformities (knocked knees, bowed legs), dental problems, calcification of ligaments and short stature. With proper treatment the bones can be strengthened, and side effects minimized.GACI type 2 occurs in 10% of patients, is caused by variants in the ABCC6 gene, and is also called ABCC6 deficiency. As they get older, patients with ABCC6 deficiency are at risk of developing characteristics similar to pseudoxanthoma elasticum (PXE), involving the elastic tissue of the skin, the eye, cardiovascular and gastrointestinal systems.Sometimes individuals affected with GACI do not have variants in the ENPP1 or ABCC6 genes, and in those cases the cause of the disorder is unknown.Currently, there is no curative treatment for GACI and survival rates vary greatly. Treatment with bisphosphonates might lead to increased survival rates. Spontaneous regression of arterial calcifications can occur, and antihypertensive treatment can be tapered off gradually. | Overview of Generalized Arterial Calcification of Infancy. SummaryGeneralized arterial calcification of infancy (GACI) is a rare genetic disorder that affects the circulatory system in addition to other body systems. It occurs in approximately 1:200,000 pregnancies. GACI affects males and females equally and occurs in populations all around the world. It has an autosomal recessive inheritance pattern and usually affects infants during the first 6 months of life. There have been slightly over 200 cases documented since GACI was first described in medical literature in 1899.Symptoms of GACI include respiratory distress, arterial calcification, gastrointestinal issues, joint calcification, hearing loss, high blood pressure, stroke, reduced or absent pulses, and heart failure. GACI manifests itself differently even within families with the same genetic cause of the disease. No two people with GACI will have identical medical characteristics.GACI type 1 occurs in 75% of patients, is caused by variants in the ENPP1 gene, and is also called ENPP1 deficiency. Patients with ENPP1 deficiency are at risk of developing autosomal recessive hypophosphatemic rickets type 2 (ARHR2). ARHR2 can cause bone pain, bone deformities (knocked knees, bowed legs), dental problems, calcification of ligaments and short stature. With proper treatment the bones can be strengthened, and side effects minimized.GACI type 2 occurs in 10% of patients, is caused by variants in the ABCC6 gene, and is also called ABCC6 deficiency. As they get older, patients with ABCC6 deficiency are at risk of developing characteristics similar to pseudoxanthoma elasticum (PXE), involving the elastic tissue of the skin, the eye, cardiovascular and gastrointestinal systems.Sometimes individuals affected with GACI do not have variants in the ENPP1 or ABCC6 genes, and in those cases the cause of the disorder is unknown.Currently, there is no curative treatment for GACI and survival rates vary greatly. Treatment with bisphosphonates might lead to increased survival rates. Spontaneous regression of arterial calcifications can occur, and antihypertensive treatment can be tapered off gradually. | 502 | Generalized Arterial Calcification of Infancy |
nord_502_1 | Symptoms of Generalized Arterial Calcification of Infancy | Newborns with GACI may exhibit symptoms such as difficulty breathing, reduced or absent pulses, cardiomyopathy, cardiomegaly or accumulation of fluid in the extremities (edema). They may struggle with heart failure or high blood pressure (hypertension). Newborns with GACI may also present with feeding difficulties, irritability or failure to thrive. On ultrasound or echocardiograph, the condition is characterized by calcification of the arteries or the valves of the heart accompanied by thickening of the lining of the arteries (intima).Calcification in blood vessels may cause arterial stiffness/hardening, therefore making pulses faint or absent altogether.Infants with GACI may suffer from gastrointestinal complications such as inflammation of the wall of the small intestine or obstruction due to stenosis. Infants with gastrointestinal complications may present with irritability and/or bloody stool. The gastrointestinal complications tend to go away as the child grows.In nearly 50% of cases, babies are diagnosed soon after birth due to these symptoms. In other babies, GACI is recognized later, usually around 1-6 months of age after gradual or persisting symptoms.Joint calcifications are seen in roughly 30% of babies with GACI. These calcifications are frequently seen in the hip, ankle, wrist, shoulder, elbow, knee, foot and sternoclavicular (SC) joint.Many patients with GACI type 1 go on to develop a rare form of rickets known as autosomal recessive hypophosphatemic rickets type 2 (ARHR2). This can result in bone and joint pain, bone deformities, calcification of ligaments and short stature.Individuals with GACI are at risk for developing hearing loss. The hearing loss can be conductive, sensorineural, or mixed and can present as early as infancy. The hearing loss might be caused by calcification of the arteries supplying the inner ear, immobility of the ear bone (stapedovestibular ankylosis) and/or abnormal remodeling of small bones (ossicles) in the middle ear.Older patients with GACI may go on to develop symptoms of pseudoxanthoma elasticum (PXE). PXE is a disorder that causes select elastic tissue in the body to become mineralized due to calcium and other minerals being deposited in the tissue. This can result in changes in the skin and eyes. The changes to the skin frequently present on the neck, underarms, inside of the elbows, the groin and behind the knees. It may resemble a rash or have a cobblestone appearance. Another complication is the possible development of angioid streaks in the eye. Angioid streaks are small breaks in Bruch’s membrane, an elastic tissue between the retina and underlying blood vessels, that may become calcified and crack.Patients with GACI frequently present with dental issues such as teeth that don’t fully erupt (infraocclusion), over-retained primary teeth, ankylosis, slow orthodontic movement and excessive build-up of normal cementum on the roots of the teeth. | Symptoms of Generalized Arterial Calcification of Infancy. Newborns with GACI may exhibit symptoms such as difficulty breathing, reduced or absent pulses, cardiomyopathy, cardiomegaly or accumulation of fluid in the extremities (edema). They may struggle with heart failure or high blood pressure (hypertension). Newborns with GACI may also present with feeding difficulties, irritability or failure to thrive. On ultrasound or echocardiograph, the condition is characterized by calcification of the arteries or the valves of the heart accompanied by thickening of the lining of the arteries (intima).Calcification in blood vessels may cause arterial stiffness/hardening, therefore making pulses faint or absent altogether.Infants with GACI may suffer from gastrointestinal complications such as inflammation of the wall of the small intestine or obstruction due to stenosis. Infants with gastrointestinal complications may present with irritability and/or bloody stool. The gastrointestinal complications tend to go away as the child grows.In nearly 50% of cases, babies are diagnosed soon after birth due to these symptoms. In other babies, GACI is recognized later, usually around 1-6 months of age after gradual or persisting symptoms.Joint calcifications are seen in roughly 30% of babies with GACI. These calcifications are frequently seen in the hip, ankle, wrist, shoulder, elbow, knee, foot and sternoclavicular (SC) joint.Many patients with GACI type 1 go on to develop a rare form of rickets known as autosomal recessive hypophosphatemic rickets type 2 (ARHR2). This can result in bone and joint pain, bone deformities, calcification of ligaments and short stature.Individuals with GACI are at risk for developing hearing loss. The hearing loss can be conductive, sensorineural, or mixed and can present as early as infancy. The hearing loss might be caused by calcification of the arteries supplying the inner ear, immobility of the ear bone (stapedovestibular ankylosis) and/or abnormal remodeling of small bones (ossicles) in the middle ear.Older patients with GACI may go on to develop symptoms of pseudoxanthoma elasticum (PXE). PXE is a disorder that causes select elastic tissue in the body to become mineralized due to calcium and other minerals being deposited in the tissue. This can result in changes in the skin and eyes. The changes to the skin frequently present on the neck, underarms, inside of the elbows, the groin and behind the knees. It may resemble a rash or have a cobblestone appearance. Another complication is the possible development of angioid streaks in the eye. Angioid streaks are small breaks in Bruch’s membrane, an elastic tissue between the retina and underlying blood vessels, that may become calcified and crack.Patients with GACI frequently present with dental issues such as teeth that don’t fully erupt (infraocclusion), over-retained primary teeth, ankylosis, slow orthodontic movement and excessive build-up of normal cementum on the roots of the teeth. | 502 | Generalized Arterial Calcification of Infancy |
nord_502_2 | Causes of Generalized Arterial Calcification of Infancy | In 2003 it was discovered that variants in the ENPP1 gene were the cause of approximately 75% of cases of GACI. The ENPP1 gene provides the instructions for making a protein that helps to break down a molecule called adenosine triphosphate (ATP), when it is found outside the cell (extracellular). Extracellular ATP is broken down into adenosine monophosphate (AMP) and pyrophosphate (PPi). Variants in the ENPP1 gene result in low levels of pyrophosphate. Pyrophosphate is important in controlling calcification and other mineralization in the body. Low pyrophosphate levels allow calcification to develop in the arteries. Low AMP levels lead to narrowing of the blood vessels, with restriction of blood flow.In 2008, variants in the ABCC6 gene were identified as a cause of GACI in approximately 10% of patients. The ABCC6 gene provides instructions for making a protein called MRP6 (ABCC6 protein). Variants in the ABCC6 gene lead to non-functional or absent MRP6 protein. Although not proven, some researchers think that the lack of MRP6 protein impedes the release of ATP from cells and as a result pyrophosphate production is limited.There are rare cases where patients with GACI do not have variants in either the ENPP1 or ABCC6 gene. Therefore, it is thought that there may still be at least one other unknown gene that could be responsible for causing GACI in patients, or that variants in one of the two known genes were missed by the sequencing technology.GACI 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 of having 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 Generalized Arterial Calcification of Infancy. In 2003 it was discovered that variants in the ENPP1 gene were the cause of approximately 75% of cases of GACI. The ENPP1 gene provides the instructions for making a protein that helps to break down a molecule called adenosine triphosphate (ATP), when it is found outside the cell (extracellular). Extracellular ATP is broken down into adenosine monophosphate (AMP) and pyrophosphate (PPi). Variants in the ENPP1 gene result in low levels of pyrophosphate. Pyrophosphate is important in controlling calcification and other mineralization in the body. Low pyrophosphate levels allow calcification to develop in the arteries. Low AMP levels lead to narrowing of the blood vessels, with restriction of blood flow.In 2008, variants in the ABCC6 gene were identified as a cause of GACI in approximately 10% of patients. The ABCC6 gene provides instructions for making a protein called MRP6 (ABCC6 protein). Variants in the ABCC6 gene lead to non-functional or absent MRP6 protein. Although not proven, some researchers think that the lack of MRP6 protein impedes the release of ATP from cells and as a result pyrophosphate production is limited.There are rare cases where patients with GACI do not have variants in either the ENPP1 or ABCC6 gene. Therefore, it is thought that there may still be at least one other unknown gene that could be responsible for causing GACI in patients, or that variants in one of the two known genes were missed by the sequencing technology.GACI 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 of having 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. | 502 | Generalized Arterial Calcification of Infancy |
nord_502_3 | Affects of Generalized Arterial Calcification of Infancy | GACI affects males and females equally and occurs in populations all across the world. There have been slightly over 200 cases documented since GACI was first described in the medical literature in 1899. It is estimated to occur in approximately 1 out of every 200,000 pregnancies with the carrier rate being 1:223. Survival statistics vary greatly but are currently estimated at around 50%.GACI usually affects infants during the first 6 months of life, but mild cases may go undiagnosed until later in life, when other complications of the condition lead to a diagnosis. | Affects of Generalized Arterial Calcification of Infancy. GACI affects males and females equally and occurs in populations all across the world. There have been slightly over 200 cases documented since GACI was first described in the medical literature in 1899. It is estimated to occur in approximately 1 out of every 200,000 pregnancies with the carrier rate being 1:223. Survival statistics vary greatly but are currently estimated at around 50%.GACI usually affects infants during the first 6 months of life, but mild cases may go undiagnosed until later in life, when other complications of the condition lead to a diagnosis. | 502 | Generalized Arterial Calcification of Infancy |
nord_502_4 | Related disorders of Generalized Arterial Calcification of Infancy | Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a very rare disease typically caused by variants in the ENPP1 gene. It is also a component of ENPP1 deficiency. Patients with ARHR2 suffer from low phosphate levels in the blood (hypophosphatemia) as a result of renal phosphate wasting. The correct balance of phosphate is essential for the normal formation of teeth and bones. The frequency of the disease is unknown. (For more information on this condition, search for “ARHR2” in the Rare Disease Database.)Pseudoxanthoma elasticum (PXE) is an inherited disorder caused by variants in the ABCC6 gene that affects connective tissue in some parts of the body. Elastic tissue in the body becomes mineralized; that is, calcium is deposited in the tissue. This can result in changes in the skin, eyes, cardiovascular system, and gastrointestinal system. Clinicians first recognized PXE more than 100 years ago. Researchers have made a number of significant advances in the past few years. (For more information on this condition, search for “PXE” in the Rare Disease Database.) | Related disorders of Generalized Arterial Calcification of Infancy. Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a very rare disease typically caused by variants in the ENPP1 gene. It is also a component of ENPP1 deficiency. Patients with ARHR2 suffer from low phosphate levels in the blood (hypophosphatemia) as a result of renal phosphate wasting. The correct balance of phosphate is essential for the normal formation of teeth and bones. The frequency of the disease is unknown. (For more information on this condition, search for “ARHR2” in the Rare Disease Database.)Pseudoxanthoma elasticum (PXE) is an inherited disorder caused by variants in the ABCC6 gene that affects connective tissue in some parts of the body. Elastic tissue in the body becomes mineralized; that is, calcium is deposited in the tissue. This can result in changes in the skin, eyes, cardiovascular system, and gastrointestinal system. Clinicians first recognized PXE more than 100 years ago. Researchers have made a number of significant advances in the past few years. (For more information on this condition, search for “PXE” in the Rare Disease Database.) | 502 | Generalized Arterial Calcification of Infancy |
nord_502_5 | Diagnosis of Generalized Arterial Calcification of Infancy | GACI should always be considered in infants and children presenting with hypertension, cardiac failure or sudden death. Ultrasonography can aid in the diagnosis. The preferred imaging modality to assess calcifications extension is whole-body computed tomography (CT) scan combined with CT angiography.Prenatal diagnosis has been reported and an ultrasound may reveal polyhydramnios (excess amniotic fluid), pericardial effusion (fluid around the heart) or echogenicity (brightness) of the major arteries, abnormal cardiac contractility, hydrops or hyperechoic kidneys.To confirm a GACI diagnosis the baby (and parents) may be genetically tested for variants in the ENPP1 or ABCC6 genes. Prenatal genetic testing for GACI can be confirmed through an amniocentesis or chorionic villus sampling (CVS) if the specific gene variants in the parents have been determined.Medical Monitoring
Newborn babies with GACI are closely observed and are usually hospitalized in the neonatal intensive care unit (NICU).Ongoing monitoring of GACI includes ultrasounds, echocardiograms, electrocardiogram (EKG/ECG’s), CT scans, X-rays, regular blood pressure measurements, checking pulses in all extremities, frequent lab and urine tests and hearing tests. | Diagnosis of Generalized Arterial Calcification of Infancy. GACI should always be considered in infants and children presenting with hypertension, cardiac failure or sudden death. Ultrasonography can aid in the diagnosis. The preferred imaging modality to assess calcifications extension is whole-body computed tomography (CT) scan combined with CT angiography.Prenatal diagnosis has been reported and an ultrasound may reveal polyhydramnios (excess amniotic fluid), pericardial effusion (fluid around the heart) or echogenicity (brightness) of the major arteries, abnormal cardiac contractility, hydrops or hyperechoic kidneys.To confirm a GACI diagnosis the baby (and parents) may be genetically tested for variants in the ENPP1 or ABCC6 genes. Prenatal genetic testing for GACI can be confirmed through an amniocentesis or chorionic villus sampling (CVS) if the specific gene variants in the parents have been determined.Medical Monitoring
Newborn babies with GACI are closely observed and are usually hospitalized in the neonatal intensive care unit (NICU).Ongoing monitoring of GACI includes ultrasounds, echocardiograms, electrocardiogram (EKG/ECG’s), CT scans, X-rays, regular blood pressure measurements, checking pulses in all extremities, frequent lab and urine tests and hearing tests. | 502 | Generalized Arterial Calcification of Infancy |
nord_502_6 | Therapies of Generalized Arterial Calcification of Infancy | Treatment
Currently, there is no curative treatment for GACI. Use of certain bisphosphonates appears to increase survival rates. Prenatal and postnatal treatment with bisphosphonates resulted in complete resolution of vascular calcifications in some patients; of note, complete resolution has also been noted in patients who never received treatment with bisphosphonates.Sodium thiosulfate (STS) is a calcium-chelating agent typically used by patients who have excess calcium in their arteries due to kidney disease. In recent years, STS has also been used anecdotally to treat patients with GACI. STS is typically administered intravenously through a central line in the chest.PGE1 infusion was successfully used in one baby with GACI complicated by severe hypertension refractory to conventional treatment.Infants must reach a certain weight to allow for a transplant. There is some clinical evidence that heart transplants can be successful, without recurrence of calcifications. Heart transplant for individuals with GACI has occurred in at least three known cases.Patients with GACI are usually followed by a team of specialists which may include cardiology, endocrinology, nephrology, orthopedics, physical therapy, dental, audiology, and ophthalmology. | Therapies of Generalized Arterial Calcification of Infancy. Treatment
Currently, there is no curative treatment for GACI. Use of certain bisphosphonates appears to increase survival rates. Prenatal and postnatal treatment with bisphosphonates resulted in complete resolution of vascular calcifications in some patients; of note, complete resolution has also been noted in patients who never received treatment with bisphosphonates.Sodium thiosulfate (STS) is a calcium-chelating agent typically used by patients who have excess calcium in their arteries due to kidney disease. In recent years, STS has also been used anecdotally to treat patients with GACI. STS is typically administered intravenously through a central line in the chest.PGE1 infusion was successfully used in one baby with GACI complicated by severe hypertension refractory to conventional treatment.Infants must reach a certain weight to allow for a transplant. There is some clinical evidence that heart transplants can be successful, without recurrence of calcifications. Heart transplant for individuals with GACI has occurred in at least three known cases.Patients with GACI are usually followed by a team of specialists which may include cardiology, endocrinology, nephrology, orthopedics, physical therapy, dental, audiology, and ophthalmology. | 502 | Generalized Arterial Calcification of Infancy |
nord_503_0 | Overview of Geographic Tongue Disease | Geographic tongue is a benign condition characterized by inflammation of the tongue (glossitis) that appears in a map-like (geographic) pattern. The normal tongue is covered by a layer of small bumps known as papillae. In affected individuals, certain areas of the tongue are missing these bumps. These affected areas usually appear as smooth, red or pink colored, degenerated (atrophic) patches. Geographic tongue tends to come and go it usually heals without treatment, but will recur again usually affecting a different area of the tongue. Most cases are not associated with any symptoms (asymptomatic) and the condition usually goes away without treatment. Geographic tongue is not associated with any long-term health complications in healthy individuals. The exact cause of geographic tongue is unknown. | Overview of Geographic Tongue Disease. Geographic tongue is a benign condition characterized by inflammation of the tongue (glossitis) that appears in a map-like (geographic) pattern. The normal tongue is covered by a layer of small bumps known as papillae. In affected individuals, certain areas of the tongue are missing these bumps. These affected areas usually appear as smooth, red or pink colored, degenerated (atrophic) patches. Geographic tongue tends to come and go it usually heals without treatment, but will recur again usually affecting a different area of the tongue. Most cases are not associated with any symptoms (asymptomatic) and the condition usually goes away without treatment. Geographic tongue is not associated with any long-term health complications in healthy individuals. The exact cause of geographic tongue is unknown. | 503 | Geographic Tongue Disease |
nord_503_1 | Symptoms of Geographic Tongue Disease | In many cases, geographic tongue does not cause symptoms (asymptomatic). Symptoms that have been reported in association with geographic tongue include general discomfort of the tongue or mouth and soreness or a burning sensation of the tongue, which is often worsened by spicy or acidic foods.The characteristic lesion in geographic tongue is reddish (erythematous), degenerated (atrophic) patch or area on the tongue that is abnormally smooth because of the lack of the small bumps that normally cover the tongue. These patches may have a slightly elevated, yellowish or white border. These patches cover the tongue in an irregular pattern giving the tongue a characteristic map-like appearance. The patches may change in size, shape and location from day to day.In some cases, pain may occur or the lymph nodes under the lower jaw (submandibular lymph nodes) may become enlarged. In rare cases, pain or discomfort may be persistent. Pain typically arises from acidic foods that burn the lesions. Avoiding acidic drinks and foods will help alleviate the discomfort.When these lesions affect areas in the mouth other than the tongue, the condition may be referred to as another name such as erythema migrans or geographic stomatitis. Such sites include the mucous membrane lining the inside of the cheek (buccal mucosa), the floor of the mouth, the roof of the mouth, and the gums (gingiva). | Symptoms of Geographic Tongue Disease. In many cases, geographic tongue does not cause symptoms (asymptomatic). Symptoms that have been reported in association with geographic tongue include general discomfort of the tongue or mouth and soreness or a burning sensation of the tongue, which is often worsened by spicy or acidic foods.The characteristic lesion in geographic tongue is reddish (erythematous), degenerated (atrophic) patch or area on the tongue that is abnormally smooth because of the lack of the small bumps that normally cover the tongue. These patches may have a slightly elevated, yellowish or white border. These patches cover the tongue in an irregular pattern giving the tongue a characteristic map-like appearance. The patches may change in size, shape and location from day to day.In some cases, pain may occur or the lymph nodes under the lower jaw (submandibular lymph nodes) may become enlarged. In rare cases, pain or discomfort may be persistent. Pain typically arises from acidic foods that burn the lesions. Avoiding acidic drinks and foods will help alleviate the discomfort.When these lesions affect areas in the mouth other than the tongue, the condition may be referred to as another name such as erythema migrans or geographic stomatitis. Such sites include the mucous membrane lining the inside of the cheek (buccal mucosa), the floor of the mouth, the roof of the mouth, and the gums (gingiva). | 503 | Geographic Tongue Disease |
nord_503_2 | Causes of Geographic Tongue Disease | The exact cause of geographic tongue is unknown. The condition often runs in families suggesting that genetics may play a role in the development of the disorder. Geographic tongue is often associated with a fissured tongue, a condition with a strong genetic link further suggesting that heredity plays a significant role in the development of geographic tongue.A fissured tongue is a benign condition that is characterized by numerous shallow or deep grooves or furrows (fissures) on the back (dorsal) surface of the tongue. The surface furrows may differ in size and depth, radiate outward, and cause the tongue to have a wrinkled appearance.In addition to fissured tongue, geographic tongue has been associated with many other conditions especially psoriasis. Psoriasis a chronic, inflammatory skin disease characterized by dry, reddish (erythematous), thickened patches of skin that are covered with silvery-gray scales. These patches may be referred to as papules or plaques and most often affect the scalp, elbows, knees, hands, feet and/or lower back.Additional conditions with that may occur in conjunction with geographic tongue include allergies, emotional stress, juvenile diabetes, Reiter’s syndrome and hormonal disturbances. However, no definitive link has been established between geographic tongue and any of these conditions. | Causes of Geographic Tongue Disease. The exact cause of geographic tongue is unknown. The condition often runs in families suggesting that genetics may play a role in the development of the disorder. Geographic tongue is often associated with a fissured tongue, a condition with a strong genetic link further suggesting that heredity plays a significant role in the development of geographic tongue.A fissured tongue is a benign condition that is characterized by numerous shallow or deep grooves or furrows (fissures) on the back (dorsal) surface of the tongue. The surface furrows may differ in size and depth, radiate outward, and cause the tongue to have a wrinkled appearance.In addition to fissured tongue, geographic tongue has been associated with many other conditions especially psoriasis. Psoriasis a chronic, inflammatory skin disease characterized by dry, reddish (erythematous), thickened patches of skin that are covered with silvery-gray scales. These patches may be referred to as papules or plaques and most often affect the scalp, elbows, knees, hands, feet and/or lower back.Additional conditions with that may occur in conjunction with geographic tongue include allergies, emotional stress, juvenile diabetes, Reiter’s syndrome and hormonal disturbances. However, no definitive link has been established between geographic tongue and any of these conditions. | 503 | Geographic Tongue Disease |
nord_503_3 | Affects of Geographic Tongue Disease | Some reports in the medical literature suggest that geographic tongue affects females slightly more often than males. It appears to occur with greater frequency in young adults. The prevalence of geographic tongue is unknown, but it is estimated to occur in approximately 1-3 percent of the general population. | Affects of Geographic Tongue Disease. Some reports in the medical literature suggest that geographic tongue affects females slightly more often than males. It appears to occur with greater frequency in young adults. The prevalence of geographic tongue is unknown, but it is estimated to occur in approximately 1-3 percent of the general population. | 503 | Geographic Tongue Disease |
nord_503_4 | Related disorders of Geographic Tongue Disease | Symptoms of the following disorders can be similar to those of geographic tongue. Comparisons may be useful for a differential diagnosis.A variety of conditions can affect the tongue including infection with a harmless type of yeast (oral candidiasis), burning mouth syndrome, an inflammatory condition characterized, in part, by gray-white spots in the mouth (lichen planus) and oral cancers. Tongue cancer is a general term for two types of cancer – one that affects the portion of the tongue that can protrude from the mouth and one that affects the base of the tongue in the back of mouth. The first form is classified as a mouth (or oral) cancer and the second form is classified as an oropharyngeal cancer. Oropharyngeal cancer refers to cancer that occurs in areas of the throat near the back of the mouth. Geographic tongue is not related to oral cancers and is not a premalignant condition. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Geographic Tongue Disease. Symptoms of the following disorders can be similar to those of geographic tongue. Comparisons may be useful for a differential diagnosis.A variety of conditions can affect the tongue including infection with a harmless type of yeast (oral candidiasis), burning mouth syndrome, an inflammatory condition characterized, in part, by gray-white spots in the mouth (lichen planus) and oral cancers. Tongue cancer is a general term for two types of cancer – one that affects the portion of the tongue that can protrude from the mouth and one that affects the base of the tongue in the back of mouth. The first form is classified as a mouth (or oral) cancer and the second form is classified as an oropharyngeal cancer. Oropharyngeal cancer refers to cancer that occurs in areas of the throat near the back of the mouth. Geographic tongue is not related to oral cancers and is not a premalignant condition. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 503 | Geographic Tongue Disease |
nord_503_5 | Diagnosis of Geographic Tongue Disease | A diagnosis of geographic tongue is made based upon a thorough clinical evaluation, a detailed patient history and the characteristic appearance of the tongue lesions associated with this disorder. In most cases, surgical removal and microscopic study (biopsy) of affected tissue is not necessary because of the distinct appearance of the tongue. | Diagnosis of Geographic Tongue Disease. A diagnosis of geographic tongue is made based upon a thorough clinical evaluation, a detailed patient history and the characteristic appearance of the tongue lesions associated with this disorder. In most cases, surgical removal and microscopic study (biopsy) of affected tissue is not necessary because of the distinct appearance of the tongue. | 503 | Geographic Tongue Disease |
nord_503_6 | Therapies of Geographic Tongue Disease | TreatmentMedical treatment is not required for this benign disorder. Some physicians advise patients to avoid irritants and substances that may sensitize the tongue. A bland or liquid diet, preferably cooled, is perhaps better. Meticulous oral hygiene is important, but care should be taken to preserve proper bacterial balance within the mouth.If pain or discomfort is persistent, some physicians may recommend anti-inflammatory drugs or numbing agents that are applied directly to the affected areas (topical analgesics). | Therapies of Geographic Tongue Disease. TreatmentMedical treatment is not required for this benign disorder. Some physicians advise patients to avoid irritants and substances that may sensitize the tongue. A bland or liquid diet, preferably cooled, is perhaps better. Meticulous oral hygiene is important, but care should be taken to preserve proper bacterial balance within the mouth.If pain or discomfort is persistent, some physicians may recommend anti-inflammatory drugs or numbing agents that are applied directly to the affected areas (topical analgesics). | 503 | Geographic Tongue Disease |
nord_504_0 | Overview of Gerstmann Syndrome | Gerstmann syndrome is a rare neurological disorder that can occur as the result of a brain injury or as a developmental disorder. The syndrome is characterized by the loss or absence of four cognitive abilities- the loss of the ability to express thoughts in writing (agraphia, dysgraphia), to perform simple arithmetic problems (acalculia), to recognize or indicate one's own or another's fingers (finger agnosia), and to distinguish between the right and left sides of one's body. Additional cognitive defects may occur in some cases.The disorder has not been found to run in families. In extremely rare cases, children who are bright and functioning intellectually at a high level may be affected by the disorder as well as those who suffer brain damage.Gerstmann syndrome is different from Gerstmann-Sträussler-Scheinker syndrome, a rare genetic degenerative brain disorder. | Overview of Gerstmann Syndrome. Gerstmann syndrome is a rare neurological disorder that can occur as the result of a brain injury or as a developmental disorder. The syndrome is characterized by the loss or absence of four cognitive abilities- the loss of the ability to express thoughts in writing (agraphia, dysgraphia), to perform simple arithmetic problems (acalculia), to recognize or indicate one's own or another's fingers (finger agnosia), and to distinguish between the right and left sides of one's body. Additional cognitive defects may occur in some cases.The disorder has not been found to run in families. In extremely rare cases, children who are bright and functioning intellectually at a high level may be affected by the disorder as well as those who suffer brain damage.Gerstmann syndrome is different from Gerstmann-Sträussler-Scheinker syndrome, a rare genetic degenerative brain disorder. | 504 | Gerstmann Syndrome |
nord_504_1 | Symptoms of Gerstmann Syndrome | Gerstmann syndrome is a rare disorder characterized by the loss of four specific neurological functions: Inability to write (dysgraphia or agraphia), the loss of the ability to do mathematics (acalculia), the inability to identify one's own or another's fingers (finger agnosia), and inability to make the distinction between the right and left side of the body. It is very rare for a person with learning disabilities to have all four of these neurologic dysfunctions. Only when all four symptoms appear together without mental retardation is the classic syndrome present.When affected individuals have all four of the characteristic symptoms of Gerstmann syndrome without other cognitive defects, the condition may be referred to as “pure” Gerstmann syndrome. However affected individuals usually have other defects in addition to the classic four findings of Gerstmann syndrome. In addition, many individuals have only two or three of the four key findings in combination with other types of cognitive defects. In such cases in addition to the four classical symptoms, affected individuals may also have difficulty expressing themselves through speech, and/or difficulty understanding another person's speech (aphasia). They may experience difficulty in reading and spelling as well. A few cases have been reported in children and called developmental Gerstmann syndrome. These cases usually become apparent when children begin school. Affected children may demonstrate poor handwriting, spelling and math skills (e.g., difficulty adding, subtracting, dividing and multiplying). Some children have difficulty reading or understanding written words (alexia) and difficulty copying or tracing simple objects (constructional apraxia). Some researchers suggest that developmental Gerstmann syndrome is not a true, unique syndrome, but rather a group of symptoms caused by another, underlying disorder. | Symptoms of Gerstmann Syndrome. Gerstmann syndrome is a rare disorder characterized by the loss of four specific neurological functions: Inability to write (dysgraphia or agraphia), the loss of the ability to do mathematics (acalculia), the inability to identify one's own or another's fingers (finger agnosia), and inability to make the distinction between the right and left side of the body. It is very rare for a person with learning disabilities to have all four of these neurologic dysfunctions. Only when all four symptoms appear together without mental retardation is the classic syndrome present.When affected individuals have all four of the characteristic symptoms of Gerstmann syndrome without other cognitive defects, the condition may be referred to as “pure” Gerstmann syndrome. However affected individuals usually have other defects in addition to the classic four findings of Gerstmann syndrome. In addition, many individuals have only two or three of the four key findings in combination with other types of cognitive defects. In such cases in addition to the four classical symptoms, affected individuals may also have difficulty expressing themselves through speech, and/or difficulty understanding another person's speech (aphasia). They may experience difficulty in reading and spelling as well. A few cases have been reported in children and called developmental Gerstmann syndrome. These cases usually become apparent when children begin school. Affected children may demonstrate poor handwriting, spelling and math skills (e.g., difficulty adding, subtracting, dividing and multiplying). Some children have difficulty reading or understanding written words (alexia) and difficulty copying or tracing simple objects (constructional apraxia). Some researchers suggest that developmental Gerstmann syndrome is not a true, unique syndrome, but rather a group of symptoms caused by another, underlying disorder. | 504 | Gerstmann Syndrome |
nord_504_2 | Causes of Gerstmann Syndrome | In adults, the syndrome can arise in adults as a result of impaired blood flow to the brain (cerebrovascular disease) such as a stroke or other damage to the brain. The parietal lobes (upper side lobes) of the brain are affected in Gerstmann syndrome. The parietal lobes are involved with sensation and perception as well as understanding sensory input. In rare cases, traumatic brain injury or a brain tumor in the same region of the brain can cause the various symptoms associated with Gerstmann syndrome. The cause of Gerstmann syndrome in children is often unknown. Although in some cases it may be linked to brain damage, children without brain damage can also be affected. | Causes of Gerstmann Syndrome. In adults, the syndrome can arise in adults as a result of impaired blood flow to the brain (cerebrovascular disease) such as a stroke or other damage to the brain. The parietal lobes (upper side lobes) of the brain are affected in Gerstmann syndrome. The parietal lobes are involved with sensation and perception as well as understanding sensory input. In rare cases, traumatic brain injury or a brain tumor in the same region of the brain can cause the various symptoms associated with Gerstmann syndrome. The cause of Gerstmann syndrome in children is often unknown. Although in some cases it may be linked to brain damage, children without brain damage can also be affected. | 504 | Gerstmann Syndrome |
nord_504_3 | Affects of Gerstmann Syndrome | Gerstmann syndrome affects males and females in equal numbers. The incidence of Gerstmann syndrome in the general population is unknown. The disorder was first described by Dr. Josef Gerstmann, a Viennese neurologist, in 1924. | Affects of Gerstmann Syndrome. Gerstmann syndrome affects males and females in equal numbers. The incidence of Gerstmann syndrome in the general population is unknown. The disorder was first described by Dr. Josef Gerstmann, a Viennese neurologist, in 1924. | 504 | Gerstmann Syndrome |
nord_504_4 | Related disorders of Gerstmann Syndrome | Symptoms of the following disorders can be similar to those of Gerstmann syndrome. Comparisons may be useful for a differential diagnosis:Alzheimer disease is a progressive condition of the brain that affects memory, thought, and language. The degenerative changes of Alzheimer disease lead to patches or plaques in the brain and the entanglement of nerve fibers (neurofibrillary tangles). Memory loss and behavioral changes occur as a result of these changes in brain tissue. The characteristic findings associated with Gerstmann syndrome can occur due to Alzheimer disease. (For more information on this disorder, choose “Alzheimer's” as your search term in the Rare Disease Database). Additional disorders may cause brain dysfunction and could potentially cause the four characteristic findings associated with Gerstmann syndrome. These characteristic findings have also been seen in alcoholics, lupus, carbon monoxide poisoning, and lead poisoning. | Related disorders of Gerstmann Syndrome. Symptoms of the following disorders can be similar to those of Gerstmann syndrome. Comparisons may be useful for a differential diagnosis:Alzheimer disease is a progressive condition of the brain that affects memory, thought, and language. The degenerative changes of Alzheimer disease lead to patches or plaques in the brain and the entanglement of nerve fibers (neurofibrillary tangles). Memory loss and behavioral changes occur as a result of these changes in brain tissue. The characteristic findings associated with Gerstmann syndrome can occur due to Alzheimer disease. (For more information on this disorder, choose “Alzheimer's” as your search term in the Rare Disease Database). Additional disorders may cause brain dysfunction and could potentially cause the four characteristic findings associated with Gerstmann syndrome. These characteristic findings have also been seen in alcoholics, lupus, carbon monoxide poisoning, and lead poisoning. | 504 | Gerstmann Syndrome |
nord_504_5 | Diagnosis of Gerstmann Syndrome | The presence in the adult of all four neurological symptoms suggests a diagnosis of Gerstmann syndrome, especially when other causes of these symptoms are ruled out. Among children, most cases are recognized at school age when the affected person has difficulty in math and writing. Affected children may also have problems in spelling, performing the basic four mathematical calculations, and distinguishing left from right. Also, they generally fail the finger identification test. Many, but not all such children will find it difficult to copy simple drawings (constructional apraxia). | Diagnosis of Gerstmann Syndrome. The presence in the adult of all four neurological symptoms suggests a diagnosis of Gerstmann syndrome, especially when other causes of these symptoms are ruled out. Among children, most cases are recognized at school age when the affected person has difficulty in math and writing. Affected children may also have problems in spelling, performing the basic four mathematical calculations, and distinguishing left from right. Also, they generally fail the finger identification test. Many, but not all such children will find it difficult to copy simple drawings (constructional apraxia). | 504 | Gerstmann Syndrome |
nord_504_6 | Therapies of Gerstmann Syndrome | TreatmentTreatment of Gerstmann syndrome in developmental cases will involve special education and related rehabilitation and counseling services. Neurological examination is necessary to tell the difference between the two causes of the condition. In adults, treatment of the underlying neurological condition is necessary. When brain injury or tumor is involved, surgery may be used to alleviate the condition. In some cases, the symptoms affecting adults with Gerstmann syndrome diminish over time. | Therapies of Gerstmann Syndrome. TreatmentTreatment of Gerstmann syndrome in developmental cases will involve special education and related rehabilitation and counseling services. Neurological examination is necessary to tell the difference between the two causes of the condition. In adults, treatment of the underlying neurological condition is necessary. When brain injury or tumor is involved, surgery may be used to alleviate the condition. In some cases, the symptoms affecting adults with Gerstmann syndrome diminish over time. | 504 | Gerstmann Syndrome |
nord_505_0 | Overview of Gerstmann-Sträussler-Scheinker Disease | Gerstmann-Sträussler-Scheinker (GSS) disease is a rare genetic degenerative brain disorder. The symptoms, the progression of the disorder, and the overall severity can vary greatly among affected families and individuals. This is true even among members of the same family. A common symptom is a progressive loss of coordination that may present as unsteadiness of gait, difficulty walking, and clumsiness. As the disease progresses, other symptoms become apparent including dementia, in which there are worsening problems with thought, cognition, memory, language, and behavior. In all instances, GSS is caused by an abnormal variant of the prion protein (PRPN) gene. The PRNP gene encodes the human prion protein (PrPc). Alterations in this gene lead to the generation of abnormally-shaped (misfolded) prion protein (PrPSc), also known simply as a “prion”, which is toxic to the body. In GSS, the abnormal prions build up primarily within the brain. This leads to the progressive loss of nerve cells (neurons) and the various symptoms associated with this disorder. The disorder most often affects people in their 40s through 50s. There is no cure, but investigators are researching ways to best treat and manage GSS.IntroductionGSS is classified as a transmissible spongiform encephalopathy (TSE) or a prion disease. Prion diseases are caused by the accumulation of misfolded prion protein in the brain. Two other prion diseases, Creutzfeldt-Jakob disease (CJD) and fatal familial insomnia (FFI), may also occur as a result of variations of the PRNP gene, although some prion diseases occur in the absence of a genetic variation. Generally, prion disorders are characterized by long incubation periods and short clinical duration, which means the abnormal prions may be build up for many years (long incubation period), but once symptoms begin the disorder rapidly worsens. | Overview of Gerstmann-Sträussler-Scheinker Disease. Gerstmann-Sträussler-Scheinker (GSS) disease is a rare genetic degenerative brain disorder. The symptoms, the progression of the disorder, and the overall severity can vary greatly among affected families and individuals. This is true even among members of the same family. A common symptom is a progressive loss of coordination that may present as unsteadiness of gait, difficulty walking, and clumsiness. As the disease progresses, other symptoms become apparent including dementia, in which there are worsening problems with thought, cognition, memory, language, and behavior. In all instances, GSS is caused by an abnormal variant of the prion protein (PRPN) gene. The PRNP gene encodes the human prion protein (PrPc). Alterations in this gene lead to the generation of abnormally-shaped (misfolded) prion protein (PrPSc), also known simply as a “prion”, which is toxic to the body. In GSS, the abnormal prions build up primarily within the brain. This leads to the progressive loss of nerve cells (neurons) and the various symptoms associated with this disorder. The disorder most often affects people in their 40s through 50s. There is no cure, but investigators are researching ways to best treat and manage GSS.IntroductionGSS is classified as a transmissible spongiform encephalopathy (TSE) or a prion disease. Prion diseases are caused by the accumulation of misfolded prion protein in the brain. Two other prion diseases, Creutzfeldt-Jakob disease (CJD) and fatal familial insomnia (FFI), may also occur as a result of variations of the PRNP gene, although some prion diseases occur in the absence of a genetic variation. Generally, prion disorders are characterized by long incubation periods and short clinical duration, which means the abnormal prions may be build up for many years (long incubation period), but once symptoms begin the disorder rapidly worsens. | 505 | Gerstmann-Sträussler-Scheinker Disease |
nord_505_1 | Symptoms of Gerstmann-Sträussler-Scheinker Disease | The initial symptoms associated with Gerstmann-Sträussler-Scheinker disease are progressive loss of coordination and mild difficulty with speech (dysarthria). Loss of coordination may present as unsteadiness, difficulty walking, and clumsiness. Affected may have problems coordinating voluntary movements (ataxia). Speech problems may present as slurred speech and progress to severe dysarthria in which people have difficulty speaking and other people have difficulties understanding what they are trying to say. There may be problems with swallowing (dysphagia) due to lack of coordination of the muscles needed for swallowing.Additional early signs include diminished reflexes (hyporeflexia), progressive weakness in the legs, and a sensation of burning, tingling or discomfort under the skin (dysesthesia). As the disorder progresses, affected individuals develop a condition called spasticity. Spasticity is characterized by rigid muscle tone and progressive muscle stiffness and weakness, causing abnormal, writhing movements, abnormal slowness of movement (bradykinesia). Some affected individuals exhibit a reduced degree of facial expression called hypomimia or masked facies. Hypomimia means that affected individuals are often do not show much expression or emotion. Some affected individuals develop rapid, involuntary eye movements (nystagmus) and have difficulties judging distance or scale (ocular dysmetria), and problems with vision. Sometimes, eye problems can progress to blindness. Less commonly, hearing loss or deafness will develop. Additional symptoms that sometimes occur include seizures, paralysis (palsy) of certain cranial nerves, and movements disorders like jerky, muscle spasms (myoclonus) or slow, writhing, involuntary movements (athetosis).Eventually, affected individual develop problems with cognition, which is thinking, remembering, reasoning, imagining and processing thoughts. Concentration and focus are particularly affected, and some individuals exhibit slowness of thought processing (bradyphrenia). As the disease progresses, other symptoms become apparent including dementia, in which there are worsening problems with thought, cognition, memory, language, and behavior. Initially, the signs may be subtle and include unintended weight loss, forgetfulness, inattentiveness, problems concentrating, or speech problems. Episodes of confusion or hallucinations can eventually occur. GSS causes slowly progressive physical and mental deterioration, although more rapid progression can occur. Eventually, affected individuals become bedridden, unable to eat unassisted, and unable to communicate. The disease ultimately progresses to coma and death. | Symptoms of Gerstmann-Sträussler-Scheinker Disease. The initial symptoms associated with Gerstmann-Sträussler-Scheinker disease are progressive loss of coordination and mild difficulty with speech (dysarthria). Loss of coordination may present as unsteadiness, difficulty walking, and clumsiness. Affected may have problems coordinating voluntary movements (ataxia). Speech problems may present as slurred speech and progress to severe dysarthria in which people have difficulty speaking and other people have difficulties understanding what they are trying to say. There may be problems with swallowing (dysphagia) due to lack of coordination of the muscles needed for swallowing.Additional early signs include diminished reflexes (hyporeflexia), progressive weakness in the legs, and a sensation of burning, tingling or discomfort under the skin (dysesthesia). As the disorder progresses, affected individuals develop a condition called spasticity. Spasticity is characterized by rigid muscle tone and progressive muscle stiffness and weakness, causing abnormal, writhing movements, abnormal slowness of movement (bradykinesia). Some affected individuals exhibit a reduced degree of facial expression called hypomimia or masked facies. Hypomimia means that affected individuals are often do not show much expression or emotion. Some affected individuals develop rapid, involuntary eye movements (nystagmus) and have difficulties judging distance or scale (ocular dysmetria), and problems with vision. Sometimes, eye problems can progress to blindness. Less commonly, hearing loss or deafness will develop. Additional symptoms that sometimes occur include seizures, paralysis (palsy) of certain cranial nerves, and movements disorders like jerky, muscle spasms (myoclonus) or slow, writhing, involuntary movements (athetosis).Eventually, affected individual develop problems with cognition, which is thinking, remembering, reasoning, imagining and processing thoughts. Concentration and focus are particularly affected, and some individuals exhibit slowness of thought processing (bradyphrenia). As the disease progresses, other symptoms become apparent including dementia, in which there are worsening problems with thought, cognition, memory, language, and behavior. Initially, the signs may be subtle and include unintended weight loss, forgetfulness, inattentiveness, problems concentrating, or speech problems. Episodes of confusion or hallucinations can eventually occur. GSS causes slowly progressive physical and mental deterioration, although more rapid progression can occur. Eventually, affected individuals become bedridden, unable to eat unassisted, and unable to communicate. The disease ultimately progresses to coma and death. | 505 | Gerstmann-Sträussler-Scheinker Disease |
nord_505_2 | Causes of Gerstmann-Sträussler-Scheinker Disease | GSS is caused by an abnormal variant (gene mutation) of the PRNP gene. Genes provide instructions for encoding proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. In rare instances, the change (variation) in the PRPN gene in individuals with GSS occurs spontaneously, without a family history of the disease. This is called a new or de novo variant. The gene variation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. However, the person who has this de novo variant could pass on the variant gene to their offspring in an autosomal dominant manner. Researchers believe that GSS is associated with almost complete penetrance, which means that virtually all individuals who have a disease-causing variation in the PRPN gene will eventually develop signs and symptoms of the disorder. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a dominant pattern occur when only a single copy of an abnormal gene is necessary for the appearance of the disorder. The abnormal gene can be inherited from either parent, or it can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.The PRNP gene encodes for a protein called prion protein, a cellular variant or PrPc. The exact function of PrPc in the body is not fully understood. However, because of the variant gene, the PrPSc that is produced develops an abnormal 3-dimensional shape that is described simply as “misfolded”. The misfolded PrPSc is toxic to the body, especially cells of the nervous system. In GSS, misfolded PrPSc is found in many brain structures, mostly the cerebellum and also in the thalamus, which is a structure deep within the brain that helps to regulate many functions of the body including sleep, appetite, and body temperature. As the misfolded PrPSc builds up, it results in a progressive destruction of nerve cells (neurons), which leads to the symptoms of the disorder. The damage to brain tissue may appear as sponge-like cavities or spaces (vacuoles) when examined under a microscope, which is why prion diseases like GSS are called transmissible spongiform encephalopathies. The term “prion” was coined to designate a “proteinaceous infectious agent” to explain the protein-only nature of the infectious agent. Extensive research has shown that a prion is essentially the misfolded PrPSc. However, it is important to know that GSS is not contagious in the traditional sense because the only way to transmit prion disease to a healthy individual is through direct exposure to disease-affected brain tissue, for instance by injection. If a person without an underlying genetic defect develops a prion disease by transmission from another prion disease, they are said to have an ‘acquired’ form. For example, variant Creutzfeldt-Jakob disease occurred in the United Kingdom when people ate prion-contaminated beef. A lesser known example is kuru. Kuru is a virtually extinct prion disease that occurred in the Fore people of Papua New Guinea. The disease spread throughout this population because of the villagers’ practice of eating the brains of deceased kuru-affected tribesmen (ritualistic cannibalism). Investigators have determined that the PRNP gene is located on the short arm (p) of chromosome 20 (20p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. | Causes of Gerstmann-Sträussler-Scheinker Disease. GSS is caused by an abnormal variant (gene mutation) of the PRNP gene. Genes provide instructions for encoding proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. In rare instances, the change (variation) in the PRPN gene in individuals with GSS occurs spontaneously, without a family history of the disease. This is called a new or de novo variant. The gene variation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. However, the person who has this de novo variant could pass on the variant gene to their offspring in an autosomal dominant manner. Researchers believe that GSS is associated with almost complete penetrance, which means that virtually all individuals who have a disease-causing variation in the PRPN gene will eventually develop signs and symptoms of the disorder. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a dominant pattern occur when only a single copy of an abnormal gene is necessary for the appearance of the disorder. The abnormal gene can be inherited from either parent, or it can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.The PRNP gene encodes for a protein called prion protein, a cellular variant or PrPc. The exact function of PrPc in the body is not fully understood. However, because of the variant gene, the PrPSc that is produced develops an abnormal 3-dimensional shape that is described simply as “misfolded”. The misfolded PrPSc is toxic to the body, especially cells of the nervous system. In GSS, misfolded PrPSc is found in many brain structures, mostly the cerebellum and also in the thalamus, which is a structure deep within the brain that helps to regulate many functions of the body including sleep, appetite, and body temperature. As the misfolded PrPSc builds up, it results in a progressive destruction of nerve cells (neurons), which leads to the symptoms of the disorder. The damage to brain tissue may appear as sponge-like cavities or spaces (vacuoles) when examined under a microscope, which is why prion diseases like GSS are called transmissible spongiform encephalopathies. The term “prion” was coined to designate a “proteinaceous infectious agent” to explain the protein-only nature of the infectious agent. Extensive research has shown that a prion is essentially the misfolded PrPSc. However, it is important to know that GSS is not contagious in the traditional sense because the only way to transmit prion disease to a healthy individual is through direct exposure to disease-affected brain tissue, for instance by injection. If a person without an underlying genetic defect develops a prion disease by transmission from another prion disease, they are said to have an ‘acquired’ form. For example, variant Creutzfeldt-Jakob disease occurred in the United Kingdom when people ate prion-contaminated beef. A lesser known example is kuru. Kuru is a virtually extinct prion disease that occurred in the Fore people of Papua New Guinea. The disease spread throughout this population because of the villagers’ practice of eating the brains of deceased kuru-affected tribesmen (ritualistic cannibalism). Investigators have determined that the PRNP gene is located on the short arm (p) of chromosome 20 (20p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. | 505 | Gerstmann-Sträussler-Scheinker Disease |
nord_505_3 | Affects of Gerstmann-Sträussler-Scheinker Disease | The exact incidence or prevalence of GSS is unknown. Estimates range from 1 to 10 in 100,000,000 people in the general population. CJD affects about 1 in 1,000,000 people in the general population per year. Genetic prion diseases are believed to make up about 15% of all individuals with prion diseases. Because rare diseases often go undiagnosed or misdiagnosed, it is difficult to determine their true frequency in the general population. GSS affects men and women in equal numbers. The average age of onset is 35-50 years old, the youngest describe occurrence was in a 10-year-old child. | Affects of Gerstmann-Sträussler-Scheinker Disease. The exact incidence or prevalence of GSS is unknown. Estimates range from 1 to 10 in 100,000,000 people in the general population. CJD affects about 1 in 1,000,000 people in the general population per year. Genetic prion diseases are believed to make up about 15% of all individuals with prion diseases. Because rare diseases often go undiagnosed or misdiagnosed, it is difficult to determine their true frequency in the general population. GSS affects men and women in equal numbers. The average age of onset is 35-50 years old, the youngest describe occurrence was in a 10-year-old child. | 505 | Gerstmann-Sträussler-Scheinker Disease |
nord_505_4 | Related disorders of Gerstmann-Sträussler-Scheinker Disease | Symptoms of the following disorders can be similar to those of GSS. Comparisons may be useful for a differential diagnosis.Other prion disorders may have symptoms similar to those seen in GSS. There are four major additional prion diseases that have been identified affecting humans. These include kuru, familial fatal insomnia, variant Creutzfeldt-Jakob disease, and Creutzfeldt-Jakob disease. These disorders are characterized by nerve cell (neuron) loss and damage to the brain. Prion diseases also affect animals including bovine spongiform encephalopathy (mad cow disease) in cows and scrapie in sheep, goats and mufflons. Very interesting and spreading rapidly is chronic wasting disease (CWD) in mule deer, elk and rain deer (the last in Norway). Variant Creutzfeldt-Jakob disease has been acquired from eating beef contaminated with the abnormal prions that cause bovine spongiform encephalopathy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Frontotemporal degeneration is a group of varied disorders that are characterized by neurodegenerative changes that affect the brain. The clinical presentation of frontotemporal degeneration is diverse. Affected individuals can experience gradual changes in their behavior and personality, and they may have difficulties in thinking and communicating effectively. The progression and the specific symptoms that develop can vary from one person to another. Generally, the clinical symptoms of these disorders can be broadly grouped into three categories which display changes in behavior, language and/or motor function. Frontotemporal degeneration is caused by progressive damage and loss of nerve cells in the frontal and temporal lobes of the brain. In most people, this is accompanied by a buildup of one or the other of two proteins, tau or TDP-43. In FTD these proteins are misfolded, which leads to their inappropriate buildup within brain cells and eventual disruption of the normal function of these cells. The FTD clinical subtypes can also be classified as ‘tauopathies’ or TDP43-opathies, depending on which misfolded protein accumulates in the brain. In about 10% of cases, a third protein, FUS, accumulates instead of tau or TDP43. The accumulation of tau protein or TDP-43 protein can also be observed in other neurological disorders. (For more information on this disorder, choose “frontotemporal dementia” as your search term in the Rare Disease Database.)Alzheimer’s disease is a progressive condition of the brain that affects memory, thought, and language. The degenerative changes of Alzheimer’s disease consist of plaques, or clumps, of misfolded protein in the brain and the accumulation of misfolded protein inside the neuron (neurofibrillary tangles composed of tau). Memory loss and behavioral changes occur as a result of these protein accumulations in brain tissue. Alzheimer’s disease is usually a slow progressive illness that is more common over the age of 65, in contrast to the frontotemporal degeneration, which is more common in midlife and under age 65. Difficulty with short-term memory is usually the first symptom and early behavioral changes may not be noticed. As the disease progresses, memory loss increases and there are changes in personality, mood and behavior. Disturbances of judgment and concentration occur, along with confusion and restlessness. The type, severity, sequence, and progression of mental changes vary widely. Long periods with little change are common, although occasionally the disease can be rapidly progressive. (For more information on this disorder, choose “Alzheimer” as your search term in the Rare Disease Database.)Additional disorders can cause signs and symptoms similar to those seen in prion diseases like GSS including Huntington disease, progressive supranuclear palsy, dementia with Lewy Bodies, corticobasal degeneration, Hashimoto encephalopathy, paraneoplastic syndromes, and multiple system atrophy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Gerstmann-Sträussler-Scheinker Disease. Symptoms of the following disorders can be similar to those of GSS. Comparisons may be useful for a differential diagnosis.Other prion disorders may have symptoms similar to those seen in GSS. There are four major additional prion diseases that have been identified affecting humans. These include kuru, familial fatal insomnia, variant Creutzfeldt-Jakob disease, and Creutzfeldt-Jakob disease. These disorders are characterized by nerve cell (neuron) loss and damage to the brain. Prion diseases also affect animals including bovine spongiform encephalopathy (mad cow disease) in cows and scrapie in sheep, goats and mufflons. Very interesting and spreading rapidly is chronic wasting disease (CWD) in mule deer, elk and rain deer (the last in Norway). Variant Creutzfeldt-Jakob disease has been acquired from eating beef contaminated with the abnormal prions that cause bovine spongiform encephalopathy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Frontotemporal degeneration is a group of varied disorders that are characterized by neurodegenerative changes that affect the brain. The clinical presentation of frontotemporal degeneration is diverse. Affected individuals can experience gradual changes in their behavior and personality, and they may have difficulties in thinking and communicating effectively. The progression and the specific symptoms that develop can vary from one person to another. Generally, the clinical symptoms of these disorders can be broadly grouped into three categories which display changes in behavior, language and/or motor function. Frontotemporal degeneration is caused by progressive damage and loss of nerve cells in the frontal and temporal lobes of the brain. In most people, this is accompanied by a buildup of one or the other of two proteins, tau or TDP-43. In FTD these proteins are misfolded, which leads to their inappropriate buildup within brain cells and eventual disruption of the normal function of these cells. The FTD clinical subtypes can also be classified as ‘tauopathies’ or TDP43-opathies, depending on which misfolded protein accumulates in the brain. In about 10% of cases, a third protein, FUS, accumulates instead of tau or TDP43. The accumulation of tau protein or TDP-43 protein can also be observed in other neurological disorders. (For more information on this disorder, choose “frontotemporal dementia” as your search term in the Rare Disease Database.)Alzheimer’s disease is a progressive condition of the brain that affects memory, thought, and language. The degenerative changes of Alzheimer’s disease consist of plaques, or clumps, of misfolded protein in the brain and the accumulation of misfolded protein inside the neuron (neurofibrillary tangles composed of tau). Memory loss and behavioral changes occur as a result of these protein accumulations in brain tissue. Alzheimer’s disease is usually a slow progressive illness that is more common over the age of 65, in contrast to the frontotemporal degeneration, which is more common in midlife and under age 65. Difficulty with short-term memory is usually the first symptom and early behavioral changes may not be noticed. As the disease progresses, memory loss increases and there are changes in personality, mood and behavior. Disturbances of judgment and concentration occur, along with confusion and restlessness. The type, severity, sequence, and progression of mental changes vary widely. Long periods with little change are common, although occasionally the disease can be rapidly progressive. (For more information on this disorder, choose “Alzheimer” as your search term in the Rare Disease Database.)Additional disorders can cause signs and symptoms similar to those seen in prion diseases like GSS including Huntington disease, progressive supranuclear palsy, dementia with Lewy Bodies, corticobasal degeneration, Hashimoto encephalopathy, paraneoplastic syndromes, and multiple system atrophy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 505 | Gerstmann-Sträussler-Scheinker Disease |
nord_505_5 | Diagnosis of Gerstmann-Sträussler-Scheinker Disease | A diagnosis of GSS is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis of GSS cannot be confirmed through laboratory tests or imaging studies. Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect an abnormal variant in the PRPN gene known to cause the disorder, but such testing is available only as a diagnostic service at specialized laboratories.Physicians may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain and may show changes in brain function and slowing of background activity. An EEG can also be used to help to detect seizures. Advanced imaging techniques include computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be conducted. CT scanning is not useful in the diagnosis of GSS or prion disease, while the MRI can show some abnormalities in the scan that may support prion disease, although its application to diagnose GSS is not well characterized. However, MRI and CT may be helpful in ruling out other conditions that may mimic GSS or prion disease. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and body tissues.Single photon emission computed tomography (SPECT) is a specialized form of CT scanning that may show reduced blood flow in the brain in some individuals GSS, particularly early in the disease. SPECT is able to show how blood flows to tissues and organs. SPECT uses a radioactive material called a tracer. This chemical tracer is injected into the body and emits gamma rays that are recorded by the computer. Sometimes, this test can demonstrate slow or inadequate flow of blood through blood vessels (hypoperfusion), potentially resulting in decreased blood flow resulting in oxygen and nutrients. | Diagnosis of Gerstmann-Sträussler-Scheinker Disease. A diagnosis of GSS is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis of GSS cannot be confirmed through laboratory tests or imaging studies. Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect an abnormal variant in the PRPN gene known to cause the disorder, but such testing is available only as a diagnostic service at specialized laboratories.Physicians may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain and may show changes in brain function and slowing of background activity. An EEG can also be used to help to detect seizures. Advanced imaging techniques include computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may be conducted. CT scanning is not useful in the diagnosis of GSS or prion disease, while the MRI can show some abnormalities in the scan that may support prion disease, although its application to diagnose GSS is not well characterized. However, MRI and CT may be helpful in ruling out other conditions that may mimic GSS or prion disease. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and body tissues.Single photon emission computed tomography (SPECT) is a specialized form of CT scanning that may show reduced blood flow in the brain in some individuals GSS, particularly early in the disease. SPECT is able to show how blood flows to tissues and organs. SPECT uses a radioactive material called a tracer. This chemical tracer is injected into the body and emits gamma rays that are recorded by the computer. Sometimes, this test can demonstrate slow or inadequate flow of blood through blood vessels (hypoperfusion), potentially resulting in decreased blood flow resulting in oxygen and nutrients. | 505 | Gerstmann-Sträussler-Scheinker Disease |
nord_505_6 | Therapies of Gerstmann-Sträussler-Scheinker Disease | Treatment
The treatment of GSS is directed toward the management of specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, psychiatrists, psychologists, pain specialists, social workers and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with GSS. Affected individuals may receive standard treatments for any associated symptoms. Antiseizure medications, known as anti-epileptics or anti-convulsants, may be prescribed for seizures. A drug called clonazepam may be used to treat myoclonus. If swallowing problems be severe enough, families can consider the option a feeding tube. A feeding tube is a device that is inserted through a small surgical cut in the abdominal wall directly into the stomach. This ensures that affected individuals receive sufficient calories and nutrients. | Therapies of Gerstmann-Sträussler-Scheinker Disease. Treatment
The treatment of GSS is directed toward the management of specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, psychiatrists, psychologists, pain specialists, social workers and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with GSS. Affected individuals may receive standard treatments for any associated symptoms. Antiseizure medications, known as anti-epileptics or anti-convulsants, may be prescribed for seizures. A drug called clonazepam may be used to treat myoclonus. If swallowing problems be severe enough, families can consider the option a feeding tube. A feeding tube is a device that is inserted through a small surgical cut in the abdominal wall directly into the stomach. This ensures that affected individuals receive sufficient calories and nutrients. | 505 | Gerstmann-Sträussler-Scheinker Disease |
nord_506_0 | Overview of Gestational Trophoblastic Disease | SummaryThe gestational trophoblastic diseases (GTDs) are a complex family of disorders. The term GTD is a general one, used to describe any of the group of diagnoses that behave out of character from what is expected of gestational trophoblastic tissue. The term GTD refers to both benign and malignant conditions. Gestational trophoblastic neoplasia (GTN) refers more specifically to malignant disease.GTDs all arise from trophoblast cells. Trophoblasts are the population of cells responsi-ble for the formation of the placenta, a temporary but essential organ responsible for both the delivery of nutrients to and removal of waste from the growing fetus. It is important to note that GTDs can arise in the context of both normal pregnancy or ‘molar pregnancy’. A molar pregnancy is one in which an ovum or sperm combine to form a genetically non-viable zygote (single-celled precursor to the fetus and placenta). In this discussion, molar pregnancy will be described in detail as it serves as the precursor to the majority of GTDs that develop.The products of conception in a molar pregnancy (the non-viable embryo and placental tissue) are described as a hydatiform mole. Hydatiform moles can be farther described as being ‘complete’ or ‘partial’. Hydatiform moles are distinct according to their several characteristics. They differ in their genetics, content of recognizable fetal components, propensity for co-morbid features, and propensity to progress to malignant disease. Malignant GTNs known to arise from hydatiform moles include the ‘invasive mole’ and choriocarcinoma. Two additional entities that arise from trophoblastic cells but which arise independently from molar pregnancy include the placental site trophoblastic tumors and epithelioid trophoblastic tumors. All of these entities are discussed in detail below. Finally, there are a series of trophoblastic cell deriveatives that will also be described, but only in brief, as their significance to patient care is unclear. This includes the benign placental site nodule and exaggerated placental site.IntroductionHydatiform MolesA molar pregnancy describes the fertilization event of a genetically non-viable ovum by sperm. The normal ovum and sperm both carry one-half of the genetic information required for a normal conception. Their fusion forms the zygote. The normal zygote is the single resultant cell that carries the full set of genetic material required for the development of a fetus. The DNA that the ovum and sperm contribute are equal in content but not function. The healthy zygote requires one half of its DNA to be from the ovum and the sperm. A zygote is non-viable in the case where there is, for example, a duplication of one half set. When there is an abnormal genetic contribution from either the ovum or the sperm, a hydatiform mole has formed. The hydatiform mole will mimic the developmental stages of a normal pregnancy. It will implant into the uterine cavity and begin to grow. The woman’s body will feel as she would in a normal pregnancy. The discussion on differentiating between a normal and a molar pregnancy is discussed in subsequent sections below.An important distinction to be made about the hydatiform moles is that their growth is contained within the uterine cavity. The benign hydatiform mole carries a risk to develop into malignant disease but is not in of itself malignant. The risk for the formation of malignancy is related to the type of hydatiform mole, whether it is partial or complete. The differences between a complete and partial hydatiform mole, are based on their genetic make-up. The genetic make-up of the zygote at the time of fertilization depends on the genetics of the ovum and sperm involved.The cells of the human body typically carry a ’diploid’ genotype of 46 chromosomes, half from the individual’s mother and half from their father. The normal set of chromosomes is described as either a 46XX or 46XY genotype. A complete mole carries a 46XX or 46XY genotype and in this way is seemingly similar to the genotype that the normal zygote carries. However, despite the normal number of DNA copies, there exists severe epigenetic abnormalities given that the source of the DNA is not derived evenly from the maternal ovum and paternal sperm. Ninety percent of complete moles result from the duplication of a sperm that fertilizes an “empty” ovum, wherein maternal chro-mosomes are absent or inactive. The other ten percent of complete molar pregnancies are due to fertilization of an empty ovum by two different sperm. A partial mole generally carries ‘triploid’ genotype, described as XXX or XXY. The partial mole results from the fertilization of a normal ovum by two sperm.Invasive MoleThe invasive mole is the malignant counterpart to the partial and complete hydatiform moles previously described. This entity is defined by the capacity to invade beyond the endometrial layer of the uterus where a normal pregnancy resides. Most often the invasive mole is seen extending into the vagina, vulva, or peritoneum (abdominal cavity). While this entity is locally destructive, it generally is limited to the region and does not carry the capacity to metastasize to distant locations such as the lungs. The invasive mole is to the hydatiform moles in terms of its histology, its appearance microscopically. Invasive moles demonstrate numerous minute projections along their surface. These projections are called villi. These villi are a structural analog to the normal placenta, where they serve as the contact surface between the maternal blood supply and that of the fetus. Other entities in the family of GTDs do not demonstrate these villi.ChoriocarcinomaThe normal placenta is formed by two cell populations, the cytotrophoblasts and syncytiotrophoblasts. The cytotrophoblasts form a layer over which syncytiotrophoblasts lay. Both two cell populations are essential in the process of implanting an embryo into the maternal uterine wall and in establishing the proper supply of blood and nutrients to the embryo. The invasion process however should be self-limiting to the endometrial layer of the uterus. When a mass of these cytotrophoblast and syncytiotrophoblast cell populations form a mass that retains the ability to invade surrounding tissue and metastasize to distant locations in the body, such as the lungs, they have formed a choriocarcinoma. On a cellular level, the choriocarcinoma also differs from the invasive mole due to the loss of previously described villi.Rare Trophoblastic Tumor VariantsPlacental site trophoblastic tumors (PSTT) and epithelioid trophoblastic tumors (ETT) are two additional entities that can arise from the aforementioned family of tropho-blastic cells. Specifically, these entities arise from ‘intermediate trophoblasts’. The in-termediate trophoblasts generally serve to anchor the placenta into the uterus. The intermediate trophoblasts can be described by location, which is associated with subtle differences in cell characteristics. The PSTT arises from intermediate trophoblasts at the villous (uterine) surface. The ETT arises from intermediate trophoblasts at the chorinic (fetal) surface. | Overview of Gestational Trophoblastic Disease. SummaryThe gestational trophoblastic diseases (GTDs) are a complex family of disorders. The term GTD is a general one, used to describe any of the group of diagnoses that behave out of character from what is expected of gestational trophoblastic tissue. The term GTD refers to both benign and malignant conditions. Gestational trophoblastic neoplasia (GTN) refers more specifically to malignant disease.GTDs all arise from trophoblast cells. Trophoblasts are the population of cells responsi-ble for the formation of the placenta, a temporary but essential organ responsible for both the delivery of nutrients to and removal of waste from the growing fetus. It is important to note that GTDs can arise in the context of both normal pregnancy or ‘molar pregnancy’. A molar pregnancy is one in which an ovum or sperm combine to form a genetically non-viable zygote (single-celled precursor to the fetus and placenta). In this discussion, molar pregnancy will be described in detail as it serves as the precursor to the majority of GTDs that develop.The products of conception in a molar pregnancy (the non-viable embryo and placental tissue) are described as a hydatiform mole. Hydatiform moles can be farther described as being ‘complete’ or ‘partial’. Hydatiform moles are distinct according to their several characteristics. They differ in their genetics, content of recognizable fetal components, propensity for co-morbid features, and propensity to progress to malignant disease. Malignant GTNs known to arise from hydatiform moles include the ‘invasive mole’ and choriocarcinoma. Two additional entities that arise from trophoblastic cells but which arise independently from molar pregnancy include the placental site trophoblastic tumors and epithelioid trophoblastic tumors. All of these entities are discussed in detail below. Finally, there are a series of trophoblastic cell deriveatives that will also be described, but only in brief, as their significance to patient care is unclear. This includes the benign placental site nodule and exaggerated placental site.IntroductionHydatiform MolesA molar pregnancy describes the fertilization event of a genetically non-viable ovum by sperm. The normal ovum and sperm both carry one-half of the genetic information required for a normal conception. Their fusion forms the zygote. The normal zygote is the single resultant cell that carries the full set of genetic material required for the development of a fetus. The DNA that the ovum and sperm contribute are equal in content but not function. The healthy zygote requires one half of its DNA to be from the ovum and the sperm. A zygote is non-viable in the case where there is, for example, a duplication of one half set. When there is an abnormal genetic contribution from either the ovum or the sperm, a hydatiform mole has formed. The hydatiform mole will mimic the developmental stages of a normal pregnancy. It will implant into the uterine cavity and begin to grow. The woman’s body will feel as she would in a normal pregnancy. The discussion on differentiating between a normal and a molar pregnancy is discussed in subsequent sections below.An important distinction to be made about the hydatiform moles is that their growth is contained within the uterine cavity. The benign hydatiform mole carries a risk to develop into malignant disease but is not in of itself malignant. The risk for the formation of malignancy is related to the type of hydatiform mole, whether it is partial or complete. The differences between a complete and partial hydatiform mole, are based on their genetic make-up. The genetic make-up of the zygote at the time of fertilization depends on the genetics of the ovum and sperm involved.The cells of the human body typically carry a ’diploid’ genotype of 46 chromosomes, half from the individual’s mother and half from their father. The normal set of chromosomes is described as either a 46XX or 46XY genotype. A complete mole carries a 46XX or 46XY genotype and in this way is seemingly similar to the genotype that the normal zygote carries. However, despite the normal number of DNA copies, there exists severe epigenetic abnormalities given that the source of the DNA is not derived evenly from the maternal ovum and paternal sperm. Ninety percent of complete moles result from the duplication of a sperm that fertilizes an “empty” ovum, wherein maternal chro-mosomes are absent or inactive. The other ten percent of complete molar pregnancies are due to fertilization of an empty ovum by two different sperm. A partial mole generally carries ‘triploid’ genotype, described as XXX or XXY. The partial mole results from the fertilization of a normal ovum by two sperm.Invasive MoleThe invasive mole is the malignant counterpart to the partial and complete hydatiform moles previously described. This entity is defined by the capacity to invade beyond the endometrial layer of the uterus where a normal pregnancy resides. Most often the invasive mole is seen extending into the vagina, vulva, or peritoneum (abdominal cavity). While this entity is locally destructive, it generally is limited to the region and does not carry the capacity to metastasize to distant locations such as the lungs. The invasive mole is to the hydatiform moles in terms of its histology, its appearance microscopically. Invasive moles demonstrate numerous minute projections along their surface. These projections are called villi. These villi are a structural analog to the normal placenta, where they serve as the contact surface between the maternal blood supply and that of the fetus. Other entities in the family of GTDs do not demonstrate these villi.ChoriocarcinomaThe normal placenta is formed by two cell populations, the cytotrophoblasts and syncytiotrophoblasts. The cytotrophoblasts form a layer over which syncytiotrophoblasts lay. Both two cell populations are essential in the process of implanting an embryo into the maternal uterine wall and in establishing the proper supply of blood and nutrients to the embryo. The invasion process however should be self-limiting to the endometrial layer of the uterus. When a mass of these cytotrophoblast and syncytiotrophoblast cell populations form a mass that retains the ability to invade surrounding tissue and metastasize to distant locations in the body, such as the lungs, they have formed a choriocarcinoma. On a cellular level, the choriocarcinoma also differs from the invasive mole due to the loss of previously described villi.Rare Trophoblastic Tumor VariantsPlacental site trophoblastic tumors (PSTT) and epithelioid trophoblastic tumors (ETT) are two additional entities that can arise from the aforementioned family of tropho-blastic cells. Specifically, these entities arise from ‘intermediate trophoblasts’. The in-termediate trophoblasts generally serve to anchor the placenta into the uterus. The intermediate trophoblasts can be described by location, which is associated with subtle differences in cell characteristics. The PSTT arises from intermediate trophoblasts at the villous (uterine) surface. The ETT arises from intermediate trophoblasts at the chorinic (fetal) surface. | 506 | Gestational Trophoblastic Disease |
nord_506_1 | Symptoms of Gestational Trophoblastic Disease | Hydatiform MolesWhile molar pregnancy represents a non-viable fertilization event, women may feel like they would in a normal, healthy pregnancy and come to the physician with a positive pregnancy test. Women may also present with complaints of passing heavy clots, even tissue from the vagina, mimicking a spontaneous abortion. Overall, the presentation of a partial molar pregnancy is different from that of a complete molar pregnancy. A partial hydatiform mole usually presents with a small uterus compared to the expected size for a given gestational age. On ultrasound, there will be an abnormal placenta with large cystic spaces, said to resemble Swiss cheese, a small amount amniotic fluid, and potentially shocking and upsetting: fetal parts, even an entire fetus. In the case that there is a formed fetus it is important to note that it is usually very growth restricted and at high risk for birth defects.A complete hydatiform mole usually presents with a large uterus compared to the expected size for a given gestational age. On ultrasound, there will be no embryo, fetus, or amniotic fluid. There will be an abnormal placenta with small cystic spaces, said to resemble a snowstorm. When a complete molar pregnancy presents with the passage of tissue from the vagina, the tissue is said to resemble large grape-like masses with a ‘prune-juice’ discharge. Finally, complete hydatiform moles are also associated with ovarian theca lutein cysts, pre-eclampsia, and hyperthyroidism. Theca lutein cysts form from overstimulation by circulating hormones produced by the complete hydatiform mole and can cause abdominal pains as they rupture or bleed. Pre-eclampsia is a disorder characterized by new onset hypertension. Patients might experience headaches over the back of their head that does not respond to medication, stars in their field of vision, pain in the right upper portion of the abdomen under the ribs, shortness of breath, and swelling in the face, arms, or legs. Hyperthyroidism can present with intolerance to heat, hair and skin changes, weight loss, and palpitations. Any of these symptoms should prompt an immediate follow-up visit with the doctor.Malignancy (Invasive Moles, Choriocarcinoma, Placental Site Trophoblastic Tumor, Ep-ithelioid Trophoblstic Tumor)The GTNs can be subtle entities in terms of clinical presentation. The physician must keep these on the differential as a cause of common complaints including vaginal bleeding, uterine size discordant to gestation age, pelvic pain, hyperemesis, and miscarriage.In dramatic clinical presentation of metastatic choriocarcinoma, patients present with symptoms based on the affected organ system. For example, metastasis to the lungs may be associated with hemoptysis, a bloody cough. Metastasis to the brain may present with seizure.Generally, these entities are identified in the follow-up of molar pregnancies as described later below. | Symptoms of Gestational Trophoblastic Disease. Hydatiform MolesWhile molar pregnancy represents a non-viable fertilization event, women may feel like they would in a normal, healthy pregnancy and come to the physician with a positive pregnancy test. Women may also present with complaints of passing heavy clots, even tissue from the vagina, mimicking a spontaneous abortion. Overall, the presentation of a partial molar pregnancy is different from that of a complete molar pregnancy. A partial hydatiform mole usually presents with a small uterus compared to the expected size for a given gestational age. On ultrasound, there will be an abnormal placenta with large cystic spaces, said to resemble Swiss cheese, a small amount amniotic fluid, and potentially shocking and upsetting: fetal parts, even an entire fetus. In the case that there is a formed fetus it is important to note that it is usually very growth restricted and at high risk for birth defects.A complete hydatiform mole usually presents with a large uterus compared to the expected size for a given gestational age. On ultrasound, there will be no embryo, fetus, or amniotic fluid. There will be an abnormal placenta with small cystic spaces, said to resemble a snowstorm. When a complete molar pregnancy presents with the passage of tissue from the vagina, the tissue is said to resemble large grape-like masses with a ‘prune-juice’ discharge. Finally, complete hydatiform moles are also associated with ovarian theca lutein cysts, pre-eclampsia, and hyperthyroidism. Theca lutein cysts form from overstimulation by circulating hormones produced by the complete hydatiform mole and can cause abdominal pains as they rupture or bleed. Pre-eclampsia is a disorder characterized by new onset hypertension. Patients might experience headaches over the back of their head that does not respond to medication, stars in their field of vision, pain in the right upper portion of the abdomen under the ribs, shortness of breath, and swelling in the face, arms, or legs. Hyperthyroidism can present with intolerance to heat, hair and skin changes, weight loss, and palpitations. Any of these symptoms should prompt an immediate follow-up visit with the doctor.Malignancy (Invasive Moles, Choriocarcinoma, Placental Site Trophoblastic Tumor, Ep-ithelioid Trophoblstic Tumor)The GTNs can be subtle entities in terms of clinical presentation. The physician must keep these on the differential as a cause of common complaints including vaginal bleeding, uterine size discordant to gestation age, pelvic pain, hyperemesis, and miscarriage.In dramatic clinical presentation of metastatic choriocarcinoma, patients present with symptoms based on the affected organ system. For example, metastasis to the lungs may be associated with hemoptysis, a bloody cough. Metastasis to the brain may present with seizure.Generally, these entities are identified in the follow-up of molar pregnancies as described later below. | 506 | Gestational Trophoblastic Disease |
nord_506_2 | Causes of Gestational Trophoblastic Disease | The female ovum and the male sperm are called human gametes. Each gamete carries half of the total genetic information required to form the future fetus. Typically, an ovum will be fertilized by exactly one sperm. Each human gamete carries 23 chromosomes, referred to as a haploid genome. Upon fertilization, the chromosomes from each parent combine and reassemble in complementary pairs of two. The hydatiform moles result from abnormal fertilization of the female ovum by male sperm. There are many aberrant forms of fertilization. Several scenarios are described throughout this report, but the trigger factor for these reactions is unknown. Farther along in this section, we describe the biology of normal pregnancy in more detail to explain where the trophoblastic cell population arises and what its normal role is.In normal fertilization as described above, the female ovum and the male sperm fuse. They form a zygote. The zygote is a single cell. It is an assembly of the maternal and paternal gametes, each contributing DNA in equal parts. The zygote contains all of the genetic maternal required to form a fetus. This single-cell zygote will divide repeatedly to form clusters of cells with the same genetic make-up. The series of divisions that the zygote undergoes are named depending on their structure and day of development but all of these cells, will differentiate to ultimately form the fetus and its placenta.The set of cells that form the placenta are called ‘trophoblasts’. Trophoblasts are an invasive species that are responsible for penetrating into the mother’s uterine lining. They are responsible for anchoring the embryo into the uterus. They are also responsible for forming an interface for maternal-fetal oxygen and exchange.Trophoblasts are generally categorized into two types: cyto-trophoblasts and syncytio-trophoblasts. These two sub-types of cells exist within a developmental stage of the growing embryo called the blastocyst. The blastocyst stage exists at day 5 following fertilization, it is composed of only 16-cells. It can be imagined as a fluid-filled balloon with a small mass of cells contained within. The mass of cells will develop into the fetus and the surface of the balloon represents the placenta. At the blastocyst stage, the forming placenta is composed of an intimate association between the cytotrophoblasts and syncytiotrophoblasts. The cytotrophoblasts form an inner surface layer, around which the syncytiotrophoblasts lay, facing the external environment.This blastocyst stage of the embryo is an early step in the growth of the embryo, which already demands a highly organized assembly of careful steps. Many pregnancies go unnoticed and a woman may become pregnant but for any of a number of reasons lose the pregnancy before she realizes that her regular cycle has stopped. GTD may be seen after these unrecognized pregnancies that spontaneously miscarry. They may also be seen after a normal, uncomplicated, full-term delivery of a healthy infant. | Causes of Gestational Trophoblastic Disease. The female ovum and the male sperm are called human gametes. Each gamete carries half of the total genetic information required to form the future fetus. Typically, an ovum will be fertilized by exactly one sperm. Each human gamete carries 23 chromosomes, referred to as a haploid genome. Upon fertilization, the chromosomes from each parent combine and reassemble in complementary pairs of two. The hydatiform moles result from abnormal fertilization of the female ovum by male sperm. There are many aberrant forms of fertilization. Several scenarios are described throughout this report, but the trigger factor for these reactions is unknown. Farther along in this section, we describe the biology of normal pregnancy in more detail to explain where the trophoblastic cell population arises and what its normal role is.In normal fertilization as described above, the female ovum and the male sperm fuse. They form a zygote. The zygote is a single cell. It is an assembly of the maternal and paternal gametes, each contributing DNA in equal parts. The zygote contains all of the genetic maternal required to form a fetus. This single-cell zygote will divide repeatedly to form clusters of cells with the same genetic make-up. The series of divisions that the zygote undergoes are named depending on their structure and day of development but all of these cells, will differentiate to ultimately form the fetus and its placenta.The set of cells that form the placenta are called ‘trophoblasts’. Trophoblasts are an invasive species that are responsible for penetrating into the mother’s uterine lining. They are responsible for anchoring the embryo into the uterus. They are also responsible for forming an interface for maternal-fetal oxygen and exchange.Trophoblasts are generally categorized into two types: cyto-trophoblasts and syncytio-trophoblasts. These two sub-types of cells exist within a developmental stage of the growing embryo called the blastocyst. The blastocyst stage exists at day 5 following fertilization, it is composed of only 16-cells. It can be imagined as a fluid-filled balloon with a small mass of cells contained within. The mass of cells will develop into the fetus and the surface of the balloon represents the placenta. At the blastocyst stage, the forming placenta is composed of an intimate association between the cytotrophoblasts and syncytiotrophoblasts. The cytotrophoblasts form an inner surface layer, around which the syncytiotrophoblasts lay, facing the external environment.This blastocyst stage of the embryo is an early step in the growth of the embryo, which already demands a highly organized assembly of careful steps. Many pregnancies go unnoticed and a woman may become pregnant but for any of a number of reasons lose the pregnancy before she realizes that her regular cycle has stopped. GTD may be seen after these unrecognized pregnancies that spontaneously miscarry. They may also be seen after a normal, uncomplicated, full-term delivery of a healthy infant. | 506 | Gestational Trophoblastic Disease |
nord_506_3 | Affects of Gestational Trophoblastic Disease | There is a strikingly, ethnic predisposition to hydatiform moles in groups of women with Asian, Hispanic, and Native American ethnicity. Additionally, women who are adolescents and women over forty years old have a higher risk. | Affects of Gestational Trophoblastic Disease. There is a strikingly, ethnic predisposition to hydatiform moles in groups of women with Asian, Hispanic, and Native American ethnicity. Additionally, women who are adolescents and women over forty years old have a higher risk. | 506 | Gestational Trophoblastic Disease |
nord_506_4 | Related disorders of Gestational Trophoblastic Disease | Recurrent Hydatidiform Syndrome
This condition is diagnosed clinically, after a woman has experienced two or more ab-normal pregnancies. It has been associated with genetic mutations in either or two genes: NLRP7 and KHDC3L. These genes are both involved in the regulation of gene activation and inactivation. Activation and inactivation govern the ability of the cellular machinery to read and use genetic information to produce protein products that carry a variety of ongoing processes. In the specific context of recurrent hydatiform mole syndrome, it is thought that NLRP7 gene mutations are the cause of a poor response against a molar pregnancy a normal immune system would recognize and eliminate before it becomes clinically apparent. | Related disorders of Gestational Trophoblastic Disease. Recurrent Hydatidiform Syndrome
This condition is diagnosed clinically, after a woman has experienced two or more ab-normal pregnancies. It has been associated with genetic mutations in either or two genes: NLRP7 and KHDC3L. These genes are both involved in the regulation of gene activation and inactivation. Activation and inactivation govern the ability of the cellular machinery to read and use genetic information to produce protein products that carry a variety of ongoing processes. In the specific context of recurrent hydatiform mole syndrome, it is thought that NLRP7 gene mutations are the cause of a poor response against a molar pregnancy a normal immune system would recognize and eliminate before it becomes clinically apparent. | 506 | Gestational Trophoblastic Disease |
nord_506_5 | Diagnosis of Gestational Trophoblastic Disease | Hydatifirm MoleThe diagnosis of normal versus molar pregnancy might remain unclear until the patient has ultrasound imaging. In the case that a molar pregnancy presents as heavy vaginal bleeding, the diagnosis can mimic miscarriage and only a microscopic analysis of the products of conception may establish the diagnosis.Hydatidiform moles can be benign with a malignancy risk (ie: partial or complete moles) or frankly malignant (ie: invasive moles). The malignant character is established on follow-up, based on whether the mole persists or not after uterine evacuation, whether distant metastases are present. Generally, no biopsy will be obtained to differentiate between these molar entities. Because trophoblast cells produce the hormone beta-human choriogonadotropin ( -hCG), commonly referred to as ‘the pregnancy hormone’, the easiest manner in which to track resolution of hydatiform moles is by measuring -hCG over time. If -hCG levels do not normalize rapidly after treatment, malignancy is suspected and a search to localize or rule out the persistent entity begins. Of complete hydatidiform mole, 20% are malignant and persistent, about 5% metastasize. Regarding partial moles, only about 2-3% are malignant.ChoriocarcinomaIn women of reproductive age with abnormal bleeding, -hCG is checked to rule out pregnancy and the GTD. For women who have recently delivered, bleeding in the postpartum period is normal. However, bleeding persistent over six weeks after delivery less usual and evaluated for GTD. Levels of -hCG may be quantified and tracked over time as previously mentioned. A down-trending of values indicates no persistent trophoblastic tissue. Should the values of -hCG plateau or even rise after a recognized conception, the diagnosis of GTN is assigned. The diagnosis of choriocarcinoma is based on persistent -hCG with a suspicious lesion on imaging. These tumors tend to bleed heavily when disrupted. They are therefore not often biopsied like other tumors.Rare VariantsThe PSTT and ETT are generally diagnosed at the time of pathologic examination after biopsy or surgical excision. These entities may be associated with low-normal elevations in -hCG but never elevations as large as are seen in choriocarcinomas. They are often identified when the placenta is sent for microscopic analysis by a pathologist after an abnormal architecture is noticed in the delivery room. PSTT may secrete the hormone, human chorionic lactogen (hPL). This hormone may be identified in blood sampled and used to inform a diagnosis but rarely used in clinical practice. ETT carry no such marker.Clinical Testing and Work-Up
The physician is likely to order routine blood tests, serum -hCG levels, renal and liver function tests and a CT or chest x-ray. It is important to note that choriocarcinoma develops a particularly rich blood supply that carries a dangerous propensity to spread to the lungs, brain, liver, pelvis, vagina, spleen, intestines, kidneys.When a lesion is excised surgically, it is sent to the pathology laboratory for careful examination. The sample can be fixed and stained to identify general changes in cell architecture. An examination into the way that the tumor cells are arranged and behave can indicate which variant of GTD, if any, the patient has. The specimen can also be stained by immunohistochemistry. Immunohistochemistry is a method of staining a sample for different cellular markers using a targeted antibody connected, conjugated to a color tag. The markers that are useful in identifying a case of trophoblastic disease include cytokeratin18, HLA-G, -hCG, hPL, Mel-CAM, p63, and Ki-67. The expected staining outcomes for the GTD are described below but the cellular functions of the given markers are far beyond the scope of this report and omitted.Benign Hydatiform MoleThe follow-up of uncomplicated (non-malignant) hydatidiform mole is weekly serum -hCG levels until three consecutive normal values are obtained. This is followed by monthly measurement of serum hCG levels for six months.Invasive MoleThe invasive mole begins to take on an amorphous mass, which loses some of the villi characteristic of normal placenta and hydatiform moles. The entity is rich in tropho-blastic cells and expands through the uterus into the myometrium. Invasive moles mimic points of placenta accreta. Placenta accreta is the abnormal implantation of otherwise normal placenta to the muscular layer of the uterus. It is often also associated with sites of uterine scarring, as associated with previous Cesarean section or myomectomy for leiomyomata. The diagnosis of invasive mole is actually seldom made since it re-quires a hysterectomy to be able to show that the molar tissue (villi and trophoblasts) invaded and destroyed the myometrium.ChoriocarcinomaChoriocarcinoma is an entity with high replicative turnover. There is an intimate association of syncitotrophoblasts and cytotrophoblasts that outgrow their blood supply and start to become necrotic. Choriocarcinoma tumors often have internal hemorrhage. The syncytiorophoblast component is often described as having a lace-like appearance along the maternal blood-filled lacunae, which bring oxygenated blood from the mother to the fetus. Patients with GTN (i.e., malignancy) are followed with weekly serum hCG levels until three to four consecutive normal values are obtained. This is followed by measurement of serum -hCG levels monthly for one year. Pregnancy is avoided dur-ing the period of follow-up. A subsequent pregnancy is confirmed by an early ultra-sound. Rare VariantsPSTT is composed of bland, polygonal trophoblastic cells that arrange in sheets or cords. These cells replicate relatively slowly and do not necrose or hemorrhage the way that choriocarcinoma does.ETT can be a solid or cystic mass. The trophoblasts arrange in nests, cords and surround blood vessels. They have a pink, eosinophilic extracellular matrix. These cells replicate moderately fast and demonstrate necrosis in a unique pattern termed ‘geo-graphic necrosis’.Laboratory Examination DetailsIn terms of the work-up conducted by the pathology laboratory, there are a number of cellular markers that can be investigated to definitively differentiate one trophoblastic disease entity from another. Trophoblastic disease can be verified when samples stain positive for cytokeratin-18 and HLA-G. Choriocarcinoma can be definitively diagnosed with a strong -hCG stain. PSTT and EPS stain positively for hPL and Mel-CAM, nega-tively for p63. PSTT will stain positive for Ki-67 in over 1% of cells while EPS will stain positive for Ki-67 in <1% of cells. ETT and PSN stain negative for hPL and Mel-CAM, positively for p63 and are differentiated Ki-67. Ki-67 will be positive in over 10% of cells in a ETT while positive in less than 10% of cells in PSN.
| Diagnosis of Gestational Trophoblastic Disease. Hydatifirm MoleThe diagnosis of normal versus molar pregnancy might remain unclear until the patient has ultrasound imaging. In the case that a molar pregnancy presents as heavy vaginal bleeding, the diagnosis can mimic miscarriage and only a microscopic analysis of the products of conception may establish the diagnosis.Hydatidiform moles can be benign with a malignancy risk (ie: partial or complete moles) or frankly malignant (ie: invasive moles). The malignant character is established on follow-up, based on whether the mole persists or not after uterine evacuation, whether distant metastases are present. Generally, no biopsy will be obtained to differentiate between these molar entities. Because trophoblast cells produce the hormone beta-human choriogonadotropin ( -hCG), commonly referred to as ‘the pregnancy hormone’, the easiest manner in which to track resolution of hydatiform moles is by measuring -hCG over time. If -hCG levels do not normalize rapidly after treatment, malignancy is suspected and a search to localize or rule out the persistent entity begins. Of complete hydatidiform mole, 20% are malignant and persistent, about 5% metastasize. Regarding partial moles, only about 2-3% are malignant.ChoriocarcinomaIn women of reproductive age with abnormal bleeding, -hCG is checked to rule out pregnancy and the GTD. For women who have recently delivered, bleeding in the postpartum period is normal. However, bleeding persistent over six weeks after delivery less usual and evaluated for GTD. Levels of -hCG may be quantified and tracked over time as previously mentioned. A down-trending of values indicates no persistent trophoblastic tissue. Should the values of -hCG plateau or even rise after a recognized conception, the diagnosis of GTN is assigned. The diagnosis of choriocarcinoma is based on persistent -hCG with a suspicious lesion on imaging. These tumors tend to bleed heavily when disrupted. They are therefore not often biopsied like other tumors.Rare VariantsThe PSTT and ETT are generally diagnosed at the time of pathologic examination after biopsy or surgical excision. These entities may be associated with low-normal elevations in -hCG but never elevations as large as are seen in choriocarcinomas. They are often identified when the placenta is sent for microscopic analysis by a pathologist after an abnormal architecture is noticed in the delivery room. PSTT may secrete the hormone, human chorionic lactogen (hPL). This hormone may be identified in blood sampled and used to inform a diagnosis but rarely used in clinical practice. ETT carry no such marker.Clinical Testing and Work-Up
The physician is likely to order routine blood tests, serum -hCG levels, renal and liver function tests and a CT or chest x-ray. It is important to note that choriocarcinoma develops a particularly rich blood supply that carries a dangerous propensity to spread to the lungs, brain, liver, pelvis, vagina, spleen, intestines, kidneys.When a lesion is excised surgically, it is sent to the pathology laboratory for careful examination. The sample can be fixed and stained to identify general changes in cell architecture. An examination into the way that the tumor cells are arranged and behave can indicate which variant of GTD, if any, the patient has. The specimen can also be stained by immunohistochemistry. Immunohistochemistry is a method of staining a sample for different cellular markers using a targeted antibody connected, conjugated to a color tag. The markers that are useful in identifying a case of trophoblastic disease include cytokeratin18, HLA-G, -hCG, hPL, Mel-CAM, p63, and Ki-67. The expected staining outcomes for the GTD are described below but the cellular functions of the given markers are far beyond the scope of this report and omitted.Benign Hydatiform MoleThe follow-up of uncomplicated (non-malignant) hydatidiform mole is weekly serum -hCG levels until three consecutive normal values are obtained. This is followed by monthly measurement of serum hCG levels for six months.Invasive MoleThe invasive mole begins to take on an amorphous mass, which loses some of the villi characteristic of normal placenta and hydatiform moles. The entity is rich in tropho-blastic cells and expands through the uterus into the myometrium. Invasive moles mimic points of placenta accreta. Placenta accreta is the abnormal implantation of otherwise normal placenta to the muscular layer of the uterus. It is often also associated with sites of uterine scarring, as associated with previous Cesarean section or myomectomy for leiomyomata. The diagnosis of invasive mole is actually seldom made since it re-quires a hysterectomy to be able to show that the molar tissue (villi and trophoblasts) invaded and destroyed the myometrium.ChoriocarcinomaChoriocarcinoma is an entity with high replicative turnover. There is an intimate association of syncitotrophoblasts and cytotrophoblasts that outgrow their blood supply and start to become necrotic. Choriocarcinoma tumors often have internal hemorrhage. The syncytiorophoblast component is often described as having a lace-like appearance along the maternal blood-filled lacunae, which bring oxygenated blood from the mother to the fetus. Patients with GTN (i.e., malignancy) are followed with weekly serum hCG levels until three to four consecutive normal values are obtained. This is followed by measurement of serum -hCG levels monthly for one year. Pregnancy is avoided dur-ing the period of follow-up. A subsequent pregnancy is confirmed by an early ultra-sound. Rare VariantsPSTT is composed of bland, polygonal trophoblastic cells that arrange in sheets or cords. These cells replicate relatively slowly and do not necrose or hemorrhage the way that choriocarcinoma does.ETT can be a solid or cystic mass. The trophoblasts arrange in nests, cords and surround blood vessels. They have a pink, eosinophilic extracellular matrix. These cells replicate moderately fast and demonstrate necrosis in a unique pattern termed ‘geo-graphic necrosis’.Laboratory Examination DetailsIn terms of the work-up conducted by the pathology laboratory, there are a number of cellular markers that can be investigated to definitively differentiate one trophoblastic disease entity from another. Trophoblastic disease can be verified when samples stain positive for cytokeratin-18 and HLA-G. Choriocarcinoma can be definitively diagnosed with a strong -hCG stain. PSTT and EPS stain positively for hPL and Mel-CAM, nega-tively for p63. PSTT will stain positive for Ki-67 in over 1% of cells while EPS will stain positive for Ki-67 in <1% of cells. ETT and PSN stain negative for hPL and Mel-CAM, positively for p63 and are differentiated Ki-67. Ki-67 will be positive in over 10% of cells in a ETT while positive in less than 10% of cells in PSN.
| 506 | Gestational Trophoblastic Disease |
nord_506_6 | Therapies of Gestational Trophoblastic Disease | First Line TreatmentIn patients with molar pregnancy (partial or complete), reliable methods of treatment primarily include suction dilation and curettage or evacuation (D&C or D&E). The procedure may be done with ultrasound image-guidance, and with or without IV oxytocin. Oxytocin is an optional medication that helps the uterus to contract and expels molar tissue. D&C has an associated with a risk of uterine scarring, which can complicate later pregnancies. Medical treatment is often the first line for malignant entities. This consists of a short course of a single medication that aims to stop the replication of rapidly dividing cells. The medication most often used is methotrexate. Methotrexate is also used as an anti-cancer drug against solid malignancy (eg: breast, lung) and liquid tumors (leukemia, lymphoma). Methotrexate is also known as a disease-modifying treatment for some au-toimmune disorders (lupus, psoriasis, rheumatoid arthritis ext).Actinomycin D is another available agent. It is often reserved for the patients whose disease does not resolve with methotrexate treatment. Actinomycin D has been suggested to carry a slightly higher cure rate than methotrexate but has also been associated with increased incidence of severe side effects. Both agents affect the blood and immune system, as well as the kidneys. Methotrexate however also affects the liver. If a patient has liver disease, this may be one reason that the treating physician may choose actinomycin D as first line treatment. Finally, two more drugs are used, generally across Asia, in the single-agent treatment of GTD. Etopside is avoided in the United States because it carries the risk of causing secondary malignancies including. leukemia, breast cancer, colon cancer, and melanoma. Finally, fluorouracil can also be used alone in the treatment of GTD. Should single-agent treatment prove ineffective, multi-agent chemotherapy may also be used, should the patient not want, or be able to have, surgery. The treatment of persistent GTD is discussed below alongside the treatment of malignant GTD.PrognosisThe prognosis and treatment of malignant GTD is determined according to a standardized tumor staging. The staging system used for GTD was developed by the International Federation or Obstetrics and Gynecology, better known also as the Federation Internationale de Gynecologie et d’Obstetrique (FIGO). The FIGO staging system includes a risk score developed by the World Health Organization (WHO). This staging system takes different factors into account such as patient age, source of GTD (molar pregnancy, abortion, term delivery), months since product of conception was identified and tumor anatomy (size, metastases). Of note, the FIGO staging system is applied to the treatment of choriocarcinoma but notably not applied to patients with placental site or epithelial trophoblastic tumors. The FIGO-WHO stratification system designates patients as having either low- or high-risk in regards to the probability to have a poor response to treatment. Patients with low- and high-risk GTD can both have metastatic disease. Low-risk GTD is highly responsive to single-agent chemotherapy. Even if a patient develops resistance to the first single-agent chemotherapy they are started on, there is a strong likelihood that they will respond well to a second agent. Patients with low-risk GTD that have metastases are at greater risk for initial non-response to treatment. Physicians may choose to turn to the -hCG levels in a patient’s blood and decided to jump directly to a multi-agent treatment for patients with low-risk GTD. Generally, the cut-off of -hCG >300IU/L at time of treatment initiation will encourage physicians to start the EMA-CO regimen. EMA-CO consists of combination etopside, methotrexate, actinomycin D, cyclophosphamide, and vincristine. Below the given cut-off, the single-agent treatment is successful and multiple-agent exposure does not merit the associated toxicity.Patients with high-risk GTD are started in EMA-CO for first line treatment. There is a significant percent however, that will require alternative treatments after non-response. No single second-line agents have proven superior to others in this clinical scenario and many of the choices are therapies re-adapted from other cancer treatments. The success seen in this series of second-line regimens used in refractory, high-risk GTD are discussed under investigational therapies.Long-Term HealthRegardless of the initial diagnosis, it is important that patients with previous GTD care-fully follow up with their health care providers after treatment to track the levels of -hCG in the blood. These levels should drop with a successful curettage. If the levels of -hCG plateau or begin to rise again, persistent disease is suspected. -hCG values within normal ranges for three consecutive weeks indicate remission, expected to be maintained monthly for six months then yearly for up to 3 years. Disease recurrence is most common in the first year after treatment. This timeline can be reduced from one year to six months if the woman is over 35 years old and desires to conceive. If it otherwise very important that patients abstain from pregnancy while in one-year follow-up for GTD as -hCG is also made by the growing embryo and thus can mistakenly suggest recurrence.Regarding PSTTs and ETTs, surgery is the primary approach to a cure. Chemotherapy is importantly ineffective in these malignancies. The primary lesion may be extensive and require a hysterectomy. Any metastases must be identified and likewise removed surgically before their size increases to cause destructive pressures on the surrounding tissue.In the treatment of these lesions, it is also important to think also of the well-being of any fetus to be conceived in the future. It is important to review some basic immunology. Cells are covered in different proteins that serve to mark the cells as belonging to one’s own body and as non-foreign. The proteins covering the cells protect ‘self’ cells from being attacked and destroyed by the immune system. These proteins are described according to different type-systems such as the ABO and Rhesus (Rh)-factor systems. When a woman conceives a fetus or develops a molar pregnancy, she runs the risk of exposure to non-self-blood cells. Specifically, women with Rh-negative blood types may be exposed to blood cells that are Rh-positive. Because the woman’s cells do not recognize Rh-proteins as belonging to their own body, they form antibodies to destroy any cells with Rh-positive markers. This exposure to non-self-blood is not immediately dangerous for the mother. If the mother with Rh-negative blood is exposed to Rh-positive blood and forms antibodies against Rh-positive blood, subsequent pregnancies she carries are at risk. The antibodies formed in the first pregnancy re-main in her blood and may attack that fetus’ forming blood supply if it is Rh-positive. This can result in fetal anemia, heart-failure, and even death. Patients with Rh-negative blood type, at risk for exposure to Rh-positive blood products, should receive anti-Rh immune globulin. This medication can potentially protect the woman from forming her antibodies against Rh-factor. This medication is known to work best when ad-ministered within 72 hours of a person’s exposure to non-Rh-compatible blood. | Therapies of Gestational Trophoblastic Disease. First Line TreatmentIn patients with molar pregnancy (partial or complete), reliable methods of treatment primarily include suction dilation and curettage or evacuation (D&C or D&E). The procedure may be done with ultrasound image-guidance, and with or without IV oxytocin. Oxytocin is an optional medication that helps the uterus to contract and expels molar tissue. D&C has an associated with a risk of uterine scarring, which can complicate later pregnancies. Medical treatment is often the first line for malignant entities. This consists of a short course of a single medication that aims to stop the replication of rapidly dividing cells. The medication most often used is methotrexate. Methotrexate is also used as an anti-cancer drug against solid malignancy (eg: breast, lung) and liquid tumors (leukemia, lymphoma). Methotrexate is also known as a disease-modifying treatment for some au-toimmune disorders (lupus, psoriasis, rheumatoid arthritis ext).Actinomycin D is another available agent. It is often reserved for the patients whose disease does not resolve with methotrexate treatment. Actinomycin D has been suggested to carry a slightly higher cure rate than methotrexate but has also been associated with increased incidence of severe side effects. Both agents affect the blood and immune system, as well as the kidneys. Methotrexate however also affects the liver. If a patient has liver disease, this may be one reason that the treating physician may choose actinomycin D as first line treatment. Finally, two more drugs are used, generally across Asia, in the single-agent treatment of GTD. Etopside is avoided in the United States because it carries the risk of causing secondary malignancies including. leukemia, breast cancer, colon cancer, and melanoma. Finally, fluorouracil can also be used alone in the treatment of GTD. Should single-agent treatment prove ineffective, multi-agent chemotherapy may also be used, should the patient not want, or be able to have, surgery. The treatment of persistent GTD is discussed below alongside the treatment of malignant GTD.PrognosisThe prognosis and treatment of malignant GTD is determined according to a standardized tumor staging. The staging system used for GTD was developed by the International Federation or Obstetrics and Gynecology, better known also as the Federation Internationale de Gynecologie et d’Obstetrique (FIGO). The FIGO staging system includes a risk score developed by the World Health Organization (WHO). This staging system takes different factors into account such as patient age, source of GTD (molar pregnancy, abortion, term delivery), months since product of conception was identified and tumor anatomy (size, metastases). Of note, the FIGO staging system is applied to the treatment of choriocarcinoma but notably not applied to patients with placental site or epithelial trophoblastic tumors. The FIGO-WHO stratification system designates patients as having either low- or high-risk in regards to the probability to have a poor response to treatment. Patients with low- and high-risk GTD can both have metastatic disease. Low-risk GTD is highly responsive to single-agent chemotherapy. Even if a patient develops resistance to the first single-agent chemotherapy they are started on, there is a strong likelihood that they will respond well to a second agent. Patients with low-risk GTD that have metastases are at greater risk for initial non-response to treatment. Physicians may choose to turn to the -hCG levels in a patient’s blood and decided to jump directly to a multi-agent treatment for patients with low-risk GTD. Generally, the cut-off of -hCG >300IU/L at time of treatment initiation will encourage physicians to start the EMA-CO regimen. EMA-CO consists of combination etopside, methotrexate, actinomycin D, cyclophosphamide, and vincristine. Below the given cut-off, the single-agent treatment is successful and multiple-agent exposure does not merit the associated toxicity.Patients with high-risk GTD are started in EMA-CO for first line treatment. There is a significant percent however, that will require alternative treatments after non-response. No single second-line agents have proven superior to others in this clinical scenario and many of the choices are therapies re-adapted from other cancer treatments. The success seen in this series of second-line regimens used in refractory, high-risk GTD are discussed under investigational therapies.Long-Term HealthRegardless of the initial diagnosis, it is important that patients with previous GTD care-fully follow up with their health care providers after treatment to track the levels of -hCG in the blood. These levels should drop with a successful curettage. If the levels of -hCG plateau or begin to rise again, persistent disease is suspected. -hCG values within normal ranges for three consecutive weeks indicate remission, expected to be maintained monthly for six months then yearly for up to 3 years. Disease recurrence is most common in the first year after treatment. This timeline can be reduced from one year to six months if the woman is over 35 years old and desires to conceive. If it otherwise very important that patients abstain from pregnancy while in one-year follow-up for GTD as -hCG is also made by the growing embryo and thus can mistakenly suggest recurrence.Regarding PSTTs and ETTs, surgery is the primary approach to a cure. Chemotherapy is importantly ineffective in these malignancies. The primary lesion may be extensive and require a hysterectomy. Any metastases must be identified and likewise removed surgically before their size increases to cause destructive pressures on the surrounding tissue.In the treatment of these lesions, it is also important to think also of the well-being of any fetus to be conceived in the future. It is important to review some basic immunology. Cells are covered in different proteins that serve to mark the cells as belonging to one’s own body and as non-foreign. The proteins covering the cells protect ‘self’ cells from being attacked and destroyed by the immune system. These proteins are described according to different type-systems such as the ABO and Rhesus (Rh)-factor systems. When a woman conceives a fetus or develops a molar pregnancy, she runs the risk of exposure to non-self-blood cells. Specifically, women with Rh-negative blood types may be exposed to blood cells that are Rh-positive. Because the woman’s cells do not recognize Rh-proteins as belonging to their own body, they form antibodies to destroy any cells with Rh-positive markers. This exposure to non-self-blood is not immediately dangerous for the mother. If the mother with Rh-negative blood is exposed to Rh-positive blood and forms antibodies against Rh-positive blood, subsequent pregnancies she carries are at risk. The antibodies formed in the first pregnancy re-main in her blood and may attack that fetus’ forming blood supply if it is Rh-positive. This can result in fetal anemia, heart-failure, and even death. Patients with Rh-negative blood type, at risk for exposure to Rh-positive blood products, should receive anti-Rh immune globulin. This medication can potentially protect the woman from forming her antibodies against Rh-factor. This medication is known to work best when ad-ministered within 72 hours of a person’s exposure to non-Rh-compatible blood. | 506 | Gestational Trophoblastic Disease |
nord_507_0 | Overview of Gianotti Crosti Syndrome | Gianotti-Crosti Syndrome is a rare skin disease affecting children between the ages of nine months and nine years. Major symptoms may include blisters on the skin of the legs, buttocks and arms. The disorder is usually preceded by a viral infection. | Overview of Gianotti Crosti Syndrome. Gianotti-Crosti Syndrome is a rare skin disease affecting children between the ages of nine months and nine years. Major symptoms may include blisters on the skin of the legs, buttocks and arms. The disorder is usually preceded by a viral infection. | 507 | Gianotti Crosti Syndrome |
nord_507_1 | Symptoms of Gianotti Crosti Syndrome | Gianotti-Crosti Syndrome is characterized by blisters on the skin that may or may not itch. They are usually found on the face, buttocks, arms or legs. The blisters consist of large, flat-topped, fluid filled sacks. They usually occur along with upper respiratory tract infection. The blisters usually last from twenty to twenty-five days; they do not usually recur. There may be an enlargement of the lymph nodes in the trunk area of the body. Gianotti-Crosti Syndrome usually occurs after a bout with a viral disease such as: Coxsackievirus, Hepatitis-B, Infectious Mononucleosis or Cytomegalovirus, or after vaccination with a live virus serum. | Symptoms of Gianotti Crosti Syndrome. Gianotti-Crosti Syndrome is characterized by blisters on the skin that may or may not itch. They are usually found on the face, buttocks, arms or legs. The blisters consist of large, flat-topped, fluid filled sacks. They usually occur along with upper respiratory tract infection. The blisters usually last from twenty to twenty-five days; they do not usually recur. There may be an enlargement of the lymph nodes in the trunk area of the body. Gianotti-Crosti Syndrome usually occurs after a bout with a viral disease such as: Coxsackievirus, Hepatitis-B, Infectious Mononucleosis or Cytomegalovirus, or after vaccination with a live virus serum. | 507 | Gianotti Crosti Syndrome |
nord_507_2 | Causes of Gianotti Crosti Syndrome | The cause of Gianotti-Crosti Syndrome is thought to be a reaction to a previous viral infection. In many countries the predisposing cause is usually the Hepatitis-B virus. In North America other viruses are more often the predisposing cause. The exact reasons for this cause and effect situation are unknown. | Causes of Gianotti Crosti Syndrome. The cause of Gianotti-Crosti Syndrome is thought to be a reaction to a previous viral infection. In many countries the predisposing cause is usually the Hepatitis-B virus. In North America other viruses are more often the predisposing cause. The exact reasons for this cause and effect situation are unknown. | 507 | Gianotti Crosti Syndrome |
nord_507_3 | Affects of Gianotti Crosti Syndrome | Gianotti-Crosti Syndrome usually affects children between the ages of nine months and nine years of age. It affects males and females in equal numbers. Although the disorder is regularly associated with Hepatitis-B infections in other countries, in North America it is rarely the cause. | Affects of Gianotti Crosti Syndrome. Gianotti-Crosti Syndrome usually affects children between the ages of nine months and nine years of age. It affects males and females in equal numbers. Although the disorder is regularly associated with Hepatitis-B infections in other countries, in North America it is rarely the cause. | 507 | Gianotti Crosti Syndrome |
nord_507_4 | Related disorders of Gianotti Crosti Syndrome | The following viral infections can cause Gianotti-Crosti.Hepatitis-B Virus (HBV) is one of three viral agents which causes inflammation of the liver known as Hepatitis or “diffuse hepatocellular inflammatory disease”. Hepatitis-B is characterized by fever, nausea, vomiting, and yellow discoloration of the skin (jaundice). In its most serious form Hepatitis-B can become a chronic infection, or may cause liver cancer. The hepatitis-B virus can be passed from mother to unborn child, and is highly contagious through bodily fluids such as blood, semen and possibly saliva. It is often spread from person to person through intravenous drug use. (For more information on this disorder, choose “Hepatitis” as your search term in the Rare Disease Database.)Coxsackievirus is characterized by infections that occur primarily during the summer. It affects mostly young children, especially boys, and includes fever, sore throat, vomiting, headache, respiratory signs and symptoms, diarrhea, abdominal pain, rash and earache.Cytomegalovirus Infection (CMV) can occur congenitally, postnatally or at any age. CMV ranges in severity from a silent infection without consequences, to a disease manifested by fever, hepatitis, and (in newborns) severe brain damage, stillbirth or perinatal death. In severe cases hemorrhaging, anemia, and liver damage can occur. In infants it may cause low birth weight, fever, hepatitis, blindness, deafness, or seizures. (For more information on this disorder, choose “Cytomegalovirus” as your search term in the Rare Disease Database.)Infectious Mononucleosis is characterized by an incubation period of from thirty to fifty days in young adults, and a shorter time in children. The symptoms include feeling unwell for a few days, headache, fever and sore throat, with extreme fatigue. The glands in the neck, armpits and groin swell and the eyes get puffy. There may be tonsillitis, rash, loss of appetite, and sensitivity to light. Other organs in the body may be affected. The spleen and liver may become enlarged. This infection is caused by the Epstein-Barr virus. (For more information on this disorder, choose “Mono” as your search term in the Rare Disease Database.) | Related disorders of Gianotti Crosti Syndrome. The following viral infections can cause Gianotti-Crosti.Hepatitis-B Virus (HBV) is one of three viral agents which causes inflammation of the liver known as Hepatitis or “diffuse hepatocellular inflammatory disease”. Hepatitis-B is characterized by fever, nausea, vomiting, and yellow discoloration of the skin (jaundice). In its most serious form Hepatitis-B can become a chronic infection, or may cause liver cancer. The hepatitis-B virus can be passed from mother to unborn child, and is highly contagious through bodily fluids such as blood, semen and possibly saliva. It is often spread from person to person through intravenous drug use. (For more information on this disorder, choose “Hepatitis” as your search term in the Rare Disease Database.)Coxsackievirus is characterized by infections that occur primarily during the summer. It affects mostly young children, especially boys, and includes fever, sore throat, vomiting, headache, respiratory signs and symptoms, diarrhea, abdominal pain, rash and earache.Cytomegalovirus Infection (CMV) can occur congenitally, postnatally or at any age. CMV ranges in severity from a silent infection without consequences, to a disease manifested by fever, hepatitis, and (in newborns) severe brain damage, stillbirth or perinatal death. In severe cases hemorrhaging, anemia, and liver damage can occur. In infants it may cause low birth weight, fever, hepatitis, blindness, deafness, or seizures. (For more information on this disorder, choose “Cytomegalovirus” as your search term in the Rare Disease Database.)Infectious Mononucleosis is characterized by an incubation period of from thirty to fifty days in young adults, and a shorter time in children. The symptoms include feeling unwell for a few days, headache, fever and sore throat, with extreme fatigue. The glands in the neck, armpits and groin swell and the eyes get puffy. There may be tonsillitis, rash, loss of appetite, and sensitivity to light. Other organs in the body may be affected. The spleen and liver may become enlarged. This infection is caused by the Epstein-Barr virus. (For more information on this disorder, choose “Mono” as your search term in the Rare Disease Database.) | 507 | Gianotti Crosti Syndrome |
nord_507_5 | Diagnosis of Gianotti Crosti Syndrome | Diagnosis of Gianotti Crosti Syndrome. | 507 | Gianotti Crosti Syndrome |
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nord_507_6 | Therapies of Gianotti Crosti Syndrome | Because Gianotti-Crosti Syndrome is a self-limiting disorder, the treatment of affected children is primarily symptomatic and supportive. For example, in some cases, the use of topical ointments or certain medications by mouth may be recommended to help alleviate mild to potentially severe itching (pruritus). The skin lesions associated with Gianotti-Crosti Syndrome typically spontaneously resolve within approximately 15 to 60 days. When associated findings include enlargement of the lymph nodes (lymphadenopathy) and/or enlargement of the liver (i.e., in association with liver inflammation [hepatitis]), such findings may persist for several months after initial symptom onset. | Therapies of Gianotti Crosti Syndrome. Because Gianotti-Crosti Syndrome is a self-limiting disorder, the treatment of affected children is primarily symptomatic and supportive. For example, in some cases, the use of topical ointments or certain medications by mouth may be recommended to help alleviate mild to potentially severe itching (pruritus). The skin lesions associated with Gianotti-Crosti Syndrome typically spontaneously resolve within approximately 15 to 60 days. When associated findings include enlargement of the lymph nodes (lymphadenopathy) and/or enlargement of the liver (i.e., in association with liver inflammation [hepatitis]), such findings may persist for several months after initial symptom onset. | 507 | Gianotti Crosti Syndrome |
nord_508_0 | Overview of Giant Axonal Neuropathy | Giant axonal neuropathy is a rare neuropathy that severely affects the peripheral as well as the central nervous system. The first symptoms appear in early childhood. This disorder is characterized by abnormalities in the peripheral and central nervous systems including low muscle tone (hypotonia), muscle weakness, decreased reflexes, impaired muscle coordination (ataxia), seizures and intellectual disability. Pale, tightly curled hair is frequently seen in those affected. Giant axonal neuropathy follows autosomal recessive genetic inheritance. | Overview of Giant Axonal Neuropathy. Giant axonal neuropathy is a rare neuropathy that severely affects the peripheral as well as the central nervous system. The first symptoms appear in early childhood. This disorder is characterized by abnormalities in the peripheral and central nervous systems including low muscle tone (hypotonia), muscle weakness, decreased reflexes, impaired muscle coordination (ataxia), seizures and intellectual disability. Pale, tightly curled hair is frequently seen in those affected. Giant axonal neuropathy follows autosomal recessive genetic inheritance. | 508 | Giant Axonal Neuropathy |
nord_508_1 | Symptoms of Giant Axonal Neuropathy | Symptoms of giant axonal neuropathy occur in early childhood before the age of seven years. Both the central and peripheral nervous systems are affected. The central nervous system includes the brain and spinal cord and the peripheral nervous system spreads out from the brain and spinal cord to all other areas of the body. Characteristics include low muscle tone (hypotonia), muscle weakness, decreased reflexes, impaired muscle coordination (ataxia), seizures and intellectual disability. In contrast to purely peripheral neuropathies, the reflex of the toes known as Babinski's sign is often positive, indicating involvement of central motor pathways. Most affected children have pale, tightly curled hair unlike their parent’s hair. Cranial nerves may also be affected leading to facial weakness, abnormal eyes and poor vision. An unusual leg posture is present in some affected children. Skeletal abnormalities such as scoliosis and foot deformities have been described and are thought to be a result of the nervous system dysfunction. Mental development is in most cases initially normal, but later in childhood degenerative mental changes (dementia) may occur as the disorder progresses. Giant axonal neuropathy is rapidly progressive, usually leading to dependence on a wheel chair by the second decade of life and death in the second or third decade. | Symptoms of Giant Axonal Neuropathy. Symptoms of giant axonal neuropathy occur in early childhood before the age of seven years. Both the central and peripheral nervous systems are affected. The central nervous system includes the brain and spinal cord and the peripheral nervous system spreads out from the brain and spinal cord to all other areas of the body. Characteristics include low muscle tone (hypotonia), muscle weakness, decreased reflexes, impaired muscle coordination (ataxia), seizures and intellectual disability. In contrast to purely peripheral neuropathies, the reflex of the toes known as Babinski's sign is often positive, indicating involvement of central motor pathways. Most affected children have pale, tightly curled hair unlike their parent’s hair. Cranial nerves may also be affected leading to facial weakness, abnormal eyes and poor vision. An unusual leg posture is present in some affected children. Skeletal abnormalities such as scoliosis and foot deformities have been described and are thought to be a result of the nervous system dysfunction. Mental development is in most cases initially normal, but later in childhood degenerative mental changes (dementia) may occur as the disorder progresses. Giant axonal neuropathy is rapidly progressive, usually leading to dependence on a wheel chair by the second decade of life and death in the second or third decade. | 508 | Giant Axonal Neuropathy |
nord_508_2 | Causes of Giant Axonal Neuropathy | Giant axonal neuropathy is an autosomal recessive genetic disorder. This condition is caused by an abnormality in the GAN gene located on chromosome 16 at 16q24.1 that codes for the gigaxonin protein. The abnormal gigaxonin protein causes a portion of the nerve cell called the axon to swell up with deposits of tiny threads of protein called neurofilaments, giving the appearance of giant axons. The giant axons cause degeneration and abnormal functioning of the peripheral nervous system. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome16q24.1” refers to band 24 on the long arm of chromosome 16. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All healthy individuals carry 4-5 recessive abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | Causes of Giant Axonal Neuropathy. Giant axonal neuropathy is an autosomal recessive genetic disorder. This condition is caused by an abnormality in the GAN gene located on chromosome 16 at 16q24.1 that codes for the gigaxonin protein. The abnormal gigaxonin protein causes a portion of the nerve cell called the axon to swell up with deposits of tiny threads of protein called neurofilaments, giving the appearance of giant axons. The giant axons cause degeneration and abnormal functioning of the peripheral nervous system. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome16q24.1” refers to band 24 on the long arm of chromosome 16. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All healthy individuals carry 4-5 recessive abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | 508 | Giant Axonal Neuropathy |
nord_508_3 | Affects of Giant Axonal Neuropathy | Giant axonal neuropathy is a rare disorder that presents in early childhood. This disorder affects equal numbers of males and females. The prevalence of giant axonal neuropathy and the frequency of carriers of one defective copy of the GAN gene is not known, but it is known that giant axonal neuropathy is a very rare disease. | Affects of Giant Axonal Neuropathy. Giant axonal neuropathy is a rare disorder that presents in early childhood. This disorder affects equal numbers of males and females. The prevalence of giant axonal neuropathy and the frequency of carriers of one defective copy of the GAN gene is not known, but it is known that giant axonal neuropathy is a very rare disease. | 508 | Giant Axonal Neuropathy |
nord_508_4 | Related disorders of Giant Axonal Neuropathy | Symptoms of the following disorders can be similar to those of giant axonal neuropathy. Comparisons may be useful for a differential diagnosis: Charcot-Marie-Tooth (CMT) hereditary neuropathies are a group of disorders in which the motor and sensory peripheral nerves are affected, resulting in muscle weakness and atrophy, primarily in the legs and sometimes in the hands. In contrast to giant axonal neuropathy, the overwhelming majority of patients with CMT shows no, or only very mild, central nervous system (CNS) involvement. The differential diagnosis between the rather common CMT and giant axonal neuropathy is, therefore, rarely difficult. CMT group hereditary neuropathies affect mainly the peripheral nerves that control many muscles in the body. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. Specific gene mutations are responsible for the abnormal function of the peripheral nerves. Charcot Marie Tooth hereditary neuropathy can be inherited in an autosomal dominant, autosomal recessive or X-linked mode of inheritance. (For more information about this condition, choose “Charcot” as your search term in the Rare Disease Database.) Seitelberger disease (infantile neuroaxonal dystrophy) is an inherited central nervous system disorder usually beginning before the age of two years. Children with Seitelberger disease may experience difficulty in walking and/or speaking. Coordination may become impaired, and decreased muscle tone (“floppiness”), muscle spasms (spasticity) and/or weakening of reflexes may also occur. In later stages, involuntary rapid eye movements, progressive vision problems and seizures can occur. (For more information on this disorder, choose “Seitelberger disease” as your search term in the Rare Disease Database.) Menkes disease is a genetic disorder of copper metabolism that is characterized by seizures, intellectual disability, stunted growth, failure to thrive, unstable body temperature, and very unusual color and texture of hair. Menkes disease is inherited as an X-linked recessive trait and is found disproportionately in male children. (For more information about this condition, choose “Menkes” as your search term in the Rare Disease Database.) Metachromatic leukodystrophy is a rare inherited disorder affecting the white matter of the brain (leukoencephalopathy). It is characterized by the accumulation of a fatty substance known as sulfatide (a sphingolipid) in the brain and other areas of the body. The fatty protective covering on the nerve fibers (myelin) is lost from areas of the central nervous system due to the buildup of sulfatide. Symptoms of metachromatic leukodystrophy may include convulsions, seizures, personality changes, spasticity, progressive dementia, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. (For more information on this condition, choose “leukodystrophy, metachromatic” as your search term in the Rare Disease Database.) Toxic substances that affect the nervous system (neurotoxins) such as n-hexane and acrylamide can cause symptoms similar to those found in giant axonal neuropathy but sufficiently severe and/or chronic intoxications with these substances are rare. | Related disorders of Giant Axonal Neuropathy. Symptoms of the following disorders can be similar to those of giant axonal neuropathy. Comparisons may be useful for a differential diagnosis: Charcot-Marie-Tooth (CMT) hereditary neuropathies are a group of disorders in which the motor and sensory peripheral nerves are affected, resulting in muscle weakness and atrophy, primarily in the legs and sometimes in the hands. In contrast to giant axonal neuropathy, the overwhelming majority of patients with CMT shows no, or only very mild, central nervous system (CNS) involvement. The differential diagnosis between the rather common CMT and giant axonal neuropathy is, therefore, rarely difficult. CMT group hereditary neuropathies affect mainly the peripheral nerves that control many muscles in the body. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. Specific gene mutations are responsible for the abnormal function of the peripheral nerves. Charcot Marie Tooth hereditary neuropathy can be inherited in an autosomal dominant, autosomal recessive or X-linked mode of inheritance. (For more information about this condition, choose “Charcot” as your search term in the Rare Disease Database.) Seitelberger disease (infantile neuroaxonal dystrophy) is an inherited central nervous system disorder usually beginning before the age of two years. Children with Seitelberger disease may experience difficulty in walking and/or speaking. Coordination may become impaired, and decreased muscle tone (“floppiness”), muscle spasms (spasticity) and/or weakening of reflexes may also occur. In later stages, involuntary rapid eye movements, progressive vision problems and seizures can occur. (For more information on this disorder, choose “Seitelberger disease” as your search term in the Rare Disease Database.) Menkes disease is a genetic disorder of copper metabolism that is characterized by seizures, intellectual disability, stunted growth, failure to thrive, unstable body temperature, and very unusual color and texture of hair. Menkes disease is inherited as an X-linked recessive trait and is found disproportionately in male children. (For more information about this condition, choose “Menkes” as your search term in the Rare Disease Database.) Metachromatic leukodystrophy is a rare inherited disorder affecting the white matter of the brain (leukoencephalopathy). It is characterized by the accumulation of a fatty substance known as sulfatide (a sphingolipid) in the brain and other areas of the body. The fatty protective covering on the nerve fibers (myelin) is lost from areas of the central nervous system due to the buildup of sulfatide. Symptoms of metachromatic leukodystrophy may include convulsions, seizures, personality changes, spasticity, progressive dementia, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. (For more information on this condition, choose “leukodystrophy, metachromatic” as your search term in the Rare Disease Database.) Toxic substances that affect the nervous system (neurotoxins) such as n-hexane and acrylamide can cause symptoms similar to those found in giant axonal neuropathy but sufficiently severe and/or chronic intoxications with these substances are rare. | 508 | Giant Axonal Neuropathy |
nord_508_5 | Diagnosis of Giant Axonal Neuropathy | Diagnosis of giant axonal neuropathy is made by clinical findings and specialized tests including nerve conduction velocity, brain MRI and peripheral nerve biopsy. The hallmark finding on a peripheral nerve biopsy is the appearance of "giant axons" which are caused by the accumulation of neurofilaments. Molecular genetic testing for abnormalities in the GAN gene is available to confirm the diagnosis. Negative mutation screening of the region of the GAN gene which encodes the protein does not exclude the diagnosis of giant axonal neuropathy. | Diagnosis of Giant Axonal Neuropathy. Diagnosis of giant axonal neuropathy is made by clinical findings and specialized tests including nerve conduction velocity, brain MRI and peripheral nerve biopsy. The hallmark finding on a peripheral nerve biopsy is the appearance of "giant axons" which are caused by the accumulation of neurofilaments. Molecular genetic testing for abnormalities in the GAN gene is available to confirm the diagnosis. Negative mutation screening of the region of the GAN gene which encodes the protein does not exclude the diagnosis of giant axonal neuropathy. | 508 | Giant Axonal Neuropathy |
nord_508_6 | Therapies of Giant Axonal Neuropathy | TreatmentTreatment of giant axonal neuropathy is symptomatic and supportive and often involves a team of professionals including pediatric neurologists, orthopedic surgeons, physiotherapists, psychologists and speech and language therapists. Services for visually and/or mobility impaired people may be of assistance to people with giant axonal neuropathy.Genetic counseling will be of benefit for patients and their families. | Therapies of Giant Axonal Neuropathy. TreatmentTreatment of giant axonal neuropathy is symptomatic and supportive and often involves a team of professionals including pediatric neurologists, orthopedic surgeons, physiotherapists, psychologists and speech and language therapists. Services for visually and/or mobility impaired people may be of assistance to people with giant axonal neuropathy.Genetic counseling will be of benefit for patients and their families. | 508 | Giant Axonal Neuropathy |
nord_509_0 | Overview of Giant Cell Arteritis | Giant cell arteritis (GCA) is the most common blood vessel disorder in persons over 50 years old that causes inflammation of medium and large-sized arteries in the body (vasculitis). GCA causes changes in blood vessel walls leading to poor blood circulation. Arteries most affected in giant cell arteritis are the temporal artery and other cranial arteries (now called cranial-GCA), but inflammation of the aorta and other large arteries in the body can occur as well and may present differently (now called large vessel-GCA). If left untreated, this can lead to a medical emergency where sudden blindness occurs without early detection and treatment. Signs and symptoms when the temporal or other cranial arteries are involved include arm pain, pulsing headaches on one side or on the back of the head, jaw pain, scalp tenderness, double vision or other visual disturbances, bulging temporal artery that is tender with skin edema and redness. It can also present with constitutional symptoms such as polymyalgia, fevers, anorexia, and weight loss, a presentation of LV-GCA. The cause of giant cell arteritis is still unknown but is thought to be from the immune system causing damage to the body’s own blood vessels. Polymyalgia rheumatica is an inflammatory disorder that is closely related to giant cell arteritis and occurs in 40% to 60% of patients with giant call arteritis. 15% to 20% of persons with polymyalgia rheumatica will have giant cell arteritis. Treatments available include steroids (corticosteroids) that will help with symptoms and reoccurrence and medications that weaken the immune system. | Overview of Giant Cell Arteritis. Giant cell arteritis (GCA) is the most common blood vessel disorder in persons over 50 years old that causes inflammation of medium and large-sized arteries in the body (vasculitis). GCA causes changes in blood vessel walls leading to poor blood circulation. Arteries most affected in giant cell arteritis are the temporal artery and other cranial arteries (now called cranial-GCA), but inflammation of the aorta and other large arteries in the body can occur as well and may present differently (now called large vessel-GCA). If left untreated, this can lead to a medical emergency where sudden blindness occurs without early detection and treatment. Signs and symptoms when the temporal or other cranial arteries are involved include arm pain, pulsing headaches on one side or on the back of the head, jaw pain, scalp tenderness, double vision or other visual disturbances, bulging temporal artery that is tender with skin edema and redness. It can also present with constitutional symptoms such as polymyalgia, fevers, anorexia, and weight loss, a presentation of LV-GCA. The cause of giant cell arteritis is still unknown but is thought to be from the immune system causing damage to the body’s own blood vessels. Polymyalgia rheumatica is an inflammatory disorder that is closely related to giant cell arteritis and occurs in 40% to 60% of patients with giant call arteritis. 15% to 20% of persons with polymyalgia rheumatica will have giant cell arteritis. Treatments available include steroids (corticosteroids) that will help with symptoms and reoccurrence and medications that weaken the immune system. | 509 | Giant Cell Arteritis |
nord_509_1 | Symptoms of Giant Cell Arteritis | Common symptoms when the temporal arteries (located on each side of the head) are affected are headaches with the artery being tender, thicker, nodular, and pulsating early-on but may become blocked later-on. Headaches are present in more than 60% of patients. The temporal artery and its parietal and frontal branches may bulge while appearing twisted/ knotted under the scalp and feel tender with skin edema and redness and may become pulseless. Visual disturbances like double vision or transient loss of vision can occur in one or both eyes that are not long lasting. However, serious complications can occur such as blindness that occurs in 15% to 30% of patients that is not reversible with steroids. Blindness in just one eye occurs as well, but if left untreated 25% to 50% of patients can experience loss of vision in the other eye.Arteries in other parts of the body can be affected as well. The aorta, the largest artery in the body can be affected as well and cause arm pain or increase risk for severe complications such as thinning of arterial wall in the artery leading to aneurysm and rarely arterial dissection. Risk for stroke and nervous system disorders can occur but is uncommon.Inflammation throughout the body is common as well and can present with fever, fatigue, weight loss, discomfort, night sweats, depression, and anemia. Respiratory symptoms can also occur with dry non-mucus cough. | Symptoms of Giant Cell Arteritis. Common symptoms when the temporal arteries (located on each side of the head) are affected are headaches with the artery being tender, thicker, nodular, and pulsating early-on but may become blocked later-on. Headaches are present in more than 60% of patients. The temporal artery and its parietal and frontal branches may bulge while appearing twisted/ knotted under the scalp and feel tender with skin edema and redness and may become pulseless. Visual disturbances like double vision or transient loss of vision can occur in one or both eyes that are not long lasting. However, serious complications can occur such as blindness that occurs in 15% to 30% of patients that is not reversible with steroids. Blindness in just one eye occurs as well, but if left untreated 25% to 50% of patients can experience loss of vision in the other eye.Arteries in other parts of the body can be affected as well. The aorta, the largest artery in the body can be affected as well and cause arm pain or increase risk for severe complications such as thinning of arterial wall in the artery leading to aneurysm and rarely arterial dissection. Risk for stroke and nervous system disorders can occur but is uncommon.Inflammation throughout the body is common as well and can present with fever, fatigue, weight loss, discomfort, night sweats, depression, and anemia. Respiratory symptoms can also occur with dry non-mucus cough. | 509 | Giant Cell Arteritis |
nord_509_2 | Causes of Giant Cell Arteritis | The cause of giant cell arteritis is still not fully known, however, studies linking genetic factors and infections have shown that the body’s immune system may play a role in the inflammation. Giant cell arteritis is thought to be an autoimmune disorder, where the body’s defense system used against invading organisms is used instead to attack normal healthy tissues. These immune cells come together at the site where they are attacking the body and form giant cells. These giant cells produce substances that damage walls of the artery and lead to further inflammation.Studies have shown genetic variations in human leukocyte antigens (HLA), which is part of the immune response are related to how likely you are to have giant cell arteritis. There are other genetic variations that have been found to be associated with giant cell arteritis and they play a role a person’s autoimmunity response. | Causes of Giant Cell Arteritis. The cause of giant cell arteritis is still not fully known, however, studies linking genetic factors and infections have shown that the body’s immune system may play a role in the inflammation. Giant cell arteritis is thought to be an autoimmune disorder, where the body’s defense system used against invading organisms is used instead to attack normal healthy tissues. These immune cells come together at the site where they are attacking the body and form giant cells. These giant cells produce substances that damage walls of the artery and lead to further inflammation.Studies have shown genetic variations in human leukocyte antigens (HLA), which is part of the immune response are related to how likely you are to have giant cell arteritis. There are other genetic variations that have been found to be associated with giant cell arteritis and they play a role a person’s autoimmunity response. | 509 | Giant Cell Arteritis |
nord_509_3 | Affects of Giant Cell Arteritis | Giant cell arteritis most commonly affects those over 50 years old (mostly above 65 years) and is more common in Caucasians, people of Nordic or northern European descent, and others in northern latitudes. Women are 2 to 3 times more likely to develop GCA than men in persons of northern European descent while there is no higher risk for women from Spain, Israel, Turkey, other Mediterranean countries, and India. Specifically, about 20 per 100,000 people among whites in northern European populations are affected, 10 per 100,000 people affected among southern European populations, and about 1 per 100,000 people affected among American populations of Asian or African descent. | Affects of Giant Cell Arteritis. Giant cell arteritis most commonly affects those over 50 years old (mostly above 65 years) and is more common in Caucasians, people of Nordic or northern European descent, and others in northern latitudes. Women are 2 to 3 times more likely to develop GCA than men in persons of northern European descent while there is no higher risk for women from Spain, Israel, Turkey, other Mediterranean countries, and India. Specifically, about 20 per 100,000 people among whites in northern European populations are affected, 10 per 100,000 people affected among southern European populations, and about 1 per 100,000 people affected among American populations of Asian or African descent. | 509 | Giant Cell Arteritis |
nord_509_4 | Related disorders of Giant Cell Arteritis | The condition that presents most commonly with giant cell arteritis is polymyalgia rheumatica, which is characterized by muscle pain, stiffness, fatigue, and with or without fever. It presents abruptly as stiffness and pain in the neck, shoulders, and hips. It is also most common in persons over the age of 50.Other vascular disorders that would need to be ruled out are granulomatosis with polyangiitis, polyarthritis nodosa, microscopic polyangiitis, and Takayasu arteritis. | Related disorders of Giant Cell Arteritis. The condition that presents most commonly with giant cell arteritis is polymyalgia rheumatica, which is characterized by muscle pain, stiffness, fatigue, and with or without fever. It presents abruptly as stiffness and pain in the neck, shoulders, and hips. It is also most common in persons over the age of 50.Other vascular disorders that would need to be ruled out are granulomatosis with polyangiitis, polyarthritis nodosa, microscopic polyangiitis, and Takayasu arteritis. | 509 | Giant Cell Arteritis |
nord_509_5 | Diagnosis of Giant Cell Arteritis | There are no universally accepted diagnostic criteria and giant cell arteritis may be diagnosed by laboratory evaluation or physical examination. The American College of Rheumatology developed provisional classification criteria which requires at least 3 of the following: age of more than 50 years, localized headache that had not happened before, temporal artery abnormalities like tenderness or pulsations, increased time it takes red blood cells to settle (erythrocyte sedimentation rate) of greater than or equal to 50mm per hour, and or abnormal arterial biopsy. Confirmation of the diagnosis can be done by obtaining a temporal artery biopsy up to 14 days after the start of treatment, however, some patients can be positive for giant cell arteritis and respond to treatment and have a negative biopsy result. The use of ultrasound and magnetic resonance are becoming more reliable to help confirm or establish early diagnosis to prevent vision loss. Internationally, the European League Against Rheumatism (EULAR) guidelines have similar recommendations with vascular ultrasound as the first diagnostic test and if not available, the temporal artery biopsy. Clinical Testing and Work-UpBlood tests are done to evaluate the erythrocyte sedimentation rate and the C-reactive protein. Patients are monitored for symptoms of headaches, jaw and tongue pain, abnormal pulsations of arteries, muscle pain/ stiffness, visual disturbance, and side effects of steroid treatment. Relapse testing is shown when there is a rise in erythrocyte sedimentation rate and c-reactive protein. Bone and chest x-ray testing is suggested every 2 years but there is little evidence of benefit for it. Follow-up appointments with doctors should be at 1 week, 3 weeks, and 6 weeks, 3 months, 9 months, and 12 months for the first year or if new symptoms occur. The important objectives of the follow up assessments is to monitor disease activity, damage, adverse events and stratification into remitting, relapsing, refractory disease. | Diagnosis of Giant Cell Arteritis. There are no universally accepted diagnostic criteria and giant cell arteritis may be diagnosed by laboratory evaluation or physical examination. The American College of Rheumatology developed provisional classification criteria which requires at least 3 of the following: age of more than 50 years, localized headache that had not happened before, temporal artery abnormalities like tenderness or pulsations, increased time it takes red blood cells to settle (erythrocyte sedimentation rate) of greater than or equal to 50mm per hour, and or abnormal arterial biopsy. Confirmation of the diagnosis can be done by obtaining a temporal artery biopsy up to 14 days after the start of treatment, however, some patients can be positive for giant cell arteritis and respond to treatment and have a negative biopsy result. The use of ultrasound and magnetic resonance are becoming more reliable to help confirm or establish early diagnosis to prevent vision loss. Internationally, the European League Against Rheumatism (EULAR) guidelines have similar recommendations with vascular ultrasound as the first diagnostic test and if not available, the temporal artery biopsy. Clinical Testing and Work-UpBlood tests are done to evaluate the erythrocyte sedimentation rate and the C-reactive protein. Patients are monitored for symptoms of headaches, jaw and tongue pain, abnormal pulsations of arteries, muscle pain/ stiffness, visual disturbance, and side effects of steroid treatment. Relapse testing is shown when there is a rise in erythrocyte sedimentation rate and c-reactive protein. Bone and chest x-ray testing is suggested every 2 years but there is little evidence of benefit for it. Follow-up appointments with doctors should be at 1 week, 3 weeks, and 6 weeks, 3 months, 9 months, and 12 months for the first year or if new symptoms occur. The important objectives of the follow up assessments is to monitor disease activity, damage, adverse events and stratification into remitting, relapsing, refractory disease. | 509 | Giant Cell Arteritis |
nord_509_6 | Therapies of Giant Cell Arteritis | Treatment
As soon as a diagnosis is made the start of steroid (corticosteroid) therapy is recommended and should not be delayed due to waiting for confirmation with other tests like biopsies or imaging. Most patients start with prednisolone. For patients with visual or cerebral symptoms, intravenous methylprednisolone should be considered and then changed to oral dosing. Steroid therapy can also be started at higher doses and then lowered (tapering) in order to reduce the reoccurrence of giant cell arteritis. Inflammation should return to normal after 2 to 4 weeks of therapy and treatment would usually last up to 24 months, but some patients may require years of therapy.Steroids have a risk of bone loss, so medications may be recommended for bone protection. Studies have shown that medications for bone health (bisphosphonates) can reduce the risk of fractures while taking steroids for inflammation. Patients receiving sulfamethoxazole-trimethoprim or dapsone for prevention and also taking methotrexate for treatment are advised to take folate or leucovorin on days after methotrexate treatment.In 2017, the U.S Food and Drug Administration (FDA) approved Actemra (tocilizumab) for use in giant cell arteritis after a study showed increased remission rates and reduced steroid use over 1 year in adults. This approval provided another treatment alternative for patients that are not able to take steroids or experience relapses with steroids. Relapses can occur and are usually treated with higher doses of steroid therapy and may require treatment with medications such as methotrexate, leflunomide or Actemra (tocilizumab). | Therapies of Giant Cell Arteritis. Treatment
As soon as a diagnosis is made the start of steroid (corticosteroid) therapy is recommended and should not be delayed due to waiting for confirmation with other tests like biopsies or imaging. Most patients start with prednisolone. For patients with visual or cerebral symptoms, intravenous methylprednisolone should be considered and then changed to oral dosing. Steroid therapy can also be started at higher doses and then lowered (tapering) in order to reduce the reoccurrence of giant cell arteritis. Inflammation should return to normal after 2 to 4 weeks of therapy and treatment would usually last up to 24 months, but some patients may require years of therapy.Steroids have a risk of bone loss, so medications may be recommended for bone protection. Studies have shown that medications for bone health (bisphosphonates) can reduce the risk of fractures while taking steroids for inflammation. Patients receiving sulfamethoxazole-trimethoprim or dapsone for prevention and also taking methotrexate for treatment are advised to take folate or leucovorin on days after methotrexate treatment.In 2017, the U.S Food and Drug Administration (FDA) approved Actemra (tocilizumab) for use in giant cell arteritis after a study showed increased remission rates and reduced steroid use over 1 year in adults. This approval provided another treatment alternative for patients that are not able to take steroids or experience relapses with steroids. Relapses can occur and are usually treated with higher doses of steroid therapy and may require treatment with medications such as methotrexate, leflunomide or Actemra (tocilizumab). | 509 | Giant Cell Arteritis |
nord_510_0 | Overview of Giant Cell Myocarditis | Giant cell myocarditis is a rare cardiovascular disorder that occurs for unknown reasons (idiopathic). It is characterized by inflammation of the heart muscle (myocardium), a condition referred to as myocarditis. Inflammation is caused by widespread infiltration of giant cells associated with other inflammatory cells and heart muscle cell destruction. Giant cells are abnormal masses produced by the fusion of inflammatory cells called macrophages. Individuals with giant cell myocarditis may develop abnormal heartbeats, chest pain and, eventually, heart failure. Many individuals eventually require a heart transplant. The disorder most often occurs in young adults. | Overview of Giant Cell Myocarditis. Giant cell myocarditis is a rare cardiovascular disorder that occurs for unknown reasons (idiopathic). It is characterized by inflammation of the heart muscle (myocardium), a condition referred to as myocarditis. Inflammation is caused by widespread infiltration of giant cells associated with other inflammatory cells and heart muscle cell destruction. Giant cells are abnormal masses produced by the fusion of inflammatory cells called macrophages. Individuals with giant cell myocarditis may develop abnormal heartbeats, chest pain and, eventually, heart failure. Many individuals eventually require a heart transplant. The disorder most often occurs in young adults. | 510 | Giant Cell Myocarditis |
nord_510_1 | Symptoms of Giant Cell Myocarditis | The onset of symptoms of giant cell myocarditis is often rapid. Initial symptoms may include swelling of the ankles, chest pain, heart palpitations, fatigue and shortness of breath (dyspnea) especially upon exertion or lying flat. Affected individuals eventually develop irregular heartbeats (arrhythmias) such as abnormally fast (tachycardia) or slow (brachycardia) heartbeats. Arrhythmias may cause sudden episodes of lightheadedness or loss of consciousness.The above-mentioned symptoms of giant cell myocarditis occur due to congestive heart failure or heart block. These two heart abnormalities are progressive and eventually result in life-threatening complications. In individuals with giant cell myocarditis, the average time from symptom onset to life-threatening complications or heart transplant is five and a half months.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood throughout the body.Congestive heart failure is a condition in which abnormal enlargement or widening (dilatation) of one or more of the chambers of the heart results in weakening of the heart’s pumping action, causing a limited ability to circulate blood to the lungs and the rest of the body. This leads to fluid buildup in the heart, lungs and various body tissues. In some cases, all four chambers of the heart may be affected. Symptoms may include fatigue, shortness of breath (dyspnea) upon exertion, swelling of the legs and feet, and chest pain.Heart block may be partial or complete. In the mild form of heart block (first degree), the two upper chambers of the heart (atria) beat normally, but the contractions of the two lower chambers (ventricles) slightly lag behind. In the more severe forms (second degree), not all of the atrial beats are conducted to the ventricles. In complete heart block (third degree), the atria and ventricles beat independently. Individuals with first- or second-degree heart block may not experience symptoms (asymptomatic). However, individuals with complete heart block may experience episodes of unconsciousness (syncope), breathlessness, and/or fatigue. | Symptoms of Giant Cell Myocarditis. The onset of symptoms of giant cell myocarditis is often rapid. Initial symptoms may include swelling of the ankles, chest pain, heart palpitations, fatigue and shortness of breath (dyspnea) especially upon exertion or lying flat. Affected individuals eventually develop irregular heartbeats (arrhythmias) such as abnormally fast (tachycardia) or slow (brachycardia) heartbeats. Arrhythmias may cause sudden episodes of lightheadedness or loss of consciousness.The above-mentioned symptoms of giant cell myocarditis occur due to congestive heart failure or heart block. These two heart abnormalities are progressive and eventually result in life-threatening complications. In individuals with giant cell myocarditis, the average time from symptom onset to life-threatening complications or heart transplant is five and a half months.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood throughout the body.Congestive heart failure is a condition in which abnormal enlargement or widening (dilatation) of one or more of the chambers of the heart results in weakening of the heart’s pumping action, causing a limited ability to circulate blood to the lungs and the rest of the body. This leads to fluid buildup in the heart, lungs and various body tissues. In some cases, all four chambers of the heart may be affected. Symptoms may include fatigue, shortness of breath (dyspnea) upon exertion, swelling of the legs and feet, and chest pain.Heart block may be partial or complete. In the mild form of heart block (first degree), the two upper chambers of the heart (atria) beat normally, but the contractions of the two lower chambers (ventricles) slightly lag behind. In the more severe forms (second degree), not all of the atrial beats are conducted to the ventricles. In complete heart block (third degree), the atria and ventricles beat independently. Individuals with first- or second-degree heart block may not experience symptoms (asymptomatic). However, individuals with complete heart block may experience episodes of unconsciousness (syncope), breathlessness, and/or fatigue. | 510 | Giant Cell Myocarditis |
nord_510_2 | Causes of Giant Cell Myocarditis | The exact cause of giant cell myocarditis is unknown. Approximately 20 percent of cases occur in individuals with autoimmune disorders suggesting that autoimmunity may play a role in the development of giant cell myocarditis. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons.Autoimmune disorders associated with giant cell myocarditis include inflammatory bowel disease such as Crohn’s disease. Some cases of giant cell myocarditis have been associated with a tumor of the thymus (thymoma). The thymus is a relatively small organ behind the breastbone that is thought to play an important role in the immune system until puberty. | Causes of Giant Cell Myocarditis. The exact cause of giant cell myocarditis is unknown. Approximately 20 percent of cases occur in individuals with autoimmune disorders suggesting that autoimmunity may play a role in the development of giant cell myocarditis. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons.Autoimmune disorders associated with giant cell myocarditis include inflammatory bowel disease such as Crohn’s disease. Some cases of giant cell myocarditis have been associated with a tumor of the thymus (thymoma). The thymus is a relatively small organ behind the breastbone that is thought to play an important role in the immune system until puberty. | 510 | Giant Cell Myocarditis |
nord_510_3 | Affects of Giant Cell Myocarditis | Giant cell myocarditis affects males and females in equal numbers. It can affect individuals of any age although most cases occur in young or middle-aged adults (median age 42 years). Approximately 300 cases have been reported in the medical literature. | Affects of Giant Cell Myocarditis. Giant cell myocarditis affects males and females in equal numbers. It can affect individuals of any age although most cases occur in young or middle-aged adults (median age 42 years). Approximately 300 cases have been reported in the medical literature. | 510 | Giant Cell Myocarditis |
nord_510_4 | Related disorders of Giant Cell Myocarditis | Symptoms of the following disorders can be similar to those of giant cell myocarditis. Comparisons may be useful for a differential diagnosis:Cardiac sarcoidosis refers to the heart abnormalities sometimes associated with sarcoidosis, a rare disease characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of certain granular white blood cells (modified macrophages or epithelioid cells) in certain organs of the body. The range and severity of symptoms associated with sarcoidosis vary greatly, depending upon the specific organ(s) involved and the degree of such involvement. In some cases, only the heart may be involved (isolated cardiac sarcoidosis). The exact cause of sarcoidosis is not known. However, infectious, environmental, genetic and immunological factors are under investigation as possible causes of the disorder. (For more information on this disorder, choose “sarcoidosis” as your search term in the Rare Disease Database.)Lymphocytic myocarditis is a rare condition in which heart muscle inflammation (myocarditis) is caused by accumulation of white blood cells (lymphocytes). Symptoms may include chest pain, heart palpitations, fatigue and shortness of breath (dyspnea) especially upon exertion or lying flat. Lymphocytic myocarditis is often caused by a virus.Hypersensitivity myocarditis is a general term for inflammation of the heart muscle (myocarditis) that occurs due to an allergic reaction (hypersensitivity) to certain agents such as drugs. Symptoms may include chest pain, heart palpitations, fatigue and shortness of breath (dyspnea) especially, upon exertion or lying flat. Some affected individuals may develop a rash or abnormal liver function studies. | Related disorders of Giant Cell Myocarditis. Symptoms of the following disorders can be similar to those of giant cell myocarditis. Comparisons may be useful for a differential diagnosis:Cardiac sarcoidosis refers to the heart abnormalities sometimes associated with sarcoidosis, a rare disease characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of certain granular white blood cells (modified macrophages or epithelioid cells) in certain organs of the body. The range and severity of symptoms associated with sarcoidosis vary greatly, depending upon the specific organ(s) involved and the degree of such involvement. In some cases, only the heart may be involved (isolated cardiac sarcoidosis). The exact cause of sarcoidosis is not known. However, infectious, environmental, genetic and immunological factors are under investigation as possible causes of the disorder. (For more information on this disorder, choose “sarcoidosis” as your search term in the Rare Disease Database.)Lymphocytic myocarditis is a rare condition in which heart muscle inflammation (myocarditis) is caused by accumulation of white blood cells (lymphocytes). Symptoms may include chest pain, heart palpitations, fatigue and shortness of breath (dyspnea) especially upon exertion or lying flat. Lymphocytic myocarditis is often caused by a virus.Hypersensitivity myocarditis is a general term for inflammation of the heart muscle (myocarditis) that occurs due to an allergic reaction (hypersensitivity) to certain agents such as drugs. Symptoms may include chest pain, heart palpitations, fatigue and shortness of breath (dyspnea) especially, upon exertion or lying flat. Some affected individuals may develop a rash or abnormal liver function studies. | 510 | Giant Cell Myocarditis |
nord_510_5 | Diagnosis of Giant Cell Myocarditis | A diagnosis of giant cell myocarditis is made by biopsy of heart tissue. A biopsy is a test in which small tissue sample is surgically removed and studied microscopically. Tests to exclude other cause of heart abnormalities may also be performed. These tests may include echocardiogram and cardiac catheterization. | Diagnosis of Giant Cell Myocarditis. A diagnosis of giant cell myocarditis is made by biopsy of heart tissue. A biopsy is a test in which small tissue sample is surgically removed and studied microscopically. Tests to exclude other cause of heart abnormalities may also be performed. These tests may include echocardiogram and cardiac catheterization. | 510 | Giant Cell Myocarditis |
nord_510_6 | Therapies of Giant Cell Myocarditis | Treatment
Standard and supportive treatment options for cardiac failure and arrhythmias are recommended. These treatment options may include the insertion of a pacemaker or implantable heart defibrillator.Affected individuals may require a heart transplant. Affected individuals are often evaluated for heart transplantation shortly after diagnosis. In 20-25% of patients, infiltration of giant cells has recurred after heart transplantation. Immunosuppresssion with drugs that include cyclosporine prolong survival free of transplantation. GCM can recur after therapy in both the native and allografted heart. | Therapies of Giant Cell Myocarditis. Treatment
Standard and supportive treatment options for cardiac failure and arrhythmias are recommended. These treatment options may include the insertion of a pacemaker or implantable heart defibrillator.Affected individuals may require a heart transplant. Affected individuals are often evaluated for heart transplantation shortly after diagnosis. In 20-25% of patients, infiltration of giant cells has recurred after heart transplantation. Immunosuppresssion with drugs that include cyclosporine prolong survival free of transplantation. GCM can recur after therapy in both the native and allografted heart. | 510 | Giant Cell Myocarditis |
nord_511_0 | Overview of Giant Congenital Melanocytic Nevus | Congenital melanocytic nevi (CMN) are visible pigmented (melanocytic) proliferations in the skin that are present at birth. CMN are benign, tumor-like malformations resulting from faulty development of pigment cell (melanocyte) precursors in the embryo, and composed of an abnormal mixture of skin elements. Defined areas of these melanocytic proliferations cover surfaces at the base of the epidermis ranging from a few millimeters in diameter to large sectors of the body. In the larger forms, the CMN (single or multiple) also extend(s) vertically into the deeper dermis and more rarely, into the hypodermis or even subcutaneous tissues. The most superficial component of the CMN is the most highly pigmented, conferring brown-to-black shades to the overlying epidermis. CMN are usually classified according to their predicted largest diameter in adulthood, as if they were circular (predicted adult diameter or PAS). The most used classification assigns small CMN as less than 1.5 cm PAS, medium sized CMN between 1.5 to 19.9 cm, and large CMN 20 cm or greater. CMN measuring 50 cm or larger in PAS have been referred to as ‘giant congenital melanocytic nevi’.CMN can be light brown to black patches or plaques, can present in variable ways, and cover nearly any size surface area or any part of the body. The incidence of CMN seems to be independent of skin color or other ethnic factors. Small to medium CMN are predicted to occur in more than one in a hundred births. Large and especially giant CMN, exceeding a predicted diameter at adult age of at least 20 cm on the body, form a much rarer subset, with prevalence estimated at around 1 in 50,000 births. Non-pigmented or small incipient congenital lesions can also be present – these are known as “tardive”; the emergence of so-called “satellite” nevi throughout the first few years of life in conjunction with larger CMN probably reflects the postnatal maturation of such precursors. On occasion, even a primary CMN can appear in a tardive manner. Treatment options currently are exclusively surgical. Neurocutaneous melanocytosis, cited in earlier literature as neurocutaneous melanosis (NCM), is a neurological and cutaneous disorder characterized by abnormal aggregations of nevomelanocytes within the central nervous system and the skin. NCM is a complication of the larger forms of CMN, or multiple smaller CMN, in a fraction of patients. Recent studies find the incidence of symptomatic and asymptomatic NCM together to range between 5 and 15 % of all persons with large and giant CMN. Melanoma develops in an estimated 1-2% of patients with LCMN or NCM, more frequently and at earlier ages than in the general population.The first recorded descriptions of children with large CMN date from observations published by the Count of Buffon before the French Revolution. Other giant, sometimes rugous CMN were described in the early 19th century.CMN tend to grow in a proportional fashion to the child’s growth; occasionally growth appears out of proportion to the child during periods of particularly rapid growth such as early infancy. A new size/color/texture classification, recently developed by Marghoob, Krengel and other experts in the field, may eventually help in better predicting patients at the greatest risk for developing melanoma or neurological disease by more reproducibly classifying similar patients. Nomograms can assist clinicians in easily determining the PAS of a nevus examined at any point during childhood. | Overview of Giant Congenital Melanocytic Nevus. Congenital melanocytic nevi (CMN) are visible pigmented (melanocytic) proliferations in the skin that are present at birth. CMN are benign, tumor-like malformations resulting from faulty development of pigment cell (melanocyte) precursors in the embryo, and composed of an abnormal mixture of skin elements. Defined areas of these melanocytic proliferations cover surfaces at the base of the epidermis ranging from a few millimeters in diameter to large sectors of the body. In the larger forms, the CMN (single or multiple) also extend(s) vertically into the deeper dermis and more rarely, into the hypodermis or even subcutaneous tissues. The most superficial component of the CMN is the most highly pigmented, conferring brown-to-black shades to the overlying epidermis. CMN are usually classified according to their predicted largest diameter in adulthood, as if they were circular (predicted adult diameter or PAS). The most used classification assigns small CMN as less than 1.5 cm PAS, medium sized CMN between 1.5 to 19.9 cm, and large CMN 20 cm or greater. CMN measuring 50 cm or larger in PAS have been referred to as ‘giant congenital melanocytic nevi’.CMN can be light brown to black patches or plaques, can present in variable ways, and cover nearly any size surface area or any part of the body. The incidence of CMN seems to be independent of skin color or other ethnic factors. Small to medium CMN are predicted to occur in more than one in a hundred births. Large and especially giant CMN, exceeding a predicted diameter at adult age of at least 20 cm on the body, form a much rarer subset, with prevalence estimated at around 1 in 50,000 births. Non-pigmented or small incipient congenital lesions can also be present – these are known as “tardive”; the emergence of so-called “satellite” nevi throughout the first few years of life in conjunction with larger CMN probably reflects the postnatal maturation of such precursors. On occasion, even a primary CMN can appear in a tardive manner. Treatment options currently are exclusively surgical. Neurocutaneous melanocytosis, cited in earlier literature as neurocutaneous melanosis (NCM), is a neurological and cutaneous disorder characterized by abnormal aggregations of nevomelanocytes within the central nervous system and the skin. NCM is a complication of the larger forms of CMN, or multiple smaller CMN, in a fraction of patients. Recent studies find the incidence of symptomatic and asymptomatic NCM together to range between 5 and 15 % of all persons with large and giant CMN. Melanoma develops in an estimated 1-2% of patients with LCMN or NCM, more frequently and at earlier ages than in the general population.The first recorded descriptions of children with large CMN date from observations published by the Count of Buffon before the French Revolution. Other giant, sometimes rugous CMN were described in the early 19th century.CMN tend to grow in a proportional fashion to the child’s growth; occasionally growth appears out of proportion to the child during periods of particularly rapid growth such as early infancy. A new size/color/texture classification, recently developed by Marghoob, Krengel and other experts in the field, may eventually help in better predicting patients at the greatest risk for developing melanoma or neurological disease by more reproducibly classifying similar patients. Nomograms can assist clinicians in easily determining the PAS of a nevus examined at any point during childhood. | 511 | Giant Congenital Melanocytic Nevus |
nord_511_1 | Symptoms of Giant Congenital Melanocytic Nevus | Large/giant CMN are obvious at birth, most commonly covering an aspect of the trunk and less common on the head, neck and extremities. Affected areas of large CMN have been designated as “cape”, “bathing trunk”, “tippet” or “garment” CMN due to their respective distributions. Lesions may have irregular or geographic borders. In about 75% of cases, multiple small CMN will accompany the large CMN, usually in a generalized manner. “Satellite” is a commonly used description of discrete small or medium CMN or tardive nevi in the presence of a large/giant CMN, though semantically and molecularly, it is more accurate to refer to “disseminated” lesions. These additional smaller, disseminated CMN may be present at birth and/or may increase to significant numbers over the first few years of life. These multiple CMN should be noted in number, as greater numbers (>20) have been correlated with neurological anomalies.In general, CMN can be tan, brown to dark-brown or black and rarely blue in color and may be flat, raised, or even quite thickened at birth. Color may be quite uniform throughout, or consist of multiple colors including shades of brown, black, red or blue. Texture may be smooth, highly nodular or cobblestone-like; hair may or may not be present at birth and may or may not develop as the child ages. This hair is fine (vellus) or more often coarse (terminal) in texture. A “cerebriform” or brain-like texture may be present, particularly in large scalp CMN. Areas of the nevus may be infiltrated by overgrowths of fatty or nerve tissue, so-called lipomatous or neurotized areas respectively, features that can be seen most often in larger CMN. Over time, CMN may become darker or lighter, more or less heterogenous in color and the surface texture may change. CMN can also develop superimposed nodules, which are usually benign but require surveillance. The CMN-involved skin can be dry and develop overlying eczema, resulting in intermittent or chronic itchiness (pruritis). CMN may also have fewer sweat glands than unaffected skin, resulting in potential overheating episodes or increased sweating in other areas of the body to compensate. Areas of larger CMN may have notably less fat under the skin, particularly around the flanks, limbs and buttocks. At birth or within the first few weeks of life, transient erosions or ulcerations may develop over large CMN due to incomplete maturation of the skin during this period. Healing usually occurs over days to weeks. Also notable during the infantile period are rapidly growing ‘proliferative nodules’ within the CMN that mimic melanoma but show benign features when examined. Evaluation of these nodules by a dermatopathologist with expertise in pigmented lesions is recommended to avoid unnecessary surgery and possible toxic adjuvant therapy if misdiagnosed as melanoma. Significant lightening of color in large CMN can also been seen in the first few years of life, especially those that involve the scalp. | Symptoms of Giant Congenital Melanocytic Nevus. Large/giant CMN are obvious at birth, most commonly covering an aspect of the trunk and less common on the head, neck and extremities. Affected areas of large CMN have been designated as “cape”, “bathing trunk”, “tippet” or “garment” CMN due to their respective distributions. Lesions may have irregular or geographic borders. In about 75% of cases, multiple small CMN will accompany the large CMN, usually in a generalized manner. “Satellite” is a commonly used description of discrete small or medium CMN or tardive nevi in the presence of a large/giant CMN, though semantically and molecularly, it is more accurate to refer to “disseminated” lesions. These additional smaller, disseminated CMN may be present at birth and/or may increase to significant numbers over the first few years of life. These multiple CMN should be noted in number, as greater numbers (>20) have been correlated with neurological anomalies.In general, CMN can be tan, brown to dark-brown or black and rarely blue in color and may be flat, raised, or even quite thickened at birth. Color may be quite uniform throughout, or consist of multiple colors including shades of brown, black, red or blue. Texture may be smooth, highly nodular or cobblestone-like; hair may or may not be present at birth and may or may not develop as the child ages. This hair is fine (vellus) or more often coarse (terminal) in texture. A “cerebriform” or brain-like texture may be present, particularly in large scalp CMN. Areas of the nevus may be infiltrated by overgrowths of fatty or nerve tissue, so-called lipomatous or neurotized areas respectively, features that can be seen most often in larger CMN. Over time, CMN may become darker or lighter, more or less heterogenous in color and the surface texture may change. CMN can also develop superimposed nodules, which are usually benign but require surveillance. The CMN-involved skin can be dry and develop overlying eczema, resulting in intermittent or chronic itchiness (pruritis). CMN may also have fewer sweat glands than unaffected skin, resulting in potential overheating episodes or increased sweating in other areas of the body to compensate. Areas of larger CMN may have notably less fat under the skin, particularly around the flanks, limbs and buttocks. At birth or within the first few weeks of life, transient erosions or ulcerations may develop over large CMN due to incomplete maturation of the skin during this period. Healing usually occurs over days to weeks. Also notable during the infantile period are rapidly growing ‘proliferative nodules’ within the CMN that mimic melanoma but show benign features when examined. Evaluation of these nodules by a dermatopathologist with expertise in pigmented lesions is recommended to avoid unnecessary surgery and possible toxic adjuvant therapy if misdiagnosed as melanoma. Significant lightening of color in large CMN can also been seen in the first few years of life, especially those that involve the scalp. | 511 | Giant Congenital Melanocytic Nevus |
nord_511_2 | Causes of Giant Congenital Melanocytic Nevus | Both CMN and acquired melanocytic nevi are associated with somatic mutations in intracellular proteins of the microtubule-associated protein signal transduction pathway. For 4 in 5 cases, a single mutation in the DNA encoding the NRAS enzyme can be found, and for up to one in 6 cases, a single mutation in the DNA for the BRAF enzyme. The currently identified mutations cause the enzymes to become permanently active, and have been found in many apparently unrelated cancers as well, perhaps driving cells to proliferate. These findings imply that other, less common and not yet identified, mutations may also contribute to cause CMN. Both CMN and normal pigment cells (melanocytes) come from an embryonic cell population that separates from the future central nervous system before the end of the first month of pregnancy, and as it multiplies, the population colonizes all the tissues of the body. Within the skin, these cells then become pigment cell precursors that are both between and at the base of hair follicles. Constant activation of NRAS or BRAF may drive the prenatal proliferation of this cell population. A second mutation that occurs in the other copy of the NRAS or BRAF gene in a CMN cell may be responsible for the onset of malignant melanoma, which happens more frequently in children affected with large/giant CMN than in the general pediatric population, where melanoma is exceedingly rare. Recent results indicate that the same NRAS mutations may also be responsible for nevomelanocyte proliferation within the central nervous system, causing NCM.Large/giant CMN are usually sporadic, but familial occurrence has been rarely reported. One of the first reports that families of patients with giant CMN had relatives with multiple small pigmented nevi was made over 40 years ago, and this observation has been made many times since. Affected siblings and first cousins have also been observed. Autosomal dominant inheritance with reduced penetrance and/or multifactorial inheritance are possible explanations for the familial cases.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause the disease. The gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Some individuals who have the abnormal gene may not display symptoms of the condition (reduced penetrance). Multifactorial inheritance means that many factors, including a combination of genes from both parents, in addition to unknown environmental factors, cause the condition. | Causes of Giant Congenital Melanocytic Nevus. Both CMN and acquired melanocytic nevi are associated with somatic mutations in intracellular proteins of the microtubule-associated protein signal transduction pathway. For 4 in 5 cases, a single mutation in the DNA encoding the NRAS enzyme can be found, and for up to one in 6 cases, a single mutation in the DNA for the BRAF enzyme. The currently identified mutations cause the enzymes to become permanently active, and have been found in many apparently unrelated cancers as well, perhaps driving cells to proliferate. These findings imply that other, less common and not yet identified, mutations may also contribute to cause CMN. Both CMN and normal pigment cells (melanocytes) come from an embryonic cell population that separates from the future central nervous system before the end of the first month of pregnancy, and as it multiplies, the population colonizes all the tissues of the body. Within the skin, these cells then become pigment cell precursors that are both between and at the base of hair follicles. Constant activation of NRAS or BRAF may drive the prenatal proliferation of this cell population. A second mutation that occurs in the other copy of the NRAS or BRAF gene in a CMN cell may be responsible for the onset of malignant melanoma, which happens more frequently in children affected with large/giant CMN than in the general pediatric population, where melanoma is exceedingly rare. Recent results indicate that the same NRAS mutations may also be responsible for nevomelanocyte proliferation within the central nervous system, causing NCM.Large/giant CMN are usually sporadic, but familial occurrence has been rarely reported. One of the first reports that families of patients with giant CMN had relatives with multiple small pigmented nevi was made over 40 years ago, and this observation has been made many times since. Affected siblings and first cousins have also been observed. Autosomal dominant inheritance with reduced penetrance and/or multifactorial inheritance are possible explanations for the familial cases.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause the disease. The gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Some individuals who have the abnormal gene may not display symptoms of the condition (reduced penetrance). Multifactorial inheritance means that many factors, including a combination of genes from both parents, in addition to unknown environmental factors, cause the condition. | 511 | Giant Congenital Melanocytic Nevus |
nord_511_3 | Affects of Giant Congenital Melanocytic Nevus | People of all races and colors of skin can be affected with large/giant CMN. A slight female preponderance has been noted in large/ giant CMN (male/female ratio of 1 to 1.4), but is not observed in the smaller population of people affected by NCM. | Affects of Giant Congenital Melanocytic Nevus. People of all races and colors of skin can be affected with large/giant CMN. A slight female preponderance has been noted in large/ giant CMN (male/female ratio of 1 to 1.4), but is not observed in the smaller population of people affected by NCM. | 511 | Giant Congenital Melanocytic Nevus |
nord_511_4 | Related disorders of Giant Congenital Melanocytic Nevus | Neurocutaneous melanocytosis is present in an estimated 5-15% of patients with large/giant CMN, while melanoma can occur in an estimated 1-2%.Melanoma:The development of melanoma is a significant complication in people with large/giant CMN. The risk of melanoma development (cutaneous or extracutaneous) in large CMN is at the most 5% over a lifetime, considering prospective and retrospective cohort studies with significant follow-up, and seemingly independent of ethnicity. About half of these melanomas occur in the first 5 years of life. Cutaneous melanomas tend to arise deep in the skin or residual fatty tissues of a large CMN, making early detection difficult. Melanomas may also arise in other non-cutaneous areas such as the brain, and sometimes the primary location of melanoma is not found. Other malignancies such as liposarcomas, rhabdomyosarcomas and malignant peripheral nerve sheath tumors have been described in association with large CMN. No reliable case of melanoma arising within an associated small CMN has yet been reported.Neurocutaneous melanocytosis and central nervous system malformations:In addition to melanoma, patients with large CMN and multiple medium CMN are also at risk for developing neurocutaneous melanocytosis (NCM), estimated to occur in 7% of individuals born with large CMN. NCM is a proliferation of pigment cells in the leptomeninges or brain parenchyma due to abnormal migration or differentiation of their precursors, which normally invest these tissues to become mostly vascular pericytes with a few melanocytes. Rokitansky is credited with the first description of NCM in a teenaged girl with hydrocephalus, giant CMN and developmental delay, complete with autopsy after her death from tuberculosis, that confirmed the meningeal melanocytosis. Although pigmented deposits are generally benign, symptoms such as hydrocephalus and seizures indeed can occur, or intracerebral melanoma develops in a small proportion of cases. NCM has been classically defined by Kadonaga and Frieden as the co-existence of large or multiple CMN (>3) in association with meningeal melanocytosis or melanoma, with no evidence of cutaneous melanoma, except in patients whom the examined areas of the meningeal lesions are histologically benign.Magnetic resonance imaging (MRI) with contrast of the brain and spine may be recommended for any individual with multiple CMN, or a large CMN with > 20 “satellite” nevi, as those with 20 or more disseminated nevi are 5 more times likely to have NCM than those with less. Individuals with giant CMN > 40cm PAS, or those with a CMN over the posterior axis (according to some authors) may also be at increased risk for NCM. Only about 4% of these ‘high-risk’ CMN individuals will develop symptomatic NCM; for these, prognosis can be poor, even without melanoma development, although many symptomatic patients survive with various neurological deficits. Ideally, MRI should be done in the first 4-6 months of life, prior to full myelinization of the brain, which may obscure the melanin signal. Technical suggestions by an experienced radiologist in demonstrating NCM are available at this link: http://www.nevus.org/page_file_download.php?id=30 (accessed Jan. 30, 2013).Based on previous studies, approximately half of those individuals with NCM will become symptomatic, often before the age of 5. Patients can present with hydrocephalus or other signs indicating increased cranial pressure, such as headaches and vomiting, or seizures. Mild to severe developmental delay and abnormal tone have also been described in children with high-risk CMN. Asymptomatic NCM (positive MRI without clinical symptoms attributed to NCM) has been diagnosed in up to 30% of patients with supposedly high risk CMN, and the percentage of patients that may eventually develop symptoms from NCM is currently unknown. Epilepsy can be responsive or refractory to standard medications and also can be treated favorably by surgical approaches used in other forms of epilepsy.Other CNS tumors and malformations found often incidentally during brain and spine imaging of CMN patients have included Dandy-Walker malformations, lissencephaly, Chiari I malformations, posterior fossa cysts, spinal and other lipomas, arachnoid cysts and tethered spinal cord.The differential diagnosis of small and medium CMN includes smooth muscle hamartoma or Becker’s nevus, mastocytoma, variants of dermal melanocytosis, and café au lait macules. Large CMN may be confused with a pigmented, plexiform neurofibroma. Histologic evaluation, dermoscopic evaluation and the development of typical CMN features over time may clarify the diagnosis. | Related disorders of Giant Congenital Melanocytic Nevus. Neurocutaneous melanocytosis is present in an estimated 5-15% of patients with large/giant CMN, while melanoma can occur in an estimated 1-2%.Melanoma:The development of melanoma is a significant complication in people with large/giant CMN. The risk of melanoma development (cutaneous or extracutaneous) in large CMN is at the most 5% over a lifetime, considering prospective and retrospective cohort studies with significant follow-up, and seemingly independent of ethnicity. About half of these melanomas occur in the first 5 years of life. Cutaneous melanomas tend to arise deep in the skin or residual fatty tissues of a large CMN, making early detection difficult. Melanomas may also arise in other non-cutaneous areas such as the brain, and sometimes the primary location of melanoma is not found. Other malignancies such as liposarcomas, rhabdomyosarcomas and malignant peripheral nerve sheath tumors have been described in association with large CMN. No reliable case of melanoma arising within an associated small CMN has yet been reported.Neurocutaneous melanocytosis and central nervous system malformations:In addition to melanoma, patients with large CMN and multiple medium CMN are also at risk for developing neurocutaneous melanocytosis (NCM), estimated to occur in 7% of individuals born with large CMN. NCM is a proliferation of pigment cells in the leptomeninges or brain parenchyma due to abnormal migration or differentiation of their precursors, which normally invest these tissues to become mostly vascular pericytes with a few melanocytes. Rokitansky is credited with the first description of NCM in a teenaged girl with hydrocephalus, giant CMN and developmental delay, complete with autopsy after her death from tuberculosis, that confirmed the meningeal melanocytosis. Although pigmented deposits are generally benign, symptoms such as hydrocephalus and seizures indeed can occur, or intracerebral melanoma develops in a small proportion of cases. NCM has been classically defined by Kadonaga and Frieden as the co-existence of large or multiple CMN (>3) in association with meningeal melanocytosis or melanoma, with no evidence of cutaneous melanoma, except in patients whom the examined areas of the meningeal lesions are histologically benign.Magnetic resonance imaging (MRI) with contrast of the brain and spine may be recommended for any individual with multiple CMN, or a large CMN with > 20 “satellite” nevi, as those with 20 or more disseminated nevi are 5 more times likely to have NCM than those with less. Individuals with giant CMN > 40cm PAS, or those with a CMN over the posterior axis (according to some authors) may also be at increased risk for NCM. Only about 4% of these ‘high-risk’ CMN individuals will develop symptomatic NCM; for these, prognosis can be poor, even without melanoma development, although many symptomatic patients survive with various neurological deficits. Ideally, MRI should be done in the first 4-6 months of life, prior to full myelinization of the brain, which may obscure the melanin signal. Technical suggestions by an experienced radiologist in demonstrating NCM are available at this link: http://www.nevus.org/page_file_download.php?id=30 (accessed Jan. 30, 2013).Based on previous studies, approximately half of those individuals with NCM will become symptomatic, often before the age of 5. Patients can present with hydrocephalus or other signs indicating increased cranial pressure, such as headaches and vomiting, or seizures. Mild to severe developmental delay and abnormal tone have also been described in children with high-risk CMN. Asymptomatic NCM (positive MRI without clinical symptoms attributed to NCM) has been diagnosed in up to 30% of patients with supposedly high risk CMN, and the percentage of patients that may eventually develop symptoms from NCM is currently unknown. Epilepsy can be responsive or refractory to standard medications and also can be treated favorably by surgical approaches used in other forms of epilepsy.Other CNS tumors and malformations found often incidentally during brain and spine imaging of CMN patients have included Dandy-Walker malformations, lissencephaly, Chiari I malformations, posterior fossa cysts, spinal and other lipomas, arachnoid cysts and tethered spinal cord.The differential diagnosis of small and medium CMN includes smooth muscle hamartoma or Becker’s nevus, mastocytoma, variants of dermal melanocytosis, and café au lait macules. Large CMN may be confused with a pigmented, plexiform neurofibroma. Histologic evaluation, dermoscopic evaluation and the development of typical CMN features over time may clarify the diagnosis. | 511 | Giant Congenital Melanocytic Nevus |
nord_511_5 | Diagnosis of Giant Congenital Melanocytic Nevus | Making the diagnosis of a CMN is most often done by examining clinical and dermoscopic features. The larger CMN can easily be diagnosed based solely on their size. For smaller CMN, their history of presence since birth, surface topography, presence of hair or globular dermoscopic pattern can assist in diagnosis. When biopsied, the histological features of CMN are similar to those found in common acquired nevi which arise later in life; however, CMN tend have a greater cellularity with deeper extension of nevus cells into the deep dermis and subcutis, and cells extend along adnexal structures such as hair follicles and around blood vessels and nerves. Histological criteria alone cannot be used to dictate with absolute certainty whether a nevus is congenital or acquired.Clinical Testing and WorkupMagnetic resonance imaging (MRI) with contrast of the brain and spine is recommended for any individual with multiple CMN, or a large CMN with > 20 satellite nevi, as those with 20 or more satellite nevi are 5 more times likely to have NCM than those with fewer, and some of these will become symptomatic. Any patient with new onset of neurological symptoms, such as enuresia (extended night-time bed-wetting) or tiptoeing which indicate the possibility of a tethered spinal cord, epilepsy, or "sunset eyes" (indicative of increased intracranial pressure due to hydrocephalus) should also undergo a neurologic evaluation and appropriate imaging. Patients with asymptomatic NCM should also be followed by a neurologist, on a yearly basis or more frequently if concerns exist. The need for subsequent MRIs in those asymptomatic patients is not clear; however, most experts will not recommend further MRI unless symptoms arise. Patients with significant symptomatic NCM should consider foregoing elective surgical removal of the CMN until prognosis is clear.Lifelong monitoring in patients with extensive CMN is mandatory regardless of the treatment employed, both with self-skin examinations and in an experienced dermatologist’s office. Serial photographs, the use of dermoscopy, palpation of nevus and scars, examination of lymph nodes and a thorough review of systems may aid physicians in early detection of melanoma. Suspicious lesions should be removed and examined histologically by an experienced pathologist. | Diagnosis of Giant Congenital Melanocytic Nevus. Making the diagnosis of a CMN is most often done by examining clinical and dermoscopic features. The larger CMN can easily be diagnosed based solely on their size. For smaller CMN, their history of presence since birth, surface topography, presence of hair or globular dermoscopic pattern can assist in diagnosis. When biopsied, the histological features of CMN are similar to those found in common acquired nevi which arise later in life; however, CMN tend have a greater cellularity with deeper extension of nevus cells into the deep dermis and subcutis, and cells extend along adnexal structures such as hair follicles and around blood vessels and nerves. Histological criteria alone cannot be used to dictate with absolute certainty whether a nevus is congenital or acquired.Clinical Testing and WorkupMagnetic resonance imaging (MRI) with contrast of the brain and spine is recommended for any individual with multiple CMN, or a large CMN with > 20 satellite nevi, as those with 20 or more satellite nevi are 5 more times likely to have NCM than those with fewer, and some of these will become symptomatic. Any patient with new onset of neurological symptoms, such as enuresia (extended night-time bed-wetting) or tiptoeing which indicate the possibility of a tethered spinal cord, epilepsy, or "sunset eyes" (indicative of increased intracranial pressure due to hydrocephalus) should also undergo a neurologic evaluation and appropriate imaging. Patients with asymptomatic NCM should also be followed by a neurologist, on a yearly basis or more frequently if concerns exist. The need for subsequent MRIs in those asymptomatic patients is not clear; however, most experts will not recommend further MRI unless symptoms arise. Patients with significant symptomatic NCM should consider foregoing elective surgical removal of the CMN until prognosis is clear.Lifelong monitoring in patients with extensive CMN is mandatory regardless of the treatment employed, both with self-skin examinations and in an experienced dermatologist’s office. Serial photographs, the use of dermoscopy, palpation of nevus and scars, examination of lymph nodes and a thorough review of systems may aid physicians in early detection of melanoma. Suspicious lesions should be removed and examined histologically by an experienced pathologist. | 511 | Giant Congenital Melanocytic Nevus |
nord_511_6 | Therapies of Giant Congenital Melanocytic Nevus | TreatmentTreatments currently rely on the arsenal of plastic surgical techniques. While partial-thickness grafts or ablations, using dermabrasion or curettage, have been used in the past and are still occasionally relevant, the gold standard is to replace the skin in its full thickness. Replacement skin can be generated from other zones by natural forced expansion from adjacent areas, or implanting expanders either adjacent to or in a donor graft site. Artificial dermis is currently an inadequate replacement for most nevi. Simple surveillance is an option for extensive, technically inaccessible and homogeneous nevi. Psychological accompaniment is highly recommended for both patients and families, irrespective of physical treatment options. Each treatment regimen is unique as a result of the highly individual distributions and combinations of textures, nodules and other attributes of CMN. | Therapies of Giant Congenital Melanocytic Nevus. TreatmentTreatments currently rely on the arsenal of plastic surgical techniques. While partial-thickness grafts or ablations, using dermabrasion or curettage, have been used in the past and are still occasionally relevant, the gold standard is to replace the skin in its full thickness. Replacement skin can be generated from other zones by natural forced expansion from adjacent areas, or implanting expanders either adjacent to or in a donor graft site. Artificial dermis is currently an inadequate replacement for most nevi. Simple surveillance is an option for extensive, technically inaccessible and homogeneous nevi. Psychological accompaniment is highly recommended for both patients and families, irrespective of physical treatment options. Each treatment regimen is unique as a result of the highly individual distributions and combinations of textures, nodules and other attributes of CMN. | 511 | Giant Congenital Melanocytic Nevus |
nord_512_0 | Overview of Gilbert Syndrome | Gilbert syndrome is a mild genetic liver disorder in which the body cannot properly process bilirubin, a yellowish waste product that is formed when old or worn out red blood cells are broken down (hemolysis). Individuals with Gilbert syndrome have elevated levels of bilirubin (hyperbilirubinemia), because they have a reduced level of a specific liver enzyme required for elimination of bilirubin. Most affected individuals have no symptoms (asymptomatic) or may only exhibit mild yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Jaundice may not be apparent until adolescence. Bilirubin levels may increase following stress, exertion, dehydration alcohol consumption, fasting, and/or infection. In some individuals, jaundice may only be apparent when triggered by one of these conditions. Gilbert syndrome is inherited as an autosomal recessive trait. | Overview of Gilbert Syndrome. Gilbert syndrome is a mild genetic liver disorder in which the body cannot properly process bilirubin, a yellowish waste product that is formed when old or worn out red blood cells are broken down (hemolysis). Individuals with Gilbert syndrome have elevated levels of bilirubin (hyperbilirubinemia), because they have a reduced level of a specific liver enzyme required for elimination of bilirubin. Most affected individuals have no symptoms (asymptomatic) or may only exhibit mild yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Jaundice may not be apparent until adolescence. Bilirubin levels may increase following stress, exertion, dehydration alcohol consumption, fasting, and/or infection. In some individuals, jaundice may only be apparent when triggered by one of these conditions. Gilbert syndrome is inherited as an autosomal recessive trait. | 512 | Gilbert Syndrome |
nord_512_1 | Symptoms of Gilbert Syndrome | Although Gilbert syndrome may become apparent shortly after birth, it may not be recognized for many years. Episodes of mild jaundice may appear in young adults and is more common in males than females. Frequently, episodes of jaundice are overlooked. Gilbert syndrome is associated with fluctuating levels of bilirubin in the blood (hyperbilirubinemia). Bilirubin levels may increase with stress, strain, dehydration, fasting, infection or exposure to cold. In many individuals, jaundice is only evident when one of these triggers raises the bilirubin levels.Some affected individuals have reported vague, unspecific symptoms including fatigue, weakness and gastrointestinal symptoms such as nausea, abdominal discomfort, and diarrhea. Researchers do not believe that these symptoms are related to excess bilirubin in the blood and may occur coincidentally or due to other reasons such as anxiety over the diagnosis. | Symptoms of Gilbert Syndrome. Although Gilbert syndrome may become apparent shortly after birth, it may not be recognized for many years. Episodes of mild jaundice may appear in young adults and is more common in males than females. Frequently, episodes of jaundice are overlooked. Gilbert syndrome is associated with fluctuating levels of bilirubin in the blood (hyperbilirubinemia). Bilirubin levels may increase with stress, strain, dehydration, fasting, infection or exposure to cold. In many individuals, jaundice is only evident when one of these triggers raises the bilirubin levels.Some affected individuals have reported vague, unspecific symptoms including fatigue, weakness and gastrointestinal symptoms such as nausea, abdominal discomfort, and diarrhea. Researchers do not believe that these symptoms are related to excess bilirubin in the blood and may occur coincidentally or due to other reasons such as anxiety over the diagnosis. | 512 | Gilbert Syndrome |
nord_512_2 | Causes of Gilbert Syndrome | Gilbert syndrome is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Researchers have determined that Gilbert syndrome is caused by mutations to the UGT1A1 gene located on the long arm (q) of chromosome 2 (2q37). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 2q37” refers to band 37 on the long arm of chromosome 2. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The UGT1A1 gene contains instructions for creating (encoding) a liver enzyme known as uridine disphosphate-glucuronosyltransferase-1A1 (UGT1A1). This enzyme is required for the conversion (conjugation) and subsequent excretion of bilirubin from the body.Mild jaundice associated with Gilbert syndrome occurs due to reduced amounts of this enzyme, which results in the accumulation of unconjugated bilirubin in the body. Bilirubin is an orange-yellow bile pigment that is mainly a byproduct of the natural breakdown (degeneration) of red blood cells (hemolysis). Bilirubin circulates in the liquid portion of the blood (plasma) bound to a protein called albumin; this is called unconjugated bilirubin, which does not dissolve in water (water-insoluble). Normally, this unconjugated bilirubin is taken up by the liver cells and, with the help of the UGT1A1 enzyme, is converted to form water-soluble bilirubin glucuronides (conjugated bilirubin), which are then excreted in the bile. The bile is stored in the gall bladder and, when called upon, passes into the common bile duct and then into the upper portion of the small intestine (duodenum) and aids in digestion. Most bilirubin is eliminated from the body in the feces.Individuals with Gilbert syndrome retain approximately one third of the normal UGT1A1 enzyme activity and are able to conjugate enough bilirubin to prevent symptoms from developing. However, in some cases, especially when an affected individual is fasting, dehydrated or not feeling well, mild jaundice may develop. | Causes of Gilbert Syndrome. Gilbert syndrome is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Researchers have determined that Gilbert syndrome is caused by mutations to the UGT1A1 gene located on the long arm (q) of chromosome 2 (2q37). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 2q37” refers to band 37 on the long arm of chromosome 2. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The UGT1A1 gene contains instructions for creating (encoding) a liver enzyme known as uridine disphosphate-glucuronosyltransferase-1A1 (UGT1A1). This enzyme is required for the conversion (conjugation) and subsequent excretion of bilirubin from the body.Mild jaundice associated with Gilbert syndrome occurs due to reduced amounts of this enzyme, which results in the accumulation of unconjugated bilirubin in the body. Bilirubin is an orange-yellow bile pigment that is mainly a byproduct of the natural breakdown (degeneration) of red blood cells (hemolysis). Bilirubin circulates in the liquid portion of the blood (plasma) bound to a protein called albumin; this is called unconjugated bilirubin, which does not dissolve in water (water-insoluble). Normally, this unconjugated bilirubin is taken up by the liver cells and, with the help of the UGT1A1 enzyme, is converted to form water-soluble bilirubin glucuronides (conjugated bilirubin), which are then excreted in the bile. The bile is stored in the gall bladder and, when called upon, passes into the common bile duct and then into the upper portion of the small intestine (duodenum) and aids in digestion. Most bilirubin is eliminated from the body in the feces.Individuals with Gilbert syndrome retain approximately one third of the normal UGT1A1 enzyme activity and are able to conjugate enough bilirubin to prevent symptoms from developing. However, in some cases, especially when an affected individual is fasting, dehydrated or not feeling well, mild jaundice may develop. | 512 | Gilbert Syndrome |
nord_512_3 | Affects of Gilbert Syndrome | Gilbert syndrome is diagnosed more often in males than females. The disorder affects approximately 3-7 percent of individuals in the general population. Gilbert syndrome affects individuals of all races. It is present at birth, but may remain undiagnosed until the late teens or early twenties. Gilbert syndrome was first described in the medical literature in 1901. | Affects of Gilbert Syndrome. Gilbert syndrome is diagnosed more often in males than females. The disorder affects approximately 3-7 percent of individuals in the general population. Gilbert syndrome affects individuals of all races. It is present at birth, but may remain undiagnosed until the late teens or early twenties. Gilbert syndrome was first described in the medical literature in 1901. | 512 | Gilbert Syndrome |
nord_512_4 | Related disorders of Gilbert Syndrome | Symptoms of the following disorders can be similar to those of Gilbert syndrome. Comparisons may be useful for a differential diagnosis.Crigler-Najjar syndrome is a rare genetic disorder characterized by elevated levels of bilirubin in the blood (hyperbilirubinemia). Bilirubin is a yellow waste product that is formed when old or worn out red blood cells are broken down (hemolysis). Individuals with Crigler-Najjar syndrome develop hyperbilirubinemia in the absence of excessive hemolysis. The elevated bilirubin levels occur because affected individuals lack a specific liver enzyme required for conversion (conjugation) and subsequent excretion of bilirubin. The hallmark finding of Crigler-Najjar syndrome is persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice). There are two forms of this disorder: Crigler-Najjar syndrome type I, characterized by a nearly complete lack of UGT1A1 enzyme activity and severe symptoms; and Crigler-Najjar syndrome type II, characterized by partial enzyme activity and milder symptoms. Crigler-Najjar syndrome is inherited as an autosomal recessive trait. In both types of Crigler-Najjar syndrome, jaundice occurs continuously and is more intense than that in Gilbert syndrome (For more information on Crigler-Najjar syndrome, choose”Crigler-Najjar” as your search term in the Rare Disease Database.)Rotor syndrome is an extremely rare inherited metabolic disorder characterized by the presence of excessive bilirubin in the blood (hyperbilirubinemia). The hyperbilirubinemia is caused by impaired storage of bilirubin in the liver. In most cases, affected individuals exhibit no symptoms of this disorder (asymptomatic). In some cases, persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is present. Unlike Crigler-Najjar syndromes or Gilbert syndrome, affected individuals have high levels of conjugated bilirubin. Rotor syndrome is thought to be inherited as an autosomal recessive trait.Dubin-Johnson syndrome is a rare genetic liver disorder characterized by elevated levels of bilirubin in blood (hyperbilirubinemia). Persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice) is usually the only symptom in most cases. Dubin-Johnson syndrome is usually diagnosed after puberty. In rare cases, enlargement of the liver or spleen may occur (hepatomegaly). Like Rotor syndrome, and unlike Crigler-Najjar syndromes or Gilbert syndrome, high levels of conjugated bilirubin characterizes this disorder. Dubin-Johnson syndrome is inherited as an autosomal recessive disorder. (For more information, choose “Dubin Johnson” as your search term in the Rare Disease Database). | Related disorders of Gilbert Syndrome. Symptoms of the following disorders can be similar to those of Gilbert syndrome. Comparisons may be useful for a differential diagnosis.Crigler-Najjar syndrome is a rare genetic disorder characterized by elevated levels of bilirubin in the blood (hyperbilirubinemia). Bilirubin is a yellow waste product that is formed when old or worn out red blood cells are broken down (hemolysis). Individuals with Crigler-Najjar syndrome develop hyperbilirubinemia in the absence of excessive hemolysis. The elevated bilirubin levels occur because affected individuals lack a specific liver enzyme required for conversion (conjugation) and subsequent excretion of bilirubin. The hallmark finding of Crigler-Najjar syndrome is persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice). There are two forms of this disorder: Crigler-Najjar syndrome type I, characterized by a nearly complete lack of UGT1A1 enzyme activity and severe symptoms; and Crigler-Najjar syndrome type II, characterized by partial enzyme activity and milder symptoms. Crigler-Najjar syndrome is inherited as an autosomal recessive trait. In both types of Crigler-Najjar syndrome, jaundice occurs continuously and is more intense than that in Gilbert syndrome (For more information on Crigler-Najjar syndrome, choose”Crigler-Najjar” as your search term in the Rare Disease Database.)Rotor syndrome is an extremely rare inherited metabolic disorder characterized by the presence of excessive bilirubin in the blood (hyperbilirubinemia). The hyperbilirubinemia is caused by impaired storage of bilirubin in the liver. In most cases, affected individuals exhibit no symptoms of this disorder (asymptomatic). In some cases, persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is present. Unlike Crigler-Najjar syndromes or Gilbert syndrome, affected individuals have high levels of conjugated bilirubin. Rotor syndrome is thought to be inherited as an autosomal recessive trait.Dubin-Johnson syndrome is a rare genetic liver disorder characterized by elevated levels of bilirubin in blood (hyperbilirubinemia). Persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice) is usually the only symptom in most cases. Dubin-Johnson syndrome is usually diagnosed after puberty. In rare cases, enlargement of the liver or spleen may occur (hepatomegaly). Like Rotor syndrome, and unlike Crigler-Najjar syndromes or Gilbert syndrome, high levels of conjugated bilirubin characterizes this disorder. Dubin-Johnson syndrome is inherited as an autosomal recessive disorder. (For more information, choose “Dubin Johnson” as your search term in the Rare Disease Database). | 512 | Gilbert Syndrome |
nord_512_5 | Diagnosis of Gilbert Syndrome | A diagnosis of Gilbert syndrome is often made when blood, drawn for routine health check up or another illness, such as an infection, detects mildly elevated bilirubin levels. Because the levels of bilirubin fluctuate, blood tests may not always show elevated bilirubin. Individuals are determined to have Gilbert syndrome by the presence of hyperbilirubinemia in the absence of hemolysis (premature breakdown of red blood cells) or structural liver damage. | Diagnosis of Gilbert Syndrome. A diagnosis of Gilbert syndrome is often made when blood, drawn for routine health check up or another illness, such as an infection, detects mildly elevated bilirubin levels. Because the levels of bilirubin fluctuate, blood tests may not always show elevated bilirubin. Individuals are determined to have Gilbert syndrome by the presence of hyperbilirubinemia in the absence of hemolysis (premature breakdown of red blood cells) or structural liver damage. | 512 | Gilbert Syndrome |
nord_512_6 | Therapies of Gilbert Syndrome | TreatmentIn most cases, Gilbert syndrome does not cause symptoms and no treatment is necessary. Mild jaundice may occur, but does not cause any problems. Gilbert syndrome is considered a mild, harmless (benign) condition and is associated with normal life expectancy. Some medicines, such as the cancer therapy drug, irinotecan, may cause diarrhea, when administered in subjects with Gilbert syndrome. | Therapies of Gilbert Syndrome. TreatmentIn most cases, Gilbert syndrome does not cause symptoms and no treatment is necessary. Mild jaundice may occur, but does not cause any problems. Gilbert syndrome is considered a mild, harmless (benign) condition and is associated with normal life expectancy. Some medicines, such as the cancer therapy drug, irinotecan, may cause diarrhea, when administered in subjects with Gilbert syndrome. | 512 | Gilbert Syndrome |
nord_513_0 | Overview of Gitelman Syndrome | SummaryGitelman syndrome, also known as familial hypokalemia-hypomagnesemia, is a rare genetic disorder in which there is a specific defect in kidney function. This defect impairs the kidney’s ability to reabsorb salt and causes changes in various electrolyte concentrations as well as contraction of extracellular fluid volume (thus causing symptoms of dehydration). The electrolytes affected are primarily mineral ions, specifically potassium, calcium, magnesium, sodium, and chloride. Fundamentally, like Bartter’s syndrome, Gitelman syndrome is a salt wasting nephropathy. The symptoms and severity of the disorder can vary greatly from one person to another and can range from mild to severe. For unknown reasons, the onset of symptoms is frequently delayed until the second decade of life. Symptoms and severity can even vary greatly among members of the same family. Common symptoms can include episodes of fatigue, muscle weakness, and muscle cramps sometimes accompanied by gastrointestinal problems such as abdominal pain, nausea and vomiting. Some individuals may need to urinate frequently and will pass a large volume of urine (polyuria). This symptom is the result of failure to fully concentrate urine in the face of dehydration. Most cases of Gitelman syndrome are caused by mutations in the SLC12A3 gene and are inherited in an autosomal recessive manner.IntroductionGitelman syndrome is often discussed along with Bartter syndrome, a group of several disorders characterized by similar defects in kidney function leading to volume depletion and similar symptoms as is seen in Gitelman syndrome. Sometimes known as a variant of Bartter syndrome, Gitelman syndrome can show significant overlap with Bartter syndrome type 3; in specific cases, it is extremely difficult to distinguish between these disorders. Some researchers believe it is better to consider the Bartter syndrome and Gitelman syndrome as a spectrum of disease rather than distinct disorders. These disorders may be broadly classified as renal tubulopathies (because certain small tubes within the kidneys are affected), salt-wasting disorders (because affected individuals excrete excess amounts of salt), salt-losing tubulopathies or channelopathies (because the ion channels in the kidneys are affected). Gitelman syndrome causes metabolic abnormalities resembling treatment with high dosage of thiazide diuretics while Bartter syndrome resembles treatment with high dosage of loop diuretics.Most medical sources will use specific terminology to describe the electrolyte imbalances that characterize Gitelman syndrome. These terms refer to findings on laboratory tests rather than specific symptoms. Such terms include low levels of potassium in the blood (hypokalemia), low levels of chloride in the blood (hypochloremia), excess alkaline levels in the body (metabolic alkalosis), low levels of magnesium in the blood (hypomagnesemia), low levels of calcium in the urine (hypocalciuria), high levels of renin in the blood (hyperreninemia), and high levels of aldosterone in the blood (hyperaldosteronemia). The latter two laboratory findings are appropriate regulatory responses to dehydration caused by salt wasting kidney. disease. | Overview of Gitelman Syndrome. SummaryGitelman syndrome, also known as familial hypokalemia-hypomagnesemia, is a rare genetic disorder in which there is a specific defect in kidney function. This defect impairs the kidney’s ability to reabsorb salt and causes changes in various electrolyte concentrations as well as contraction of extracellular fluid volume (thus causing symptoms of dehydration). The electrolytes affected are primarily mineral ions, specifically potassium, calcium, magnesium, sodium, and chloride. Fundamentally, like Bartter’s syndrome, Gitelman syndrome is a salt wasting nephropathy. The symptoms and severity of the disorder can vary greatly from one person to another and can range from mild to severe. For unknown reasons, the onset of symptoms is frequently delayed until the second decade of life. Symptoms and severity can even vary greatly among members of the same family. Common symptoms can include episodes of fatigue, muscle weakness, and muscle cramps sometimes accompanied by gastrointestinal problems such as abdominal pain, nausea and vomiting. Some individuals may need to urinate frequently and will pass a large volume of urine (polyuria). This symptom is the result of failure to fully concentrate urine in the face of dehydration. Most cases of Gitelman syndrome are caused by mutations in the SLC12A3 gene and are inherited in an autosomal recessive manner.IntroductionGitelman syndrome is often discussed along with Bartter syndrome, a group of several disorders characterized by similar defects in kidney function leading to volume depletion and similar symptoms as is seen in Gitelman syndrome. Sometimes known as a variant of Bartter syndrome, Gitelman syndrome can show significant overlap with Bartter syndrome type 3; in specific cases, it is extremely difficult to distinguish between these disorders. Some researchers believe it is better to consider the Bartter syndrome and Gitelman syndrome as a spectrum of disease rather than distinct disorders. These disorders may be broadly classified as renal tubulopathies (because certain small tubes within the kidneys are affected), salt-wasting disorders (because affected individuals excrete excess amounts of salt), salt-losing tubulopathies or channelopathies (because the ion channels in the kidneys are affected). Gitelman syndrome causes metabolic abnormalities resembling treatment with high dosage of thiazide diuretics while Bartter syndrome resembles treatment with high dosage of loop diuretics.Most medical sources will use specific terminology to describe the electrolyte imbalances that characterize Gitelman syndrome. These terms refer to findings on laboratory tests rather than specific symptoms. Such terms include low levels of potassium in the blood (hypokalemia), low levels of chloride in the blood (hypochloremia), excess alkaline levels in the body (metabolic alkalosis), low levels of magnesium in the blood (hypomagnesemia), low levels of calcium in the urine (hypocalciuria), high levels of renin in the blood (hyperreninemia), and high levels of aldosterone in the blood (hyperaldosteronemia). The latter two laboratory findings are appropriate regulatory responses to dehydration caused by salt wasting kidney. disease. | 513 | Gitelman Syndrome |
nord_513_1 | Symptoms of Gitelman Syndrome | Gitelman syndrome usually becomes apparent anywhere from late childhood (usually over the age of six) to early adulthood. The disorder is highly variable, even among individuals in the same family. Some people do not develop any symptoms (asymptomatic), while others can develop chronic issues that can impact their quality of life.Muscle weakness, spasms, and cramps may occur and generally are more common in Gitelman syndrome than the related Bartter syndrome. Affected individuals may experiences episodes of fatigue, dizziness, fainting (due to low blood pressure), muscle weakness, muscle aches, cramps and spasms. Affected individuals may also experience a specific form of cramping spasms called tetany. Tetany is marked by cramping spasms of certain muscles, particularly those of the hands and feet, arms, legs and/or face. Tetany may be provoked by hyperventilation during periods of anxiety.Symptomatic episodes may also be accompanied by abdominal pain, vomiting, diarrhea or constipation, and fever. Vomiting or diarrhea in a patient with Gitelman syndrome may lead to the misdiagnosis of eating disorder or cathartic abuse as the cause of hypokalemia. Falsely accusing a patient with Gitelman or Bartter syndrome of these behaviors can cause loss of trust as well as adverse psychological and emotional consequences. Measurement of urinary chloride will help differentiate Gitelman syndrome (high urinary chloride) from hypokalemia resulting from GI fluid losses. (urine chloride < 10 meQ/L). Seizures may also occur and in some people may be the initial reason they seek medical assistance. A loss of sensation or feeling of the face (facial paresthesia) characterized by numbness or tingling is common. Less often, tingling or numbness may affect the hands. The severity of fatigue can vary widely. Some individuals are severely fatigued to the point where it interferes with daily activities; other individuals never report fatigue as a specific symptom.Affected individuals may or may not experience excessive thirst (polydipsia) and a frequent need to urinate (polyuria) including the excessive need to urinate at night (nocturia). When these symptoms do occur they are usually mild. Blood pressure can be abnormally low (hypotension) in comparison to the general population. Affected individuals often crave salt or high-salt foods. Salt craving frequently begins in childhood and is helpful in making a correct diagnosis.Some affected adults develop chondrocalcinosis, a condition characterized by the accumulation of calcium in the joints. Its development is thought to be related to hypomagnesemia. Affected joints may be swollen, tender, reddened, and warm to the touch. In some individuals, chondrocalcinosis and its complications are the only symptoms that develop.Gitelman syndrome is generally considered to be a milder variant of Bartter syndrome, with symptoms often overlapping with Bartter syndrome type 3 (classic Bartter syndrome). Renal salt wasting is more severe and begins earlier in life in Bartter syndrome than in Gitelman syndrome. However, researchers have determined that in rare cases more severe complications can occur in the newborn (neonatal) period. In these cases, affected infants experience severe hypokalemia and hypomagnesemia, which can be associated with an increased need to urinate and passage of large amounts of urine (polyuria), diminished muscle tone (hypotonia), muscle spasms, growth delays and a failure to grow and gain weight as would be expected based on age and gender (failure to thrive). Earlier-onset, more severe cases have occurred in greater frequency in male infants than female infants.In affected individuals who experience significant electrolyte imbalances, irregular heartbeats (cardiac arrhythmias) may develop. Although rare, if untreated, these cardiac arrhythmias can potentially progress to cause sudden cardiac arrest and potentially sudden death. These cardiac issues result from a prolonged QT interval. The QT-interval is measured on the electrocardiogram and, if prolonged, indicates that the heart muscle is taking longer than usual to recharge between beats.Some affected individuals may develop the breakdown of muscle tissue causing the release of toxic content of muscle cells into the body fluids (rhabdomyolysis). Rhabdomyolysis is a serious condition that can potentially damage the kidneys. Additional symptoms have been reported in the medical literature but are quite rare. These symptoms include blurred vision, vertigo, and an impaired ability to coordinate voluntary movements (ataxia). A study from Yale indicated that Gitelman and Bartter syndrome have significant impact to quality of life (Cruz D et al., 2001).In a study of a series of individuals with Gitelman syndrome (Berry et al. 2013), it was determined that affected individuals can develop abnormally high blood pressure (hypertension) later during life (median 55 years of age). This is counterintuitive in a salt-wasting disorder that can cause low blood pressure earlier in life. The exact reason for the development of hypertension is unknown, but may be related to prolonged exposure to renin and aldosterone levels (see Causes section below) and often occurs in the presence of traditional risk factors for hypertension. Some women have experienced severe potassium wasting during pregnancy and have required increased potassium and magnesium supplementation. | Symptoms of Gitelman Syndrome. Gitelman syndrome usually becomes apparent anywhere from late childhood (usually over the age of six) to early adulthood. The disorder is highly variable, even among individuals in the same family. Some people do not develop any symptoms (asymptomatic), while others can develop chronic issues that can impact their quality of life.Muscle weakness, spasms, and cramps may occur and generally are more common in Gitelman syndrome than the related Bartter syndrome. Affected individuals may experiences episodes of fatigue, dizziness, fainting (due to low blood pressure), muscle weakness, muscle aches, cramps and spasms. Affected individuals may also experience a specific form of cramping spasms called tetany. Tetany is marked by cramping spasms of certain muscles, particularly those of the hands and feet, arms, legs and/or face. Tetany may be provoked by hyperventilation during periods of anxiety.Symptomatic episodes may also be accompanied by abdominal pain, vomiting, diarrhea or constipation, and fever. Vomiting or diarrhea in a patient with Gitelman syndrome may lead to the misdiagnosis of eating disorder or cathartic abuse as the cause of hypokalemia. Falsely accusing a patient with Gitelman or Bartter syndrome of these behaviors can cause loss of trust as well as adverse psychological and emotional consequences. Measurement of urinary chloride will help differentiate Gitelman syndrome (high urinary chloride) from hypokalemia resulting from GI fluid losses. (urine chloride < 10 meQ/L). Seizures may also occur and in some people may be the initial reason they seek medical assistance. A loss of sensation or feeling of the face (facial paresthesia) characterized by numbness or tingling is common. Less often, tingling or numbness may affect the hands. The severity of fatigue can vary widely. Some individuals are severely fatigued to the point where it interferes with daily activities; other individuals never report fatigue as a specific symptom.Affected individuals may or may not experience excessive thirst (polydipsia) and a frequent need to urinate (polyuria) including the excessive need to urinate at night (nocturia). When these symptoms do occur they are usually mild. Blood pressure can be abnormally low (hypotension) in comparison to the general population. Affected individuals often crave salt or high-salt foods. Salt craving frequently begins in childhood and is helpful in making a correct diagnosis.Some affected adults develop chondrocalcinosis, a condition characterized by the accumulation of calcium in the joints. Its development is thought to be related to hypomagnesemia. Affected joints may be swollen, tender, reddened, and warm to the touch. In some individuals, chondrocalcinosis and its complications are the only symptoms that develop.Gitelman syndrome is generally considered to be a milder variant of Bartter syndrome, with symptoms often overlapping with Bartter syndrome type 3 (classic Bartter syndrome). Renal salt wasting is more severe and begins earlier in life in Bartter syndrome than in Gitelman syndrome. However, researchers have determined that in rare cases more severe complications can occur in the newborn (neonatal) period. In these cases, affected infants experience severe hypokalemia and hypomagnesemia, which can be associated with an increased need to urinate and passage of large amounts of urine (polyuria), diminished muscle tone (hypotonia), muscle spasms, growth delays and a failure to grow and gain weight as would be expected based on age and gender (failure to thrive). Earlier-onset, more severe cases have occurred in greater frequency in male infants than female infants.In affected individuals who experience significant electrolyte imbalances, irregular heartbeats (cardiac arrhythmias) may develop. Although rare, if untreated, these cardiac arrhythmias can potentially progress to cause sudden cardiac arrest and potentially sudden death. These cardiac issues result from a prolonged QT interval. The QT-interval is measured on the electrocardiogram and, if prolonged, indicates that the heart muscle is taking longer than usual to recharge between beats.Some affected individuals may develop the breakdown of muscle tissue causing the release of toxic content of muscle cells into the body fluids (rhabdomyolysis). Rhabdomyolysis is a serious condition that can potentially damage the kidneys. Additional symptoms have been reported in the medical literature but are quite rare. These symptoms include blurred vision, vertigo, and an impaired ability to coordinate voluntary movements (ataxia). A study from Yale indicated that Gitelman and Bartter syndrome have significant impact to quality of life (Cruz D et al., 2001).In a study of a series of individuals with Gitelman syndrome (Berry et al. 2013), it was determined that affected individuals can develop abnormally high blood pressure (hypertension) later during life (median 55 years of age). This is counterintuitive in a salt-wasting disorder that can cause low blood pressure earlier in life. The exact reason for the development of hypertension is unknown, but may be related to prolonged exposure to renin and aldosterone levels (see Causes section below) and often occurs in the presence of traditional risk factors for hypertension. Some women have experienced severe potassium wasting during pregnancy and have required increased potassium and magnesium supplementation. | 513 | Gitelman Syndrome |
nord_513_2 | Causes of Gitelman Syndrome | Most cases of Gitelman syndrome are caused by mutations in the SLC12A3 gene. In a minority of cases, mutations in the CLCNKB gene cause the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or not inserted in a tubule membrane properly. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In the case of Gitelman syndrome, defective protein structure causes failure to reclaim filtered sodium and chloride (channelopathy). More severe salt wasting is caused by a defect in a different channel in Bartter syndrome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.The SLC12A3 gene that causes the majority of cases of Gitelman syndrome produces (encodes) a protein known as thiazide-sensitive NaCl cotransporter (NCC), which helps to transport salts through ion channels in the kidney. Ion channels, which are pores in cell membranes, regulate the movement of electrically-charged particles called ions, which include electrolytes such as potassium and sodium ions, in certain structures of the kidneys. Mutations in this gene result in abnormal functioning of the NCC protein that transports electrolytes through the ion channels. This abnormal functioning or channel inception in the tubular membrane prevents sodium and chloride (salt) from being reabsorbed (reclaimed) from the distal renal tubule. This causes salt and water wastage (negative balance) and results in volume depletion (dehydration). The kidney attempts to attenuate dehydration by activating the renin angiotensin aldosterone system (RAAS). Hypokalemia is the adverse consequence of RAAS activation. Because salt balance can never be fully achieved; the hypokalemia in Gitelman syndrome can only rarely be corrected.The human kidney filters 180 liters of serum each day through selective filtration in glomeruli. All but 1-1.5 liters of this glomerular filtrate is selectively reclaimed) by renal tubules including the distal convoluted tubule (which functions abnormally in Gitelman syndrome) and the thick ascending limb (which functions abnormally in Bartter syndrome). Both abnormalities cause salt wasting and, in turn, symptoms related to dehydration as well as those due to secondary electrolyte disturbances (hypokalemia and hypomagnesemia.) | Causes of Gitelman Syndrome. Most cases of Gitelman syndrome are caused by mutations in the SLC12A3 gene. In a minority of cases, mutations in the CLCNKB gene cause the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or not inserted in a tubule membrane properly. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In the case of Gitelman syndrome, defective protein structure causes failure to reclaim filtered sodium and chloride (channelopathy). More severe salt wasting is caused by a defect in a different channel in Bartter syndrome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.The SLC12A3 gene that causes the majority of cases of Gitelman syndrome produces (encodes) a protein known as thiazide-sensitive NaCl cotransporter (NCC), which helps to transport salts through ion channels in the kidney. Ion channels, which are pores in cell membranes, regulate the movement of electrically-charged particles called ions, which include electrolytes such as potassium and sodium ions, in certain structures of the kidneys. Mutations in this gene result in abnormal functioning of the NCC protein that transports electrolytes through the ion channels. This abnormal functioning or channel inception in the tubular membrane prevents sodium and chloride (salt) from being reabsorbed (reclaimed) from the distal renal tubule. This causes salt and water wastage (negative balance) and results in volume depletion (dehydration). The kidney attempts to attenuate dehydration by activating the renin angiotensin aldosterone system (RAAS). Hypokalemia is the adverse consequence of RAAS activation. Because salt balance can never be fully achieved; the hypokalemia in Gitelman syndrome can only rarely be corrected.The human kidney filters 180 liters of serum each day through selective filtration in glomeruli. All but 1-1.5 liters of this glomerular filtrate is selectively reclaimed) by renal tubules including the distal convoluted tubule (which functions abnormally in Gitelman syndrome) and the thick ascending limb (which functions abnormally in Bartter syndrome). Both abnormalities cause salt wasting and, in turn, symptoms related to dehydration as well as those due to secondary electrolyte disturbances (hypokalemia and hypomagnesemia.) | 513 | Gitelman Syndrome |
nord_513_3 | Affects of Gitelman Syndrome | Gitelman syndrome affects males and females in equally. The disorder occurs in approximately 1 in 40,000 Caucasian individuals. However, many cases of these disorders may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of Gitelman syndrome in the general population. The prevalence of individuals with one mutated copy of a gene (known as heterozygotes or carriers of the disease) is approximately 1% of European populations. These heterozygotes may enjoy a benefit of a small degree of salt wasting: they have lower blood pressures than the general population. | Affects of Gitelman Syndrome. Gitelman syndrome affects males and females in equally. The disorder occurs in approximately 1 in 40,000 Caucasian individuals. However, many cases of these disorders may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of Gitelman syndrome in the general population. The prevalence of individuals with one mutated copy of a gene (known as heterozygotes or carriers of the disease) is approximately 1% of European populations. These heterozygotes may enjoy a benefit of a small degree of salt wasting: they have lower blood pressures than the general population. | 513 | Gitelman Syndrome |
nord_513_4 | Related disorders of Gitelman Syndrome | Symptoms of the following disorders can be similar to those of Gitelman syndrome.Comparisons may be useful for a differential diagnosis.Bartter syndrome is a general term for a group of rare, closely-related genetic disorders in which there are specific defects in kidney function. These defects impair the kidney’s ability to reabsorb salt and cause imbalances in various electrolyte and fluid concentrations in the body. The electrolytes affected are primarily mineral salts such as potassium, sodium, and chloride. Hypomagnesemia is not found in Bartter syndrome and urinary calcium tends to be high rather than low as seen in Gitelman syndrome. The symptoms and severity of Bartter syndrome vary from one person to another and can range from mild to severe. Age of onset can range from at birth to adulthood. Generally, Bartter syndrome is broken down into five subtypes. Bartter syndrome is caused by alterations (mutations) in one of several different genes. Most subtypes of Bartter syndrome are inherited in an autosomal recessive manner. One subtype, Bartter syndrome type 5, is inherited as in an autosomal dominant manner. (For more information on this disorder, choose “Bartter” as your search term in the Rare Disease Database.)Pseudo-Bartter syndrome is a general term that refers to certain conditions that cause the same symptoms and signs of Bartter syndrome and Gitelman syndrome, but in which there is no renal tubular dysfunction. These conditions include the use of certain diuretics, conditions in which frequent vomiting occurs including bulimia and cyclic vomiting syndrome, and the abuse of laxatives. | Related disorders of Gitelman Syndrome. Symptoms of the following disorders can be similar to those of Gitelman syndrome.Comparisons may be useful for a differential diagnosis.Bartter syndrome is a general term for a group of rare, closely-related genetic disorders in which there are specific defects in kidney function. These defects impair the kidney’s ability to reabsorb salt and cause imbalances in various electrolyte and fluid concentrations in the body. The electrolytes affected are primarily mineral salts such as potassium, sodium, and chloride. Hypomagnesemia is not found in Bartter syndrome and urinary calcium tends to be high rather than low as seen in Gitelman syndrome. The symptoms and severity of Bartter syndrome vary from one person to another and can range from mild to severe. Age of onset can range from at birth to adulthood. Generally, Bartter syndrome is broken down into five subtypes. Bartter syndrome is caused by alterations (mutations) in one of several different genes. Most subtypes of Bartter syndrome are inherited in an autosomal recessive manner. One subtype, Bartter syndrome type 5, is inherited as in an autosomal dominant manner. (For more information on this disorder, choose “Bartter” as your search term in the Rare Disease Database.)Pseudo-Bartter syndrome is a general term that refers to certain conditions that cause the same symptoms and signs of Bartter syndrome and Gitelman syndrome, but in which there is no renal tubular dysfunction. These conditions include the use of certain diuretics, conditions in which frequent vomiting occurs including bulimia and cyclic vomiting syndrome, and the abuse of laxatives. | 513 | Gitelman Syndrome |
nord_513_5 | Diagnosis of Gitelman Syndrome | A diagnosis of Gitelman syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected after other more common causes of hypokalemia and metabolic alkalosis are ruled out.Clinical Testing and WorkupLaboratory tests that are used to diagnose Gitelman syndrome include blood tests to determine serum electrolyte levels, specifically low serum concentrations of magnesium and potassium and/or elevated serum concentrations of renin, and aldosterone. Urine electrolyte measurement seeks to determine the presence inappropriately high urine potassium in the face of hypokalemia. Low urine chloride should always suggest GI losses from vomiting and/or diarrhea. Low urinary calcium is comparable with a diagnosis of Gitelman syndrome. Hypertension in a hypokalemic patient who is not taking diuretics should always suggest primary hyperaldosteronism, not Gitelman or Bartter syndromes.Molecular genetic testing can confirm a diagnosis of Gitelman syndrome. Genetic testing can detect mutations in the specific genes known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. Generally, genetic testing is not needed to make a diagnosis. | Diagnosis of Gitelman Syndrome. A diagnosis of Gitelman syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected after other more common causes of hypokalemia and metabolic alkalosis are ruled out.Clinical Testing and WorkupLaboratory tests that are used to diagnose Gitelman syndrome include blood tests to determine serum electrolyte levels, specifically low serum concentrations of magnesium and potassium and/or elevated serum concentrations of renin, and aldosterone. Urine electrolyte measurement seeks to determine the presence inappropriately high urine potassium in the face of hypokalemia. Low urine chloride should always suggest GI losses from vomiting and/or diarrhea. Low urinary calcium is comparable with a diagnosis of Gitelman syndrome. Hypertension in a hypokalemic patient who is not taking diuretics should always suggest primary hyperaldosteronism, not Gitelman or Bartter syndromes.Molecular genetic testing can confirm a diagnosis of Gitelman syndrome. Genetic testing can detect mutations in the specific genes known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. Generally, genetic testing is not needed to make a diagnosis. | 513 | Gitelman Syndrome |
nord_513_6 | Therapies of Gitelman Syndrome | TreatmentThe treatment of Gitelman 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 or general internists, kidney specialists (nephrologists or pediatric nephrologists), cardiologists, social workers and other healthcare professionals may need to systematically and comprehensively plan individual’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Because this is a rare disease, even well trained private practice or academic nephrologists may have little experience diagnosing or treating this disease.Individuals who do not develop symptoms (asymptomatic) often do not require treatment, but it is recommended that they receive outpatient monitoring one or twice a year. They should be aware that they will be prone to rapidly become dehydrated should they experience vomiting or diarrhea from GI illness. They may require saline and intravenous potassium supplementation during these illnesses. All individuals with Gitelman syndrome are encouraged to follow a high-sodium chloride added diet. Dietary potassium should also be high. Dried fruit is an excellent source of supplemental potassium. Such a diet can help reduce exposure to potassium chloride supplements which irritate the stomach lining. These patents should never be treated with ACE inhibitors or ARBs.There is no cure for Gitelman syndrome. The mainstay of treatment for affected individuals is a high salt diet with oral potassium and magnesium supplements. Potassium rich foods such as dried fruit are helpful. Magnesium supplements in single large doses cause diarrhea and should be avoided. Magnesium supplements should be taken in small frequent (4-6 times/ day) in order to avoid magnesium associated diarrhea which may worsen hypokalemia and symptoms of volume depletion. For many individuals, lifelong daily supplementation with magnesium is recommended. In some cases, during severe muscle cramps, magnesium has been given intravenously. In general, the goal of therapy should always be attenuation of symptoms rather than normalization of electrolyte abnormalities. Because of the risk of infection and thrombosis, central catheters should be discouraged. Some affected individuals may receive medications known as potassium-sparing diuretics such as spironolactone, eplerenone or amiloride. These drugs are mild diuretics that spare potassium excretion. While these agents improve hypokalemia, they rarely normalize serum potassium concentrations. The goal of therapy is to improve symptoms not to normalize laboratory abnormalities. When chondrocalcinosis causes symptoms, supplementation with magnesium, pain medications and/or nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen may be beneficial.A specific nonsteroidal anti-inflammatory drug (NSAID) known as indomethacin has been used to treat some infants and children with Gitelman syndrome. This drug is commonly used to treat individuals with Bartter syndrome, but is being used more often in Gitelman syndrome, particularly to treat growth deficiency in severe, early-onset forms of the disorder.
Affected individuals may be encouraged to undergo a cardiac workup to screen for risk factors for cardiac arrhythmias. Individuals with a prolonged QT interval should avoid drugs that prolong the QT interval. For a list of such drugs, contact the Sudden Arrhythmia Death Syndromes Foundation.Finally, the initial report of two patients with Gitelman syndrome by Hillel Gitelman and associates at the University of North Carolina at Chapel Hill in 1966 opened the door to understanding the role of the kidney’s handling of salt in not only rare genetic diseases but more importantly in high blood pressure which effects millions of people world- wide. Dr. Gitelman showed that a well- studied orphan disease can open our eyes to more wide spread health issues. (http://www.sads.org/). | Therapies of Gitelman Syndrome. TreatmentThe treatment of Gitelman 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 or general internists, kidney specialists (nephrologists or pediatric nephrologists), cardiologists, social workers and other healthcare professionals may need to systematically and comprehensively plan individual’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Because this is a rare disease, even well trained private practice or academic nephrologists may have little experience diagnosing or treating this disease.Individuals who do not develop symptoms (asymptomatic) often do not require treatment, but it is recommended that they receive outpatient monitoring one or twice a year. They should be aware that they will be prone to rapidly become dehydrated should they experience vomiting or diarrhea from GI illness. They may require saline and intravenous potassium supplementation during these illnesses. All individuals with Gitelman syndrome are encouraged to follow a high-sodium chloride added diet. Dietary potassium should also be high. Dried fruit is an excellent source of supplemental potassium. Such a diet can help reduce exposure to potassium chloride supplements which irritate the stomach lining. These patents should never be treated with ACE inhibitors or ARBs.There is no cure for Gitelman syndrome. The mainstay of treatment for affected individuals is a high salt diet with oral potassium and magnesium supplements. Potassium rich foods such as dried fruit are helpful. Magnesium supplements in single large doses cause diarrhea and should be avoided. Magnesium supplements should be taken in small frequent (4-6 times/ day) in order to avoid magnesium associated diarrhea which may worsen hypokalemia and symptoms of volume depletion. For many individuals, lifelong daily supplementation with magnesium is recommended. In some cases, during severe muscle cramps, magnesium has been given intravenously. In general, the goal of therapy should always be attenuation of symptoms rather than normalization of electrolyte abnormalities. Because of the risk of infection and thrombosis, central catheters should be discouraged. Some affected individuals may receive medications known as potassium-sparing diuretics such as spironolactone, eplerenone or amiloride. These drugs are mild diuretics that spare potassium excretion. While these agents improve hypokalemia, they rarely normalize serum potassium concentrations. The goal of therapy is to improve symptoms not to normalize laboratory abnormalities. When chondrocalcinosis causes symptoms, supplementation with magnesium, pain medications and/or nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen may be beneficial.A specific nonsteroidal anti-inflammatory drug (NSAID) known as indomethacin has been used to treat some infants and children with Gitelman syndrome. This drug is commonly used to treat individuals with Bartter syndrome, but is being used more often in Gitelman syndrome, particularly to treat growth deficiency in severe, early-onset forms of the disorder.
Affected individuals may be encouraged to undergo a cardiac workup to screen for risk factors for cardiac arrhythmias. Individuals with a prolonged QT interval should avoid drugs that prolong the QT interval. For a list of such drugs, contact the Sudden Arrhythmia Death Syndromes Foundation.Finally, the initial report of two patients with Gitelman syndrome by Hillel Gitelman and associates at the University of North Carolina at Chapel Hill in 1966 opened the door to understanding the role of the kidney’s handling of salt in not only rare genetic diseases but more importantly in high blood pressure which effects millions of people world- wide. Dr. Gitelman showed that a well- studied orphan disease can open our eyes to more wide spread health issues. (http://www.sads.org/). | 513 | Gitelman Syndrome |
nord_514_0 | Overview of Glanzmann Thrombasthenia | Glanzmann thrombasthenia (GT) is a rare inherited blood clotting (coagulation) disorder characterized by the impaired function of specialized cells (platelets) that are essential for proper blood clotting. Symptoms of this disorder usually include abnormal bleeding, which may be severe. Prolonged untreated or unsuccessfully treated hemorrhaging associated with Glanzmann thrombasthenia may be life threatening. | Overview of Glanzmann Thrombasthenia. Glanzmann thrombasthenia (GT) is a rare inherited blood clotting (coagulation) disorder characterized by the impaired function of specialized cells (platelets) that are essential for proper blood clotting. Symptoms of this disorder usually include abnormal bleeding, which may be severe. Prolonged untreated or unsuccessfully treated hemorrhaging associated with Glanzmann thrombasthenia may be life threatening. | 514 | Glanzmann Thrombasthenia |
nord_514_1 | Symptoms of Glanzmann Thrombasthenia | The symptoms of Glanzmann thrombasthenia usually begin at birth or shortly thereafter and include the tendency to bruise and bleed easily and sometimes profusely, especially after surgical procedures. Other symptoms may include susceptibility to easy bruising, nosebleeds (epistaxis), bleeding from the gums (gingival), intermittent gastrointestinal bleeding and/or variably small or large red or purple-colored spots on the skin that are caused by bleeding in the skin (purpura). Women with GT often also have unusually heavy menstrual bleeding, irregular uterine bleeding and excess bleeding in childbirth. Rarely, gastrointestinal bleeding and blood in the urine (hematuria) can occur. The severity of the symptoms varies greatly. Some affected individuals have mild bruising and others have severe hemorrhages that can be life threatening. | Symptoms of Glanzmann Thrombasthenia. The symptoms of Glanzmann thrombasthenia usually begin at birth or shortly thereafter and include the tendency to bruise and bleed easily and sometimes profusely, especially after surgical procedures. Other symptoms may include susceptibility to easy bruising, nosebleeds (epistaxis), bleeding from the gums (gingival), intermittent gastrointestinal bleeding and/or variably small or large red or purple-colored spots on the skin that are caused by bleeding in the skin (purpura). Women with GT often also have unusually heavy menstrual bleeding, irregular uterine bleeding and excess bleeding in childbirth. Rarely, gastrointestinal bleeding and blood in the urine (hematuria) can occur. The severity of the symptoms varies greatly. Some affected individuals have mild bruising and others have severe hemorrhages that can be life threatening. | 514 | Glanzmann Thrombasthenia |
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