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nord_1042_6
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Therapies of Pyridoxine-Dependent Epilepsy
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TreatmentWhile the effective treatment of patients with PDE requires lifelong pharmacologic supplements of pyridoxine, given the rarity of this disorder there have been no controlled studies to determine the optimal dose. The RDA for pyridoxine is 0.5 mg for infants and 2 mg for adults. Patients with PDE generally have had excellent seizure control when treated with 50 – 100 mg of pyridoxine per day; some patients may be controlled on much smaller doses while others need higher doses. Some recent studies suggest that higher doses may enhance the intellectual development of these patients, and a dose of 15 – 30 mg/kg/day may be optimal. Particular patients with PDE who have associated abnormalities in brain development such as hydrocephalus or heterotopia (forms of birth defects in brain structure) may not have all of their seizures controlled with pyridoxine alone, and these patients require the use of one or more anticonvulsant drugs. However, the excessive use of pyridoxine must be avoided, as pyridoxine may damage the peripheral nervous system (neurotoxicity) manifesting as a reversible sensory neuropathy. While pyridoxine neurotoxicity has been reported primarily in adults who received “mega-vitamin therapy”, one adolescent with possible PDE who received 2 grams of pyridoxine per day has been reported with a non-disabling sensory neuropathy. Therefore, it is recommended that doses remain in the 15 – 30 mg/kg/day range, not exceed 500 mg per day.Physicians interested in obtaining clinical and/or therapeutic information on pyridoxine-dependent epilepsy may wish to contact:Sidney M. Gospe, Jr, MD, PhD
Professor Emeritus of Neurology and Pediatrics
University of Washington
e-mail: [email protected]Physicians and patients interested in obtaining additional information regarding the management of pyridoxine-dependent epilepsy and current clinical research may contact the PDE Consortium:Web Site: www.pdeonline.org
e-mail: [email protected]
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Therapies of Pyridoxine-Dependent Epilepsy. TreatmentWhile the effective treatment of patients with PDE requires lifelong pharmacologic supplements of pyridoxine, given the rarity of this disorder there have been no controlled studies to determine the optimal dose. The RDA for pyridoxine is 0.5 mg for infants and 2 mg for adults. Patients with PDE generally have had excellent seizure control when treated with 50 – 100 mg of pyridoxine per day; some patients may be controlled on much smaller doses while others need higher doses. Some recent studies suggest that higher doses may enhance the intellectual development of these patients, and a dose of 15 – 30 mg/kg/day may be optimal. Particular patients with PDE who have associated abnormalities in brain development such as hydrocephalus or heterotopia (forms of birth defects in brain structure) may not have all of their seizures controlled with pyridoxine alone, and these patients require the use of one or more anticonvulsant drugs. However, the excessive use of pyridoxine must be avoided, as pyridoxine may damage the peripheral nervous system (neurotoxicity) manifesting as a reversible sensory neuropathy. While pyridoxine neurotoxicity has been reported primarily in adults who received “mega-vitamin therapy”, one adolescent with possible PDE who received 2 grams of pyridoxine per day has been reported with a non-disabling sensory neuropathy. Therefore, it is recommended that doses remain in the 15 – 30 mg/kg/day range, not exceed 500 mg per day.Physicians interested in obtaining clinical and/or therapeutic information on pyridoxine-dependent epilepsy may wish to contact:Sidney M. Gospe, Jr, MD, PhD
Professor Emeritus of Neurology and Pediatrics
University of Washington
e-mail: [email protected]Physicians and patients interested in obtaining additional information regarding the management of pyridoxine-dependent epilepsy and current clinical research may contact the PDE Consortium:Web Site: www.pdeonline.org
e-mail: [email protected]
| 1,042 |
Pyridoxine-Dependent Epilepsy
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nord_1043_0
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Overview of Pyruvate Carboxylase Deficiency
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Pyruvate carboxylase deficiency (PC deficiency) is a rare genetic disorder present at birth characterized by failure to thrive, developmental delay, recurrent seizures and a failure of the body to produce the necessary fuels for energy and neurotransmitters important for brain function. In its most severe form, PC deficiency leads to progressive damage to the tissue and organs, especially in the nervous system. PC deficiency is inherited as an autosomal recessive genetic condition.
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Overview of Pyruvate Carboxylase Deficiency. Pyruvate carboxylase deficiency (PC deficiency) is a rare genetic disorder present at birth characterized by failure to thrive, developmental delay, recurrent seizures and a failure of the body to produce the necessary fuels for energy and neurotransmitters important for brain function. In its most severe form, PC deficiency leads to progressive damage to the tissue and organs, especially in the nervous system. PC deficiency is inherited as an autosomal recessive genetic condition.
| 1,043 |
Pyruvate Carboxylase Deficiency
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nord_1043_1
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Symptoms of Pyruvate Carboxylase Deficiency
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Three types of PC deficiency have been described and are called type A, type B and type C.PC deficiency type A (infantile form) begins in infancy and symptoms include developmental delay, intellectual disability, mixed acid-base disturbance with mild to moderate elevations in lactic acid and ketone bodies in the blood (lactic acidosis/ketoacidosis), abdominal pain, vomiting, tiredness and muscle weakness. Children with this type of PC deficiency usually die in infancy or early childhood, but some survive to adulthood.PC deficiency type B (severe neonatal form) usually begins at or shortly after birth. Lactic acidosis, ketoacidosis and elevated ammonia (hyperammonemia) are characteristic. Liver failure, decreased muscle tone (hypotonia), intellectual disability, abnormal eye movements, irregular signs and reflexes due to damage of upper motor neurons (pyramidal tract signs), seizures and coma are common. Children with this type of pyruvate carboxylase deficiency usually die within the first three months of life, but two longer-term survivors have been described.PC deficiency type C is characterized by normal or mildly delayed development and normal life expectancy. Lactic acidosis is mild and intermittent.
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Symptoms of Pyruvate Carboxylase Deficiency. Three types of PC deficiency have been described and are called type A, type B and type C.PC deficiency type A (infantile form) begins in infancy and symptoms include developmental delay, intellectual disability, mixed acid-base disturbance with mild to moderate elevations in lactic acid and ketone bodies in the blood (lactic acidosis/ketoacidosis), abdominal pain, vomiting, tiredness and muscle weakness. Children with this type of PC deficiency usually die in infancy or early childhood, but some survive to adulthood.PC deficiency type B (severe neonatal form) usually begins at or shortly after birth. Lactic acidosis, ketoacidosis and elevated ammonia (hyperammonemia) are characteristic. Liver failure, decreased muscle tone (hypotonia), intellectual disability, abnormal eye movements, irregular signs and reflexes due to damage of upper motor neurons (pyramidal tract signs), seizures and coma are common. Children with this type of pyruvate carboxylase deficiency usually die within the first three months of life, but two longer-term survivors have been described.PC deficiency type C is characterized by normal or mildly delayed development and normal life expectancy. Lactic acidosis is mild and intermittent.
| 1,043 |
Pyruvate Carboxylase Deficiency
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nord_1043_2
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Causes of Pyruvate Carboxylase Deficiency
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PC deficiency is caused by changes (mutations) in the pyruvate carboxylase (PC) gene resulting in a missing or decreased amount of pyruvate carboxylase enzyme. This enzyme functions in the energy producing centers of cells (mitochondria) to make oxaloacetate. Brain energy is essential for the production of the protective sheath around some nerve cells (myelin) and the production of neurotransmitters in the brain.PC deficiency is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to inherit normal genes from both parents is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Pyruvate Carboxylase Deficiency. PC deficiency is caused by changes (mutations) in the pyruvate carboxylase (PC) gene resulting in a missing or decreased amount of pyruvate carboxylase enzyme. This enzyme functions in the energy producing centers of cells (mitochondria) to make oxaloacetate. Brain energy is essential for the production of the protective sheath around some nerve cells (myelin) and the production of neurotransmitters in the brain.PC deficiency is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to inherit normal genes from both parents is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
| 1,043 |
Pyruvate Carboxylase Deficiency
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nord_1043_3
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Affects of Pyruvate Carboxylase Deficiency
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PC deficiency is a very rare disorder that affects males and females in equal numbers. The frequency of this condition has been estimated to be 1 in 250,000 births. Type A occurs more often in native tribes of North America and type B occurs more often in Europe, especially in France, but also in Germany and England.
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Affects of Pyruvate Carboxylase Deficiency. PC deficiency is a very rare disorder that affects males and females in equal numbers. The frequency of this condition has been estimated to be 1 in 250,000 births. Type A occurs more often in native tribes of North America and type B occurs more often in Europe, especially in France, but also in Germany and England.
| 1,043 |
Pyruvate Carboxylase Deficiency
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nord_1043_4
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Related disorders of Pyruvate Carboxylase Deficiency
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Symptoms of the following disorders can be similar to those of pyruvate carboxylase deficiency. Comparison may be useful for a differential diagnosis.Leigh syndrome is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, hypotonia, and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. Several different genetically determined enzyme defects can cause the syndrome. Most individuals with Leigh syndrome have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most people, Leigh syndrome is inherited as an autosomal recessive trait. However, X-linked recessive and mitochondrial inheritance have also been described. (For more information about this disorder, choose “Leigh” as your search term in the Rare Disease Database.)Pyruvate dehydrogenase complex deficiency (PDCD) is a rare disorder of carbohydrate metabolism caused by a deficiency of one of the three enzymes in the pyruvate dehydrogenase complex (PDC). The age of onset and severity of disease depends on the activity level of the PDC enzymes. Individuals with PDCD beginning prenatally or postnatally in early infancy usually die in early childhood. Those who develop PDCD later in childhood may have intellectual disability and other neurological symptoms and usually survive into adulthood. Most individuals with PDCD have an abnormality in the PDHA1 gene located on the X chromosome. Some affected individuals have rarer forms of the disorder that follow autosomal recessive inheritance. Some individuals have a thiamine responsive form of this disorder. (For more information about this disorder, choose “pyruvate dehydrogenase” as your search term in the Rare Disease Database.)Biotinidase deficiency is a treatable, metabolic disorder that is the result of a low concentration or absence of the biotinidase enzyme. The body is not able to properly recycle the vitamin, biotin, which is sometimes referred to as Vitamin H. Biotin is an essential vitamin in the metabolic process and biotinidase allows biotin to become available for re-use by the body. Biotinidase deficiency is inherited as an autosomal recessive genetic condition. Most affected infants show a widespread red skin rash (eczema), seizures, and hypotonia. Older children may also have other developmental delays, lactic acidosis, hearing loss, recurrent infections, optic nerve damage (optic atrophy), and hair loss (alopecia). Daily treatment with biotin is an effective treatment. (For more information about this disorder, choose “biotinidase” as your search term in the Rare Disease Database.)
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Related disorders of Pyruvate Carboxylase Deficiency. Symptoms of the following disorders can be similar to those of pyruvate carboxylase deficiency. Comparison may be useful for a differential diagnosis.Leigh syndrome is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, hypotonia, and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. Several different genetically determined enzyme defects can cause the syndrome. Most individuals with Leigh syndrome have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most people, Leigh syndrome is inherited as an autosomal recessive trait. However, X-linked recessive and mitochondrial inheritance have also been described. (For more information about this disorder, choose “Leigh” as your search term in the Rare Disease Database.)Pyruvate dehydrogenase complex deficiency (PDCD) is a rare disorder of carbohydrate metabolism caused by a deficiency of one of the three enzymes in the pyruvate dehydrogenase complex (PDC). The age of onset and severity of disease depends on the activity level of the PDC enzymes. Individuals with PDCD beginning prenatally or postnatally in early infancy usually die in early childhood. Those who develop PDCD later in childhood may have intellectual disability and other neurological symptoms and usually survive into adulthood. Most individuals with PDCD have an abnormality in the PDHA1 gene located on the X chromosome. Some affected individuals have rarer forms of the disorder that follow autosomal recessive inheritance. Some individuals have a thiamine responsive form of this disorder. (For more information about this disorder, choose “pyruvate dehydrogenase” as your search term in the Rare Disease Database.)Biotinidase deficiency is a treatable, metabolic disorder that is the result of a low concentration or absence of the biotinidase enzyme. The body is not able to properly recycle the vitamin, biotin, which is sometimes referred to as Vitamin H. Biotin is an essential vitamin in the metabolic process and biotinidase allows biotin to become available for re-use by the body. Biotinidase deficiency is inherited as an autosomal recessive genetic condition. Most affected infants show a widespread red skin rash (eczema), seizures, and hypotonia. Older children may also have other developmental delays, lactic acidosis, hearing loss, recurrent infections, optic nerve damage (optic atrophy), and hair loss (alopecia). Daily treatment with biotin is an effective treatment. (For more information about this disorder, choose “biotinidase” as your search term in the Rare Disease Database.)
| 1,043 |
Pyruvate Carboxylase Deficiency
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nord_1043_5
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Diagnosis of Pyruvate Carboxylase Deficiency
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PC deficiency is suspected in individuals with failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis.PC deficiency is diagnosed by physical symptoms and laboratory studies. Levels of ammonia, pyruvate, lactate, acetoacetate and beta-hydroxybutyrate in the blood are high. Testing can be performed on samples of skin cells to determine if the pyruvate carboxylase enzyme activity is abnormally low. When deficient, the PC enzyme activity is usually less than 5% of normal activity. Molecular genetic testing for PC gene mutations is available to confirm the diagnosis.Carrier testing and prenatal diagnosis may be possible by molecular genetic testing if the specific PC gene mutations have been identified in an affected family member.
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Diagnosis of Pyruvate Carboxylase Deficiency. PC deficiency is suspected in individuals with failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis.PC deficiency is diagnosed by physical symptoms and laboratory studies. Levels of ammonia, pyruvate, lactate, acetoacetate and beta-hydroxybutyrate in the blood are high. Testing can be performed on samples of skin cells to determine if the pyruvate carboxylase enzyme activity is abnormally low. When deficient, the PC enzyme activity is usually less than 5% of normal activity. Molecular genetic testing for PC gene mutations is available to confirm the diagnosis.Carrier testing and prenatal diagnosis may be possible by molecular genetic testing if the specific PC gene mutations have been identified in an affected family member.
| 1,043 |
Pyruvate Carboxylase Deficiency
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nord_1043_6
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Therapies of Pyruvate Carboxylase Deficiency
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Treatment of PC deficiency is aimed at providing alternative sources of energy for the body and alternative means of metabolizing pyruvate (anaplerotic therapy). A diet that is low in fat and high in carbohydrates and protein is recommended. Intravenous fluids, hydration and correction of the metabolic acidosis can aid in individual flare-ups for disease management. Thiamine, lipoic acid, dichloroacetate, aspartic acid, and citrate can sometimes help to reduce the levels of pyruvate and lactate. Biotin can sometimes improve the function of the pyruvate carboxylase enzyme. Triheptanoin has reportedly reversed hepatic failure and biochemical abnormalities in one case by presumably providing an anaplerotic source of acetyl-CoA and propionyl-CoA. Triheptanoin also may show promise in reversing neurological manifestations but further studies are essential to address this suggestion. Life expectancy was not prolonged in this single reported case.There is no proven therapy currently available to correct or improve the neurological symptoms.Genetic counseling is recommended for families that have a child with pyruvate carboxylase deficiency.
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Therapies of Pyruvate Carboxylase Deficiency. Treatment of PC deficiency is aimed at providing alternative sources of energy for the body and alternative means of metabolizing pyruvate (anaplerotic therapy). A diet that is low in fat and high in carbohydrates and protein is recommended. Intravenous fluids, hydration and correction of the metabolic acidosis can aid in individual flare-ups for disease management. Thiamine, lipoic acid, dichloroacetate, aspartic acid, and citrate can sometimes help to reduce the levels of pyruvate and lactate. Biotin can sometimes improve the function of the pyruvate carboxylase enzyme. Triheptanoin has reportedly reversed hepatic failure and biochemical abnormalities in one case by presumably providing an anaplerotic source of acetyl-CoA and propionyl-CoA. Triheptanoin also may show promise in reversing neurological manifestations but further studies are essential to address this suggestion. Life expectancy was not prolonged in this single reported case.There is no proven therapy currently available to correct or improve the neurological symptoms.Genetic counseling is recommended for families that have a child with pyruvate carboxylase deficiency.
| 1,043 |
Pyruvate Carboxylase Deficiency
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nord_1044_0
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Overview of Pyruvate Dehydrogenase Complex Deficiency
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Pyruvate dehydrogenase complex deficiency (PDCD) is a rare disorder of carbohydrate metabolism caused by a deficiency of one of the three enzymes in the pyruvate dehydrogenase complex (PDC). The age of onset and severity of disease symptoms vary widely. Individuals with PDCD symptom onset in the prenatal period or in infancy usually die in early childhood. Those who develop PDCD later in childhood may have neurological symptoms but usually survive into adulthood. Most individuals with PDCD have an abnormality in the PDHA1 gene located on the X chromosome. A smaller percentage of affected individuals have forms of the disorder that follow autosomal recessive inheritance.
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Overview of Pyruvate Dehydrogenase Complex Deficiency. Pyruvate dehydrogenase complex deficiency (PDCD) is a rare disorder of carbohydrate metabolism caused by a deficiency of one of the three enzymes in the pyruvate dehydrogenase complex (PDC). The age of onset and severity of disease symptoms vary widely. Individuals with PDCD symptom onset in the prenatal period or in infancy usually die in early childhood. Those who develop PDCD later in childhood may have neurological symptoms but usually survive into adulthood. Most individuals with PDCD have an abnormality in the PDHA1 gene located on the X chromosome. A smaller percentage of affected individuals have forms of the disorder that follow autosomal recessive inheritance.
| 1,044 |
Pyruvate Dehydrogenase Complex Deficiency
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nord_1044_1
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Symptoms of Pyruvate Dehydrogenase Complex Deficiency
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Individuals with PDCD are affected by a broad spectrum of symptoms ranging from fatal lactic acidosis in infancy to chronic neurological dysfunction. Not all individuals with PDCD are affected at birth, but almost all show signs of the disease during their first year of life. The most common presenting features of PDCD, including poor feeding, lethargy and rapid breathing (tachypnea), are due to increased blood levels of lactic acid. Other early symptoms include neurological function impairments, such as motor delays, poor muscle tone (hypotonia) and seizures, as well as brain structural abnormalities on neuroimaging. Many individuals with PDCD also have developmental delays, incoordination (ataxia) and respiratory infections/distress. When symptoms begin during the prenatal period or soon after birth, neurological development can be severely impacted leading to major deficits. However, individuals with symptom onset well after birth may have normal neurologic development with intermittent displays of symptoms such as ataxia.
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Symptoms of Pyruvate Dehydrogenase Complex Deficiency. Individuals with PDCD are affected by a broad spectrum of symptoms ranging from fatal lactic acidosis in infancy to chronic neurological dysfunction. Not all individuals with PDCD are affected at birth, but almost all show signs of the disease during their first year of life. The most common presenting features of PDCD, including poor feeding, lethargy and rapid breathing (tachypnea), are due to increased blood levels of lactic acid. Other early symptoms include neurological function impairments, such as motor delays, poor muscle tone (hypotonia) and seizures, as well as brain structural abnormalities on neuroimaging. Many individuals with PDCD also have developmental delays, incoordination (ataxia) and respiratory infections/distress. When symptoms begin during the prenatal period or soon after birth, neurological development can be severely impacted leading to major deficits. However, individuals with symptom onset well after birth may have normal neurologic development with intermittent displays of symptoms such as ataxia.
| 1,044 |
Pyruvate Dehydrogenase Complex Deficiency
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nord_1044_2
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Causes of Pyruvate Dehydrogenase Complex Deficiency
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PDCD is caused by abnormalities in the genes that encode the components of the pyruvate dehydrogenase complex. The pyruvate dehydrogenase complex contains three enzymes, E1, E2, and E3, and multiple coenzymes. The E1 enzyme is comprised of an alpha and a beta subunit. PDCD is most commonly caused by abnormalities in the gene that encodes the E1 alpha subunit, E1-alpha subunit pyruvate dehydrogenase gene or PDHA1. There are many different abnormalities in the PDHA1 gene, also called PDHA1 variants, which are known to cause PDCD. Most PDHA1 variants are sporadic meaning they are new changes to the PDHA1 gene and were not inherited. However, because this gene is located on the X chromosome, when it is inherited, it follows an X-linked recessive pattern of inheritance.X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Sometimes, PDCD is caused by abnormalities in genes that encode different subunits of the pyruvate dehydrogenase complex. These genes include PDHX, PDHB, DLAT, PDP1 and DLD. Abnormalities in these genes follow an autosomal recessive inheritance pattern.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of Pyruvate Dehydrogenase Complex Deficiency. PDCD is caused by abnormalities in the genes that encode the components of the pyruvate dehydrogenase complex. The pyruvate dehydrogenase complex contains three enzymes, E1, E2, and E3, and multiple coenzymes. The E1 enzyme is comprised of an alpha and a beta subunit. PDCD is most commonly caused by abnormalities in the gene that encodes the E1 alpha subunit, E1-alpha subunit pyruvate dehydrogenase gene or PDHA1. There are many different abnormalities in the PDHA1 gene, also called PDHA1 variants, which are known to cause PDCD. Most PDHA1 variants are sporadic meaning they are new changes to the PDHA1 gene and were not inherited. However, because this gene is located on the X chromosome, when it is inherited, it follows an X-linked recessive pattern of inheritance.X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Sometimes, PDCD is caused by abnormalities in genes that encode different subunits of the pyruvate dehydrogenase complex. These genes include PDHX, PDHB, DLAT, PDP1 and DLD. Abnormalities in these genes follow an autosomal recessive inheritance pattern.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
| 1,044 |
Pyruvate Dehydrogenase Complex Deficiency
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nord_1044_3
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Affects of Pyruvate Dehydrogenase Complex Deficiency
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Several hundred children with PDCD have been reported, but the overall frequency is unknown. More males than females are affected by X-linked PDCD. Female carriers of X-linked PDCD may be less severely affected and more difficult to diagnose.
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Affects of Pyruvate Dehydrogenase Complex Deficiency. Several hundred children with PDCD have been reported, but the overall frequency is unknown. More males than females are affected by X-linked PDCD. Female carriers of X-linked PDCD may be less severely affected and more difficult to diagnose.
| 1,044 |
Pyruvate Dehydrogenase Complex Deficiency
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nord_1044_4
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Related disorders of Pyruvate Dehydrogenase Complex Deficiency
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Symptoms of the following disorders can be similar to those of pyruvate carboxylase complex deficiency. Comparison may be useful for a differential diagnosis.Many other conditions present with increased blood levels of lactic acid during infancy. These conditions are most often due to mutations in genes for enzymes encoded by either nuclear or mitochondrial DNA. (For more information, choose “congenital lactic acidosis” as your search term in the Rare Disease Database.)Leigh syndrome is a rare genetic neurometabolic disorder characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). Symptom onset usually begins between three and 24 months. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia) and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function.There are several different genetically determined enzyme abnormalities that cause Leigh syndrome. Most individuals with Leigh syndrome have abnormalities in mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex. When an individual with Leigh syndrome has a mutation in a gene for one of the enzymes of the pyruvate dehydrogenase complex, their diagnosis is called Leigh syndrome associated with pyruvate dehydrogenase complex deficiency. In most patients, Leigh syndrome is inherited in an autosomal recessive pattern. However, X-linked recessive and mitochondrial inheritance have also been noted. (For more information about this disorder, choose “Leigh syndrome” as your search term in the Rare Disease Database.)
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Related disorders of Pyruvate Dehydrogenase Complex Deficiency. Symptoms of the following disorders can be similar to those of pyruvate carboxylase complex deficiency. Comparison may be useful for a differential diagnosis.Many other conditions present with increased blood levels of lactic acid during infancy. These conditions are most often due to mutations in genes for enzymes encoded by either nuclear or mitochondrial DNA. (For more information, choose “congenital lactic acidosis” as your search term in the Rare Disease Database.)Leigh syndrome is a rare genetic neurometabolic disorder characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). Symptom onset usually begins between three and 24 months. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia) and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function.There are several different genetically determined enzyme abnormalities that cause Leigh syndrome. Most individuals with Leigh syndrome have abnormalities in mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex. When an individual with Leigh syndrome has a mutation in a gene for one of the enzymes of the pyruvate dehydrogenase complex, their diagnosis is called Leigh syndrome associated with pyruvate dehydrogenase complex deficiency. In most patients, Leigh syndrome is inherited in an autosomal recessive pattern. However, X-linked recessive and mitochondrial inheritance have also been noted. (For more information about this disorder, choose “Leigh syndrome” as your search term in the Rare Disease Database.)
| 1,044 |
Pyruvate Dehydrogenase Complex Deficiency
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nord_1044_5
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Diagnosis of Pyruvate Dehydrogenase Complex Deficiency
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Biochemical abnormalities vary from severe acidosis (abnormally high blood levels of lactic acid) shortly after birth to mildly elevated levels, oftentimes following a meal high in carbohydrates. In some patients, elevation of blood lactate levels is seen only during the acute episodes. Excretion of abnormally large amounts of the amino acid alanine (alaninuria) may occur only during acute episodes. Imaging studies such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) may reveal structural brain abnormalities associated with severe disease. A definitive clinical diagnosis can be made by measuring abnormal PDC enzyme levels or function in leukocytes, fibroblasts or from a tissue biopsy.Genetic diagnosis can be made by the identification of pathogenic variants in the PDHA1, PDHX, PDHB, DLAT, PDP1 or DLD genes.
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Diagnosis of Pyruvate Dehydrogenase Complex Deficiency. Biochemical abnormalities vary from severe acidosis (abnormally high blood levels of lactic acid) shortly after birth to mildly elevated levels, oftentimes following a meal high in carbohydrates. In some patients, elevation of blood lactate levels is seen only during the acute episodes. Excretion of abnormally large amounts of the amino acid alanine (alaninuria) may occur only during acute episodes. Imaging studies such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) may reveal structural brain abnormalities associated with severe disease. A definitive clinical diagnosis can be made by measuring abnormal PDC enzyme levels or function in leukocytes, fibroblasts or from a tissue biopsy.Genetic diagnosis can be made by the identification of pathogenic variants in the PDHA1, PDHX, PDHB, DLAT, PDP1 or DLD genes.
| 1,044 |
Pyruvate Dehydrogenase Complex Deficiency
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nord_1044_6
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Therapies of Pyruvate Dehydrogenase Complex Deficiency
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TreatmentThere are no treatments available that are specific to PDCD. Dichloroacetate may be administered to treat lactic acidosis, either intravenously during acute episodes or orally on a regular basis. Many affected individuals benefit from maintaining a ketogenic (low carb, high fat) diet and taking antiepileptic drugs to prevent seizures. Some affected individuals respond to treatment with thiamine, a cofactor for the E1 subunit of the pyruvate dehydrogenase complex. Individuals with mutations that affect this binding site specifically may require higher doses of thiamine supplementation. Genetic counseling is recommended for families of children with pyruvate dehydrogenase complex deficiency.
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Therapies of Pyruvate Dehydrogenase Complex Deficiency. TreatmentThere are no treatments available that are specific to PDCD. Dichloroacetate may be administered to treat lactic acidosis, either intravenously during acute episodes or orally on a regular basis. Many affected individuals benefit from maintaining a ketogenic (low carb, high fat) diet and taking antiepileptic drugs to prevent seizures. Some affected individuals respond to treatment with thiamine, a cofactor for the E1 subunit of the pyruvate dehydrogenase complex. Individuals with mutations that affect this binding site specifically may require higher doses of thiamine supplementation. Genetic counseling is recommended for families of children with pyruvate dehydrogenase complex deficiency.
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Pyruvate Dehydrogenase Complex Deficiency
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nord_1045_0
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Overview of Pyruvate Kinase Deficiency
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SummaryPyruvate kinase deficiency (PKD) is a rare genetic disorder characterized by the premature destruction of red blood cells, which is called hemolytic anemia. Anemia is a general term for when there are low levels of red blood cells in the bloodstream, and hemolytic (or hemolysis) means that the red blood cells break down prematurely. Red blood cells are formed in the bone marrow and then are released into the bloodstream. When the youngest red cells are first released into the bloodstream, they are called reticulocytes. Red blood cells travel throughout the body delivering oxygen to the tissues. Healthy red blood cells last approximately 120 days.PKD is caused by changes (variants or mutations) in the PKLR gene, which lead to a deficiency of the enzyme pyruvate kinase. These variants are inherited in an autosomal recessive manner. Pyruvate kinase is an enzyme that helps cells turn sugar (glucose) into energy (called adenosine triphosphate, ATP) in a process called glycolysis. Red cells rely on this process for energy, and so, pyruvate kinase deficiency leads to a deficiency in red cell energy and to premature red cell destruction (hemolysis). Instead of lasting 120 days, red cells with pyruvate kinase deficiency last only a few days to weeks.The severity of PKD can vary greatly. In some people, it may cause mild symptoms, while in others more severe symptoms may develop.
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Overview of Pyruvate Kinase Deficiency. SummaryPyruvate kinase deficiency (PKD) is a rare genetic disorder characterized by the premature destruction of red blood cells, which is called hemolytic anemia. Anemia is a general term for when there are low levels of red blood cells in the bloodstream, and hemolytic (or hemolysis) means that the red blood cells break down prematurely. Red blood cells are formed in the bone marrow and then are released into the bloodstream. When the youngest red cells are first released into the bloodstream, they are called reticulocytes. Red blood cells travel throughout the body delivering oxygen to the tissues. Healthy red blood cells last approximately 120 days.PKD is caused by changes (variants or mutations) in the PKLR gene, which lead to a deficiency of the enzyme pyruvate kinase. These variants are inherited in an autosomal recessive manner. Pyruvate kinase is an enzyme that helps cells turn sugar (glucose) into energy (called adenosine triphosphate, ATP) in a process called glycolysis. Red cells rely on this process for energy, and so, pyruvate kinase deficiency leads to a deficiency in red cell energy and to premature red cell destruction (hemolysis). Instead of lasting 120 days, red cells with pyruvate kinase deficiency last only a few days to weeks.The severity of PKD can vary greatly. In some people, it may cause mild symptoms, while in others more severe symptoms may develop.
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Pyruvate Kinase Deficiency
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nord_1045_1
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Symptoms of Pyruvate Kinase Deficiency
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Symptoms from pyruvate kinase deficiency can be highly variable. How it affects one person can be significantly different from how it affects another person. In some people, the disorder can be life-threatening at birth. Other individuals may have mild or no symptoms of the disorder and go undiagnosed into adulthood. Others may develop symptoms during childhood or as adults. The main finding, hemolytic anemia, is a chronic, lifelong condition.Newborns
Before birth, some developing fetuses with anemia can develop a condition called fetal hydrops. This is a serious condition in which large amounts of fluid builds up in the tissues and organs of the fetus. It develops because the heart must pump a greater volume of blood to deliver oxygen than normal because of anemia. Anemia in the developing fetus can also lead to poor growth or premature birth. Some newborns can have severe symptoms at birth with an enlarged liver and/or spleen, high blood pressure in the arteries in the lungs and the right side of the heart (pulmonary hypertension), evidence of inflammation and/or liver disease. At birth, some infants may have significant anemia and severe jaundice, which is yellowing of the skin and the whites of the eyes. Jaundice is caused by high levels of bilirubin in the body. Normally, when old or damaged red blood cells are broken down in the spleen, bilirubin is released into the bloodstream. This type of bilirubin is called unconjugated (or indirect) bilirubin. The unconjugated bilirubin is taken up by the liver cells, converted to conjugated bilirubin and excreted into the intestines and then into the stools. With hemolysis, an excess of bilirubin is released into the bloodstream and the liver cannot keep up with the conjugation process. Unlike children and adults with elevated bilirubin levels, high bilirubin levels in infants can lead to kernicterus, a neurologic condition characterized by the accumulation of toxic levels of bilirubin. High bilirubin levels in newborns require aggressive treatment to attempt to avoid the risk of kernicterus.Children and Adults
The most common finding in children and adults is anemia. Anemia can cause tiredness, fatigue, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea), shortness of breath and cardiac symptoms.The degree of jaundice or scleral icterus is linked to the amount of total unconjugated bilirubin. This is determined both by the degree of hemolysis and by an individual’s ability to metabolize bilirubin, which is genetically determined. People with Gilbert syndrome have an inherited condition (two copies of a gene variant) that reduces the production of an enzyme involved in the processing of bilirubin in the liver. Gilbert syndrome is common, so it is possible for someone to inherit both PKD and Gilbert syndrome. Children and adults with PKD can develop gallstones. Gallstones are small, hard masses that form in the gallbladder and block the bile ducts and cause pain. Gallstones are a frequent complication in children and adults with PKD because of the increased unconjugated bilirubin. The risk of gallstones is life-long due to ongoing hemolysis.Affected individuals can also develop an enlarged spleen (splenomegaly). One function of the spleen is to filter red blood cells. The spleen becomes enlarged because it filters out the abnormal red blood cells. An enlarged spleen does not typically cause pain.Hemolytic episodes develop in the presence of stressors or triggers of hemolysis, which most often are infections and, therefore, more frequent in childhood. Pregnancy can also be a common hemolytic trigger. During these episodes, an individual’s symptoms worsen, such as fatigue, paleness, scleral icterus, jaundice and/or dark urine. An aplastic crisis is caused by parvovirus B19 infection (also called Fifth disease). This commonly causes a high fever and facial rash. In individuals with PKD, parvovirus infection reduces or stops reticulocyte production in the bone marrow and thereby decreases the hemoglobin level. Aplastic crises in individuals with PKD often require a blood transfusion.Iron overload is one of the most common findings in patients with PKD. Iron overload can occur both in individuals who receive blood transfusions and in those who have never been transfused. Iron overload is the abnormal accumulation of iron in various organs of the body most commonly in the liver, but iron loading can also occur in the heart and hormone-producing organs (endocrine organs). Iron loading is not associated with symptoms until a significant amount of iron is deposited, so it is important to monitor iron studies regularly in all individuals with PKD.Other complications can occur in PKD. Adolescents and adults commonly develop weakened bones (osteopenia or osteoporosis) with an increased risk of bone fractures. Adults can develop skin sores (ulcers), typically around the ankles. Other less common complications include pulmonary hypertension and blood cell production outside of the bone marrow (extramedullary hematopoiesis). Patients can develop mental health issues related to the chronic effects of PKD.
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Symptoms of Pyruvate Kinase Deficiency. Symptoms from pyruvate kinase deficiency can be highly variable. How it affects one person can be significantly different from how it affects another person. In some people, the disorder can be life-threatening at birth. Other individuals may have mild or no symptoms of the disorder and go undiagnosed into adulthood. Others may develop symptoms during childhood or as adults. The main finding, hemolytic anemia, is a chronic, lifelong condition.Newborns
Before birth, some developing fetuses with anemia can develop a condition called fetal hydrops. This is a serious condition in which large amounts of fluid builds up in the tissues and organs of the fetus. It develops because the heart must pump a greater volume of blood to deliver oxygen than normal because of anemia. Anemia in the developing fetus can also lead to poor growth or premature birth. Some newborns can have severe symptoms at birth with an enlarged liver and/or spleen, high blood pressure in the arteries in the lungs and the right side of the heart (pulmonary hypertension), evidence of inflammation and/or liver disease. At birth, some infants may have significant anemia and severe jaundice, which is yellowing of the skin and the whites of the eyes. Jaundice is caused by high levels of bilirubin in the body. Normally, when old or damaged red blood cells are broken down in the spleen, bilirubin is released into the bloodstream. This type of bilirubin is called unconjugated (or indirect) bilirubin. The unconjugated bilirubin is taken up by the liver cells, converted to conjugated bilirubin and excreted into the intestines and then into the stools. With hemolysis, an excess of bilirubin is released into the bloodstream and the liver cannot keep up with the conjugation process. Unlike children and adults with elevated bilirubin levels, high bilirubin levels in infants can lead to kernicterus, a neurologic condition characterized by the accumulation of toxic levels of bilirubin. High bilirubin levels in newborns require aggressive treatment to attempt to avoid the risk of kernicterus.Children and Adults
The most common finding in children and adults is anemia. Anemia can cause tiredness, fatigue, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea), shortness of breath and cardiac symptoms.The degree of jaundice or scleral icterus is linked to the amount of total unconjugated bilirubin. This is determined both by the degree of hemolysis and by an individual’s ability to metabolize bilirubin, which is genetically determined. People with Gilbert syndrome have an inherited condition (two copies of a gene variant) that reduces the production of an enzyme involved in the processing of bilirubin in the liver. Gilbert syndrome is common, so it is possible for someone to inherit both PKD and Gilbert syndrome. Children and adults with PKD can develop gallstones. Gallstones are small, hard masses that form in the gallbladder and block the bile ducts and cause pain. Gallstones are a frequent complication in children and adults with PKD because of the increased unconjugated bilirubin. The risk of gallstones is life-long due to ongoing hemolysis.Affected individuals can also develop an enlarged spleen (splenomegaly). One function of the spleen is to filter red blood cells. The spleen becomes enlarged because it filters out the abnormal red blood cells. An enlarged spleen does not typically cause pain.Hemolytic episodes develop in the presence of stressors or triggers of hemolysis, which most often are infections and, therefore, more frequent in childhood. Pregnancy can also be a common hemolytic trigger. During these episodes, an individual’s symptoms worsen, such as fatigue, paleness, scleral icterus, jaundice and/or dark urine. An aplastic crisis is caused by parvovirus B19 infection (also called Fifth disease). This commonly causes a high fever and facial rash. In individuals with PKD, parvovirus infection reduces or stops reticulocyte production in the bone marrow and thereby decreases the hemoglobin level. Aplastic crises in individuals with PKD often require a blood transfusion.Iron overload is one of the most common findings in patients with PKD. Iron overload can occur both in individuals who receive blood transfusions and in those who have never been transfused. Iron overload is the abnormal accumulation of iron in various organs of the body most commonly in the liver, but iron loading can also occur in the heart and hormone-producing organs (endocrine organs). Iron loading is not associated with symptoms until a significant amount of iron is deposited, so it is important to monitor iron studies regularly in all individuals with PKD.Other complications can occur in PKD. Adolescents and adults commonly develop weakened bones (osteopenia or osteoporosis) with an increased risk of bone fractures. Adults can develop skin sores (ulcers), typically around the ankles. Other less common complications include pulmonary hypertension and blood cell production outside of the bone marrow (extramedullary hematopoiesis). Patients can develop mental health issues related to the chronic effects of PKD.
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Pyruvate Kinase Deficiency
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nord_1045_2
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Causes of Pyruvate Kinase Deficiency
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Pyruvate kinase deficiency is caused by an alteration in the PKLR gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent.The PKLR gene contains instructions for creating (encoding) a specialized protein (enzyme) known as pyruvate kinase. Because this gene is altered, there is a deficiency of functional pyruvate kinase enzyme. Red blood cells use several enzymes to ensure proper energy production. Energy is produced through a chemical process called glycolysis. Glycolysis is a chemical pathway in which sugar (glucose) is broken down to produce energy for the cell. Pyruvate kinase enzyme breaks down a chemical compound called adenosine triphosphate (ATP). Because this enzyme is deficient, there is a lack of ATP. This leads to dehydration of red blood cells and abnormal red cell shapes. The altered red blood cell has a shortened lifespan leading to hemolytic anemia. As the altered red cells are destroyed, new red cells (reticulocytes) are created, creating a balance of increased red cell destruction, and increased red cell production.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 recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene variant for the disease, the person will be a carrier for the disease, but will not show symptoms. The risk for two carrier parents to both pass the gene variant and 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 normal genes from both parents is 25%. The risk is the same for males and females. Most individuals with PKD have two different PKLR gene variants (compound heterozygotes).
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Causes of Pyruvate Kinase Deficiency. Pyruvate kinase deficiency is caused by an alteration in the PKLR gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent.The PKLR gene contains instructions for creating (encoding) a specialized protein (enzyme) known as pyruvate kinase. Because this gene is altered, there is a deficiency of functional pyruvate kinase enzyme. Red blood cells use several enzymes to ensure proper energy production. Energy is produced through a chemical process called glycolysis. Glycolysis is a chemical pathway in which sugar (glucose) is broken down to produce energy for the cell. Pyruvate kinase enzyme breaks down a chemical compound called adenosine triphosphate (ATP). Because this enzyme is deficient, there is a lack of ATP. This leads to dehydration of red blood cells and abnormal red cell shapes. The altered red blood cell has a shortened lifespan leading to hemolytic anemia. As the altered red cells are destroyed, new red cells (reticulocytes) are created, creating a balance of increased red cell destruction, and increased red cell production.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 recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene variant for the disease, the person will be a carrier for the disease, but will not show symptoms. The risk for two carrier parents to both pass the gene variant and 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 normal genes from both parents is 25%. The risk is the same for males and females. Most individuals with PKD have two different PKLR gene variants (compound heterozygotes).
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Pyruvate Kinase Deficiency
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nord_1045_3
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Affects of Pyruvate Kinase Deficiency
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Pyruvate kinase deficiency is a rare disorder that affects both males and females. The frequency of the disorder is unknown, although one estimate suggests that approximately 1 in 20,000 Caucasian people develop the disorder. In clinical practice, the frequency is closer to 1 in 1,000,000 people. PKD has been identified most in the US and Europe. However, rare disorders like PKD often go misdiagnosed or undiagnosed making it difficult to determine their true frequency in the general population.
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Affects of Pyruvate Kinase Deficiency. Pyruvate kinase deficiency is a rare disorder that affects both males and females. The frequency of the disorder is unknown, although one estimate suggests that approximately 1 in 20,000 Caucasian people develop the disorder. In clinical practice, the frequency is closer to 1 in 1,000,000 people. PKD has been identified most in the US and Europe. However, rare disorders like PKD often go misdiagnosed or undiagnosed making it difficult to determine their true frequency in the general population.
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Pyruvate Kinase Deficiency
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nord_1045_4
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Related disorders of Pyruvate Kinase Deficiency
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Symptoms of the following disorders can be similar to those of pyruvate kinase deficiency. Comparisons may be useful for a differential diagnosis.Acquired hemolytic anemias
Autoimmune hemolytic anemia is an acquired hemolytic anemia that develops when an individual’s immune system attacks their own red blood cells.Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder of hematopoietic stem cells characterized by chronic hemolysis, thrombosis (blot clots), increased risk of infections and bone marrow failure.Microangiopathic hemolytic anemia is characterized by mechanical destruction of RBCs, and includes disorders such as thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and disseminated intravascular coagulation. Some of these disorders are associated with infections.Infections and medications can cause direct destruction of red cells. Shear within the blood vessels can also cause hemolysis.Congenital hemolytic anemias
Red cell membrane defects: Hereditary spherocytosis and hereditary ellipocytosis are genetic disorders of the red cell membrane (outer shell) which leads the red cell to be shaped like a sphere or oval rather than a disc. These abnormal shapes cause the red cells to break apart in the spleen more easily.Red cell permeability defects: Hereditary xerocytosis and related disorders are hemolytic conditions caused by abnormal water content within the red cells.Hemoglobin disorders: Sickle cell disease and thalassemia are genetic disorders of hemoglobin. Sickle cell disease causes chronic hemolysis and can be associated with episodes of pain and increased risk of infection and stroke, among other complications.Enzyme defects are caused by problems in the glycolytic pathway or a related pathway. The diagnosis of all these conditions is based on the demonstration of a reduced enzymatic activity and on the detection of gene variants in the associated genes. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common red cell enzyme defect and is a genetic metabolic disorder caused by deficiency of the enzyme, G6PD. G6PD deficiency is most commonly an episodic disorder triggered by certain medications or by eating fava beans.For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.
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Related disorders of Pyruvate Kinase Deficiency. Symptoms of the following disorders can be similar to those of pyruvate kinase deficiency. Comparisons may be useful for a differential diagnosis.Acquired hemolytic anemias
Autoimmune hemolytic anemia is an acquired hemolytic anemia that develops when an individual’s immune system attacks their own red blood cells.Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder of hematopoietic stem cells characterized by chronic hemolysis, thrombosis (blot clots), increased risk of infections and bone marrow failure.Microangiopathic hemolytic anemia is characterized by mechanical destruction of RBCs, and includes disorders such as thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and disseminated intravascular coagulation. Some of these disorders are associated with infections.Infections and medications can cause direct destruction of red cells. Shear within the blood vessels can also cause hemolysis.Congenital hemolytic anemias
Red cell membrane defects: Hereditary spherocytosis and hereditary ellipocytosis are genetic disorders of the red cell membrane (outer shell) which leads the red cell to be shaped like a sphere or oval rather than a disc. These abnormal shapes cause the red cells to break apart in the spleen more easily.Red cell permeability defects: Hereditary xerocytosis and related disorders are hemolytic conditions caused by abnormal water content within the red cells.Hemoglobin disorders: Sickle cell disease and thalassemia are genetic disorders of hemoglobin. Sickle cell disease causes chronic hemolysis and can be associated with episodes of pain and increased risk of infection and stroke, among other complications.Enzyme defects are caused by problems in the glycolytic pathway or a related pathway. The diagnosis of all these conditions is based on the demonstration of a reduced enzymatic activity and on the detection of gene variants in the associated genes. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common red cell enzyme defect and is a genetic metabolic disorder caused by deficiency of the enzyme, G6PD. G6PD deficiency is most commonly an episodic disorder triggered by certain medications or by eating fava beans.For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.
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Pyruvate Kinase Deficiency
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nord_1045_5
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Diagnosis of Pyruvate Kinase Deficiency
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A diagnosis of pyruvate kinase deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, an initial laboratory evaluation, and a variety of specialized tests.Clinical Testing and Workup
Initial lab tests may be performed to determine that anemia is present and whether it is due to hemolysis. Signs of hemolysis include a low hemoglobin level, an elevated unconjugated bilirubin level, an elevated reticulocyte count and low levels of haptoglobin in the blood.The standard diagnostic test for PKD is to measure the activity of the pyruvate kinase enzyme in red blood cells. Low activity of this enzyme is indictive of the disorder. Falsely normal levels can occur in patients with elevated reticulocyte counts. This test is only run at specialized laboratories; most clinics and hospitals send this test to be run at these specialized centers.Molecular genetic testing helps to confirm a diagnosis of PKD. Molecular genetic testing can detect variants in the PKLR gene known to cause the disorder. This test is only run at specialized laboratories; most clinics and hospitals send this test to be run at these specialized centers.
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Diagnosis of Pyruvate Kinase Deficiency. A diagnosis of pyruvate kinase deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, an initial laboratory evaluation, and a variety of specialized tests.Clinical Testing and Workup
Initial lab tests may be performed to determine that anemia is present and whether it is due to hemolysis. Signs of hemolysis include a low hemoglobin level, an elevated unconjugated bilirubin level, an elevated reticulocyte count and low levels of haptoglobin in the blood.The standard diagnostic test for PKD is to measure the activity of the pyruvate kinase enzyme in red blood cells. Low activity of this enzyme is indictive of the disorder. Falsely normal levels can occur in patients with elevated reticulocyte counts. This test is only run at specialized laboratories; most clinics and hospitals send this test to be run at these specialized centers.Molecular genetic testing helps to confirm a diagnosis of PKD. Molecular genetic testing can detect variants in the PKLR gene known to cause the disorder. This test is only run at specialized laboratories; most clinics and hospitals send this test to be run at these specialized centers.
| 1,045 |
Pyruvate Kinase Deficiency
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nord_1045_6
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Therapies of Pyruvate Kinase Deficiency
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Treatment
Treatment may require the coordinated efforts of a team of specialists. Pediatricians or general internists, physicians who specialize in diagnosing and treating blood disorders (hematologists) and other healthcare professionals may need to plan treatment systematically and comprehensively. Symptoms vary between patients so an individualized treatment plan should be developed.Genetic counseling is recommended for affected individuals and their families.Newborns
A blood transfusion may be necessary for the developing fetus (intrauterine transfusion) if fetal hydrops develops, or there are signs of poor growth related to anemia during pregnancy. Most newborns with PKD will develop jaundice because of the breakdown of red cells and the inability of their immature livers to conjugate bilirubin. Some affected infants may require phototherapy for bilirubinemia. During this procedure, intense light is focused on the bare skin, while the eyes are shielded. This helps to speed up the bilirubin metabolism and excretion. In some newborns with severe jaundice, an exchange transfusion may be necessary. An exchange transfusion is when an individual’s blood is removed and replaced by a donor’s blood.Infants, Children and Adults
In infants, children, and adults with PKD, blood transfusions may be used. The decision to transfuse is not based on the level of hemoglobin, but, rather, how an individual is tolerating the hemolytic anemia. The goal is to avoid transfusions, if possible, but they may be necessary, particularly in the first years of life, to support growth and development and avoid symptoms, such as fatigue or poor feeding. In older children and adults, there are no standard criteria or schedule for transfusions, especially since the symptoms differ so widely between individuals. For individuals with daily symptoms from anemia, regular blood transfusions may be recommended. Others may only be transfused for acute infections or in pregnancy. Other individuals may never have a blood transfusion.Red cell transfusions cause a buildup of iron over time. The body does not have a mechanism for getting rid of iron and so with repeated red cell transfusions, iron begins to deposit in the liver. Iron overload occurs commonly in individuals with PKD, even in the absence of red cell transfusions, through increased absorption from the diet. Chelation agents bind with iron to form substances that can be excreted from the body easily. Phlebotomy (regular removal of blood) can be used to unload iron from the body but is often not well-tolerated in individuals with anemia.In 2022, mitapivat (Pyrukynd) was approved by the U.S. Food and Drug Administration (FDA) to treat hemolytic anemia in adults with PKD. Studies have shown that mitapivat increases hemoglobin, decreases hemolysis and improves everyday quality of life in subset of patients with PKD. The effect can be maintained for years with ongoing treatment. There is ongoing research on the long-term safety and effectiveness of mitapivat for individuals with PKD. The hemoglobin response may be more likely in patients with certain PKLR gene variants.Sometimes, surgical removal of the spleen (splenectomy) may be recommended. Removal of the spleen may be considered if individuals require frequent blood transfusions or have frequent symptoms from anemia. Splenectomy, both open surgical and laparoscopic, has led to a partial improvement of the anemia in most individuals. However, this surgical procedure carries potential risks such as life-threatening bloodstream infections and blood clot formation (thrombosis), which are weighed against the potential benefits of splenectomy. Given the risk of infection after splenectomy, most individuals wait until at least the age of 5 years before proceeding with splenectomy. It is also important that individuals receive additional vaccines prior to and after splenectomy, take prophylactic antibiotics after splenectomy and follow lifelong strict fever guidelines.Supportive care can include gallbladder monitoring due to risk of gallstones. Gallbladder removal (cholecystectomy) is pursued in individuals with symptomatic gallstones and in individuals at the time of splenectomy. Folic acid supplementation, which supports increased red cell production, is often prescribed. Regular monitoring with bone density scans should occur starting in late adolescents or early adulthood. Vitamin D, calcium and exercise may be important for bone health.Allogeneic hematopoietic stem cell transplantation (HSCT) can cure PKD. This has been pursued in a limited number of individuals, particularly individuals who require chronic blood transfusions. In allogeneic stem cell transplantation, affected individuals, after treatment with chemotherapy, receive hematopoietic stem cells from a healthy donor. This is a major medical procedure that carries significant risk, including dying from complications related to transplant. Only a small number of individuals with PKD have undergone HSCT in Europe and Asia. Most doctors think the risk-benefit ratio is in favor of splenectomy over HSCT. More research is necessary to determine the long-term safety and effectiveness of this therapy for certain individuals with PKD.
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Therapies of Pyruvate Kinase Deficiency. Treatment
Treatment may require the coordinated efforts of a team of specialists. Pediatricians or general internists, physicians who specialize in diagnosing and treating blood disorders (hematologists) and other healthcare professionals may need to plan treatment systematically and comprehensively. Symptoms vary between patients so an individualized treatment plan should be developed.Genetic counseling is recommended for affected individuals and their families.Newborns
A blood transfusion may be necessary for the developing fetus (intrauterine transfusion) if fetal hydrops develops, or there are signs of poor growth related to anemia during pregnancy. Most newborns with PKD will develop jaundice because of the breakdown of red cells and the inability of their immature livers to conjugate bilirubin. Some affected infants may require phototherapy for bilirubinemia. During this procedure, intense light is focused on the bare skin, while the eyes are shielded. This helps to speed up the bilirubin metabolism and excretion. In some newborns with severe jaundice, an exchange transfusion may be necessary. An exchange transfusion is when an individual’s blood is removed and replaced by a donor’s blood.Infants, Children and Adults
In infants, children, and adults with PKD, blood transfusions may be used. The decision to transfuse is not based on the level of hemoglobin, but, rather, how an individual is tolerating the hemolytic anemia. The goal is to avoid transfusions, if possible, but they may be necessary, particularly in the first years of life, to support growth and development and avoid symptoms, such as fatigue or poor feeding. In older children and adults, there are no standard criteria or schedule for transfusions, especially since the symptoms differ so widely between individuals. For individuals with daily symptoms from anemia, regular blood transfusions may be recommended. Others may only be transfused for acute infections or in pregnancy. Other individuals may never have a blood transfusion.Red cell transfusions cause a buildup of iron over time. The body does not have a mechanism for getting rid of iron and so with repeated red cell transfusions, iron begins to deposit in the liver. Iron overload occurs commonly in individuals with PKD, even in the absence of red cell transfusions, through increased absorption from the diet. Chelation agents bind with iron to form substances that can be excreted from the body easily. Phlebotomy (regular removal of blood) can be used to unload iron from the body but is often not well-tolerated in individuals with anemia.In 2022, mitapivat (Pyrukynd) was approved by the U.S. Food and Drug Administration (FDA) to treat hemolytic anemia in adults with PKD. Studies have shown that mitapivat increases hemoglobin, decreases hemolysis and improves everyday quality of life in subset of patients with PKD. The effect can be maintained for years with ongoing treatment. There is ongoing research on the long-term safety and effectiveness of mitapivat for individuals with PKD. The hemoglobin response may be more likely in patients with certain PKLR gene variants.Sometimes, surgical removal of the spleen (splenectomy) may be recommended. Removal of the spleen may be considered if individuals require frequent blood transfusions or have frequent symptoms from anemia. Splenectomy, both open surgical and laparoscopic, has led to a partial improvement of the anemia in most individuals. However, this surgical procedure carries potential risks such as life-threatening bloodstream infections and blood clot formation (thrombosis), which are weighed against the potential benefits of splenectomy. Given the risk of infection after splenectomy, most individuals wait until at least the age of 5 years before proceeding with splenectomy. It is also important that individuals receive additional vaccines prior to and after splenectomy, take prophylactic antibiotics after splenectomy and follow lifelong strict fever guidelines.Supportive care can include gallbladder monitoring due to risk of gallstones. Gallbladder removal (cholecystectomy) is pursued in individuals with symptomatic gallstones and in individuals at the time of splenectomy. Folic acid supplementation, which supports increased red cell production, is often prescribed. Regular monitoring with bone density scans should occur starting in late adolescents or early adulthood. Vitamin D, calcium and exercise may be important for bone health.Allogeneic hematopoietic stem cell transplantation (HSCT) can cure PKD. This has been pursued in a limited number of individuals, particularly individuals who require chronic blood transfusions. In allogeneic stem cell transplantation, affected individuals, after treatment with chemotherapy, receive hematopoietic stem cells from a healthy donor. This is a major medical procedure that carries significant risk, including dying from complications related to transplant. Only a small number of individuals with PKD have undergone HSCT in Europe and Asia. Most doctors think the risk-benefit ratio is in favor of splenectomy over HSCT. More research is necessary to determine the long-term safety and effectiveness of this therapy for certain individuals with PKD.
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Pyruvate Kinase Deficiency
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nord_1046_0
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Overview of Q fever
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SummaryQ fever is an infectious disease that is spread by the inhalation or ingestion of a bacterium known as Coxiella burnetii, which belongs to the order of Legionellales. Animals such as cattle, sheep and goats are common bacterial hosts for this bacterium. C. burnetii is spread mainly by breathing contaminated air or eating or drinking contaminated food. Farm workers, especially those who work with animals, people who work in slaughterhouses and veterinarians are especially vulnerable to this disease. Other forms of transmission are rare but include tick bites and human to human transmission. Q fever causes highly variable symptoms ranging from acute (often self-limited) infection to fatal chronic infection. Progression of Q fever from acute infection to chronic fever occurs in less than 5% of patients. Infections that do not cause outward symptoms (subclinical) or no symptoms (asymptomatic) are also common. Acute Q fever is treated with antibiotics. Treatment for chronic Q fever is more complex and depends on an individual’s presenting symptoms. People of all ages are susceptible to Q fever.IntroductionSince infection can occur because of airborne transmission and the bacterium is very resistant to environmental conditions such heat and pressure, C. burnetti was included on the list of possible bacteriological weapons.
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Overview of Q fever. SummaryQ fever is an infectious disease that is spread by the inhalation or ingestion of a bacterium known as Coxiella burnetii, which belongs to the order of Legionellales. Animals such as cattle, sheep and goats are common bacterial hosts for this bacterium. C. burnetii is spread mainly by breathing contaminated air or eating or drinking contaminated food. Farm workers, especially those who work with animals, people who work in slaughterhouses and veterinarians are especially vulnerable to this disease. Other forms of transmission are rare but include tick bites and human to human transmission. Q fever causes highly variable symptoms ranging from acute (often self-limited) infection to fatal chronic infection. Progression of Q fever from acute infection to chronic fever occurs in less than 5% of patients. Infections that do not cause outward symptoms (subclinical) or no symptoms (asymptomatic) are also common. Acute Q fever is treated with antibiotics. Treatment for chronic Q fever is more complex and depends on an individual’s presenting symptoms. People of all ages are susceptible to Q fever.IntroductionSince infection can occur because of airborne transmission and the bacterium is very resistant to environmental conditions such heat and pressure, C. burnetti was included on the list of possible bacteriological weapons.
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Symptoms of Q fever
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The symptoms of Q fever can vary dramatically from one person to another. Infection can result in no apparent symptoms (asymptomatic); an acute form of disease characterized by a flu-like illness that either goes away on its own (self-limited) or causes more serious symptoms; or a chronic form that can be associated with serious complications. Researchers believe that a variety of factors may influence the severity of Q fever including age, gender and a person’s general health, including pre-existing medical conditions (e.g., heart disease).Acute Q FeverThe acute form of Q fever starts approximately two to three weeks after exposure to the bacterium. Acute Q fever is characterized by flu-like symptoms such as high fevers, chills, muscle pain (myalgia), muscle weakness, fatigue and headaches. In some patients, fevers do not occur. Additional nonspecific symptoms can potentially occur including cough, chest pain, sore throat, skin rash or gastrointestinal symptoms. Many people also suffer from small areas of inflammation (granuloma). Pneumonia and inflammation of the liver (hepatitis) are commonly associated with acute Q fever. Pneumonia is often mild but can potentially progress to cause acute respiratory distress syndrome (ARDS). Hepatitis may cause abnormal enlargement of the liver (hepatomegaly). More rarely, it can cause yellowing of the skin and the whites of the eyes (jaundice). Other symptoms can occur in some affected individuals including inflammation of the muscular wall of the heart (myocarditis), inflammation of the sac-like membrane that surrounds the heart (pericarditis) and the development of a purple skin rash caused by bleeding (hemorrhaging) from tiny blood vessels just below the surface of the skin.Acute Q fever may present as a neurological disease caused by inflammation of the thin membrane covering the brain and spinal cord or the brain (meningoencephalitis). In some individuals, acute Q fever can affect the kidneys, thyroids or genitals.Chronic Q FeverChronic Q fever may occur months to years after acute disease or may occur without a previous history of symptomatic acute Q fever. Most cases of chronic Q fever occur in individuals with predisposing conditions such as existing heart valve or blood vessel (vascular) abnormalities or a compromised immune system.The most common manifestation of chronic Q fever is inflammation of the thin membrane lining the inside of the heart and heart valves (infective endocarditis), potentially damaging the heart valves or heart tissue. Inflammation of heart muscle (myocarditis) is rarely seen but also possible. Other symptoms include inflammation of blood vessels (vasculitis), low red blood cell count (hemoglobin), low platelet count (thrombocytopenia), anticardiolipin IgG antibody positivity, antimitochondrial antibody positivity and blood in urine (hematuria). Affected individuals can develop congestive heart failure, a serious complication in which a limited ability to circulate blood to the lungs and the rest of the body results in fluid buildup in the heart, lungs and various body tissues. In addition, Q fever can cause liver inflammation (hepatitis), enlarged liver (hepatomegaly), enlarged liver and spleen (hepatosplenomegaly), fluid around lungs (pleural effusions) and respiratory distress.Less commonly, chronic Q fever can present as an infection of the bones and joints (osteoarticular infection) such as osteomyelitis or osteoarthritis, which can cause bone and joint pain. Vascular infections, chronic hepatitis and chronic pulmonary disease are also seen in some patients. Chronic hepatitis can cause enlargement of the liver or jaundice. Chronic pulmonary disease can cause difficulty breathing (dyspnea) and other respiratory abnormalities. Other less common symptoms include abnormal heart valve morphology, immunodeficiency, increased circulating antibody level, flat and raised skin lesions (maculopapular exanthema), pneumonia, red or purple spots on the skin (purpura) and rheumatoid factor positivity.Individuals with chronic Q fever may also experience a variety of symptoms similar to those experienced by acute Q Fever patients, including prolonged fevers (although fevers are often absent), joint pain (arthralgia), muscle pain (myalgia), night sweats, chills, fatigue and unintended weight loss.
Some individuals with Q fever develop long-term complications such as chronic, persistent fatigue. Some researchers believe that infection with Q fever increases an individual’s risk of developing cardiovascular disease later in life.The rarest symptoms (approximately 1%- 4% of individuals) include abnormal function of the left ventricle, abnormal amyloid build-up (amyloidosis), inflammation of the gallbladder (cholecystitis), inflammation of the brain (encephalitis), lupus anticoagulant, swollen lymph nodes (lymphadenopathy) or inflammation of fluid and membrane around the brain and spinal cord (meningitis).
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Symptoms of Q fever. The symptoms of Q fever can vary dramatically from one person to another. Infection can result in no apparent symptoms (asymptomatic); an acute form of disease characterized by a flu-like illness that either goes away on its own (self-limited) or causes more serious symptoms; or a chronic form that can be associated with serious complications. Researchers believe that a variety of factors may influence the severity of Q fever including age, gender and a person’s general health, including pre-existing medical conditions (e.g., heart disease).Acute Q FeverThe acute form of Q fever starts approximately two to three weeks after exposure to the bacterium. Acute Q fever is characterized by flu-like symptoms such as high fevers, chills, muscle pain (myalgia), muscle weakness, fatigue and headaches. In some patients, fevers do not occur. Additional nonspecific symptoms can potentially occur including cough, chest pain, sore throat, skin rash or gastrointestinal symptoms. Many people also suffer from small areas of inflammation (granuloma). Pneumonia and inflammation of the liver (hepatitis) are commonly associated with acute Q fever. Pneumonia is often mild but can potentially progress to cause acute respiratory distress syndrome (ARDS). Hepatitis may cause abnormal enlargement of the liver (hepatomegaly). More rarely, it can cause yellowing of the skin and the whites of the eyes (jaundice). Other symptoms can occur in some affected individuals including inflammation of the muscular wall of the heart (myocarditis), inflammation of the sac-like membrane that surrounds the heart (pericarditis) and the development of a purple skin rash caused by bleeding (hemorrhaging) from tiny blood vessels just below the surface of the skin.Acute Q fever may present as a neurological disease caused by inflammation of the thin membrane covering the brain and spinal cord or the brain (meningoencephalitis). In some individuals, acute Q fever can affect the kidneys, thyroids or genitals.Chronic Q FeverChronic Q fever may occur months to years after acute disease or may occur without a previous history of symptomatic acute Q fever. Most cases of chronic Q fever occur in individuals with predisposing conditions such as existing heart valve or blood vessel (vascular) abnormalities or a compromised immune system.The most common manifestation of chronic Q fever is inflammation of the thin membrane lining the inside of the heart and heart valves (infective endocarditis), potentially damaging the heart valves or heart tissue. Inflammation of heart muscle (myocarditis) is rarely seen but also possible. Other symptoms include inflammation of blood vessels (vasculitis), low red blood cell count (hemoglobin), low platelet count (thrombocytopenia), anticardiolipin IgG antibody positivity, antimitochondrial antibody positivity and blood in urine (hematuria). Affected individuals can develop congestive heart failure, a serious complication in which a limited ability to circulate blood to the lungs and the rest of the body results in fluid buildup in the heart, lungs and various body tissues. In addition, Q fever can cause liver inflammation (hepatitis), enlarged liver (hepatomegaly), enlarged liver and spleen (hepatosplenomegaly), fluid around lungs (pleural effusions) and respiratory distress.Less commonly, chronic Q fever can present as an infection of the bones and joints (osteoarticular infection) such as osteomyelitis or osteoarthritis, which can cause bone and joint pain. Vascular infections, chronic hepatitis and chronic pulmonary disease are also seen in some patients. Chronic hepatitis can cause enlargement of the liver or jaundice. Chronic pulmonary disease can cause difficulty breathing (dyspnea) and other respiratory abnormalities. Other less common symptoms include abnormal heart valve morphology, immunodeficiency, increased circulating antibody level, flat and raised skin lesions (maculopapular exanthema), pneumonia, red or purple spots on the skin (purpura) and rheumatoid factor positivity.Individuals with chronic Q fever may also experience a variety of symptoms similar to those experienced by acute Q Fever patients, including prolonged fevers (although fevers are often absent), joint pain (arthralgia), muscle pain (myalgia), night sweats, chills, fatigue and unintended weight loss.
Some individuals with Q fever develop long-term complications such as chronic, persistent fatigue. Some researchers believe that infection with Q fever increases an individual’s risk of developing cardiovascular disease later in life.The rarest symptoms (approximately 1%- 4% of individuals) include abnormal function of the left ventricle, abnormal amyloid build-up (amyloidosis), inflammation of the gallbladder (cholecystitis), inflammation of the brain (encephalitis), lupus anticoagulant, swollen lymph nodes (lymphadenopathy) or inflammation of fluid and membrane around the brain and spinal cord (meningitis).
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Causes of Q fever
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Q fever is caused by inhalation or ingestion of the bacterium Coxiella burnetii. People are most often exposed to the bacterium from the milk, urine and feces of infected animals (for example, by inhaling contaminated air in a barnyard). When these waste substances dry in the air, the bacteria are able to mix with the barnyard dust that floats around. Consequently, this infection is primarily transferred to humans through their lungs when they breathe the contaminated dust. Also, when an infected animal gives birth, the bacteria may be present in high numbers in the amniotic fluid and placenta. Q fever bacterium primarily infects farm animals such as cattle sheep and goats. However, it has been reported in a wide variety of animals including domesticated animals such as dogs, cats and rabbits. The C. burnetii bacterium is highly infectious. The bacterium can survive in the environment for lengthy periods of time because it is resistant to environmental conditions such heat and pressure. It is also resistant to many common disinfectants.Less common modes of transmission to humans include working in a slaughterhouse, drinking unpasteurized milk and hunting, slaughtering or dressing infected animals. According to the medical literature, in extremely rare cases, human-to-human transmission has been reported.
The mode of transmission in wild and domestic animals is different from the mode of transmission in humans. Animals become infected with C. burnetii from infected ticks. Originally, Q fever was classified as a rickettsial disease, a group of infectious diseases most often spread to humans from ticks. However, based on DNA-DNA hybridization studies and genome sequencing, C. burnetii was placed to the order of Legionellales, which also contains Legionella pneumophila, the bacterium that causes Legionnaires disease.People with pre-existing conditions are at higher risk of developing chronic Q fever. These conditions include heart valve disease, blood vessel abnormalities, weakened immune system or an impaired kidney function.
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Causes of Q fever. Q fever is caused by inhalation or ingestion of the bacterium Coxiella burnetii. People are most often exposed to the bacterium from the milk, urine and feces of infected animals (for example, by inhaling contaminated air in a barnyard). When these waste substances dry in the air, the bacteria are able to mix with the barnyard dust that floats around. Consequently, this infection is primarily transferred to humans through their lungs when they breathe the contaminated dust. Also, when an infected animal gives birth, the bacteria may be present in high numbers in the amniotic fluid and placenta. Q fever bacterium primarily infects farm animals such as cattle sheep and goats. However, it has been reported in a wide variety of animals including domesticated animals such as dogs, cats and rabbits. The C. burnetii bacterium is highly infectious. The bacterium can survive in the environment for lengthy periods of time because it is resistant to environmental conditions such heat and pressure. It is also resistant to many common disinfectants.Less common modes of transmission to humans include working in a slaughterhouse, drinking unpasteurized milk and hunting, slaughtering or dressing infected animals. According to the medical literature, in extremely rare cases, human-to-human transmission has been reported.
The mode of transmission in wild and domestic animals is different from the mode of transmission in humans. Animals become infected with C. burnetii from infected ticks. Originally, Q fever was classified as a rickettsial disease, a group of infectious diseases most often spread to humans from ticks. However, based on DNA-DNA hybridization studies and genome sequencing, C. burnetii was placed to the order of Legionellales, which also contains Legionella pneumophila, the bacterium that causes Legionnaires disease.People with pre-existing conditions are at higher risk of developing chronic Q fever. These conditions include heart valve disease, blood vessel abnormalities, weakened immune system or an impaired kidney function.
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Affects of Q fever
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Q fever occurs worldwide and can affect individuals of every racial and ethnic background. The incidence of Q fever is unknown because in many countries it is not a reportable disease. Researchers believe that the infection is underreported. From 2000-2012, the incidence rate for this disease in the United States was 0.38 cases per million people per year. There have been higher incidence rates in certain countries such as the Netherlands, where there were reports of thousands of human cases.Q fever has occurred more often in men than women, however, this trend is attributed to the fact that more men work in occupations where exposure to C. burnetii bacterium is likely to occur. Q fever can affect individuals of any age, but affected children are rarely reported. Some researchers have speculated that children develop symptoms that are milder and occur less often compared to adults.
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Affects of Q fever. Q fever occurs worldwide and can affect individuals of every racial and ethnic background. The incidence of Q fever is unknown because in many countries it is not a reportable disease. Researchers believe that the infection is underreported. From 2000-2012, the incidence rate for this disease in the United States was 0.38 cases per million people per year. There have been higher incidence rates in certain countries such as the Netherlands, where there were reports of thousands of human cases.Q fever has occurred more often in men than women, however, this trend is attributed to the fact that more men work in occupations where exposure to C. burnetii bacterium is likely to occur. Q fever can affect individuals of any age, but affected children are rarely reported. Some researchers have speculated that children develop symptoms that are milder and occur less often compared to adults.
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Related disorders of Q fever
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Symptoms of the following disorders can be similar to those of Q fever. Comparisons may be useful for a differential diagnosis.Q fever must be differentiated from other, more common causes of fever, chronic fatigue, weakness, other nonspecific flu-like symptoms and endocarditis. Q fever must also be differentiated from other atypical pneumonias. Atypical pneumonias are a group of diseases in which pneumonia is caused by infection with certain bacteria. This group includes chlamydiosis, bartonellosis, the rickettsial diseases, legionellosis, brucellosis, tularemia and other diseases, including some viral infections.The rickettsial diseases are a group of infectious disorders caused by exposure to bacteria belonging to the Rickettsiaceae family. The most common rickettsial disease is Rocky Mountain spotted fever (RMSF), caused by the bacterium Rickettsia rickettsii (R. rickettsii). In most cases, the bacteria responsible are thought to be carried and transmitted by certain ticks. The severity of the rickettsial diseases varies greatly. Some affected individuals develop mild symptoms, while others may potentially lead to life-threatening complications. Associated symptoms may include headache, fever, chills, muscle aches (myalgia), joint pain (arthralgia), extreme exhaustion (prostration) and/or a characteristic skin rash. In some people, additional symptoms may include nausea, vomiting, abdominal pain and/or other abnormalities. In some severe forms of the disease, damage to endothelial cells lining blood vessels may result in tissue injury of the heart, lungs, central nervous system, kidneys, liver and/or other organs, leading to potentially life-threatening complications. (For more information on this disorder, choose “Rocky Mountain Spotted Fever” as your search term in the Rare Disease Database).Legionellosis is due to infection with Legionella species and clinically is seen most commonly as a severe community-acquired pneumonia called Legionnaire’s disease or a less severe form of pulmonary illness called Pontiac fever. Legionnaires’ disease is a rare infectious disease that is caused by the bacterium Legionella pneumophila. The first known outbreak occurred at a hotel that was hosting a meeting of the American Legion organization in Pennsylvania in 1976. In that outbreak, it was found that water in the hotel’s air conditioning system was contaminated with the bacteria. Legionnaires’ disease is most often contracted by inhaling contaminated water from sources such as showers and whirlpool baths. Legionnaires’ disease causes severe pneumonia, chills, fevers, cough and a sharp pain in the side of the chest. There is no evidence of human-to-human transmission. (For more information on this disorder, choose “Legionnaires'” as your search term in the Rare Disease Database).Brucellosis is an infectious disease that affects livestock and may be transmitted to humans. It is rare in the United States (100 to 200 cases occur each year) but occurs more frequently in other parts of the world. The disorder is caused by bacteria belonging to the genus Brucella. Initial symptoms of infection may be nonspecific including fevers, muscle pain, headache, loss of appetite, profuse sweating and physical weakness. In some people, the symptoms occur suddenly (acute), whereas, in others, symptoms may develop over the course of a few months. If brucellosis is not treated, the disease may take months to resolve once appropriate therapy is begun. Brucellosis may be confined to a certain area of the body (local) or have serious widespread complications that affect various organ systems of the body, including the central nervous system. Brucellosis may be prevented by pasteurizing cow and goat’s milk before drinking. However, farmers and people exposed to butchered meat may also be affected by brucellosis. (For more information on this disorder, choose “brucellosis” as your search term in the Rare Disease Database). Tularemia is found worldwide but this infectious disease is rare in the U.S. (approximately 120 cases are reported annually). It most often affects small mammals such as rabbits, rodents and hares. It is highly infectious and is most often transmitted to humans by handling an infected animal or being bit by an infected tick or fly. People have not been known to transmit the infection to others. The disease is caused by the bacterium Francisella tularensis. The severity of tularemia varies from mild and self-limiting, to serious and life threatening (about 2%). (For more information on this disorder, choose “tularemia” as your search term in the Rare Disease Database).
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Related disorders of Q fever. Symptoms of the following disorders can be similar to those of Q fever. Comparisons may be useful for a differential diagnosis.Q fever must be differentiated from other, more common causes of fever, chronic fatigue, weakness, other nonspecific flu-like symptoms and endocarditis. Q fever must also be differentiated from other atypical pneumonias. Atypical pneumonias are a group of diseases in which pneumonia is caused by infection with certain bacteria. This group includes chlamydiosis, bartonellosis, the rickettsial diseases, legionellosis, brucellosis, tularemia and other diseases, including some viral infections.The rickettsial diseases are a group of infectious disorders caused by exposure to bacteria belonging to the Rickettsiaceae family. The most common rickettsial disease is Rocky Mountain spotted fever (RMSF), caused by the bacterium Rickettsia rickettsii (R. rickettsii). In most cases, the bacteria responsible are thought to be carried and transmitted by certain ticks. The severity of the rickettsial diseases varies greatly. Some affected individuals develop mild symptoms, while others may potentially lead to life-threatening complications. Associated symptoms may include headache, fever, chills, muscle aches (myalgia), joint pain (arthralgia), extreme exhaustion (prostration) and/or a characteristic skin rash. In some people, additional symptoms may include nausea, vomiting, abdominal pain and/or other abnormalities. In some severe forms of the disease, damage to endothelial cells lining blood vessels may result in tissue injury of the heart, lungs, central nervous system, kidneys, liver and/or other organs, leading to potentially life-threatening complications. (For more information on this disorder, choose “Rocky Mountain Spotted Fever” as your search term in the Rare Disease Database).Legionellosis is due to infection with Legionella species and clinically is seen most commonly as a severe community-acquired pneumonia called Legionnaire’s disease or a less severe form of pulmonary illness called Pontiac fever. Legionnaires’ disease is a rare infectious disease that is caused by the bacterium Legionella pneumophila. The first known outbreak occurred at a hotel that was hosting a meeting of the American Legion organization in Pennsylvania in 1976. In that outbreak, it was found that water in the hotel’s air conditioning system was contaminated with the bacteria. Legionnaires’ disease is most often contracted by inhaling contaminated water from sources such as showers and whirlpool baths. Legionnaires’ disease causes severe pneumonia, chills, fevers, cough and a sharp pain in the side of the chest. There is no evidence of human-to-human transmission. (For more information on this disorder, choose “Legionnaires'” as your search term in the Rare Disease Database).Brucellosis is an infectious disease that affects livestock and may be transmitted to humans. It is rare in the United States (100 to 200 cases occur each year) but occurs more frequently in other parts of the world. The disorder is caused by bacteria belonging to the genus Brucella. Initial symptoms of infection may be nonspecific including fevers, muscle pain, headache, loss of appetite, profuse sweating and physical weakness. In some people, the symptoms occur suddenly (acute), whereas, in others, symptoms may develop over the course of a few months. If brucellosis is not treated, the disease may take months to resolve once appropriate therapy is begun. Brucellosis may be confined to a certain area of the body (local) or have serious widespread complications that affect various organ systems of the body, including the central nervous system. Brucellosis may be prevented by pasteurizing cow and goat’s milk before drinking. However, farmers and people exposed to butchered meat may also be affected by brucellosis. (For more information on this disorder, choose “brucellosis” as your search term in the Rare Disease Database). Tularemia is found worldwide but this infectious disease is rare in the U.S. (approximately 120 cases are reported annually). It most often affects small mammals such as rabbits, rodents and hares. It is highly infectious and is most often transmitted to humans by handling an infected animal or being bit by an infected tick or fly. People have not been known to transmit the infection to others. The disease is caused by the bacterium Francisella tularensis. The severity of tularemia varies from mild and self-limiting, to serious and life threatening (about 2%). (For more information on this disorder, choose “tularemia” as your search term in the Rare Disease Database).
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Diagnosis of Q fever
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The signs and symptoms of Q fever are nonspecific and can be associated with a wide variety of diseases. A diagnosis of Q fever usually requires serological examination, which measures and characterizes antibodies. Q fever has two antibody-producing (antigenic) phases called phase I and phase II. These phases can help confirm a diagnosis and can help distinguish acute Q fever infection from chronic Q fever infection. Infected individuals develop specific antibodies against Q fever including immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM). Measuring the levels of these classes of antibodies can help confirm a diagnosis of Q fever. During the acute phase of Q fever, IgG and IgM antibodies may be detected. In chronic Q fever, IgG or IgA levels may be detected.In acute Q fever, the levels of antibodies to phase II antigen of C. burnetii are higher than those to the phase I antigen. Phase II antigens of C. burnetii are normally detected during the second week of the illness. In chronic Q fever, a high level of phase I antibodies with a constant or falling level of phase II antibodies are common along with other elevated inflammatory markers. The three most common serological tests for Q fever are indirect immunofluorescence, complement fixation and enzyme-linked immunosorbent assay (ELISA). Indirect immunofluorescence is a test that can detect the presence of specific antibodies in the blood or other fluids. The antibodies are tagged with a substance that causes them to glow when exposed to ultraviolet light. Complement fixation and ELISA tests can also detect the presence of specific antibodies or antigens. Isolation of the infectious agent in cell cultures, embryonated hen’s eggs and laboratory animals is also possible, but requires a special laboratory with biosafety level three (BSL3).A common test that has been used to aid in the diagnosis of Q fever in some cases is a polymerase chain reaction (PCR) test. A PCR test is a highly sensitive test that amplifies a specific segment or sample of DNA, creating billions of copies of that segment There are three key steps to create the multitude of copies of a segment. First, the DNA strands are heated so they separate. Next, the reaction is cooled so the primer can bind to the DNA. A primer is a short sequence of nucleotides used to provide a starting point for the DNA synthesis reaction. Finally, the temperature of the reaction is raised again to extend the primers and synthesize new DNA strands. This amplified segment can then be studied to detect the presence of C. burnetii infection. It has been employed successfully to detect C. burnetii DNA in cell cultures and biological samples. Although a PCR test is highly sensitive, a negative result does not necessarily rule out a Q fever infection. Reasons for a negative result include inhibition of the PCR or low levels of C. burnetti that are not detectable by the polymerase chain reaction. Clinical Testing and Work-UpA physician may order some imaging tests to check the health of the internal organs. A chest X-ray may be used to evaluate for pneumonia, which affects some individuals with Q fever. Additionally, an echocardiography is used if chronic Q fever is suspected. This test can reveal any issues with heart valves.
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Diagnosis of Q fever. The signs and symptoms of Q fever are nonspecific and can be associated with a wide variety of diseases. A diagnosis of Q fever usually requires serological examination, which measures and characterizes antibodies. Q fever has two antibody-producing (antigenic) phases called phase I and phase II. These phases can help confirm a diagnosis and can help distinguish acute Q fever infection from chronic Q fever infection. Infected individuals develop specific antibodies against Q fever including immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM). Measuring the levels of these classes of antibodies can help confirm a diagnosis of Q fever. During the acute phase of Q fever, IgG and IgM antibodies may be detected. In chronic Q fever, IgG or IgA levels may be detected.In acute Q fever, the levels of antibodies to phase II antigen of C. burnetii are higher than those to the phase I antigen. Phase II antigens of C. burnetii are normally detected during the second week of the illness. In chronic Q fever, a high level of phase I antibodies with a constant or falling level of phase II antibodies are common along with other elevated inflammatory markers. The three most common serological tests for Q fever are indirect immunofluorescence, complement fixation and enzyme-linked immunosorbent assay (ELISA). Indirect immunofluorescence is a test that can detect the presence of specific antibodies in the blood or other fluids. The antibodies are tagged with a substance that causes them to glow when exposed to ultraviolet light. Complement fixation and ELISA tests can also detect the presence of specific antibodies or antigens. Isolation of the infectious agent in cell cultures, embryonated hen’s eggs and laboratory animals is also possible, but requires a special laboratory with biosafety level three (BSL3).A common test that has been used to aid in the diagnosis of Q fever in some cases is a polymerase chain reaction (PCR) test. A PCR test is a highly sensitive test that amplifies a specific segment or sample of DNA, creating billions of copies of that segment There are three key steps to create the multitude of copies of a segment. First, the DNA strands are heated so they separate. Next, the reaction is cooled so the primer can bind to the DNA. A primer is a short sequence of nucleotides used to provide a starting point for the DNA synthesis reaction. Finally, the temperature of the reaction is raised again to extend the primers and synthesize new DNA strands. This amplified segment can then be studied to detect the presence of C. burnetii infection. It has been employed successfully to detect C. burnetii DNA in cell cultures and biological samples. Although a PCR test is highly sensitive, a negative result does not necessarily rule out a Q fever infection. Reasons for a negative result include inhibition of the PCR or low levels of C. burnetti that are not detectable by the polymerase chain reaction. Clinical Testing and Work-UpA physician may order some imaging tests to check the health of the internal organs. A chest X-ray may be used to evaluate for pneumonia, which affects some individuals with Q fever. Additionally, an echocardiography is used if chronic Q fever is suspected. This test can reveal any issues with heart valves.
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Therapies of Q fever
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Antibiotic therapy is used to treat individuals with Q fever. Some mild cases of Q fever may improve without treatment, although antibiotic therapy can usually help reduce the duration of the infection. Physicians recommend that all individuals in whom Q fever is detected receive antibiotic therapy, even those with no recognizable symptoms.Doxycycline is currently the most used antibiotic therapy for the treatment of individuals with Q fever and is most effective when started within three days of infection. Anti-inflammatory drugs may be used if individuals do not respond to antibiotics. Hydroxychloroquine, which is often used to treat malaria, has also been used to treat Q fever. Hydroxychloroquine can help raise the pH of lysosomal compartments, allowing more effective antibiotic activity toward the bacteria.Chronic Q fever is more difficult to treat. Endocarditis may require prolonged antibiotic treatment which usually involves treatment with multiple drugs. One such combination is the use of doxycycline and hydroxychloroquine. For patients allergic to doxycycline, trimethoprim-sulfamethoxazole may be used instead. The optimal duration of therapy is unknown and varies from person to person. In individuals with damage to the heart valves or a history of heart failure, surgery may be necessary. There is currently no vaccine approved by the U.S. Food and Drug Administration (FDA) for Q fever.
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Therapies of Q fever. Antibiotic therapy is used to treat individuals with Q fever. Some mild cases of Q fever may improve without treatment, although antibiotic therapy can usually help reduce the duration of the infection. Physicians recommend that all individuals in whom Q fever is detected receive antibiotic therapy, even those with no recognizable symptoms.Doxycycline is currently the most used antibiotic therapy for the treatment of individuals with Q fever and is most effective when started within three days of infection. Anti-inflammatory drugs may be used if individuals do not respond to antibiotics. Hydroxychloroquine, which is often used to treat malaria, has also been used to treat Q fever. Hydroxychloroquine can help raise the pH of lysosomal compartments, allowing more effective antibiotic activity toward the bacteria.Chronic Q fever is more difficult to treat. Endocarditis may require prolonged antibiotic treatment which usually involves treatment with multiple drugs. One such combination is the use of doxycycline and hydroxychloroquine. For patients allergic to doxycycline, trimethoprim-sulfamethoxazole may be used instead. The optimal duration of therapy is unknown and varies from person to person. In individuals with damage to the heart valves or a history of heart failure, surgery may be necessary. There is currently no vaccine approved by the U.S. Food and Drug Administration (FDA) for Q fever.
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Overview of Rabies
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Rabies is an infectious disease that can affect all species of warmblooded animals, including man. This disorder is transmitted by the saliva of an infected animal and is caused by a virus (Neurotropic lyssavirus) that affects the salivary glands and the central nervous system. The symptoms may lead to serious complications if the virus is not treated immediately.
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Overview of Rabies. Rabies is an infectious disease that can affect all species of warmblooded animals, including man. This disorder is transmitted by the saliva of an infected animal and is caused by a virus (Neurotropic lyssavirus) that affects the salivary glands and the central nervous system. The symptoms may lead to serious complications if the virus is not treated immediately.
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Symptoms of Rabies
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The symptoms of rabies usually develop within 20-60 days after a bite or scratch from an animal infected with the rabies virus. The incubation period is the time between the exposure and the appearance of the first neurologic symptoms. The incubation period is usually shorter when the sight of exposure is closer to the brain. The initial symptoms may be a general feeling of discomfort or uneasiness, nervousness, anxiety, insomnia, depression, loss of appetite, fever, chills, cough, sore throat, headache, nausea, vomiting, and pain at the site of exposure. Serious neurological symptoms usually present themselves two to ten days after the initial symptoms. There are two types of syndromes that may develop during this neurological period: furious and/or paralytic (sluggishness and early paralysis).The hyperactive or “furious” syndrome is usually characterized by thrashing, agitation, biting, spasms of the pharynx and larynx, choking, gagging, fear of water (hydrophobia), hyperventilation (very rapid breathing), and an alteration in the rhythm of the heart beat (cardiac arrhythmias). In about twenty percent of the patients a “paralytic” syndrome may occur. This syndrome is characterized by paralysis that starts at the bottom of a limb and moves upward (especially in the extremity that has been bitten), increased blood pressure, rapid heart rate, confusion, hallucinations and disorientation. During this time the patient may have increased periods of hyperactivity, stiffness in the back of the neck, and an abnormal increase in the number of cells in the cerebrospinal fluid ending with the onset of coma or respiratory failure.
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Symptoms of Rabies. The symptoms of rabies usually develop within 20-60 days after a bite or scratch from an animal infected with the rabies virus. The incubation period is the time between the exposure and the appearance of the first neurologic symptoms. The incubation period is usually shorter when the sight of exposure is closer to the brain. The initial symptoms may be a general feeling of discomfort or uneasiness, nervousness, anxiety, insomnia, depression, loss of appetite, fever, chills, cough, sore throat, headache, nausea, vomiting, and pain at the site of exposure. Serious neurological symptoms usually present themselves two to ten days after the initial symptoms. There are two types of syndromes that may develop during this neurological period: furious and/or paralytic (sluggishness and early paralysis).The hyperactive or “furious” syndrome is usually characterized by thrashing, agitation, biting, spasms of the pharynx and larynx, choking, gagging, fear of water (hydrophobia), hyperventilation (very rapid breathing), and an alteration in the rhythm of the heart beat (cardiac arrhythmias). In about twenty percent of the patients a “paralytic” syndrome may occur. This syndrome is characterized by paralysis that starts at the bottom of a limb and moves upward (especially in the extremity that has been bitten), increased blood pressure, rapid heart rate, confusion, hallucinations and disorientation. During this time the patient may have increased periods of hyperactivity, stiffness in the back of the neck, and an abnormal increase in the number of cells in the cerebrospinal fluid ending with the onset of coma or respiratory failure.
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Causes of Rabies
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Rabies is caused by a lyssavirus (a form of virus that causes encephalitis) that affects the saliva and nervous system. Most cases of rabies in humans are caused by a bite or scratch from an infected animal. It is possible, but rare, for people to get rabies if infectious material from a rabid animal, such as saliva, gets directly into their eyes, nose, mouth, or a wound. At least two known cases of rabies has been contracted by breathing the air in caves where there were a large number of infected bats. There have also been a few recorded cases of rabies acquired by humans after cornea transplants from donors who had undiagnosed rabies.Any mammal can get rabies. Wild animals typically thought to be carriers include raccoons, skunks, bats, foxes, and coyotes. Dogs, cats, and cattle are among the domestical animals that may develop rabies in the United States.
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Causes of Rabies. Rabies is caused by a lyssavirus (a form of virus that causes encephalitis) that affects the saliva and nervous system. Most cases of rabies in humans are caused by a bite or scratch from an infected animal. It is possible, but rare, for people to get rabies if infectious material from a rabid animal, such as saliva, gets directly into their eyes, nose, mouth, or a wound. At least two known cases of rabies has been contracted by breathing the air in caves where there were a large number of infected bats. There have also been a few recorded cases of rabies acquired by humans after cornea transplants from donors who had undiagnosed rabies.Any mammal can get rabies. Wild animals typically thought to be carriers include raccoons, skunks, bats, foxes, and coyotes. Dogs, cats, and cattle are among the domestical animals that may develop rabies in the United States.
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Affects of Rabies
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Rabies in humans has been almost completely eliminated in most developed countries. The vaccinations of domesticated animals and elimination of stray dogs has helped control this problem. In the 1980's the U.S. Centers for Disease Control had one case per year reported. In the United States rabies is found primarily among wild animals such as skunks, foxes, bats, and raccoons. There were 49 cases of human rabies reported in the U.S. between 1960 and 1986. Only 7 of the 49 cases were acquired by exposure to rabid domesticated animals. The remainder were from wild animals.
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Affects of Rabies. Rabies in humans has been almost completely eliminated in most developed countries. The vaccinations of domesticated animals and elimination of stray dogs has helped control this problem. In the 1980's the U.S. Centers for Disease Control had one case per year reported. In the United States rabies is found primarily among wild animals such as skunks, foxes, bats, and raccoons. There were 49 cases of human rabies reported in the U.S. between 1960 and 1986. Only 7 of the 49 cases were acquired by exposure to rabid domesticated animals. The remainder were from wild animals.
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Related disorders of Rabies
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Symptoms of the following disorders can be similar to those of Rabies. Comparisons may be useful for a differential diagnosis:Cerebral Malaria is a serious complication of falciparum malaria. This disorder is usually seen in infants, pregnant women, and travelers who are not immune to parasites of certain regions. It is caused by a communicable parasite and is spread through the bite of the Anopheles mosquito. The symptoms may be fever of up to 104 F, severe headache, drowsiness, confusion, or delirium. (For more information on this disorder choose “Malaria” as your search term in the Rare Disease Database.)Herpes Simplex Encephalitis is a sporadic disease caused by a complication of the Herpes Simplex Virus infection. The symptoms of Herpes Simplex Encephalitis may be fever, headache, convulsions, disorientation, delusions, personality changes, and coma. Paralysis may occur in less than half of the cases. Antiviral therapy is the treatment of choice. The prognosis is improved when the treatment is given during the early stages of the disease. (For more information on this disorder, choose “Herpetic Encephalitis” as your search term in the Rare Disease Database.)Rasmussen's Encephalitis is a rare central nervous system disorder characterized by chronic active encephalitis (inflammation of the brain) and epileptic seizures of varying degrees of severity. Progressive symptoms including paralysis (usually of one side of the body) and mental retardation may also occur. Although the exact cause of this disorder is not known, it is thought to result from an unidentified viral infection.Tetanus (Lock Jaw) is a neurologic syndrome caused by the microorganism Clostridius tetani. This microorganism usually enters the body through wounds, injections, or skin ulcers. The incubation period of tetanus is usually seven to twenty one days. Symptoms of this syndrome may be a closed mouth (Lock Jaw), low-grade fever, fear, restlessness, difficulty swallowing, stiffness, alteration in the rhythm of the heart beat, muscle spasms, and convulsions. These symptoms usually last for three to four weeks. Although tetanus is a treatable disease, vaccination is recommended during infancy and every few years thereafter.Typhoid is a bacterial infection caused by the bacterium Salmonella Typhi. Contaminated food of water is the source of typhoid is most cases. The major symptoms of this infection may include high fever, headache, loss of appetite, fatigue, abdominal pain, diarrhea, delirium, intestinal bleeding, rash, and in rare untreated cases, heart failure. (For more information on this disorder, choose “Typhoid” as your search term in the Rare Disease Database.)
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Related disorders of Rabies. Symptoms of the following disorders can be similar to those of Rabies. Comparisons may be useful for a differential diagnosis:Cerebral Malaria is a serious complication of falciparum malaria. This disorder is usually seen in infants, pregnant women, and travelers who are not immune to parasites of certain regions. It is caused by a communicable parasite and is spread through the bite of the Anopheles mosquito. The symptoms may be fever of up to 104 F, severe headache, drowsiness, confusion, or delirium. (For more information on this disorder choose “Malaria” as your search term in the Rare Disease Database.)Herpes Simplex Encephalitis is a sporadic disease caused by a complication of the Herpes Simplex Virus infection. The symptoms of Herpes Simplex Encephalitis may be fever, headache, convulsions, disorientation, delusions, personality changes, and coma. Paralysis may occur in less than half of the cases. Antiviral therapy is the treatment of choice. The prognosis is improved when the treatment is given during the early stages of the disease. (For more information on this disorder, choose “Herpetic Encephalitis” as your search term in the Rare Disease Database.)Rasmussen's Encephalitis is a rare central nervous system disorder characterized by chronic active encephalitis (inflammation of the brain) and epileptic seizures of varying degrees of severity. Progressive symptoms including paralysis (usually of one side of the body) and mental retardation may also occur. Although the exact cause of this disorder is not known, it is thought to result from an unidentified viral infection.Tetanus (Lock Jaw) is a neurologic syndrome caused by the microorganism Clostridius tetani. This microorganism usually enters the body through wounds, injections, or skin ulcers. The incubation period of tetanus is usually seven to twenty one days. Symptoms of this syndrome may be a closed mouth (Lock Jaw), low-grade fever, fear, restlessness, difficulty swallowing, stiffness, alteration in the rhythm of the heart beat, muscle spasms, and convulsions. These symptoms usually last for three to four weeks. Although tetanus is a treatable disease, vaccination is recommended during infancy and every few years thereafter.Typhoid is a bacterial infection caused by the bacterium Salmonella Typhi. Contaminated food of water is the source of typhoid is most cases. The major symptoms of this infection may include high fever, headache, loss of appetite, fatigue, abdominal pain, diarrhea, delirium, intestinal bleeding, rash, and in rare untreated cases, heart failure. (For more information on this disorder, choose “Typhoid” as your search term in the Rare Disease Database.)
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Diagnosis of Rabies
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Diagnosis of Rabies.
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Therapies of Rabies
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Medical assistance should be obtained as soon as possible after an exposure or possible exposure to rabies. The most effective treatment for rabies is immediate treatment of the wound followed by immunization with the rabies vaccine. The wound should be cleansed thoroughly with soap and water and medical attention sought immediately. If the wound has broken the skin, a tetanus shot should be given. If the patient has been bitten by a wild animal that has escaped, or a domestic animal that shows signs of rabies, a series of vaccinations to prevent rabies is prescribed before the onset of symptoms. Once the disease presents itself in the patient there is no effective treatment to stop the progression.In the United States, there have been no cases in which an individual developed rabies after treatment with the vaccine. Specific medical attention for someone exposed to rabies is called postexposure prophylaxis (PEP). This involves one dose of immune globulin and five doses of rabies vaccine over a 28-day period. Rabies immune globulin and the first dose of rabies vaccine should be given by a health car eprovider as soon as possible after exposure. For additional information related to treatment, contact the Centers for Disease Prevention and Treatment listed in the Resources section of this report or go to www.cdc.gov.
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Therapies of Rabies. Medical assistance should be obtained as soon as possible after an exposure or possible exposure to rabies. The most effective treatment for rabies is immediate treatment of the wound followed by immunization with the rabies vaccine. The wound should be cleansed thoroughly with soap and water and medical attention sought immediately. If the wound has broken the skin, a tetanus shot should be given. If the patient has been bitten by a wild animal that has escaped, or a domestic animal that shows signs of rabies, a series of vaccinations to prevent rabies is prescribed before the onset of symptoms. Once the disease presents itself in the patient there is no effective treatment to stop the progression.In the United States, there have been no cases in which an individual developed rabies after treatment with the vaccine. Specific medical attention for someone exposed to rabies is called postexposure prophylaxis (PEP). This involves one dose of immune globulin and five doses of rabies vaccine over a 28-day period. Rabies immune globulin and the first dose of rabies vaccine should be given by a health car eprovider as soon as possible after exposure. For additional information related to treatment, contact the Centers for Disease Prevention and Treatment listed in the Resources section of this report or go to www.cdc.gov.
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Overview of Rabson-Mendenhall Syndrome
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Rabson-Mendenhall syndrome is an extremely rare genetic disorder characterized by severe insulin resistance. Insulin, a hormone produced by the pancreas, regulates blood sugar levels by promoting the movement of glucose (a simple sugar) into cells for energy production or into the liver and fat cells for storage.Initial symptoms of Rabson-Mendenhall syndrome include abnormalities of the head and face (craniofacial region), abnormalities of the teeth and nails, and skin abnormalities such as acanthosis nigricans, a skin disorder characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck, groin, and under the arms. In most cases, additional symptoms are present. Infants are found to have very little fat, and there will be concern about failure to thrive, as the infant is not meeting weight standards on a growth chart, despite frequent feedings. Rabson-Mendenhall syndrome is inherited in an autosomal recessive pattern.
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Overview of Rabson-Mendenhall Syndrome. Rabson-Mendenhall syndrome is an extremely rare genetic disorder characterized by severe insulin resistance. Insulin, a hormone produced by the pancreas, regulates blood sugar levels by promoting the movement of glucose (a simple sugar) into cells for energy production or into the liver and fat cells for storage.Initial symptoms of Rabson-Mendenhall syndrome include abnormalities of the head and face (craniofacial region), abnormalities of the teeth and nails, and skin abnormalities such as acanthosis nigricans, a skin disorder characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck, groin, and under the arms. In most cases, additional symptoms are present. Infants are found to have very little fat, and there will be concern about failure to thrive, as the infant is not meeting weight standards on a growth chart, despite frequent feedings. Rabson-Mendenhall syndrome is inherited in an autosomal recessive pattern.
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Symptoms of Rabson-Mendenhall Syndrome
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The symptoms of Rabson-Mendenhall syndrome vary greatly from person to person. Some individuals may be affected more severely than others. The disorder can potentially cause life-threatening complications during childhood or adolescence. Affected individuals will not have all of the symptoms listed below. Affected individuals or parents of affected children should talk to their physicians and medical team about their specific case and associated symptoms.Rabson-Mendenhall syndrome may become apparent during the first year of life or early during childhood. Initial symptoms include failure to thrive, abnormalities of the teeth and nails including early eruption of teeth (premature dentition), abnormally large teeth (macrodontia), irregular and crowded teeth, and thickened nails. Individuals with Rabson-Mendenhall syndrome may also have a coarse, prematurely-aged facial appearance with an abnormally prominent jaw (prognathism). Affected individuals also have abnormally large ears, full lips, and a furrowed tongue.Another early symptom of Rabson-Mendenhall syndrome is abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (acanthosis nigricans). Affected individuals may also have abnormally dry skin.Additional symptoms associated with Rabson-Mendenhall syndrome may include abdominal swelling (distension) and abnormal enlargement of the clitoris in females and the penis in males. Affected individuals may experience excessive hair growth (hypertrichosis) and some females may exhibit a male pattern of hair growth (hirsutism). Deficiency or absence of fatty tissue (adipose tissue) may also be present. Some individuals may attain puberty at an abnormally early age (precocious puberty). Short stature is an additional characteristic that may also be observed.Rarely, individuals with Rabson-Mendenhall syndrome may have an abnormally large pineal gland (pineal hyperplasia). The pineal gland is a tiny organ in the brain that secretes melatonin, a hormone that helps to regulate sleep cycles and metabolism and is involved with certain aspects of sexual development. Affected individuals often have altered melatonin secrete, which contributes to the development of certain symptoms associated with Rabson-Mendenhall syndrome.Because individuals with Rabson-Mendenhall syndrome fail to use insulin properly they may experience abnormally high blood sugar levels (hyperglycemia) after eating a meal (postprandial) and abnormally low blood sugar levels (hypoglycemia) when not eating. Along with the high blood sugars after eating and frequent low blood sugars in the fasting state, the blood insulin level will be quite elevated.As children with Rabson-Mendenhall syndrome age they may develop more serious complications including diabetes mellitus, enlarged, cystic ovaries, and risk for dehydration. Diabetes may result in individuals having decreased resistance to life-threatening infections. Another life-threatening complication called ketoacidosis may also occur, secondary to diabetes mellitus. Ketoacidosis is elevated levels of acids in the body accompanied by abnormal accumulation of ketone bodies. (Ketone bodies are chemical substances normally produced by fatty acid metabolism in the liver.)
Most individuals with Rabson-Mendenhall syndrome also have abnormalities affecting the kidneys, such as nephrocalcinosis.
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Symptoms of Rabson-Mendenhall Syndrome. The symptoms of Rabson-Mendenhall syndrome vary greatly from person to person. Some individuals may be affected more severely than others. The disorder can potentially cause life-threatening complications during childhood or adolescence. Affected individuals will not have all of the symptoms listed below. Affected individuals or parents of affected children should talk to their physicians and medical team about their specific case and associated symptoms.Rabson-Mendenhall syndrome may become apparent during the first year of life or early during childhood. Initial symptoms include failure to thrive, abnormalities of the teeth and nails including early eruption of teeth (premature dentition), abnormally large teeth (macrodontia), irregular and crowded teeth, and thickened nails. Individuals with Rabson-Mendenhall syndrome may also have a coarse, prematurely-aged facial appearance with an abnormally prominent jaw (prognathism). Affected individuals also have abnormally large ears, full lips, and a furrowed tongue.Another early symptom of Rabson-Mendenhall syndrome is abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (acanthosis nigricans). Affected individuals may also have abnormally dry skin.Additional symptoms associated with Rabson-Mendenhall syndrome may include abdominal swelling (distension) and abnormal enlargement of the clitoris in females and the penis in males. Affected individuals may experience excessive hair growth (hypertrichosis) and some females may exhibit a male pattern of hair growth (hirsutism). Deficiency or absence of fatty tissue (adipose tissue) may also be present. Some individuals may attain puberty at an abnormally early age (precocious puberty). Short stature is an additional characteristic that may also be observed.Rarely, individuals with Rabson-Mendenhall syndrome may have an abnormally large pineal gland (pineal hyperplasia). The pineal gland is a tiny organ in the brain that secretes melatonin, a hormone that helps to regulate sleep cycles and metabolism and is involved with certain aspects of sexual development. Affected individuals often have altered melatonin secrete, which contributes to the development of certain symptoms associated with Rabson-Mendenhall syndrome.Because individuals with Rabson-Mendenhall syndrome fail to use insulin properly they may experience abnormally high blood sugar levels (hyperglycemia) after eating a meal (postprandial) and abnormally low blood sugar levels (hypoglycemia) when not eating. Along with the high blood sugars after eating and frequent low blood sugars in the fasting state, the blood insulin level will be quite elevated.As children with Rabson-Mendenhall syndrome age they may develop more serious complications including diabetes mellitus, enlarged, cystic ovaries, and risk for dehydration. Diabetes may result in individuals having decreased resistance to life-threatening infections. Another life-threatening complication called ketoacidosis may also occur, secondary to diabetes mellitus. Ketoacidosis is elevated levels of acids in the body accompanied by abnormal accumulation of ketone bodies. (Ketone bodies are chemical substances normally produced by fatty acid metabolism in the liver.)
Most individuals with Rabson-Mendenhall syndrome also have abnormalities affecting the kidneys, such as nephrocalcinosis.
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Causes of Rabson-Mendenhall Syndrome
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Rabson-Mendenhall syndrome is inherited in an autosomal recessive patern with variable expressivity, which means the physical findings and symptoms associated with the disorder vary greatly in severity from one person to another.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Rabson-Mendenhall syndrome may be caused by disruption or changes (mutations) of the insulin receptor gene. Insulin receptors are molecular structures on the surfaces of certain “target” cells that bind with insulin, triggering cellular response. In Rabson-Mendenhall syndrome, mutations of the insulin receptor gene result in a reduced number or an altered structure of insulin receptors. This results in reduced binding with insulin or abnormalities of the post-receptor pathway, with an impaired response to insulin within targeted cells.In individuals with Rabson-Mendenhall syndrome, the body may attempt to compensate for insulin resistance by increasing insulin secretion, which may lead to excessive insulin levels in the blood (hyperinsulinemia). Hyperinsulinemia may result in certain features associated with Rabson-Mendenhall syndrome such as acanthosis nigricans, hypertrichosis, and polycystic ovaries. Conversely, and quite distinctively, despite these extremely high levels of insulin, triglyceride levels are strikingly low in affected individuals, along with an unexpectedly high adiponectin level (which would be typically low in this extreme degree of insulin resistance).
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Causes of Rabson-Mendenhall Syndrome. Rabson-Mendenhall syndrome is inherited in an autosomal recessive patern with variable expressivity, which means the physical findings and symptoms associated with the disorder vary greatly in severity from one person to another.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Rabson-Mendenhall syndrome may be caused by disruption or changes (mutations) of the insulin receptor gene. Insulin receptors are molecular structures on the surfaces of certain “target” cells that bind with insulin, triggering cellular response. In Rabson-Mendenhall syndrome, mutations of the insulin receptor gene result in a reduced number or an altered structure of insulin receptors. This results in reduced binding with insulin or abnormalities of the post-receptor pathway, with an impaired response to insulin within targeted cells.In individuals with Rabson-Mendenhall syndrome, the body may attempt to compensate for insulin resistance by increasing insulin secretion, which may lead to excessive insulin levels in the blood (hyperinsulinemia). Hyperinsulinemia may result in certain features associated with Rabson-Mendenhall syndrome such as acanthosis nigricans, hypertrichosis, and polycystic ovaries. Conversely, and quite distinctively, despite these extremely high levels of insulin, triglyceride levels are strikingly low in affected individuals, along with an unexpectedly high adiponectin level (which would be typically low in this extreme degree of insulin resistance).
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Affects of Rabson-Mendenhall Syndrome
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Rabson-Mendenhall syndrome affects males and females in equal numbers. Fewer than 50 cases have been reported in the medical literature. The exact incidence of Rabson-Mendenhall syndrome is unknown. Because rare disorders like Rabson-Mendenhall syndrome often go unrecognized, these disorders are under-diagnosed or misdiagnosed, making it difficult to determine the true frequency of Rabson-Mendenhall syndrome in the general population.
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Affects of Rabson-Mendenhall Syndrome. Rabson-Mendenhall syndrome affects males and females in equal numbers. Fewer than 50 cases have been reported in the medical literature. The exact incidence of Rabson-Mendenhall syndrome is unknown. Because rare disorders like Rabson-Mendenhall syndrome often go unrecognized, these disorders are under-diagnosed or misdiagnosed, making it difficult to determine the true frequency of Rabson-Mendenhall syndrome in the general population.
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Related disorders of Rabson-Mendenhall Syndrome
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Symptoms of the following disorders can be similar to those of Rabson-Mendenhall syndrome. Comparisons may be useful for a differential diagnosis:Two other disorders, leprechaunism and insulin resistance type A, are also caused by mutations in the insulin receptor gene. Some researchers believe that these three disorders represent a continuum or spectrum of disease. Rabson-Mendenhall would represent an intermediate form of the disorder.Leprechaunism, also known as Donohue syndrome, is an extremely rare disorder characterized by abnormal resistance to insulin that results in a variety of abnormalities including growth delays and abnormalities affecting the endocrine system (i.e., the system of glands that secrete hormones into the blood system). Affected infants may also have distinctive abnormalities of the head and face (craniofacial) region, low birth weight, skin abnormalities, and abnormal enlargement of the breast and clitoris in females and the penis in males. In many cases, additional abnormalities may be present. Leprechaunism is more severe than Rabson-Mendenhall syndrome. Leprechaunism is inherited as an autosomal recessive trait. (For more information on this disorder, choose “leprechaunism” as your search term in the Rare Disease Database.)Acanthosis nigricans with insulin resistance type A is a rare form of extreme insulin resistance characterized by skin abnormalities; insulin resistance; increased levels of insulin in the blood (hyperinsulinemia); potential develop of diabetes; multiple cysts on the ovaries; increased secretion of male hormones known as androgens; and/or a male pattern of hair growth in females (hirsutism). Like Rabson-Mendenhall syndrome, the lipid panels can have unusually normal findings not typical with such severe insulin resistance, such as low to normal triglyceride levels, high HDL levels. Additionally, the adiponectin level will be elevated, whereas, in such a state of severe insulin resistance, it should be low. In type A insulin resistance, the mutation is also in the insulin receptor, but often in the beta subunit, rather than the alpha subunit in Rabson Mendenhall syndrome, and though extreme, the degree of insulin resistance is not as extreme as Rabson Mendenhall syndrome. Patients tend to have normal height, no dental abnormalities, or unusual facial features. (For more information on this disorder, choose “acanthosis nigricans” as your search term in the Rare Disease Database.)Lipodystrophies are a group of rare metabolic disorders, also associated with extreme insulin resistance, which can be either inherited or acquired. They are characterized by abnormalities in fatty (adipose) tissue associated with total or partial loss of body fat, abnormalities of carbohydrate and lipid metabolism, severe resistance to naturally occurring and synthetic insulin, and immune system dysfunction. These disorders are differentiated by degrees of severity, and by areas or systems of the body affected. Lipodystrophies can also be associated with other disorders and various developmental abnormalities. Unlike syndromes caused by mutations in the insulin receptor (Rabson-Mendenhall, leprechaunism, and type A insulin resistance), high triglyceride levels are frequently observed in patients with lipodystrophy, and low HDL levels, as distinguishing laboratory findings, apart from the physical appearance. (For more information on these disorders, choose “lipodystrophy” as your search term in the Rare Disease Database.)
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Related disorders of Rabson-Mendenhall Syndrome. Symptoms of the following disorders can be similar to those of Rabson-Mendenhall syndrome. Comparisons may be useful for a differential diagnosis:Two other disorders, leprechaunism and insulin resistance type A, are also caused by mutations in the insulin receptor gene. Some researchers believe that these three disorders represent a continuum or spectrum of disease. Rabson-Mendenhall would represent an intermediate form of the disorder.Leprechaunism, also known as Donohue syndrome, is an extremely rare disorder characterized by abnormal resistance to insulin that results in a variety of abnormalities including growth delays and abnormalities affecting the endocrine system (i.e., the system of glands that secrete hormones into the blood system). Affected infants may also have distinctive abnormalities of the head and face (craniofacial) region, low birth weight, skin abnormalities, and abnormal enlargement of the breast and clitoris in females and the penis in males. In many cases, additional abnormalities may be present. Leprechaunism is more severe than Rabson-Mendenhall syndrome. Leprechaunism is inherited as an autosomal recessive trait. (For more information on this disorder, choose “leprechaunism” as your search term in the Rare Disease Database.)Acanthosis nigricans with insulin resistance type A is a rare form of extreme insulin resistance characterized by skin abnormalities; insulin resistance; increased levels of insulin in the blood (hyperinsulinemia); potential develop of diabetes; multiple cysts on the ovaries; increased secretion of male hormones known as androgens; and/or a male pattern of hair growth in females (hirsutism). Like Rabson-Mendenhall syndrome, the lipid panels can have unusually normal findings not typical with such severe insulin resistance, such as low to normal triglyceride levels, high HDL levels. Additionally, the adiponectin level will be elevated, whereas, in such a state of severe insulin resistance, it should be low. In type A insulin resistance, the mutation is also in the insulin receptor, but often in the beta subunit, rather than the alpha subunit in Rabson Mendenhall syndrome, and though extreme, the degree of insulin resistance is not as extreme as Rabson Mendenhall syndrome. Patients tend to have normal height, no dental abnormalities, or unusual facial features. (For more information on this disorder, choose “acanthosis nigricans” as your search term in the Rare Disease Database.)Lipodystrophies are a group of rare metabolic disorders, also associated with extreme insulin resistance, which can be either inherited or acquired. They are characterized by abnormalities in fatty (adipose) tissue associated with total or partial loss of body fat, abnormalities of carbohydrate and lipid metabolism, severe resistance to naturally occurring and synthetic insulin, and immune system dysfunction. These disorders are differentiated by degrees of severity, and by areas or systems of the body affected. Lipodystrophies can also be associated with other disorders and various developmental abnormalities. Unlike syndromes caused by mutations in the insulin receptor (Rabson-Mendenhall, leprechaunism, and type A insulin resistance), high triglyceride levels are frequently observed in patients with lipodystrophy, and low HDL levels, as distinguishing laboratory findings, apart from the physical appearance. (For more information on these disorders, choose “lipodystrophy” as your search term in the Rare Disease Database.)
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Diagnosis of Rabson-Mendenhall Syndrome
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Diagnosis of Rabson-Mendenhall Syndrome.
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Therapies of Rabson-Mendenhall Syndrome
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TreatmentThere is no specific treatment for individuals with Rabson-Mendenhall syndrome. The treatment of the disorder is directed toward the specific symptoms that are apparent in each individual (e.g., surgery may be performed to treat cystic ovaries or dental abnormalities). Affected individuals may receive high doses of insulin or insulin sensitizers, but in most cases this therapy ultimately proves unsuccessful. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dental specialists, and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Rabson-Mendenhall Syndrome. TreatmentThere is no specific treatment for individuals with Rabson-Mendenhall syndrome. The treatment of the disorder is directed toward the specific symptoms that are apparent in each individual (e.g., surgery may be performed to treat cystic ovaries or dental abnormalities). Affected individuals may receive high doses of insulin or insulin sensitizers, but in most cases this therapy ultimately proves unsuccessful. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dental specialists, and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of Radiation Sickness
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Radiation sickness describes the harmful effects–acute, delayed, or chronic–produced by exposure to ionizing radiation. An observable effect due to radiation exposure becomes quite certain after a single dose of several hundred rads. As a rule, large doses of radiation are of concern because of their immediate effects on the body (somatic), while low doses are of concern because of the potential for possible late somatic and long-term genetic effects. The effects of radiation exposure on an individual are cumulative.Although there is currently no treatment to repair cells that have already been damaged by radiation, the FDA has recently approved drugs that are very effective at removing radioactive elements from the body. Because the damage is irreversible, patients exposed to radiation that are experiencing symptoms should seek medical help immediately so that drugs can be administered.The first observable cases of radiation sickness occurred after the nuclear bombing of Hiroshima and Nagasaki. Japanese doctors described an unknown disease with symptoms that “suddenly appeared in certain patients with no apparent injuries.” It is now known that these first patients were suffering delayed effects of radiation exposure. Radiation sickness can result in patients with low exposure levels, such as cancer treatments, and leave them with symptoms similar to a case of the flu. However, in cases of extreme exposure caused from atomic weapons or a power plant meltdown, such as Chernobyl, the effects can be fatal.Total dose and dose rate determine somatic or genetic effects of radiation. The units of measurement commonly used in determining radiation exposure or dose are the roentgen, the rad, and the rem. The roentgen (R) is a measure of quantity of x or gamma ionizing radiation in air. The radiation absorbed dose (rad) is the amount of energy absorbed in any substance from exposure, and applies to all types of radiation. The R and the rad are nearly equivalent in energy for practical purposes. The rem is used to correct for the observation that some types of radiation, such as neutrons, may produce more biological effect for an equivalent amount of absorbed energy; thus the rem is equal to the rad multiplied by a constant called the “quality factor”. For x and gamma radiation the rem is equal to the rad. The rad and the rem are currently being replaced in the scientific nomenclature by two units that are compatible with the International System of Units, namely the gray (Gy), equal to 100 rads and the Sievert (Sv), equal to 100 rem.
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Overview of Radiation Sickness. Radiation sickness describes the harmful effects–acute, delayed, or chronic–produced by exposure to ionizing radiation. An observable effect due to radiation exposure becomes quite certain after a single dose of several hundred rads. As a rule, large doses of radiation are of concern because of their immediate effects on the body (somatic), while low doses are of concern because of the potential for possible late somatic and long-term genetic effects. The effects of radiation exposure on an individual are cumulative.Although there is currently no treatment to repair cells that have already been damaged by radiation, the FDA has recently approved drugs that are very effective at removing radioactive elements from the body. Because the damage is irreversible, patients exposed to radiation that are experiencing symptoms should seek medical help immediately so that drugs can be administered.The first observable cases of radiation sickness occurred after the nuclear bombing of Hiroshima and Nagasaki. Japanese doctors described an unknown disease with symptoms that “suddenly appeared in certain patients with no apparent injuries.” It is now known that these first patients were suffering delayed effects of radiation exposure. Radiation sickness can result in patients with low exposure levels, such as cancer treatments, and leave them with symptoms similar to a case of the flu. However, in cases of extreme exposure caused from atomic weapons or a power plant meltdown, such as Chernobyl, the effects can be fatal.Total dose and dose rate determine somatic or genetic effects of radiation. The units of measurement commonly used in determining radiation exposure or dose are the roentgen, the rad, and the rem. The roentgen (R) is a measure of quantity of x or gamma ionizing radiation in air. The radiation absorbed dose (rad) is the amount of energy absorbed in any substance from exposure, and applies to all types of radiation. The R and the rad are nearly equivalent in energy for practical purposes. The rem is used to correct for the observation that some types of radiation, such as neutrons, may produce more biological effect for an equivalent amount of absorbed energy; thus the rem is equal to the rad multiplied by a constant called the “quality factor”. For x and gamma radiation the rem is equal to the rad. The rad and the rem are currently being replaced in the scientific nomenclature by two units that are compatible with the International System of Units, namely the gray (Gy), equal to 100 rads and the Sievert (Sv), equal to 100 rem.
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Radiation Sickness
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Symptoms of Radiation Sickness
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Acute radiation sickness is characterized by nausea, vomiting, diarrhea, anorexia, headache, malaise and rapid heartbeat (tachycardia). With mild ARS, the discomfort subsides within a few hours or days. However, there are three different types of severe ARS, which can develop as a result of high doses (e.g., an atomic explosion) to small doses (e.g., repeated x-rays over a period of days or weeks):The type of severe ARS depends on dose, dose rate, affected area of the body, and the period of time elapsing after exposure. The severe ARS is due to penetrating radiation to most or all of the body in a short period of time, usually a few minutes. A patient with any type of severe ARS usually goes through three stages: In the prodromal stage, the classic symptoms are nausea, diarrhea and vomiting. This stage can last for a few minutes up to a few days. In the next stage, called the latent stage, a patient seems to improve to the point where they are generally healthy for a few hours or even a few weeks. The last stage, called the overt or manifest illness stage is specific to each type. They are cardiovascular/central nervous system sickness, gastrointestinal sickness, and hematopoietic sickness.Cardiovascular/central nervous system sickness is the type of ARS produced by extremely high total body doses of radiation (greater than 3000 rads). This type is the most severe and is always fatal. In addition to nausea and vomiting in the prodromal stage, patients with cerebral syndrome will also experience anxiety, confusion, and loss of consciousness within a few hours, the latent period will occur. 5 or 6 hours after the initial radiation exposure, tremors, and convulsions will begin, and eventually coma and death are inevitable within 3 days.Gastrointestinal sickness is the type of ARS that can occur when the total dose of radiation is lower but still high (400 or more rads). It is characterized by intractable nausea, vomiting, imbalance of electrolytes, and diarrhea that lead to severe dehydration, diminished plasma volume, vascular collapse, infection and life-threatening complications.Hematopoietic sickness (bone marrow sickness)is the type of ARS occurs at exposure of between 200 to 1000 rads. Initially it is characterized by lack of appetite (anorexia), fever, malaise, nausea and vomiting, which may be maximal within 6 to 12 hours after exposure. Symptoms then subside so that within 24 to 36 hours after exposure. During the latent period for this type, the lymph nodes, spleen and bone marrow begin to atrophy, leading to underproduction of all types of blood cells (pancytopenia). In the peripheral blood, lack of lymph cells (lymphopenia) commences immediately, reaching a peak within 24 to 36 hours. Lack of neutrophils, a type of white blood cell, develops more slowly. Lack of blood platelets (thrombocytopenia) may become prominent within 3 or 4 weeks. Increased susceptibility to infection develops due to a decrease in granulocytes and lymphocytes, impairment of antibody production and granulocyte migration, decreased ability to attack and kill bacteria, diminished resistance to diffusion in subcutaneous tissues, and bleeding (hemorrhagic) areas of the skin and bowel that encourage entrance and growth of bacteria. Hemorrhage occurs mainly due to the lack of blood platelets.Delayed effects of radiation can lead to intermediate effects and late somatic and genetic effects. Intermediate effects from prolonged or repeated exposure to low radiation doses from a variety of sources may produce absence of menstruation (amenorrhea), decreased fertility in both sexes, decreased libido in the female, anemia, decreased white blood cells (leukopenia), decreased blood platelets (thrombocytopenia), skin redness (erythema), and cataracts. More severe or highly localized exposure causes loss of hair, skin atrophy and ulceration, thickening of the skin (keratosis), and vascular changes in the skin (telangiectasia). Ultimately it may cause a type of skin cancer called squamous cell carcinoma.Kidney function changes include a decrease in renal plasma flow, glomerular filtration rate (GFR), and tubular function. Following a latent period of six months to one year after extremely high does of radiation, protein in the urine, kidney insufficiency, anemia and high blood pressure may develop. When cumulative kidney exposure is greater than 2000 rads in less than 5 weeks, kidney failure with diminished urine output may occur in about 37% of cases.Large accumulated doses of radiation to muscles may result in painful myopathy with atrophy and calcification.Inflammation of the sac around the heart (pericarditis) and of the heart muscle (myocarditis) have been produced by extensive radiotherapy of the middle region between the lungs (mediastinum).Myelopathy may develop after a segment of the spinal cord has received cumulative doses of greater than 4000 rads. Following vigorous therapy of abdominal lymph nodes for seminoma, lymphoma, ovarian carcinoma, or chronic ulceration, fibrosis and perforation of the bowel may develop.Late somatic and genetic effects of radiation can alter the genes in proliferating cells of the body and germ cells. With body cells this may be manifested ultimately as somatic disease such as cancer (leukemia, thyroid, skin, bone), or cataracts. Another type of cancer, osteosarcoma, may appear years after swallowing radioactive bone-seeking nuclides such as radium salts. Injury to exposed organs may occur occasionally after extensive radiation therapy for treatment of cancer.When cells are exposed to radiation, the number of mutations is increased. If mutations are passed down to children, this can cause genetic defects in the offspring.
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Symptoms of Radiation Sickness. Acute radiation sickness is characterized by nausea, vomiting, diarrhea, anorexia, headache, malaise and rapid heartbeat (tachycardia). With mild ARS, the discomfort subsides within a few hours or days. However, there are three different types of severe ARS, which can develop as a result of high doses (e.g., an atomic explosion) to small doses (e.g., repeated x-rays over a period of days or weeks):The type of severe ARS depends on dose, dose rate, affected area of the body, and the period of time elapsing after exposure. The severe ARS is due to penetrating radiation to most or all of the body in a short period of time, usually a few minutes. A patient with any type of severe ARS usually goes through three stages: In the prodromal stage, the classic symptoms are nausea, diarrhea and vomiting. This stage can last for a few minutes up to a few days. In the next stage, called the latent stage, a patient seems to improve to the point where they are generally healthy for a few hours or even a few weeks. The last stage, called the overt or manifest illness stage is specific to each type. They are cardiovascular/central nervous system sickness, gastrointestinal sickness, and hematopoietic sickness.Cardiovascular/central nervous system sickness is the type of ARS produced by extremely high total body doses of radiation (greater than 3000 rads). This type is the most severe and is always fatal. In addition to nausea and vomiting in the prodromal stage, patients with cerebral syndrome will also experience anxiety, confusion, and loss of consciousness within a few hours, the latent period will occur. 5 or 6 hours after the initial radiation exposure, tremors, and convulsions will begin, and eventually coma and death are inevitable within 3 days.Gastrointestinal sickness is the type of ARS that can occur when the total dose of radiation is lower but still high (400 or more rads). It is characterized by intractable nausea, vomiting, imbalance of electrolytes, and diarrhea that lead to severe dehydration, diminished plasma volume, vascular collapse, infection and life-threatening complications.Hematopoietic sickness (bone marrow sickness)is the type of ARS occurs at exposure of between 200 to 1000 rads. Initially it is characterized by lack of appetite (anorexia), fever, malaise, nausea and vomiting, which may be maximal within 6 to 12 hours after exposure. Symptoms then subside so that within 24 to 36 hours after exposure. During the latent period for this type, the lymph nodes, spleen and bone marrow begin to atrophy, leading to underproduction of all types of blood cells (pancytopenia). In the peripheral blood, lack of lymph cells (lymphopenia) commences immediately, reaching a peak within 24 to 36 hours. Lack of neutrophils, a type of white blood cell, develops more slowly. Lack of blood platelets (thrombocytopenia) may become prominent within 3 or 4 weeks. Increased susceptibility to infection develops due to a decrease in granulocytes and lymphocytes, impairment of antibody production and granulocyte migration, decreased ability to attack and kill bacteria, diminished resistance to diffusion in subcutaneous tissues, and bleeding (hemorrhagic) areas of the skin and bowel that encourage entrance and growth of bacteria. Hemorrhage occurs mainly due to the lack of blood platelets.Delayed effects of radiation can lead to intermediate effects and late somatic and genetic effects. Intermediate effects from prolonged or repeated exposure to low radiation doses from a variety of sources may produce absence of menstruation (amenorrhea), decreased fertility in both sexes, decreased libido in the female, anemia, decreased white blood cells (leukopenia), decreased blood platelets (thrombocytopenia), skin redness (erythema), and cataracts. More severe or highly localized exposure causes loss of hair, skin atrophy and ulceration, thickening of the skin (keratosis), and vascular changes in the skin (telangiectasia). Ultimately it may cause a type of skin cancer called squamous cell carcinoma.Kidney function changes include a decrease in renal plasma flow, glomerular filtration rate (GFR), and tubular function. Following a latent period of six months to one year after extremely high does of radiation, protein in the urine, kidney insufficiency, anemia and high blood pressure may develop. When cumulative kidney exposure is greater than 2000 rads in less than 5 weeks, kidney failure with diminished urine output may occur in about 37% of cases.Large accumulated doses of radiation to muscles may result in painful myopathy with atrophy and calcification.Inflammation of the sac around the heart (pericarditis) and of the heart muscle (myocarditis) have been produced by extensive radiotherapy of the middle region between the lungs (mediastinum).Myelopathy may develop after a segment of the spinal cord has received cumulative doses of greater than 4000 rads. Following vigorous therapy of abdominal lymph nodes for seminoma, lymphoma, ovarian carcinoma, or chronic ulceration, fibrosis and perforation of the bowel may develop.Late somatic and genetic effects of radiation can alter the genes in proliferating cells of the body and germ cells. With body cells this may be manifested ultimately as somatic disease such as cancer (leukemia, thyroid, skin, bone), or cataracts. Another type of cancer, osteosarcoma, may appear years after swallowing radioactive bone-seeking nuclides such as radium salts. Injury to exposed organs may occur occasionally after extensive radiation therapy for treatment of cancer.When cells are exposed to radiation, the number of mutations is increased. If mutations are passed down to children, this can cause genetic defects in the offspring.
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Causes of Radiation Sickness
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Harmful sources of ionizing radiation are limited primarily to high-energy x-rays used for diagnosis and therapy, and to radium and related radioactive materials. Present sources of potential radiation include nuclear reactors, cyclotrons, linear accelerators, alternating gradient synchrotons, and sealed cobalt and cesium sources for cancer therapy. Numerous artificial radioactive materials have been produced for use in medicine and industry by neutron activation in reactors.The accidental escape of moderate to large amounts of radiation from reactors has occurred several times. The radiation from the atomic bombs dropped in Hiroshima and Nagasaki caused hundred of cases of cancer, mutations, and genetic defects years after the explosion. Radiation exposure from reactor accidents like Chernobyl, for example, resulted in 134 illnesses and 28 deaths.Very low doses of radiation such as unavoidable background radiation (about 0.1 rad/yr), produce no measureable effect. Mild symptoms have been observed with doses as low as 30 rad. The probability of measurable effects increases as the dose rate and/or total dose increases.The area of the body exposed to radiation is also an important factor. The entire human body can probably absorb up to 200 rads acutely without fatality. However, as the whole-body dose approaches 450 rads the death rate will approximate 50%, and a total whole-body dose of greater than 600 rads received in a very short time will almost certainly be fatal. By contrast, many thousands of rads delivered over a long period of time (e.g. for cancer treatment), can be tolerated by the body when small volumes of tissue are irradiated. Distribution of the dose within the body is also important. For example, protection of bowel or bone marrow by appropriate shielding will permit survival of the exposed individual from what would be an otherwise fatal whole-body dose.
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Causes of Radiation Sickness. Harmful sources of ionizing radiation are limited primarily to high-energy x-rays used for diagnosis and therapy, and to radium and related radioactive materials. Present sources of potential radiation include nuclear reactors, cyclotrons, linear accelerators, alternating gradient synchrotons, and sealed cobalt and cesium sources for cancer therapy. Numerous artificial radioactive materials have been produced for use in medicine and industry by neutron activation in reactors.The accidental escape of moderate to large amounts of radiation from reactors has occurred several times. The radiation from the atomic bombs dropped in Hiroshima and Nagasaki caused hundred of cases of cancer, mutations, and genetic defects years after the explosion. Radiation exposure from reactor accidents like Chernobyl, for example, resulted in 134 illnesses and 28 deaths.Very low doses of radiation such as unavoidable background radiation (about 0.1 rad/yr), produce no measureable effect. Mild symptoms have been observed with doses as low as 30 rad. The probability of measurable effects increases as the dose rate and/or total dose increases.The area of the body exposed to radiation is also an important factor. The entire human body can probably absorb up to 200 rads acutely without fatality. However, as the whole-body dose approaches 450 rads the death rate will approximate 50%, and a total whole-body dose of greater than 600 rads received in a very short time will almost certainly be fatal. By contrast, many thousands of rads delivered over a long period of time (e.g. for cancer treatment), can be tolerated by the body when small volumes of tissue are irradiated. Distribution of the dose within the body is also important. For example, protection of bowel or bone marrow by appropriate shielding will permit survival of the exposed individual from what would be an otherwise fatal whole-body dose.
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Radiation Sickness
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Affects of Radiation Sickness
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Radiation sickness can affect males and females in equal numbers.
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Affects of Radiation Sickness. Radiation sickness can affect males and females in equal numbers.
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Related disorders of Radiation Sickness
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Related disorders of Radiation Sickness.
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Diagnosis of Radiation Sickness
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Diagnosis is typically made based on a history of significant radiation exposure. The time between exposure and vomiting also can give good estimates of exposure levels in a patient.Clinical Testing and Work-UpMonitoring of exposed patients is mandatory, using Geiger counters or sophisticated whole-body counters. Urine should be analyzed for non-gamma-emitting radionuclides if exposure to these agents is suspected. Radon breath analysis can be done in cases of suspected radium ingestion.
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Diagnosis of Radiation Sickness. Diagnosis is typically made based on a history of significant radiation exposure. The time between exposure and vomiting also can give good estimates of exposure levels in a patient.Clinical Testing and Work-UpMonitoring of exposed patients is mandatory, using Geiger counters or sophisticated whole-body counters. Urine should be analyzed for non-gamma-emitting radionuclides if exposure to these agents is suspected. Radon breath analysis can be done in cases of suspected radium ingestion.
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Therapies of Radiation Sickness
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Therapies of Radiation Sickness.
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Overview of Ramsay Hunt Syndrome
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Ramsay Hunt syndrome is a rare neurological disorder that typically affects adults over 60 years of age. The disorder is characterized by facial weakness or paralysis of the facial nerve (facial palsy) and a rash affecting the ear or mouth. Symptoms are usually on one side of the face (unilateral). Ringing in the ears (tinnitus) and hearing loss may also be present. Ramsay Hunt syndrome is caused by the varicella zoster virus (VZV), the same virus that causes chickenpox in children and shingles (herpes zoster) in adults. In Ramsay Hunt syndrome, previously inactive (dormant) varicella-zoster virus is reactivated and spreads to affect the facial nerve.Treatment for Ramsay Hunt syndrome includes anti-inflammatory drugs (steroids) to reduce pain and swelling of the nerves. There is usually a good prognosis when treatment is started within three days of the onset of symptoms. However, some patients may have permanent facial paralysis or hearing loss.
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Overview of Ramsay Hunt Syndrome. Ramsay Hunt syndrome is a rare neurological disorder that typically affects adults over 60 years of age. The disorder is characterized by facial weakness or paralysis of the facial nerve (facial palsy) and a rash affecting the ear or mouth. Symptoms are usually on one side of the face (unilateral). Ringing in the ears (tinnitus) and hearing loss may also be present. Ramsay Hunt syndrome is caused by the varicella zoster virus (VZV), the same virus that causes chickenpox in children and shingles (herpes zoster) in adults. In Ramsay Hunt syndrome, previously inactive (dormant) varicella-zoster virus is reactivated and spreads to affect the facial nerve.Treatment for Ramsay Hunt syndrome includes anti-inflammatory drugs (steroids) to reduce pain and swelling of the nerves. There is usually a good prognosis when treatment is started within three days of the onset of symptoms. However, some patients may have permanent facial paralysis or hearing loss.
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Symptoms of Ramsay Hunt Syndrome
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The symptoms of Ramsay Hunt syndrome vary from person to person. Affected individuals usually experience paralysis of the facial nerve and a rash affecting the ear. These two symptoms do not always occur at the same time. In most people, only one side of the face is affected.Facial muscles affected by nerve palsy may be weak or feel stiff and result in the inability to smile or wrinkle the forehead, creating the appearance of a “saggy face”. After the onset of symptoms, facial weakness is usually most severe within one week. Asymmetric muscle tone may be visible and some people may have a drooping mouth and drool saliva.The inability to close the eye usually occurs and results in irritation. In rare cases, the clear, front part of the eye (cornea) can become damaged and blur vision.Most patients with Ramsay Hunt syndrome have a reddish (erythematous), painful, fluid-filled blistering (vesicular) rash that affects the outer portion of the ear (pinna) and often the external ear canal. Vesicular rashes of the ear and mouth have been reported in as many as 80% of patients. The rash, including painful blisters, may also affect the eardrum, mouth, soft palate and top portion of the throat, notably on the side with the affected nerve. Additional symptoms affecting the ear include ringing in the ear (tinnitus) and ear pain (otalgia). In some patients, ear pain may be intense. Some affected individuals develop sensorineural hearing loss, a condition in which sound vibrations are not properly transmitted to the brain due to a defect of the inner ear or the auditory nerve, resulting in hearing loss on the symptomatic side of the body (ipsilateral). Hearing loss is usually temporary and occurs in as many as 50% of patients. Rarely, hearing loss may become permanent. Some affected individuals may experience hyperacusis, a condition in which sounds seem louder (often dramatically) than normal due to an abnormality of the stapedius muscle in the eardrum, causing tremendous discomfort. In certain people, pain may spread to affect the neck.Additional symptoms that may be present include nausea, vomiting and a sensation that one’s surroundings are spinning (vertigo).Possible complications in rare cases of Ramsay Hunt syndrome include a change in taste perception, loss of vision caused by eye damage from corneal ulcers and infections, abnormal reactions to facial movements caused by nerves growing back to the wrong muscles, persistent pain (postherpetic neuralgia) and facial weakness. In rare cases, the virus may spread to other nerves or to the brain and spinal cord, causing confusion, drowsiness, limb weakness, headaches and nerve pain.Ramsay Hunt syndrome is not contagious, but reactivation of the varicella-zoster virus can cause chickenpox in people who have not had it or have not been vaccinated. Patients should avoid contact with these individuals as well as people with a weakened immune system until there is scabbing over the blistered rash.Some individuals with Ramsay Hunt syndrome may have facial palsy with evidence of varicella-zoster virus through testing (e.g., blood tests), but without the associated skin abnormalities. These cases may be referred to as zoster sine herpete.
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Symptoms of Ramsay Hunt Syndrome. The symptoms of Ramsay Hunt syndrome vary from person to person. Affected individuals usually experience paralysis of the facial nerve and a rash affecting the ear. These two symptoms do not always occur at the same time. In most people, only one side of the face is affected.Facial muscles affected by nerve palsy may be weak or feel stiff and result in the inability to smile or wrinkle the forehead, creating the appearance of a “saggy face”. After the onset of symptoms, facial weakness is usually most severe within one week. Asymmetric muscle tone may be visible and some people may have a drooping mouth and drool saliva.The inability to close the eye usually occurs and results in irritation. In rare cases, the clear, front part of the eye (cornea) can become damaged and blur vision.Most patients with Ramsay Hunt syndrome have a reddish (erythematous), painful, fluid-filled blistering (vesicular) rash that affects the outer portion of the ear (pinna) and often the external ear canal. Vesicular rashes of the ear and mouth have been reported in as many as 80% of patients. The rash, including painful blisters, may also affect the eardrum, mouth, soft palate and top portion of the throat, notably on the side with the affected nerve. Additional symptoms affecting the ear include ringing in the ear (tinnitus) and ear pain (otalgia). In some patients, ear pain may be intense. Some affected individuals develop sensorineural hearing loss, a condition in which sound vibrations are not properly transmitted to the brain due to a defect of the inner ear or the auditory nerve, resulting in hearing loss on the symptomatic side of the body (ipsilateral). Hearing loss is usually temporary and occurs in as many as 50% of patients. Rarely, hearing loss may become permanent. Some affected individuals may experience hyperacusis, a condition in which sounds seem louder (often dramatically) than normal due to an abnormality of the stapedius muscle in the eardrum, causing tremendous discomfort. In certain people, pain may spread to affect the neck.Additional symptoms that may be present include nausea, vomiting and a sensation that one’s surroundings are spinning (vertigo).Possible complications in rare cases of Ramsay Hunt syndrome include a change in taste perception, loss of vision caused by eye damage from corneal ulcers and infections, abnormal reactions to facial movements caused by nerves growing back to the wrong muscles, persistent pain (postherpetic neuralgia) and facial weakness. In rare cases, the virus may spread to other nerves or to the brain and spinal cord, causing confusion, drowsiness, limb weakness, headaches and nerve pain.Ramsay Hunt syndrome is not contagious, but reactivation of the varicella-zoster virus can cause chickenpox in people who have not had it or have not been vaccinated. Patients should avoid contact with these individuals as well as people with a weakened immune system until there is scabbing over the blistered rash.Some individuals with Ramsay Hunt syndrome may have facial palsy with evidence of varicella-zoster virus through testing (e.g., blood tests), but without the associated skin abnormalities. These cases may be referred to as zoster sine herpete.
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Causes of Ramsay Hunt Syndrome
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Ramsay Hunt syndrome is caused by the varicella-zoster virus, which is the same virus that causes chickenpox and shingles. The virus can remain dormant for decades in a person who has had chickenpox as a child. Reactivation of the varicella-zoster virus results in a shingles outbreak and, in cases where the varicella-zoster virus spreads to the facial nerves, develops into Ramsay Hunt syndrome. The reason why the virus reactivates and affects the facial nerve in Ramsay Hunt syndrome is unknown.
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Causes of Ramsay Hunt Syndrome. Ramsay Hunt syndrome is caused by the varicella-zoster virus, which is the same virus that causes chickenpox and shingles. The virus can remain dormant for decades in a person who has had chickenpox as a child. Reactivation of the varicella-zoster virus results in a shingles outbreak and, in cases where the varicella-zoster virus spreads to the facial nerves, develops into Ramsay Hunt syndrome. The reason why the virus reactivates and affects the facial nerve in Ramsay Hunt syndrome is unknown.
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Affects of Ramsay Hunt Syndrome
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According to one estimate, 5 out of every 100,000 people develop Ramsay Hunt syndrome each year in the United States. Ramsay Hunt syndrome affects males and females in equal numbers. Anyone who has previously had chickenpox can potentially develop Ramsay Hunt syndrome. However, most patients are adults over the age of 60. Ramsay Hunt syndrome is extremely rare in children.Ramsay Hunt syndrome may go undiagnosed or misdiagnosed making it difficult to determine the true frequency of this condition in the general population.
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Affects of Ramsay Hunt Syndrome. According to one estimate, 5 out of every 100,000 people develop Ramsay Hunt syndrome each year in the United States. Ramsay Hunt syndrome affects males and females in equal numbers. Anyone who has previously had chickenpox can potentially develop Ramsay Hunt syndrome. However, most patients are adults over the age of 60. Ramsay Hunt syndrome is extremely rare in children.Ramsay Hunt syndrome may go undiagnosed or misdiagnosed making it difficult to determine the true frequency of this condition in the general population.
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Related disorders of Ramsay Hunt Syndrome
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Shingles, which results in a painful rash, is caused by the reactivation of the varicella zoster virus which lays dormant in people who have had a prior infection with chickenpox. It can affect nerves all over the body, not specific to just the facial region.Symptoms of the following disorders can be similar to those of Ramsay Hunt syndrome.Bell’s palsy is a nonprogressive neurological disorder of the facial nerve (7th cranial nerve). This disorder is characterized by the sudden onset of facial paralysis that may be preceded by a slight fever, pain behind the ear on the affected side, a stiff neck and weakness and/or stiffness on one side of the face. In contrast to Ramsay Hunt syndrome, no rash is present, and paralysis is less severe at onset. Paralysis is thought to be caused by non-infective inflammation, and swelling of the 7th cranial nerve. The cause of Bell’s palsy is not known, but viral and immune disorders may be involved. There may also be an inherited tendency toward developing Bell’s palsy. (For more information on this disorder, choose “Bell’s palsy” as your search term in the Rare Disease Database.)Acoustic neuroma is a benign tumor of the 8th cranial nerve. Also known as the vestibulocochlear nerve, the 8th cranial nerve is responsible for relaying sound information to the brain as well as information about a person’s movement and position in space. This nerve lies within the internal ear canal. Pressure on this nerve results in the early symptoms of acoustic neuroma; tinnitus and/or hearing loss may occur. An associated compression of the facial nerve (7th cranial nerve) may produce muscle weakness; pressure on the trigeminal nerve (5th cranial nerve) may lead to facial numbness. The expansion of the tumor into different areas may result in impaired ability to coordinate movement of the legs and arms (ataxia), numbness in the mouth, slurred speech (dysphagia) and/or hoarseness. (For more information in this disorder, choose “acoustic neuroma” as your search term on the Rare Disease Database.)Trigeminal neuralgia is a disorder of the 5th cranial nerve (trigeminal nerve) characterized by attacks of intense, stabbing pain affecting the mouth, cheek, nose and/or other areas on one side of the face. The exact cause of trigeminal neuralgia is not fully understood. (For more information on this disorder, choose “trigeminal neuralgia” as your search term in the Rare Disease Database.)
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Related disorders of Ramsay Hunt Syndrome. Shingles, which results in a painful rash, is caused by the reactivation of the varicella zoster virus which lays dormant in people who have had a prior infection with chickenpox. It can affect nerves all over the body, not specific to just the facial region.Symptoms of the following disorders can be similar to those of Ramsay Hunt syndrome.Bell’s palsy is a nonprogressive neurological disorder of the facial nerve (7th cranial nerve). This disorder is characterized by the sudden onset of facial paralysis that may be preceded by a slight fever, pain behind the ear on the affected side, a stiff neck and weakness and/or stiffness on one side of the face. In contrast to Ramsay Hunt syndrome, no rash is present, and paralysis is less severe at onset. Paralysis is thought to be caused by non-infective inflammation, and swelling of the 7th cranial nerve. The cause of Bell’s palsy is not known, but viral and immune disorders may be involved. There may also be an inherited tendency toward developing Bell’s palsy. (For more information on this disorder, choose “Bell’s palsy” as your search term in the Rare Disease Database.)Acoustic neuroma is a benign tumor of the 8th cranial nerve. Also known as the vestibulocochlear nerve, the 8th cranial nerve is responsible for relaying sound information to the brain as well as information about a person’s movement and position in space. This nerve lies within the internal ear canal. Pressure on this nerve results in the early symptoms of acoustic neuroma; tinnitus and/or hearing loss may occur. An associated compression of the facial nerve (7th cranial nerve) may produce muscle weakness; pressure on the trigeminal nerve (5th cranial nerve) may lead to facial numbness. The expansion of the tumor into different areas may result in impaired ability to coordinate movement of the legs and arms (ataxia), numbness in the mouth, slurred speech (dysphagia) and/or hoarseness. (For more information in this disorder, choose “acoustic neuroma” as your search term on the Rare Disease Database.)Trigeminal neuralgia is a disorder of the 5th cranial nerve (trigeminal nerve) characterized by attacks of intense, stabbing pain affecting the mouth, cheek, nose and/or other areas on one side of the face. The exact cause of trigeminal neuralgia is not fully understood. (For more information on this disorder, choose “trigeminal neuralgia” as your search term in the Rare Disease Database.)
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Ramsay Hunt Syndrome
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Diagnosis of Ramsay Hunt Syndrome
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Diagnosis of Ramsay Hunt syndrome can be difficult because the symptoms of the disorder (earache, facial paralysis and the distinctive rash) do not always develop at the same time.Diagnosis is based on a thorough clinical evaluation, detailed patient history and identification of characteristic symptoms (i.e., one-sided facial palsy and/or a rash around the ear). A sample from the fluid-filled blistering rash surrounding the ear can be used to confirm the diagnosis. This rash is a good indicator that the disease is Ramsay Hunt syndrome and not Bell's palsy, acoustic neuroma or trigeminal neuralgia.Viral studies can detect varicella-zoster virus in saliva, tears, and blood but are not necessary to establish a diagnosis of Ramsay Hunt syndrome.
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Diagnosis of Ramsay Hunt Syndrome. Diagnosis of Ramsay Hunt syndrome can be difficult because the symptoms of the disorder (earache, facial paralysis and the distinctive rash) do not always develop at the same time.Diagnosis is based on a thorough clinical evaluation, detailed patient history and identification of characteristic symptoms (i.e., one-sided facial palsy and/or a rash around the ear). A sample from the fluid-filled blistering rash surrounding the ear can be used to confirm the diagnosis. This rash is a good indicator that the disease is Ramsay Hunt syndrome and not Bell's palsy, acoustic neuroma or trigeminal neuralgia.Viral studies can detect varicella-zoster virus in saliva, tears, and blood but are not necessary to establish a diagnosis of Ramsay Hunt syndrome.
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Ramsay Hunt Syndrome
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Therapies of Ramsay Hunt Syndrome
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Treatment The treatment of Ramsay Hunt syndrome involves antiviral medications like acyclovir or famciclovir, as well as corticosteroids like prednisone. The drugs work together to boost effectiveness in combating the varicella zoster virus. Specifically, anti-inflammatory drugs, or steroids, may help diminish pain by reducing inflammation of the nerves. However, it should be noted that the effectiveness and benefits of antiviral medications have not been confirmed. Despite therapy, some degree of facial paralysis and hearing loss may become permanent in some people.Further treatment is directed towards specific symptoms that are apparent in each individual. This includes pain medication, carbamazepine, an anti-seizure medicine which may help reduce neuralgic pain and vertigo suppressants like antihistamines and anticholinergics. Anti-anxiety medications such as diazepam (Valium) can also be helpful in treatment of pain and vertigo.Capsaicin has been approved by the U.S. Food and Drug Administration (FDA) to manage neuropathic pain associated with postherpetic neuralgia.Beginning treatment within three days of the onset of symptoms is important to have the greatest benefit.Individuals with Ramsay Hunt syndrome need to take special care to prevent corneal injury because they have difficulty closing one eye. This can expose the cornea to abnormal drying and foreign body irritation. Artificial tears and lubricating ointments may be prescribed to protect the cornea. Some patients may be recommended to wear an eye patch.Prevention against the varicella zoster virus is available through a chickenpox vaccine in children and a shingles vaccine for people 50 years of age and older. These vaccinations can greatly reduce the chance of becoming infected with the varicella zoster virus, which reduces the chances of contracting Ramsay Hunt syndrome.
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Therapies of Ramsay Hunt Syndrome. Treatment The treatment of Ramsay Hunt syndrome involves antiviral medications like acyclovir or famciclovir, as well as corticosteroids like prednisone. The drugs work together to boost effectiveness in combating the varicella zoster virus. Specifically, anti-inflammatory drugs, or steroids, may help diminish pain by reducing inflammation of the nerves. However, it should be noted that the effectiveness and benefits of antiviral medications have not been confirmed. Despite therapy, some degree of facial paralysis and hearing loss may become permanent in some people.Further treatment is directed towards specific symptoms that are apparent in each individual. This includes pain medication, carbamazepine, an anti-seizure medicine which may help reduce neuralgic pain and vertigo suppressants like antihistamines and anticholinergics. Anti-anxiety medications such as diazepam (Valium) can also be helpful in treatment of pain and vertigo.Capsaicin has been approved by the U.S. Food and Drug Administration (FDA) to manage neuropathic pain associated with postherpetic neuralgia.Beginning treatment within three days of the onset of symptoms is important to have the greatest benefit.Individuals with Ramsay Hunt syndrome need to take special care to prevent corneal injury because they have difficulty closing one eye. This can expose the cornea to abnormal drying and foreign body irritation. Artificial tears and lubricating ointments may be prescribed to protect the cornea. Some patients may be recommended to wear an eye patch.Prevention against the varicella zoster virus is available through a chickenpox vaccine in children and a shingles vaccine for people 50 years of age and older. These vaccinations can greatly reduce the chance of becoming infected with the varicella zoster virus, which reduces the chances of contracting Ramsay Hunt syndrome.
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Ramsay Hunt Syndrome
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Overview of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is an ultra-rare disorder of respiratory control and autonomic nervous system (ANS) regulation, with endocrine system abnormalities. Respiratory control is a function of the ANS that is responsible for changing breathing in response to varied activities of daily living (ex. exercise, sleep, eating) and in response to changes in oxygen and carbon dioxide. The ANS is the portion of the nervous system that controls or regulates many automatic involuntary body functions including breathing, heart rate, blood pressure, temperature regulation, bowel and bladder control, and more. The endocrine system is regulated by the hypothalamus, and through hormones it controls growth, energy and water balance, sexual maturation and fertility as well as response to stress.ROHHAD presents after 1.5 years of age, in otherwise healthy children. The rapid-onset weight gain (often 20-30 pounds in 3-12 months) is typically the herald of the disease and the harbinger of the later features of the ROHHAD phenotype. The acronym ROHHAD describes the typical sequence of symptoms experienced by children with ROHHAD, in the order of their appearance. The clinical features of ROHHAD seem to “unfold” with advancing age in each child. ROHHAD was first described in 1965 (albeit under a different name) and since that time at least 200 children have been reported in the literature or identified with this disorder. Because of the high prevalence of cardiorespiratory arrest, early recognition and treatment of the symptoms associated with ROHHAD are essential and may be lifesaving.
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Overview of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is an ultra-rare disorder of respiratory control and autonomic nervous system (ANS) regulation, with endocrine system abnormalities. Respiratory control is a function of the ANS that is responsible for changing breathing in response to varied activities of daily living (ex. exercise, sleep, eating) and in response to changes in oxygen and carbon dioxide. The ANS is the portion of the nervous system that controls or regulates many automatic involuntary body functions including breathing, heart rate, blood pressure, temperature regulation, bowel and bladder control, and more. The endocrine system is regulated by the hypothalamus, and through hormones it controls growth, energy and water balance, sexual maturation and fertility as well as response to stress.ROHHAD presents after 1.5 years of age, in otherwise healthy children. The rapid-onset weight gain (often 20-30 pounds in 3-12 months) is typically the herald of the disease and the harbinger of the later features of the ROHHAD phenotype. The acronym ROHHAD describes the typical sequence of symptoms experienced by children with ROHHAD, in the order of their appearance. The clinical features of ROHHAD seem to “unfold” with advancing age in each child. ROHHAD was first described in 1965 (albeit under a different name) and since that time at least 200 children have been reported in the literature or identified with this disorder. Because of the high prevalence of cardiorespiratory arrest, early recognition and treatment of the symptoms associated with ROHHAD are essential and may be lifesaving.
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Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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Symptoms of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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Children with ROHHAD are seemingly healthy before the rapid-onset weight gain, making the diagnosis even more challenging to parents and health care personnel. Between 1.5 and 7 years of age, these children begin to manifest abnormalities that will evolve into the features of ROHHAD. Most commonly, the first sign is dramatic (often 20-30 pounds) and rapid (over 3 to 12 months) weight gain without associated abnormal increase in hunger (hyperphagia). This rapid-onset obesity is considered a sign of hypothalamic dysfunction (abnormality of the endocrine system). Other hypothalamic abnormalities may not be detected at the time of the rapid weight gain but will be identified any time from months to years following the rapid-onset obesity. These other hypothalamic/endocrine abnormalities may include inability to maintain normal water balance in the body (leading to abnormally high or low sodium levels), high prolactin levels, low thyroid hormone, growth hormone insufficiency, early or late puberty, and low cortisol among other abnormalities. Children with ROHHAD can have variable timing and number of these symptoms of hypothalamic dysfunction, but all will have some abnormalities, especially increased prolactin. After the rapid weight gain, children with ROHHAD will begin to show breathing abnormalities despite normal lungs. Some children may present with obstructive sleep apnea which means that airflow is intermittently blocked during sleep; they may have snoring and they may have pauses in breathing related to the air flow blockage (obstructive apnea). Because obstructive sleep apnea is not unusual in young obese children, health care personnel may not be alarmed at this stage, and a connection to the ROHHAD phenotype might be delayed. All children with ROHHAD, whether they had preceding OSA or not, develop alveolar hypoventilation with very shallow breathing during sleep (nap and night). In more severely affected patients with ROHHAD, the hypoventilation is apparent awake and asleep. As a result of altered control of breathing, low oxygen saturation and elevated carbon dioxide occur during wakefulness as well as sleep, without any shortness of breath (awake) or awakening (from sleep). This hypoventilation/control of breathing deficit is the most life-threatening feature of ROHHAD, yet it is often unnoticed until after a dramatic event such as a cardiorespiratory arrest. Therefore, all children with ROHHAD will require help with their breathing, relying on a ventilator to prevent low oxygen or increased carbon dioxide. Approximately half of the children with ROHHAD require ventilator support during sleep only and the other half require ventilator support awake and asleep (24-hours per day), though the ventilatory needs of a child with ROHHAD may vary with advancing age (and unfolding of the clinical features of ROHHAD). This ventilator support can be provided with bi-level positive airway pressure through a mask that fits tightly at the nose or with nasal pillows or a full-face mask or with a mechanical ventilator through a surgically made hole in the airway called a tracheostomy, or potentially with diaphragm pacing (still requiring a tracheostomy).Also, after the rapid weight gain, the symptoms of ANS dysregulation (ANSD) become more apparent. As described above, ANSD means that there are abnormalities with the “automatic” regulation of different organ systems of the body. At some point, all patients with ROHHAD have signs of ANSD. These include eye abnormalities such as altered pupil response to light, “lazy eye”(strabismus), intestinal abnormalities such as altered motility which causes chronic constipation or diarrhea, temperature dysregulation with episodes of very high body temperature (hyperthermia) or more typically very low body temperatures (hypothermia), icy cold hands and feet, decreased sensation of pain, low heart rate that may be so slow that a cardiac pacemaker is required, altered sweating, and many other symptoms reflecting dysregulation of automatic functions.Some individuals (approximately 40%) with ROHHAD will develop anatomic malformations of the ANS which include tumors of neural crest origin (meaning, they originate from a specific type of cell that is seen very early in development of the body). These neural crest tumors found in children with ROHHAD are most commonly ganglioneuromas or ganglioneuroblastomas, but neuroblastomas have also been reported. These neural crest tumors are found in the chest or abdomen, or anywhere along the sympathetic nervous system chain (part of ANS), are present but likely very small in early infancy, and can be identified at any age (though characteristically in early childhood). Thus far, no children with ROHHAD have anatomic/structural malformations of the intestine such as Hirschsprung disease (absent ganglion cells of the distal intestine). This is in contrast to children with another ultra-rare disorder termed congenital central hypoventilation syndrome (CCHS), which co-occurs with Hirschsprung disease in ~30% of individuals with CCHS. Tumors of neural crest origin have been described in patients with CCHS, though rarely with polyalanine repeat expansion PHOX2B mutations (PARMs) (genotypes 20/29 and 20/33; if present typically ganglioneuromas and ganglioneuroblastomas) but more commonly with the non-PARMs (NPARMs) (~40% of cases; most will have a neuroblastoma but less commonly ganglioneuroma or ganglioneuroblastoma).Bougneres, et al. suggested the suffix “NET” be added to the name designated by Ize-Ludlow et al in 2007, “ROHHAD”, because of the findings of associated neural crest tumors in a subset of patients with ROHHAD. Because only a subset of patients (~40%) with ROHHAD have been shown to develop these neuroendocrine tumors, and they may be ganglioneuromas or ganglioneuroblastomas but not typically neuroblastoma, the name ROHHADNET is potentially misleading. Currently, there is insufficient evidence that individuals presenting with tumors represent a distinct entity. Further, the development of neural crest tumors has been reported to occur as late as 7 and even in one case 16 years after the onset of obesity. Consequently, making co-occurrence of tumors of neural crest origin requisite to the diagnosis of ROHHAD would lead to missed diagnosis of many of the children and may subsequently lead to devastating consequences due to the high incidence of cardiorespiratory arrest in this population.A remarkably high percentage of children with ROHHAD have normal or high IQs, suggesting that IQ in children with ROHHAD likely has many related factors. A small subset of individuals with ROHHAD have behavioral, mood, and developmental disorders such that the intelligence quotient (IQ) score may be reduced. Preliminarily, those children with the behavioral and mood disorders have more typically had delayed diagnosis and/or suboptimal ventilatory support. Some children with ROHHAD may develop seizures, though this feature may be related to episodes of low oxygen (hypoxemia) levels due to inadequate ventilator support.
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Symptoms of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation. Children with ROHHAD are seemingly healthy before the rapid-onset weight gain, making the diagnosis even more challenging to parents and health care personnel. Between 1.5 and 7 years of age, these children begin to manifest abnormalities that will evolve into the features of ROHHAD. Most commonly, the first sign is dramatic (often 20-30 pounds) and rapid (over 3 to 12 months) weight gain without associated abnormal increase in hunger (hyperphagia). This rapid-onset obesity is considered a sign of hypothalamic dysfunction (abnormality of the endocrine system). Other hypothalamic abnormalities may not be detected at the time of the rapid weight gain but will be identified any time from months to years following the rapid-onset obesity. These other hypothalamic/endocrine abnormalities may include inability to maintain normal water balance in the body (leading to abnormally high or low sodium levels), high prolactin levels, low thyroid hormone, growth hormone insufficiency, early or late puberty, and low cortisol among other abnormalities. Children with ROHHAD can have variable timing and number of these symptoms of hypothalamic dysfunction, but all will have some abnormalities, especially increased prolactin. After the rapid weight gain, children with ROHHAD will begin to show breathing abnormalities despite normal lungs. Some children may present with obstructive sleep apnea which means that airflow is intermittently blocked during sleep; they may have snoring and they may have pauses in breathing related to the air flow blockage (obstructive apnea). Because obstructive sleep apnea is not unusual in young obese children, health care personnel may not be alarmed at this stage, and a connection to the ROHHAD phenotype might be delayed. All children with ROHHAD, whether they had preceding OSA or not, develop alveolar hypoventilation with very shallow breathing during sleep (nap and night). In more severely affected patients with ROHHAD, the hypoventilation is apparent awake and asleep. As a result of altered control of breathing, low oxygen saturation and elevated carbon dioxide occur during wakefulness as well as sleep, without any shortness of breath (awake) or awakening (from sleep). This hypoventilation/control of breathing deficit is the most life-threatening feature of ROHHAD, yet it is often unnoticed until after a dramatic event such as a cardiorespiratory arrest. Therefore, all children with ROHHAD will require help with their breathing, relying on a ventilator to prevent low oxygen or increased carbon dioxide. Approximately half of the children with ROHHAD require ventilator support during sleep only and the other half require ventilator support awake and asleep (24-hours per day), though the ventilatory needs of a child with ROHHAD may vary with advancing age (and unfolding of the clinical features of ROHHAD). This ventilator support can be provided with bi-level positive airway pressure through a mask that fits tightly at the nose or with nasal pillows or a full-face mask or with a mechanical ventilator through a surgically made hole in the airway called a tracheostomy, or potentially with diaphragm pacing (still requiring a tracheostomy).Also, after the rapid weight gain, the symptoms of ANS dysregulation (ANSD) become more apparent. As described above, ANSD means that there are abnormalities with the “automatic” regulation of different organ systems of the body. At some point, all patients with ROHHAD have signs of ANSD. These include eye abnormalities such as altered pupil response to light, “lazy eye”(strabismus), intestinal abnormalities such as altered motility which causes chronic constipation or diarrhea, temperature dysregulation with episodes of very high body temperature (hyperthermia) or more typically very low body temperatures (hypothermia), icy cold hands and feet, decreased sensation of pain, low heart rate that may be so slow that a cardiac pacemaker is required, altered sweating, and many other symptoms reflecting dysregulation of automatic functions.Some individuals (approximately 40%) with ROHHAD will develop anatomic malformations of the ANS which include tumors of neural crest origin (meaning, they originate from a specific type of cell that is seen very early in development of the body). These neural crest tumors found in children with ROHHAD are most commonly ganglioneuromas or ganglioneuroblastomas, but neuroblastomas have also been reported. These neural crest tumors are found in the chest or abdomen, or anywhere along the sympathetic nervous system chain (part of ANS), are present but likely very small in early infancy, and can be identified at any age (though characteristically in early childhood). Thus far, no children with ROHHAD have anatomic/structural malformations of the intestine such as Hirschsprung disease (absent ganglion cells of the distal intestine). This is in contrast to children with another ultra-rare disorder termed congenital central hypoventilation syndrome (CCHS), which co-occurs with Hirschsprung disease in ~30% of individuals with CCHS. Tumors of neural crest origin have been described in patients with CCHS, though rarely with polyalanine repeat expansion PHOX2B mutations (PARMs) (genotypes 20/29 and 20/33; if present typically ganglioneuromas and ganglioneuroblastomas) but more commonly with the non-PARMs (NPARMs) (~40% of cases; most will have a neuroblastoma but less commonly ganglioneuroma or ganglioneuroblastoma).Bougneres, et al. suggested the suffix “NET” be added to the name designated by Ize-Ludlow et al in 2007, “ROHHAD”, because of the findings of associated neural crest tumors in a subset of patients with ROHHAD. Because only a subset of patients (~40%) with ROHHAD have been shown to develop these neuroendocrine tumors, and they may be ganglioneuromas or ganglioneuroblastomas but not typically neuroblastoma, the name ROHHADNET is potentially misleading. Currently, there is insufficient evidence that individuals presenting with tumors represent a distinct entity. Further, the development of neural crest tumors has been reported to occur as late as 7 and even in one case 16 years after the onset of obesity. Consequently, making co-occurrence of tumors of neural crest origin requisite to the diagnosis of ROHHAD would lead to missed diagnosis of many of the children and may subsequently lead to devastating consequences due to the high incidence of cardiorespiratory arrest in this population.A remarkably high percentage of children with ROHHAD have normal or high IQs, suggesting that IQ in children with ROHHAD likely has many related factors. A small subset of individuals with ROHHAD have behavioral, mood, and developmental disorders such that the intelligence quotient (IQ) score may be reduced. Preliminarily, those children with the behavioral and mood disorders have more typically had delayed diagnosis and/or suboptimal ventilatory support. Some children with ROHHAD may develop seizures, though this feature may be related to episodes of low oxygen (hypoxemia) levels due to inadequate ventilator support.
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Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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Causes of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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The diagnosis of ROHHAD is currently based on clinical criteria and though investigation of genetic changes (pathogenic variants or mutations) is underway, no specific cause for ROHHAD has been found to date.
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Causes of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation. The diagnosis of ROHHAD is currently based on clinical criteria and though investigation of genetic changes (pathogenic variants or mutations) is underway, no specific cause for ROHHAD has been found to date.
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Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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Affects of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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ROHHAD is a very rare disorder with approximately 200 cases reported in the literature and clinically to date. Though first described under a different name in 1965, it was not re-named until 2007 nor shown to be distinct from CCHS (documented absence of CCHS-related PHOX2B mutations). Therefore, as ROHHAD is a relatively “new” disorder without many cases identified thus far, it is not yet clear if any certain population is at greater risk for developing ROHHAD. Because of the explosion of children with exogenous obesity worldwide, a very high level of vigilance in consideration of ROHHAD is essential.
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Affects of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation. ROHHAD is a very rare disorder with approximately 200 cases reported in the literature and clinically to date. Though first described under a different name in 1965, it was not re-named until 2007 nor shown to be distinct from CCHS (documented absence of CCHS-related PHOX2B mutations). Therefore, as ROHHAD is a relatively “new” disorder without many cases identified thus far, it is not yet clear if any certain population is at greater risk for developing ROHHAD. Because of the explosion of children with exogenous obesity worldwide, a very high level of vigilance in consideration of ROHHAD is essential.
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Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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nord_1051_4
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Related disorders of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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Congenital central hypoventilation syndrome (CCHS) is a disorder of the ANS caused by a harmful variant in the PHOX2B gene that affects the embryologic development of the ANS. Similar to ROHHAD, the “automatic” control of breathing, heartbeat, digestion, and other features of ANSD are among the affected features. In CCHS, the hallmark is hypoventilation while sleeping and, in severe cases, hypoventilation while awake and asleep – despite anatomically normal heart, lung, and airways. Both CCHS and ROHHAD fall within the rubric of respiratory and autonomic disorders of infancy, childhood, and adulthood (RADICA). CCHS is a rare disorder with approximately 3,000 cases described or identified worldwide. Numbers of reported CCHS cases continue to grow, likely because of increased awareness and introduction of a clinically available genetic test (in 2003) – allowing for early diagnosis and improved treatment. CCHS is often diagnosed in the newborn period because of the hypoventilation and related cyanosis upon falling asleep and/or associated Hirschsprung disease, but milder forms of CCHS may go undiagnosed through infancy, childhood, and even adulthood. A simple blood test can be done to look for a PHOX2B gene variant. Different PHOX2B gene variants can occur, and this will determine how severely an individual with CCHS is affected. Stepwise testing for PHOX2B variants should be done with close involvement by a physician and genetic counselor. (For more information about this disease, choose “CCHS” as your search term in the Rare Disease Database.)
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Related disorders of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation. Congenital central hypoventilation syndrome (CCHS) is a disorder of the ANS caused by a harmful variant in the PHOX2B gene that affects the embryologic development of the ANS. Similar to ROHHAD, the “automatic” control of breathing, heartbeat, digestion, and other features of ANSD are among the affected features. In CCHS, the hallmark is hypoventilation while sleeping and, in severe cases, hypoventilation while awake and asleep – despite anatomically normal heart, lung, and airways. Both CCHS and ROHHAD fall within the rubric of respiratory and autonomic disorders of infancy, childhood, and adulthood (RADICA). CCHS is a rare disorder with approximately 3,000 cases described or identified worldwide. Numbers of reported CCHS cases continue to grow, likely because of increased awareness and introduction of a clinically available genetic test (in 2003) – allowing for early diagnosis and improved treatment. CCHS is often diagnosed in the newborn period because of the hypoventilation and related cyanosis upon falling asleep and/or associated Hirschsprung disease, but milder forms of CCHS may go undiagnosed through infancy, childhood, and even adulthood. A simple blood test can be done to look for a PHOX2B gene variant. Different PHOX2B gene variants can occur, and this will determine how severely an individual with CCHS is affected. Stepwise testing for PHOX2B variants should be done with close involvement by a physician and genetic counselor. (For more information about this disease, choose “CCHS” as your search term in the Rare Disease Database.)
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Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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Diagnosis of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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The criteria for diagnosis of ROHHAD include the following: 1) rapid-onset obesity and alveolar hypoventilation during sleep starting after the age of 1.5 years, 2) evidence of hypothalamic dysfunction, as defined by at least 1 of the following findings: rapid-onset obesity, hyperprolactinemia, central hypothyroidism, disordered water balance, growth hormone deficiency, corticotrophin deficiency, or altered onset of puberty (delayed or precocious), and 3) absence of a CCHS-related PHOX2B variant (to genetically distinguish ROHHAD from CCHS). At present there is no genetic testing available to diagnose ROHHAD, so the diagnosis is based on the clinical presentation and clinical course which should include cooperative consultation by pediatric experts in the fields of pulmonology, endocrinology, autonomic medicine, oncology, psychology, nutrition, otolaryngology, surgery, cardiology and sleep medicine.Clinical Testing and Work-UpAs the symptoms of ROHHAD can have variable presentation in severity and timing, it is essential that an initial comprehensive evaluation be performed to characterize the nature of the hypoventilation and ANSD and to address appropriate intervention—especially regarding the child’s breathing. Initial evaluation can include overnight polysomnography to evaluate for any signs of obstructive sleep apnea and, more importantly, evidence of central hypoventilation, imaging (chest x-ray of chest and ultrasound of abdomen) to screen for evidence of neural crest tumors, and comprehensive cardiac evaluation. As the prevalence of cardiorespiratory arrest is relatively high (up to 40% as reported in the literature), it is essential that a comprehensive respiratory, cardiac, endocrine, and oncology evaluation be performed as soon as the diagnosis of ROHHAD is considered.Sequential comprehensive evaluation is recommended, ideally at a center with expertise in respiratory and autonomic medicine–including expertise specifically with ROHHAD, and in keeping with the current recommendations in the 2010 ATS Statement on CCHS, as there is not an ATS Statement on ROHHAD at present. Broadly speaking, these evaluations include detailed respiratory physiologic evaluation while awake in varied age-appropriate activities of daily living and while asleep, comprehensive cardiac evaluation including Holter recordings, exercise testing, and echocardiogram, neurocognitive testing for tracking intellectual function as a marker for neurologic stability vs. decline, endocrine evaluation for development of new symptoms of hypothalamic dysfunction, and age-appropriate non-invasive evaluation of ANSD. The frequency of these comprehensive evaluations is dependent upon each patient’s clinical condition and may be as frequent as 3 months and as extended as 12 months, depending upon the rate of the phenotype “unfolding”.Described more specifically, for children with ROHHAD, the physiologic evaluation should include annual comprehensive physiologic assessment during spontaneous breathing awake (in varying levels of concentration and activity) and during sleep in a pediatric respiratory physiology laboratory with extensive expertise in ROHHAD (often referred to as Centers of Excellence). Responses to endogenous (the result of the child’s own hypoventilation) and exogenous (ventilatory challenges from inhaled gas mixtures) hypercarbia, hypoxemia, and hyperoxia should be assessed, ideally awake and asleep. 72-hour Holter recording should be performed annually to evaluate for bradycardia that might (rarely) require a cardiac pacemaker. A head up tilt test should be performed annually to better understand the autonomic response to positional changes. An echocardiogram should be performed annually to rule out cor pulmonale or right ventricular hypertrophy (response to low oxygen from insufficient ventilator management). Neurocognitive testing should be performed annually to determine the effectiveness of the ventilatory management and compliance. In children under the age of three years, the above-described age-appropriate testing should be performed every 6 months. Gastrointestinal motility studies should be performed in the event of severe constipation. All of the above-described tests are part of routine standard of care for individuals with ROHHAD. Efforts are underway to create an expanded comprehensive testing profile for autonomic regulation in children which will also be considered standard of care for children with ROHHAD (testing of temperature regulation, vasomotor tone, integration of breathing, heart rate, and blood pressure, cerebrovascular regional blood flow, and pupillometry have already been integrated into care). These comprehensive evaluations are typically performed inpatient to optimize safety and assure the test results are representative of the patient’s condition.A complete evaluation of endocrine function should be performed with particular attention to water balance regulation, obesity, and other signs of pituitary dysfunction. The lab work should include: complete blood count with differential, reticulocytes, blood comprehensive metabolic profile, urine osmolality, prolactin, leptin, thyroxine free (FT4), thyroid-stimulating hormone-sensitive (S-TSH), lipid panel, cortisol (urine and serum), vitamin B12, vitamin D (25-hydroxy vitamin D2 and D3 serum), insulin-like growth factor binding protein, insulin-like growth factor I.If hypernatremic dehydration is found, formal testing of antidiuretic hormone secretion should be done before assuming the patient has diabetes insipidus. Patients with ROHHAD can become dehydrated due to lack of thirst with normal or partial antidiuretic hormone function. Obesity can alter growth hormone secretion and levels of insulin-like growth factor-1 (IGF-1) which should be considered when assessing growth hormone function.Complications of obesity including fatty liver, elevated lipids, or diabetes mellitus should be considered. A high suspicion should be maintained, and recurrent screening performed for tumors of neural crest origin, especially with imaging performed upon recognition of scoliosis or an unidentified shadow on chest x-ray. A chest x-ray and abdominal ultrasound to view the sympathetic chain and both adrenals are an effective serial evaluation to monitor for neural crest tumors in children with ROHHAD.
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Diagnosis of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation. The criteria for diagnosis of ROHHAD include the following: 1) rapid-onset obesity and alveolar hypoventilation during sleep starting after the age of 1.5 years, 2) evidence of hypothalamic dysfunction, as defined by at least 1 of the following findings: rapid-onset obesity, hyperprolactinemia, central hypothyroidism, disordered water balance, growth hormone deficiency, corticotrophin deficiency, or altered onset of puberty (delayed or precocious), and 3) absence of a CCHS-related PHOX2B variant (to genetically distinguish ROHHAD from CCHS). At present there is no genetic testing available to diagnose ROHHAD, so the diagnosis is based on the clinical presentation and clinical course which should include cooperative consultation by pediatric experts in the fields of pulmonology, endocrinology, autonomic medicine, oncology, psychology, nutrition, otolaryngology, surgery, cardiology and sleep medicine.Clinical Testing and Work-UpAs the symptoms of ROHHAD can have variable presentation in severity and timing, it is essential that an initial comprehensive evaluation be performed to characterize the nature of the hypoventilation and ANSD and to address appropriate intervention—especially regarding the child’s breathing. Initial evaluation can include overnight polysomnography to evaluate for any signs of obstructive sleep apnea and, more importantly, evidence of central hypoventilation, imaging (chest x-ray of chest and ultrasound of abdomen) to screen for evidence of neural crest tumors, and comprehensive cardiac evaluation. As the prevalence of cardiorespiratory arrest is relatively high (up to 40% as reported in the literature), it is essential that a comprehensive respiratory, cardiac, endocrine, and oncology evaluation be performed as soon as the diagnosis of ROHHAD is considered.Sequential comprehensive evaluation is recommended, ideally at a center with expertise in respiratory and autonomic medicine–including expertise specifically with ROHHAD, and in keeping with the current recommendations in the 2010 ATS Statement on CCHS, as there is not an ATS Statement on ROHHAD at present. Broadly speaking, these evaluations include detailed respiratory physiologic evaluation while awake in varied age-appropriate activities of daily living and while asleep, comprehensive cardiac evaluation including Holter recordings, exercise testing, and echocardiogram, neurocognitive testing for tracking intellectual function as a marker for neurologic stability vs. decline, endocrine evaluation for development of new symptoms of hypothalamic dysfunction, and age-appropriate non-invasive evaluation of ANSD. The frequency of these comprehensive evaluations is dependent upon each patient’s clinical condition and may be as frequent as 3 months and as extended as 12 months, depending upon the rate of the phenotype “unfolding”.Described more specifically, for children with ROHHAD, the physiologic evaluation should include annual comprehensive physiologic assessment during spontaneous breathing awake (in varying levels of concentration and activity) and during sleep in a pediatric respiratory physiology laboratory with extensive expertise in ROHHAD (often referred to as Centers of Excellence). Responses to endogenous (the result of the child’s own hypoventilation) and exogenous (ventilatory challenges from inhaled gas mixtures) hypercarbia, hypoxemia, and hyperoxia should be assessed, ideally awake and asleep. 72-hour Holter recording should be performed annually to evaluate for bradycardia that might (rarely) require a cardiac pacemaker. A head up tilt test should be performed annually to better understand the autonomic response to positional changes. An echocardiogram should be performed annually to rule out cor pulmonale or right ventricular hypertrophy (response to low oxygen from insufficient ventilator management). Neurocognitive testing should be performed annually to determine the effectiveness of the ventilatory management and compliance. In children under the age of three years, the above-described age-appropriate testing should be performed every 6 months. Gastrointestinal motility studies should be performed in the event of severe constipation. All of the above-described tests are part of routine standard of care for individuals with ROHHAD. Efforts are underway to create an expanded comprehensive testing profile for autonomic regulation in children which will also be considered standard of care for children with ROHHAD (testing of temperature regulation, vasomotor tone, integration of breathing, heart rate, and blood pressure, cerebrovascular regional blood flow, and pupillometry have already been integrated into care). These comprehensive evaluations are typically performed inpatient to optimize safety and assure the test results are representative of the patient’s condition.A complete evaluation of endocrine function should be performed with particular attention to water balance regulation, obesity, and other signs of pituitary dysfunction. The lab work should include: complete blood count with differential, reticulocytes, blood comprehensive metabolic profile, urine osmolality, prolactin, leptin, thyroxine free (FT4), thyroid-stimulating hormone-sensitive (S-TSH), lipid panel, cortisol (urine and serum), vitamin B12, vitamin D (25-hydroxy vitamin D2 and D3 serum), insulin-like growth factor binding protein, insulin-like growth factor I.If hypernatremic dehydration is found, formal testing of antidiuretic hormone secretion should be done before assuming the patient has diabetes insipidus. Patients with ROHHAD can become dehydrated due to lack of thirst with normal or partial antidiuretic hormone function. Obesity can alter growth hormone secretion and levels of insulin-like growth factor-1 (IGF-1) which should be considered when assessing growth hormone function.Complications of obesity including fatty liver, elevated lipids, or diabetes mellitus should be considered. A high suspicion should be maintained, and recurrent screening performed for tumors of neural crest origin, especially with imaging performed upon recognition of scoliosis or an unidentified shadow on chest x-ray. A chest x-ray and abdominal ultrasound to view the sympathetic chain and both adrenals are an effective serial evaluation to monitor for neural crest tumors in children with ROHHAD.
| 1,051 |
Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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nord_1051_6
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Therapies of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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TreatmentThe treatment of ROHHAD at present is based on the clinical features and their relative severity. The obesity is exceedingly difficult to control with diet and exercise. More effective is special emphasis to avoid further weight gain as the child grows vertically (with or without growth hormone supplement to treat growth hormone deficiency), but intervention requires consultation with a nutritionist and endocrinologist. Since patients with ROHHAD do not increase their breathing adequately during physical exertion, it is important to recommend only mild exertion until safe parameters have been established by a physician based on end tidal carbon dioxide and pulse oximetry monitoring during exercise.The hypothalamic dysfunction seen in these patients must be evaluated and treated by a pediatric endocrinologist, with long-term evaluations and labwork every three months. Since patients with ROHHAD have variable hypothalamic abnormalities, it is important that their care be individualized to meet their needs. These treatments may include hormone replacement, a strict fluid intake regimen, and other measures designed to make up for a dysfunctional hypothalamus. Growth hormone supplementation has improved vertical growth though evaluation of change in body composition has not been reported. Use of a dopamine agonist to normalize prolactin levels has not been systematically evaluated to determine effect on the clinical course.One of the main challenges in ROHHAD is the control of breathing deficit that is typically unapparent at the time of the rapid-onset weight gain but seems to worsen with advancing age. Some children may initially need artificial ventilation during sleep only, then progress to need for continuous support (awake and asleep). From the beginning, the key goal is optimization of oxygenation and ventilation. Many patients with ROHHAD can be managed with mask ventilation and bi-level positive airway pressure at night only (but provided with an actual mechanical ventilator); those children requiring 24 hour/day mechanical ventilation will need a tracheostomy (surgically creating a temporary opening in the throat into which a small tracheostomy tube is inserted), through which the patient is then mechanically ventilated. These children require a mechanical ventilator at home (with a back-up ventilator, pulse oximeter, end tidal carbon dioxide monitor, and power generator) as well as experienced registered nursing care ideally 24 hours/day. Other assistive breathing techniques such as diaphragm pacing may have limited success due to the obesity associated with ROHHAD but may be considered in select patients. Though gastric sleeve surgery has not been formally assessed in ROHHAD patients especially in terms of potential effect on control of breathing (gut-brain interaction), this is not an unreasonable consideration.In terms of ANSD, individuals with ROHHAD are at risk for severely low heart rates (bradycardia). Their lack of temperature control requires careful regulation of ambient temperature and attention to reduced body temperatures. Ophthalmologic findings including pupillary or other ocular abnormalities (such as “lazy eye”) should be evaluated by a pediatric ophthalmologist. Often, chronic constipation due to gastrointestinal motility dysfunction can be symptomatically treated with stool softeners. Lastly, tumors of neural crest origin, thought to be a form of anatomic (as opposed to physiologic) ANSD, require surgical removal and should be treated in consultation with a pediatric oncologist. To date, surgical removal of the neural crest tumors has not interrupted the unfolding of the ROHHAD phenotype nor induced recovery from the ROHHAD phenotype, but it averts local organ and vascular compression if the tumor grows large.Multidisciplinary care with input from a Center with expertise in ROHHAD is crucial to the successful management of these patients. This team may include primary care physicians, pulmonologists, endocrinologists, cardiologists, intensivists, otolaryngologists, surgeons, gastroenterologists, neurologists, ophthalmologists, psychologists, psychiatrists, respiratory therapists, nurses, social workers, speech and language therapists, special education teachers, and more, all working together with the child and the family to optimize care and quality of life.A high index of suspicion, early detection, and aggressive conservative intervention are critical to optimizing neurocognitive outcome. If the diagnosis of ROHHAD is delayed and/or if the clinical symptoms are not anticipated and adequately treated, the affected child will likely suffer neurocognitive compromise and may be at heightened risk for sudden death. If identified promptly, treated conservatively, and followed comprehensively, individuals with ROHHAD can have a good quality of life. It remains unknown if optimally managed children with ROHHAD will have a normal life span, but the anecdotal observation of improved breathing while awake with advancing age (refolding of the phenotype) is remarkably heartening.
|
Therapies of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation. TreatmentThe treatment of ROHHAD at present is based on the clinical features and their relative severity. The obesity is exceedingly difficult to control with diet and exercise. More effective is special emphasis to avoid further weight gain as the child grows vertically (with or without growth hormone supplement to treat growth hormone deficiency), but intervention requires consultation with a nutritionist and endocrinologist. Since patients with ROHHAD do not increase their breathing adequately during physical exertion, it is important to recommend only mild exertion until safe parameters have been established by a physician based on end tidal carbon dioxide and pulse oximetry monitoring during exercise.The hypothalamic dysfunction seen in these patients must be evaluated and treated by a pediatric endocrinologist, with long-term evaluations and labwork every three months. Since patients with ROHHAD have variable hypothalamic abnormalities, it is important that their care be individualized to meet their needs. These treatments may include hormone replacement, a strict fluid intake regimen, and other measures designed to make up for a dysfunctional hypothalamus. Growth hormone supplementation has improved vertical growth though evaluation of change in body composition has not been reported. Use of a dopamine agonist to normalize prolactin levels has not been systematically evaluated to determine effect on the clinical course.One of the main challenges in ROHHAD is the control of breathing deficit that is typically unapparent at the time of the rapid-onset weight gain but seems to worsen with advancing age. Some children may initially need artificial ventilation during sleep only, then progress to need for continuous support (awake and asleep). From the beginning, the key goal is optimization of oxygenation and ventilation. Many patients with ROHHAD can be managed with mask ventilation and bi-level positive airway pressure at night only (but provided with an actual mechanical ventilator); those children requiring 24 hour/day mechanical ventilation will need a tracheostomy (surgically creating a temporary opening in the throat into which a small tracheostomy tube is inserted), through which the patient is then mechanically ventilated. These children require a mechanical ventilator at home (with a back-up ventilator, pulse oximeter, end tidal carbon dioxide monitor, and power generator) as well as experienced registered nursing care ideally 24 hours/day. Other assistive breathing techniques such as diaphragm pacing may have limited success due to the obesity associated with ROHHAD but may be considered in select patients. Though gastric sleeve surgery has not been formally assessed in ROHHAD patients especially in terms of potential effect on control of breathing (gut-brain interaction), this is not an unreasonable consideration.In terms of ANSD, individuals with ROHHAD are at risk for severely low heart rates (bradycardia). Their lack of temperature control requires careful regulation of ambient temperature and attention to reduced body temperatures. Ophthalmologic findings including pupillary or other ocular abnormalities (such as “lazy eye”) should be evaluated by a pediatric ophthalmologist. Often, chronic constipation due to gastrointestinal motility dysfunction can be symptomatically treated with stool softeners. Lastly, tumors of neural crest origin, thought to be a form of anatomic (as opposed to physiologic) ANSD, require surgical removal and should be treated in consultation with a pediatric oncologist. To date, surgical removal of the neural crest tumors has not interrupted the unfolding of the ROHHAD phenotype nor induced recovery from the ROHHAD phenotype, but it averts local organ and vascular compression if the tumor grows large.Multidisciplinary care with input from a Center with expertise in ROHHAD is crucial to the successful management of these patients. This team may include primary care physicians, pulmonologists, endocrinologists, cardiologists, intensivists, otolaryngologists, surgeons, gastroenterologists, neurologists, ophthalmologists, psychologists, psychiatrists, respiratory therapists, nurses, social workers, speech and language therapists, special education teachers, and more, all working together with the child and the family to optimize care and quality of life.A high index of suspicion, early detection, and aggressive conservative intervention are critical to optimizing neurocognitive outcome. If the diagnosis of ROHHAD is delayed and/or if the clinical symptoms are not anticipated and adequately treated, the affected child will likely suffer neurocognitive compromise and may be at heightened risk for sudden death. If identified promptly, treated conservatively, and followed comprehensively, individuals with ROHHAD can have a good quality of life. It remains unknown if optimally managed children with ROHHAD will have a normal life span, but the anecdotal observation of improved breathing while awake with advancing age (refolding of the phenotype) is remarkably heartening.
| 1,051 |
Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation
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nord_1052_0
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Overview of Rasmussen Encephalitis
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Rasmussen encephalitis, sometimes referred to as Rasmussen syndrome, is a rare disorder of the central nervous system characterized by chronic progressive inflammation (encephalitis) of one cerebral hemisphere. As a result, the patient usually experiences frequent episodes of uncontrolled electrical disturbances in the brain that cause epileptic seizures (epilepsy) and progressive cerebral destruction. With time, further symptoms may include progressive weakness of one side of the body (hemiparesis), language problems (if on the left side of the brain) and intellectual disabilities. The exact cause of this disorder is not known. The two leading ideas are that the brain inflammation might be a reaction of a foreign antigen (infection) or an autoimmune disease limited to one side of the brain resulting in brain damage. It occurs mostly, but not always, in children between the ages of two and ten years, and in many patients the course of the disease is most severe during the first 8 to 12 months. After the peak inflammatory response is reached, the progression of this disorder appears to slow or stop, and the patient is left with permanent neurological deficits.
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Overview of Rasmussen Encephalitis. Rasmussen encephalitis, sometimes referred to as Rasmussen syndrome, is a rare disorder of the central nervous system characterized by chronic progressive inflammation (encephalitis) of one cerebral hemisphere. As a result, the patient usually experiences frequent episodes of uncontrolled electrical disturbances in the brain that cause epileptic seizures (epilepsy) and progressive cerebral destruction. With time, further symptoms may include progressive weakness of one side of the body (hemiparesis), language problems (if on the left side of the brain) and intellectual disabilities. The exact cause of this disorder is not known. The two leading ideas are that the brain inflammation might be a reaction of a foreign antigen (infection) or an autoimmune disease limited to one side of the brain resulting in brain damage. It occurs mostly, but not always, in children between the ages of two and ten years, and in many patients the course of the disease is most severe during the first 8 to 12 months. After the peak inflammatory response is reached, the progression of this disorder appears to slow or stop, and the patient is left with permanent neurological deficits.
| 1,052 |
Rasmussen Encephalitis
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nord_1052_1
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Symptoms of Rasmussen Encephalitis
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Typically, affected individuals develop focal seizures that may progress to near continuous seizures termed epilepsia partialis continua (EPC). EPC is characterized by a rapid, rhythmic succession of contractions and relaxations of a muscle or muscle group (myoclonus), particularly of the arms, legs, and face, that may occur singularly or in a repetitive, continuous series. In Rasmussen this occurs consistently on one side of the body opposite the side of the inflammation.Most affected children will exhibit progressive paralysis of one side of the body (hemiparesis) and if the seizures continue developmental disabilities. In many cases, the development of physical and mental abilities of affected children may cease (developmental arrest). In addition, affected children may lose previously acquired physical and mental abilities (developmental regression). Some affected children may exhibit degeneration (atrophy) of one side of the brain and/or progressive confusion, disorientation and deterioration of intellectual abilities (dementia).
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Symptoms of Rasmussen Encephalitis. Typically, affected individuals develop focal seizures that may progress to near continuous seizures termed epilepsia partialis continua (EPC). EPC is characterized by a rapid, rhythmic succession of contractions and relaxations of a muscle or muscle group (myoclonus), particularly of the arms, legs, and face, that may occur singularly or in a repetitive, continuous series. In Rasmussen this occurs consistently on one side of the body opposite the side of the inflammation.Most affected children will exhibit progressive paralysis of one side of the body (hemiparesis) and if the seizures continue developmental disabilities. In many cases, the development of physical and mental abilities of affected children may cease (developmental arrest). In addition, affected children may lose previously acquired physical and mental abilities (developmental regression). Some affected children may exhibit degeneration (atrophy) of one side of the brain and/or progressive confusion, disorientation and deterioration of intellectual abilities (dementia).
| 1,052 |
Rasmussen Encephalitis
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nord_1052_2
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Causes of Rasmussen Encephalitis
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The exact cause of Rasmussen encephalitis is not known. Most researchers now suspect that Rasmussen encephalitis is an autoimmune disorder following histopathologic review of the tissue involved under the microscope. In autoimmune disorders, the body’s natural defenses (antibodies and T-cells) fight its own tissue, mistaking it for foreign organisms for no apparent reason.Some researchers believe that Rasmussen encephalitis may be triggered by an unidentified infection such as influenza, measles or cytomegalovirus.
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Causes of Rasmussen Encephalitis. The exact cause of Rasmussen encephalitis is not known. Most researchers now suspect that Rasmussen encephalitis is an autoimmune disorder following histopathologic review of the tissue involved under the microscope. In autoimmune disorders, the body’s natural defenses (antibodies and T-cells) fight its own tissue, mistaking it for foreign organisms for no apparent reason.Some researchers believe that Rasmussen encephalitis may be triggered by an unidentified infection such as influenza, measles or cytomegalovirus.
| 1,052 |
Rasmussen Encephalitis
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nord_1052_3
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Affects of Rasmussen Encephalitis
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Rasmussen encephalitis mostly affects children ten years of age and younger. It is unusual to affect children under two years of age. Adolescents and young adults in much smaller proportions are also affected. There may be a history of some prior mild cold or flu prior to the onset of the seizures. The annual number of new-onset Rasmussen has been estimated as 2.4/10,000,000 persons less than or equal to 18 years of age.
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Affects of Rasmussen Encephalitis. Rasmussen encephalitis mostly affects children ten years of age and younger. It is unusual to affect children under two years of age. Adolescents and young adults in much smaller proportions are also affected. There may be a history of some prior mild cold or flu prior to the onset of the seizures. The annual number of new-onset Rasmussen has been estimated as 2.4/10,000,000 persons less than or equal to 18 years of age.
| 1,052 |
Rasmussen Encephalitis
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nord_1052_4
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Related disorders of Rasmussen Encephalitis
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Symptoms of the following disorders may be similar to those of Rasmussen encephalitis. Comparisons may be useful for a differential diagnosis:Focal cortical dysplasia in the motor region refers to lesions near the motor-sensory cortex that can provoke EPC which is similar to RE.Alpers-Huttenlocher syndrome is caused by changes (mutations or variants) in the POLG1 gene and characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and liver failure.
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Related disorders of Rasmussen Encephalitis. Symptoms of the following disorders may be similar to those of Rasmussen encephalitis. Comparisons may be useful for a differential diagnosis:Focal cortical dysplasia in the motor region refers to lesions near the motor-sensory cortex that can provoke EPC which is similar to RE.Alpers-Huttenlocher syndrome is caused by changes (mutations or variants) in the POLG1 gene and characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and liver failure.
| 1,052 |
Rasmussen Encephalitis
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nord_1052_5
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Diagnosis of Rasmussen Encephalitis
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Rasmussen encephalitis may be diagnosed clinically based upon a thorough clinical evaluation, a detailed patient history, and a complete neurological evaluation including advanced techniques such as electroencephalography (EEG) and magnetic resonance imaging (MRI).During an EEG, the brain’s electrical impulses are recorded. Such studies may reveal brain wave patterns that are characteristic of certain types of epilepsy. During MRI, a magnetic field and radio waves are used to create cross-sectional detailed images of the brain. It is usual that the diagnosis is made after a minimum of two scans which will detail progressive shrinkage of the affected side of the brain.
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Diagnosis of Rasmussen Encephalitis. Rasmussen encephalitis may be diagnosed clinically based upon a thorough clinical evaluation, a detailed patient history, and a complete neurological evaluation including advanced techniques such as electroencephalography (EEG) and magnetic resonance imaging (MRI).During an EEG, the brain’s electrical impulses are recorded. Such studies may reveal brain wave patterns that are characteristic of certain types of epilepsy. During MRI, a magnetic field and radio waves are used to create cross-sectional detailed images of the brain. It is usual that the diagnosis is made after a minimum of two scans which will detail progressive shrinkage of the affected side of the brain.
| 1,052 |
Rasmussen Encephalitis
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nord_1052_6
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Therapies of Rasmussen Encephalitis
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TreatmentTreatment of Rasmussen encephalitis is mostly symptomatic and supportive. Special services that may be beneficial to affected children include special social support, physical therapy and other medical, social, and/or vocational services.Various anti-seizure medications (anticonvulsants) may be prescribed to treat seizures. However, in most patients, anticonvulsants have proven ineffective. Medical treatments targeted at possible autoimmune disease may be tried, including steroids, immunoglobulin and tacrolimus. Immunological therapies (tacrolimus, intravenous immunoglobulins, potentially others as well) may slow down the neurological and structural deterioration but usually does not improve the epilepsy or progressive brain atrophy. Its precise role in management of Rasmussen encephalitis remains to be determined.Surgery usually in the form of a cerebral hemispherectomy is the only way to cure the seizures and halt neurodevelopmental regression. However, there are inevitable functional deficits including hemiparesis (weakness of one side) and hemifield defect (impairment of vision to one side), and where the dominant side of the brain is affected, there may be an effect on language. The difficulty is often deciding on the necessary and best timing of surgery, dependent on the severity of epilepsy and degree of effect on learning and progression of the disease. The decision should be made jointly by the family and specialist center that has experience treating patients with this condition.
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Therapies of Rasmussen Encephalitis. TreatmentTreatment of Rasmussen encephalitis is mostly symptomatic and supportive. Special services that may be beneficial to affected children include special social support, physical therapy and other medical, social, and/or vocational services.Various anti-seizure medications (anticonvulsants) may be prescribed to treat seizures. However, in most patients, anticonvulsants have proven ineffective. Medical treatments targeted at possible autoimmune disease may be tried, including steroids, immunoglobulin and tacrolimus. Immunological therapies (tacrolimus, intravenous immunoglobulins, potentially others as well) may slow down the neurological and structural deterioration but usually does not improve the epilepsy or progressive brain atrophy. Its precise role in management of Rasmussen encephalitis remains to be determined.Surgery usually in the form of a cerebral hemispherectomy is the only way to cure the seizures and halt neurodevelopmental regression. However, there are inevitable functional deficits including hemiparesis (weakness of one side) and hemifield defect (impairment of vision to one side), and where the dominant side of the brain is affected, there may be an effect on language. The difficulty is often deciding on the necessary and best timing of surgery, dependent on the severity of epilepsy and degree of effect on learning and progression of the disease. The decision should be made jointly by the family and specialist center that has experience treating patients with this condition.
| 1,052 |
Rasmussen Encephalitis
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nord_1053_0
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Overview of Reactive Arthritis
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Reactive arthritis is a general term for a form of joint inflammation (arthritis) that develops as a “reaction” to an infection in another area of the body (i.e., outside of the joints). Joint inflammation is characterized by redness, swelling, pain and warmth in and around the affected joint. In reactive arthritis, the large joints of the lower limbs and the sacroiliac joints are most often affected. Two other common symptoms of reactive arthritis are inflammation of the urinary tract and inflammation of the membrane (conjunctiva) that lines the eyelids (conjunctivitis). These three characteristic symptoms may occur separately, all at once or not at all. Additional symptoms such as fever, weight loss, lower back pain and heel pain may also occur. Reactive arthritis usually develops following a bout with certain bacterial infections including Chlamydia, Salmonella, Shigella, Yersinia, and Campylobacter.Reactive arthritis belongs to a group of related disorders known as the spondyloarthritidies. These disorders are linked by the association of similar symptoms and a specific genetic marker called HLA-B27. Symptoms common to these disorders include arthritis, especially of the lower limbs, lower back pain and enthesitis, a condition characterized by inflammation at the spot where tendons attach to bone. This group of disorders includes reactive arthritis, ankylosing spondylitis, psoriatic arthritis, undifferentiated spondyloarthritis and spondyloarthritis associated with inflammatory bowel disease.Reactive arthritis is a poorly defined disorder that has been described in the medical literature under many different names. No precise diagnostic or classification criteria have been developed that are universally agreed upon in the medical community.
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Overview of Reactive Arthritis. Reactive arthritis is a general term for a form of joint inflammation (arthritis) that develops as a “reaction” to an infection in another area of the body (i.e., outside of the joints). Joint inflammation is characterized by redness, swelling, pain and warmth in and around the affected joint. In reactive arthritis, the large joints of the lower limbs and the sacroiliac joints are most often affected. Two other common symptoms of reactive arthritis are inflammation of the urinary tract and inflammation of the membrane (conjunctiva) that lines the eyelids (conjunctivitis). These three characteristic symptoms may occur separately, all at once or not at all. Additional symptoms such as fever, weight loss, lower back pain and heel pain may also occur. Reactive arthritis usually develops following a bout with certain bacterial infections including Chlamydia, Salmonella, Shigella, Yersinia, and Campylobacter.Reactive arthritis belongs to a group of related disorders known as the spondyloarthritidies. These disorders are linked by the association of similar symptoms and a specific genetic marker called HLA-B27. Symptoms common to these disorders include arthritis, especially of the lower limbs, lower back pain and enthesitis, a condition characterized by inflammation at the spot where tendons attach to bone. This group of disorders includes reactive arthritis, ankylosing spondylitis, psoriatic arthritis, undifferentiated spondyloarthritis and spondyloarthritis associated with inflammatory bowel disease.Reactive arthritis is a poorly defined disorder that has been described in the medical literature under many different names. No precise diagnostic or classification criteria have been developed that are universally agreed upon in the medical community.
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Reactive Arthritis
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nord_1053_1
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Symptoms of Reactive Arthritis
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Some individuals with reactive arthritis may only develop mild arthritis without eye or urinary tract involvement. Other individuals may develop a severe case of reactive arthritis that can dramatically limit daily activity. Symptoms usually last anywhere from 3 to 12 months and may come and go. In approximately 30-50 percent of patients, symptoms may return later or become a chronic (greater than 6 month) long-term problem. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. The specific symptoms and their severity can vary greatly from one person to another.The symptoms of reactive arthritis may come and go over a period of time ranging from several weeks to several months. Symptoms usually develop one to six weeks after a gastrointestinal or genitourinary infection. Inflammation of the joints, urinary tract and eyes are the most common findings. Additional symptoms may also develop.Arthritis can occur before or at the same time as eye and urinary symptoms or after they have subsided. Arthritis usually affects the joints of the lower legs causing pain, redness and swelling in the knees, ankles and feet. Other joints such as the wrists, elbows, and fingers are affected less frequently. Onset is usually rapid with two to four joints becoming involved within a few days. Heel pain is also common. Heel pain is caused by enthesitis, a condition characterized by inflammation at the spot where the tendon attaches to bone. In some cases, the toes and/or fingers may become inflamed and swollen (dactylitis) so that they appear large and stubby. Pain in the lower back or buttocks may also occur.Urinary tract involvement in reactive arthritis may not cause any symptoms (asymptomatic). In other cases, urinary tract inflammation may be the first symptom to develop, especially in men. Urinary tract symptoms are often absent in women. In some men, urinary tract inflammation can cause pain or a burning sensation when urinating, increased frequency of urination, or fluid discharge when urinating. In severe cases, inflammation of the prostate gland (prostatitis) may occur. In spite of these symptoms, the urine culture will typically be negative.Women with urinary tract inflammation due to reactive arthritis may develop inflammation of the cervix, inflammation of the fallopian tubes (salpingitis), or inflammation of the vulva and vagina (vulvovaginitis). Some affected women may experience a burning sensation when urinating.Some affected individuals develop inflammation of the membrane (conjunctiva) lining the eyelids (conjunctivitis). Some people may also develop inflammation of the anterior uvea (uveitis), the part of the eye that consists of the iris, choroid and the ciliary body. Conjunctivitis and uveitis may cause redness and swelling of the eyes, eye pain, blurred vision, an abnormal sensitivity to light (photophobia) and crusting in the morning. Blurred vision and photophobia are more common with uveitis. Eye symptoms may occur early in the course of reactive arthritis. In some cases, symptoms may come and go during the duration of the disease (wax and wane).General, vague symptoms that can be associated with many different diseases may also occur in individuals with reactive arthritis. Such symptoms including fatigue, fever, unintended weight loss, and a general feeling of poor health (malaise).Additional symptoms may potentially affect individuals with reactive arthritis. In some men, small, shallow, painless ulcers may form on the penis; this is referred to as circinate balanitis. These ulcers may precede the development of arthritis. Occasionally these ulcers can form a plaque-like lesion and become chronic. In addition, some individuals may develop small, superficial ulcers in the mouth, especially the tongue or hard palate. These lesions may come and go, are usually painless and often go unnoticed. Acute diarrhea may occur in cases that develop after infection with Shigella, Yersinia, Campylobacter or Salmonella. Diarrhea may precede the development of musculoskeletal symptoms by up to one month.Some individuals with reactive arthritis develop a skin condition called keratoderma blennorrhagia. This skin lesion usually affects the palms or soles and may consist of reddish, raised, waxy bumps or nodules. These bumps usually spread, eventually coming together (coalescing) to form one larger, scaly rash that may resemble psoriasis. The nails of some individuals with reactive arthritis may become thickened.
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Symptoms of Reactive Arthritis. Some individuals with reactive arthritis may only develop mild arthritis without eye or urinary tract involvement. Other individuals may develop a severe case of reactive arthritis that can dramatically limit daily activity. Symptoms usually last anywhere from 3 to 12 months and may come and go. In approximately 30-50 percent of patients, symptoms may return later or become a chronic (greater than 6 month) long-term problem. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. The specific symptoms and their severity can vary greatly from one person to another.The symptoms of reactive arthritis may come and go over a period of time ranging from several weeks to several months. Symptoms usually develop one to six weeks after a gastrointestinal or genitourinary infection. Inflammation of the joints, urinary tract and eyes are the most common findings. Additional symptoms may also develop.Arthritis can occur before or at the same time as eye and urinary symptoms or after they have subsided. Arthritis usually affects the joints of the lower legs causing pain, redness and swelling in the knees, ankles and feet. Other joints such as the wrists, elbows, and fingers are affected less frequently. Onset is usually rapid with two to four joints becoming involved within a few days. Heel pain is also common. Heel pain is caused by enthesitis, a condition characterized by inflammation at the spot where the tendon attaches to bone. In some cases, the toes and/or fingers may become inflamed and swollen (dactylitis) so that they appear large and stubby. Pain in the lower back or buttocks may also occur.Urinary tract involvement in reactive arthritis may not cause any symptoms (asymptomatic). In other cases, urinary tract inflammation may be the first symptom to develop, especially in men. Urinary tract symptoms are often absent in women. In some men, urinary tract inflammation can cause pain or a burning sensation when urinating, increased frequency of urination, or fluid discharge when urinating. In severe cases, inflammation of the prostate gland (prostatitis) may occur. In spite of these symptoms, the urine culture will typically be negative.Women with urinary tract inflammation due to reactive arthritis may develop inflammation of the cervix, inflammation of the fallopian tubes (salpingitis), or inflammation of the vulva and vagina (vulvovaginitis). Some affected women may experience a burning sensation when urinating.Some affected individuals develop inflammation of the membrane (conjunctiva) lining the eyelids (conjunctivitis). Some people may also develop inflammation of the anterior uvea (uveitis), the part of the eye that consists of the iris, choroid and the ciliary body. Conjunctivitis and uveitis may cause redness and swelling of the eyes, eye pain, blurred vision, an abnormal sensitivity to light (photophobia) and crusting in the morning. Blurred vision and photophobia are more common with uveitis. Eye symptoms may occur early in the course of reactive arthritis. In some cases, symptoms may come and go during the duration of the disease (wax and wane).General, vague symptoms that can be associated with many different diseases may also occur in individuals with reactive arthritis. Such symptoms including fatigue, fever, unintended weight loss, and a general feeling of poor health (malaise).Additional symptoms may potentially affect individuals with reactive arthritis. In some men, small, shallow, painless ulcers may form on the penis; this is referred to as circinate balanitis. These ulcers may precede the development of arthritis. Occasionally these ulcers can form a plaque-like lesion and become chronic. In addition, some individuals may develop small, superficial ulcers in the mouth, especially the tongue or hard palate. These lesions may come and go, are usually painless and often go unnoticed. Acute diarrhea may occur in cases that develop after infection with Shigella, Yersinia, Campylobacter or Salmonella. Diarrhea may precede the development of musculoskeletal symptoms by up to one month.Some individuals with reactive arthritis develop a skin condition called keratoderma blennorrhagia. This skin lesion usually affects the palms or soles and may consist of reddish, raised, waxy bumps or nodules. These bumps usually spread, eventually coming together (coalescing) to form one larger, scaly rash that may resemble psoriasis. The nails of some individuals with reactive arthritis may become thickened.
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Causes of Reactive Arthritis
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Reactive arthritis develops because of an infection that occurs in another part of the body. Even mild infections, which may go unnoticed, can cause reactive arthritis. This may be particularly true with chlamydial infections, which appear to be a rather frequent cause of reactive arthritis. The lack of a symptomatic, preceding infection in some cases obscures the diagnosis. The five bacterial infections most commonly associated with reactive arthritis are Chlamydia, Salmonella, Shigella, Yersinia, and Campylobacter. These bacteria usually cause gastrointestinal or genitourinary infections. Chlamydia is the most common cause of reactive arthritis in the United States and is usually acquired through sexual contact. Salmonella, Shigella, Yersinia, and Campylobacter may cause a gastrointestinal infection that can trigger reactive arthritis. Salmonella, Shigella, Yersinia, and Campylobacter are often acquired after eating contaminated food, handling improperly prepared food or coming into contact with the feces of a contaminated person. Less often, several other bacteria have been implicated as causative agents in reactive arthritis. However, some researchers reserve the term reactive arthritis only for those cases caused by the five abovementioned bacteria.The exact underlying mechanisms that cause reactive arthritis are not fully understood. Researchers believe that reactive arthritis is an autoimmune disorder. An autoimmune disorder occurs when the body’s immune system mistakenly attacks healthy tissue. In reactive arthritis, a preceding infection induces an immune system response. Studies have demonstrated that the bacteria, or bacterial products, travel from the initial site of infection through the blood to the tissue lining the joints (synovial tissue). In the case of chlamydiae, these synovial-based organisms are viable, albeit in an aberrant state. The significance of these synovial-based organisms or bacterial products is not completely understood.It is important to note that not everyone who develops these bacterial infections will develop reactive arthritis. In fact, reactive arthritis only develops in a minority of individuals exposed to one of the causative organisms. Researchers do not know exactly why some people develop reactive arthritis, while others do not. Some individuals may have a genetic predisposition to developing the disorder. Researchers have determined that many affected individuals have a particular, genetically-determined “human leukocyte antigen” (HLA) known as HLA-B27. HLAs are proteins that play an important role in the body’s immune system; they influence the outcome of organ transplants and appear to affect an individual’s predisposition to certain diseases. Specifically, the HLA-B27 antigen is present in many individuals with reactive arthritis and related disorders. However, it is important to note that the majority of patients who develop reactive arthritis are HLA-B27 negative, so the genetic component of reactive arthritis is not fully understood. Some researchers believe that HLA-B27 is a better indicator of disease severity rather than susceptibility.Many people who have the HLA-B27 gene do not develop reactive arthritis even after contracting one of the abovementioned infections, which suggests that additional genetic (e.g., additional genes), environmental and/or immunologic factors may all play a role in the development of reactive arthritis. More research is necessary to determine the exact, underlying mechanisms that cause reactive arthritis.
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Causes of Reactive Arthritis. Reactive arthritis develops because of an infection that occurs in another part of the body. Even mild infections, which may go unnoticed, can cause reactive arthritis. This may be particularly true with chlamydial infections, which appear to be a rather frequent cause of reactive arthritis. The lack of a symptomatic, preceding infection in some cases obscures the diagnosis. The five bacterial infections most commonly associated with reactive arthritis are Chlamydia, Salmonella, Shigella, Yersinia, and Campylobacter. These bacteria usually cause gastrointestinal or genitourinary infections. Chlamydia is the most common cause of reactive arthritis in the United States and is usually acquired through sexual contact. Salmonella, Shigella, Yersinia, and Campylobacter may cause a gastrointestinal infection that can trigger reactive arthritis. Salmonella, Shigella, Yersinia, and Campylobacter are often acquired after eating contaminated food, handling improperly prepared food or coming into contact with the feces of a contaminated person. Less often, several other bacteria have been implicated as causative agents in reactive arthritis. However, some researchers reserve the term reactive arthritis only for those cases caused by the five abovementioned bacteria.The exact underlying mechanisms that cause reactive arthritis are not fully understood. Researchers believe that reactive arthritis is an autoimmune disorder. An autoimmune disorder occurs when the body’s immune system mistakenly attacks healthy tissue. In reactive arthritis, a preceding infection induces an immune system response. Studies have demonstrated that the bacteria, or bacterial products, travel from the initial site of infection through the blood to the tissue lining the joints (synovial tissue). In the case of chlamydiae, these synovial-based organisms are viable, albeit in an aberrant state. The significance of these synovial-based organisms or bacterial products is not completely understood.It is important to note that not everyone who develops these bacterial infections will develop reactive arthritis. In fact, reactive arthritis only develops in a minority of individuals exposed to one of the causative organisms. Researchers do not know exactly why some people develop reactive arthritis, while others do not. Some individuals may have a genetic predisposition to developing the disorder. Researchers have determined that many affected individuals have a particular, genetically-determined “human leukocyte antigen” (HLA) known as HLA-B27. HLAs are proteins that play an important role in the body’s immune system; they influence the outcome of organ transplants and appear to affect an individual’s predisposition to certain diseases. Specifically, the HLA-B27 antigen is present in many individuals with reactive arthritis and related disorders. However, it is important to note that the majority of patients who develop reactive arthritis are HLA-B27 negative, so the genetic component of reactive arthritis is not fully understood. Some researchers believe that HLA-B27 is a better indicator of disease severity rather than susceptibility.Many people who have the HLA-B27 gene do not develop reactive arthritis even after contracting one of the abovementioned infections, which suggests that additional genetic (e.g., additional genes), environmental and/or immunologic factors may all play a role in the development of reactive arthritis. More research is necessary to determine the exact, underlying mechanisms that cause reactive arthritis.
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Affects of Reactive Arthritis
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Reactive arthritis most often affects white men between the ages of 20 and 40. However, it has also been reported in children and the elderly. Women usually develop milder symptoms and may often go undiagnosed. Men are estimated to be approximately nine times more likely to develop reactive arthritis following a sexually-acquired infection. The risk of developing reactive arthritis following a gastrointestinal infection is the same between men and women. The exact incidence of reactive arthritis is unknown and estimates vary. Some researchers believe that many cases often go misdiagnosed or undiagnosed.Reactive arthritis has appeared in the medical literature under many different names including Reiter’s syndrome, named after a physician, Hans Reiter, who reported on the disorder in 1916. However, because of concerns about the unethical activities of Dr. Reiter in Germany during World War II, the term has gradually been replaced by the more appropriate and more descriptive term reactive arthritis.
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Affects of Reactive Arthritis. Reactive arthritis most often affects white men between the ages of 20 and 40. However, it has also been reported in children and the elderly. Women usually develop milder symptoms and may often go undiagnosed. Men are estimated to be approximately nine times more likely to develop reactive arthritis following a sexually-acquired infection. The risk of developing reactive arthritis following a gastrointestinal infection is the same between men and women. The exact incidence of reactive arthritis is unknown and estimates vary. Some researchers believe that many cases often go misdiagnosed or undiagnosed.Reactive arthritis has appeared in the medical literature under many different names including Reiter’s syndrome, named after a physician, Hans Reiter, who reported on the disorder in 1916. However, because of concerns about the unethical activities of Dr. Reiter in Germany during World War II, the term has gradually been replaced by the more appropriate and more descriptive term reactive arthritis.
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Related disorders of Reactive Arthritis
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Symptoms of the following disorders can be similar to those of reactive arthritis. Comparisons may be useful for a differential diagnosis.Infectious arthritis, also known as septic arthritis, is a general term for joint inflammation that develops because of an infection in one or more joints. The symptoms of infectious arthritis depend on the specific infectious agent and specific joints involved. General symptoms common to many illnesses may occur including fever, chills, headaches, general weakness and a general feeling of poor health (malaise). These symptoms may precede the development of joint pain and swelling. Most often the infection begins at some other location in the body and travels via the bloodstream to the joint. Less commonly, the infection starts in the joint in the course of a surgical procedure, injection (or similar action), or trauma. Infectious arthritis can be caused by bacteria, viruses or, less frequently, fungi or parasites. (For more information on this disorder, choose “infectious arthritis” as your search term in the Rare Disease Database.)A variety of other rheumatic and infectious diseases may cause joint inflammation and additional symptoms that can resemble those seen in reactive arthritis. These disorders include rheumatoid arthritis, adult-onset Still’s disease, osteoarthritis, gout and Lyme disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Reactive Arthritis. Symptoms of the following disorders can be similar to those of reactive arthritis. Comparisons may be useful for a differential diagnosis.Infectious arthritis, also known as septic arthritis, is a general term for joint inflammation that develops because of an infection in one or more joints. The symptoms of infectious arthritis depend on the specific infectious agent and specific joints involved. General symptoms common to many illnesses may occur including fever, chills, headaches, general weakness and a general feeling of poor health (malaise). These symptoms may precede the development of joint pain and swelling. Most often the infection begins at some other location in the body and travels via the bloodstream to the joint. Less commonly, the infection starts in the joint in the course of a surgical procedure, injection (or similar action), or trauma. Infectious arthritis can be caused by bacteria, viruses or, less frequently, fungi or parasites. (For more information on this disorder, choose “infectious arthritis” as your search term in the Rare Disease Database.)A variety of other rheumatic and infectious diseases may cause joint inflammation and additional symptoms that can resemble those seen in reactive arthritis. These disorders include rheumatoid arthritis, adult-onset Still’s disease, osteoarthritis, gout and Lyme disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Reactive Arthritis
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There is no specific, conclusive diagnostic test for reactive arthritis. Several groups have published diagnostic guidelines for reactive arthritis. However, these guidelines are often in disagreement as to what specifically is required for a diagnosis. Specific, consistent diagnostic guidelines have yet to be established for reactive arthritis.A diagnosis of reactive arthritis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including blood tests, joint fluid tests, and specialized imaging tests. These tests can aid in a diagnosis of reactive arthritis or rule out the disorder. However, none of these tests is conclusive as to whether a person has the disorder or not. Blood tests can reveal certain findings associated with reactive arthritis, including:The HLA-B27 genetic marker: This genetic marker is associated with spondyloarthropathies including reactive arthritis. It can aid in the diagnosis of reactive arthritis, but not every person who has this marker develops the disorder.The presence of bacteria such as Chlamydia, which can cause reactive arthritis: However, because the symptoms of reactive arthritis often do not become apparent until after an individual has recovered from the infection, no signs of the infection may be present. If the patient had an acute diarrheal illness and tested positive for Salmonella, Shigella, Campylobacter, or Yersinia 1-6 weeks prior to the onset of symptoms, then this is a very good indicator the patient probably has post-enteric reactive arthritis.An elevated sedimentation rate: Sedimentation rate is the time it takes red blood cells to settle on the bottom of a test tube. An elevated sedimentation rate is indicative of inflammation somewhere in the body, but cannot distinguish between disorders that cause inflammation. This is most useful during the acute stage of reactive arthritis and is typically normal with the chronic form of this condition.Rule out other conditions: Blood tests can reveal certain findings associated with other disorders that have similar symptoms to reactive arthritis such as rheumatoid arthritis, which is associated with a specific antibody called rheumatoid factor or an anti-cyclic citrullinate peptide (CCP) antibody, or lupus, which is associated with antinuclear antibodies.Physicians may also test the fluid in the joints (synovial fluid). Examining synovial fluid is done to rule out an infection in the joint, assess the amount of inflammation in the joint, and rule out other conditions such as gout or other types of crystal-related arthritis.Physicians may also use specialized imaging techniques (x-rays) to aid in the diagnosis of reactive arthritis or to rule out other conditions. X-ray studies may reveal distinctive characteristics of spondyloarthropathies such as reactive arthritis including inflammation of the sacroiliac joints (sacroiliitis). X-ray examination can also rule out other conditions. It is important to note that the typical changes on x-rays can take months to develop so x-rays are less useful in the acute setting. Specialized imaging techniques that may be used include computed tomography (CT) scans, magnetic resonance imaging (MRIs), or ultrasound. These advanced imaging techniques are more useful at detecting early or acute changes.
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Diagnosis of Reactive Arthritis. There is no specific, conclusive diagnostic test for reactive arthritis. Several groups have published diagnostic guidelines for reactive arthritis. However, these guidelines are often in disagreement as to what specifically is required for a diagnosis. Specific, consistent diagnostic guidelines have yet to be established for reactive arthritis.A diagnosis of reactive arthritis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including blood tests, joint fluid tests, and specialized imaging tests. These tests can aid in a diagnosis of reactive arthritis or rule out the disorder. However, none of these tests is conclusive as to whether a person has the disorder or not. Blood tests can reveal certain findings associated with reactive arthritis, including:The HLA-B27 genetic marker: This genetic marker is associated with spondyloarthropathies including reactive arthritis. It can aid in the diagnosis of reactive arthritis, but not every person who has this marker develops the disorder.The presence of bacteria such as Chlamydia, which can cause reactive arthritis: However, because the symptoms of reactive arthritis often do not become apparent until after an individual has recovered from the infection, no signs of the infection may be present. If the patient had an acute diarrheal illness and tested positive for Salmonella, Shigella, Campylobacter, or Yersinia 1-6 weeks prior to the onset of symptoms, then this is a very good indicator the patient probably has post-enteric reactive arthritis.An elevated sedimentation rate: Sedimentation rate is the time it takes red blood cells to settle on the bottom of a test tube. An elevated sedimentation rate is indicative of inflammation somewhere in the body, but cannot distinguish between disorders that cause inflammation. This is most useful during the acute stage of reactive arthritis and is typically normal with the chronic form of this condition.Rule out other conditions: Blood tests can reveal certain findings associated with other disorders that have similar symptoms to reactive arthritis such as rheumatoid arthritis, which is associated with a specific antibody called rheumatoid factor or an anti-cyclic citrullinate peptide (CCP) antibody, or lupus, which is associated with antinuclear antibodies.Physicians may also test the fluid in the joints (synovial fluid). Examining synovial fluid is done to rule out an infection in the joint, assess the amount of inflammation in the joint, and rule out other conditions such as gout or other types of crystal-related arthritis.Physicians may also use specialized imaging techniques (x-rays) to aid in the diagnosis of reactive arthritis or to rule out other conditions. X-ray studies may reveal distinctive characteristics of spondyloarthropathies such as reactive arthritis including inflammation of the sacroiliac joints (sacroiliitis). X-ray examination can also rule out other conditions. It is important to note that the typical changes on x-rays can take months to develop so x-rays are less useful in the acute setting. Specialized imaging techniques that may be used include computed tomography (CT) scans, magnetic resonance imaging (MRIs), or ultrasound. These advanced imaging techniques are more useful at detecting early or acute changes.
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Therapies of Reactive Arthritis
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TreatmentThe treatment of reactive arthritis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Orthopedists, ophthalmologists, dermatologists, urologists, gynecologists and other health care professionals may need to systematically and comprehensively plan appropriate therapy.Individuals with reactive arthritis may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), which include ibuprofen, naproxen sodium, and aspirin. NSAIDs can help minimize the inflammation and pain associated with reactive arthritis. Corticosteroids may be used to treat joint inflammation. Usually, corticosteroids are injected directly (locally) into the affected joints and/or around tendons to relieve severe inflammation. Topical corticosteroids, usually a cream or lotion, can be applied to skin abnormalities to reduce inflammation and promote healing. Systemic corticosteroids have generally been less effective than treating other types of inflammatory arthritis.Physical therapy and exercise can be beneficial in promoting and improving joint function. Strengthening and range-of-motion exercises can be used to help preserve or improve joint function. These techniques can build muscle around the joints, which strengthens support, improve the flexibility of joints, and help to reduce joint stiffness.Because reactive arthritis occurs following a bacterial infection, the use of antibiotics has been studied as a potential therapy. Antibiotics are prescribed to eradicate the bacterial infection that causes reactive arthritis. The type of antibiotic used depends on the type of infection. Studies into the benefit of prolonged antibiotic therapy for individuals with reactive arthritis have been inconsistent and inconclusive and, consequently, there is disagreement in the medical literature as to the overall value and benefit of antibiotic therapy for individuals with reactive arthritis. Recent data suggest that Chlamydia-induced reactive arthritis might respond to prolonged (6-month) administration of a combination of antibiotics.
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Therapies of Reactive Arthritis. TreatmentThe treatment of reactive arthritis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Orthopedists, ophthalmologists, dermatologists, urologists, gynecologists and other health care professionals may need to systematically and comprehensively plan appropriate therapy.Individuals with reactive arthritis may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), which include ibuprofen, naproxen sodium, and aspirin. NSAIDs can help minimize the inflammation and pain associated with reactive arthritis. Corticosteroids may be used to treat joint inflammation. Usually, corticosteroids are injected directly (locally) into the affected joints and/or around tendons to relieve severe inflammation. Topical corticosteroids, usually a cream or lotion, can be applied to skin abnormalities to reduce inflammation and promote healing. Systemic corticosteroids have generally been less effective than treating other types of inflammatory arthritis.Physical therapy and exercise can be beneficial in promoting and improving joint function. Strengthening and range-of-motion exercises can be used to help preserve or improve joint function. These techniques can build muscle around the joints, which strengthens support, improve the flexibility of joints, and help to reduce joint stiffness.Because reactive arthritis occurs following a bacterial infection, the use of antibiotics has been studied as a potential therapy. Antibiotics are prescribed to eradicate the bacterial infection that causes reactive arthritis. The type of antibiotic used depends on the type of infection. Studies into the benefit of prolonged antibiotic therapy for individuals with reactive arthritis have been inconsistent and inconclusive and, consequently, there is disagreement in the medical literature as to the overall value and benefit of antibiotic therapy for individuals with reactive arthritis. Recent data suggest that Chlamydia-induced reactive arthritis might respond to prolonged (6-month) administration of a combination of antibiotics.
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Overview of Recessive Multiple Epiphyseal Dysplasia
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SummaryRecessive multiple epiphyseal dysplasia (rMED) is a rare genetic disorder characterized by abnormal skeletal development mainly affecting the growth zones of the long tubular bones (dysplasia) including those affecting bones of the hands, hips, knees and feet. Joint pain, particularly of the hips and/or knees, is also common and develops during childhood. Affected individuals may exhibit additional abnormalities such as mild sideways curvature of the spine (scoliosis). Certain malformations such as clubfoot or cleft palate can be present at birth (congenital). rMED is caused by mutations in the SLC26A2 gene. This gene is also known as the diastrophic dysplasia sulfate transport or DTDST gene. The term ‘recessive’ in the disorder’s name refers to the how the disorder is inherited (autosomal recessive inheritance). rMED is a form of skeletal dysplasia (osteochondrodysplasia), a broad term for a group of disorders characterized by abnormal growth or development of cartilage and bone. The disorder is also known as multiple epiphyseal dysplasia type 4.IntroductionMultiple epiphyseal dysplasia is a general term for a group of disorders characterized by abnormal development of the bone and cartilage of the epiphyses, which are the rounded ends or “heads” of the long bones. In the past, the disorder was subdivided into the milder Ribbing type and the more severe Fairbank type. According to new classification, multiple epiphyseal dysplasia represents a group of disorders and these disorders are classified according to mutations in different genes, and the types of MED are classified according to the causative gene. However, not all genes behind MED have been identified yet. Most subtypes are inherited in an autosomal dominant manner. rMED belongs to a family of skeletal diseases with a variable severity of phenotype caused by different mutations in the same gene. This group includes the following diagnoses from the most severe to the mildest end of the spectrum: achondrogenesis type 1B, atelogenesis type 2, diastrophic dysplasia and rMED is the mildest form.
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Overview of Recessive Multiple Epiphyseal Dysplasia. SummaryRecessive multiple epiphyseal dysplasia (rMED) is a rare genetic disorder characterized by abnormal skeletal development mainly affecting the growth zones of the long tubular bones (dysplasia) including those affecting bones of the hands, hips, knees and feet. Joint pain, particularly of the hips and/or knees, is also common and develops during childhood. Affected individuals may exhibit additional abnormalities such as mild sideways curvature of the spine (scoliosis). Certain malformations such as clubfoot or cleft palate can be present at birth (congenital). rMED is caused by mutations in the SLC26A2 gene. This gene is also known as the diastrophic dysplasia sulfate transport or DTDST gene. The term ‘recessive’ in the disorder’s name refers to the how the disorder is inherited (autosomal recessive inheritance). rMED is a form of skeletal dysplasia (osteochondrodysplasia), a broad term for a group of disorders characterized by abnormal growth or development of cartilage and bone. The disorder is also known as multiple epiphyseal dysplasia type 4.IntroductionMultiple epiphyseal dysplasia is a general term for a group of disorders characterized by abnormal development of the bone and cartilage of the epiphyses, which are the rounded ends or “heads” of the long bones. In the past, the disorder was subdivided into the milder Ribbing type and the more severe Fairbank type. According to new classification, multiple epiphyseal dysplasia represents a group of disorders and these disorders are classified according to mutations in different genes, and the types of MED are classified according to the causative gene. However, not all genes behind MED have been identified yet. Most subtypes are inherited in an autosomal dominant manner. rMED belongs to a family of skeletal diseases with a variable severity of phenotype caused by different mutations in the same gene. This group includes the following diagnoses from the most severe to the mildest end of the spectrum: achondrogenesis type 1B, atelogenesis type 2, diastrophic dysplasia and rMED is the mildest form.
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Symptoms of Recessive Multiple Epiphyseal Dysplasia
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The specific symptoms and physical findings may vary from one person to another. Affected individuals may develop relatively mild symptoms and, in some cases, individuals reach adulthood without ever receiving a diagnosis of recessive multiple epiphyseal dysplasia. However, most individuals are diagnosed with a skeletal dysplasia at some point during childhood. Other individuals may have more severe complications.Approximately 50% of affected infants have a skeletal malformation that is present at birth such as clubfoot, fingers may be fixed or ‘locked’ in a bent position (clinodactyly), or abnormal closure of the roof of the mouth (cleft palate).Affected children will usually display symptoms or signs of abnormal bone and cartilage development (skeletal dysplasia) that can include short, stubby fingers and toes (brachydactyly), broadening of the space between the first and second toes, and mild, abnormal sideways curvature of the spine (scoliosis). Clubfoot, clinodactyly or cleft palate may also first become apparent during childhood. In some children, ears may get swollen in infancy as in diastrophic dysplasias. Diminished muscle tone (muscular hypotonia) may be significant but improves with physical therapy. Also attention has to be paid to the cervical spine especially if an operation is needed with general anesthesia.Affected individuals also experience early onset pain and stiffness in affected joints (early-onset arthritis) that can develop in chronic joint pain (arthralgia) and damage to the joints. The hips and the knees are commonly affected. Affected individuals often develop misalignment or malformation of the hips (hip dysplasia). Some affected individuals develop a waddling manner of walking (abnormal gait), and mild short stature can occur, but is not a frequent finding. Multiple joints may be affected, particularly in adolescents. Joint pain is usually worse after physical exercise. Some individuals develop deformity or rigidity of affected joints due to shortening or hardening of muscles, tendons or other tissue (contractures).A specific finding associated with rMED is a double-layered or partitioned patella. The patella, or the kneecap, is the triangular bone that protects the front of the knee joint. A double patella has two bony (osseous) layers instead of one with cartilage in between. A double patella may not be associated with any symptoms (asymptomatic) or may lead to frequent dislocations, knee pain, and potentially functional disability of the knee. In some cases, a double patella resolves on its own in adulthood.
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Symptoms of Recessive Multiple Epiphyseal Dysplasia. The specific symptoms and physical findings may vary from one person to another. Affected individuals may develop relatively mild symptoms and, in some cases, individuals reach adulthood without ever receiving a diagnosis of recessive multiple epiphyseal dysplasia. However, most individuals are diagnosed with a skeletal dysplasia at some point during childhood. Other individuals may have more severe complications.Approximately 50% of affected infants have a skeletal malformation that is present at birth such as clubfoot, fingers may be fixed or ‘locked’ in a bent position (clinodactyly), or abnormal closure of the roof of the mouth (cleft palate).Affected children will usually display symptoms or signs of abnormal bone and cartilage development (skeletal dysplasia) that can include short, stubby fingers and toes (brachydactyly), broadening of the space between the first and second toes, and mild, abnormal sideways curvature of the spine (scoliosis). Clubfoot, clinodactyly or cleft palate may also first become apparent during childhood. In some children, ears may get swollen in infancy as in diastrophic dysplasias. Diminished muscle tone (muscular hypotonia) may be significant but improves with physical therapy. Also attention has to be paid to the cervical spine especially if an operation is needed with general anesthesia.Affected individuals also experience early onset pain and stiffness in affected joints (early-onset arthritis) that can develop in chronic joint pain (arthralgia) and damage to the joints. The hips and the knees are commonly affected. Affected individuals often develop misalignment or malformation of the hips (hip dysplasia). Some affected individuals develop a waddling manner of walking (abnormal gait), and mild short stature can occur, but is not a frequent finding. Multiple joints may be affected, particularly in adolescents. Joint pain is usually worse after physical exercise. Some individuals develop deformity or rigidity of affected joints due to shortening or hardening of muscles, tendons or other tissue (contractures).A specific finding associated with rMED is a double-layered or partitioned patella. The patella, or the kneecap, is the triangular bone that protects the front of the knee joint. A double patella has two bony (osseous) layers instead of one with cartilage in between. A double patella may not be associated with any symptoms (asymptomatic) or may lead to frequent dislocations, knee pain, and potentially functional disability of the knee. In some cases, a double patella resolves on its own in adulthood.
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Recessive Multiple Epiphyseal Dysplasia
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Causes of Recessive Multiple Epiphyseal Dysplasia
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Recessive multiple epiphyseal dysplasia is caused by a mutation in the SLC26A2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.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 SLC26A2 gene is located on the long arm (q) of chromosome 5 (5q32). 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.The protein production of the SLC26A gene is required for efficient cellular transport of certain cartilage proteins needed to build skeleton and other tissues. The protein is a sulfate transporter that is involved in the proper development and function of molecules that build cartilage. Cartilage is the specialized tissue that serves as a buffer or cushion at joints.
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Causes of Recessive Multiple Epiphyseal Dysplasia. Recessive multiple epiphyseal dysplasia is caused by a mutation in the SLC26A2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.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 SLC26A2 gene is located on the long arm (q) of chromosome 5 (5q32). 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.The protein production of the SLC26A gene is required for efficient cellular transport of certain cartilage proteins needed to build skeleton and other tissues. The protein is a sulfate transporter that is involved in the proper development and function of molecules that build cartilage. Cartilage is the specialized tissue that serves as a buffer or cushion at joints.
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Recessive Multiple Epiphyseal Dysplasia
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Affects of Recessive Multiple Epiphyseal Dysplasia
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Recessive multiple epiphyseal dysplasia affects males and females in equal numbers. The exact incidence or prevalence of the disorder is unknown, but multiple epiphyseal dysplasia, collectively, has been estimated to occur in approximately 1 in 20,000 people in the general population. rMED is estimated to account for approximately 25% of all cases of multiple epiphyseal dysplasia. Because some cases go undiagnosed or misdiagnosed, determining the true frequency these disorders in the general population is difficult.
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Affects of Recessive Multiple Epiphyseal Dysplasia. Recessive multiple epiphyseal dysplasia affects males and females in equal numbers. The exact incidence or prevalence of the disorder is unknown, but multiple epiphyseal dysplasia, collectively, has been estimated to occur in approximately 1 in 20,000 people in the general population. rMED is estimated to account for approximately 25% of all cases of multiple epiphyseal dysplasia. Because some cases go undiagnosed or misdiagnosed, determining the true frequency these disorders in the general population is difficult.
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Recessive Multiple Epiphyseal Dysplasia
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Related disorders of Recessive Multiple Epiphyseal Dysplasia
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Symptoms of the following disorders can be similar to those of recessive multiple epiphyseal dysplasia. Comparisons may be useful for a differential diagnosis.Skeletal dysplasias (osteochondrodysplasias) are a general term for a group of disorders characterized by abnormal growth or development or cartilage and bone. Some forms cause life-threatening complications shortly after birth, while others are only may or may not cause life-threatening complications. Some forms do not cause life-threatening complications early in life. Skeletal dysplasias can be associated with short-limbed short stature or with more proportional shortening of the trunk and limbs. Various additional abnormalities or malformations may be present depending upon the specific disorder. There are approximately 500 types of skeletal dysplasias with more than 300 causative genes.Autosomal dominant multiple epiphyseal dysplasia refers to group of disorders characterized by skeletal malformations (dysplasia) including those affecting bones of the hands, feet, and knees. There is significant overlap between the signs of autosomal dominant forms of multiple epiphyseal dysplasia and the autosomal recessive form (type 4). The dominant forms are usually not associated with additional findings such as clubfoot, clinodactyly, cleft palate and double patella. These disorders are due to mutations in specific genes; they are inherited as autosomal dominant traits. (For more information on this disorder, choose “multiple epiphyseal dysplasia” as your search term in the Rare Disease Database.)Multiple epiphyseal dysplasia can occur as part of a larger syndrome characterized by additional specific symptoms. Several extremely rare genetic disorders, which are inherited as autosomal recessive traits, have multiple epiphyseal dysplasia as a characteristic symptoms. These disorders include Wolcott-Rallison syndrome, Lowry-Wood syndrome, Hunter-MacDonald syndrome, and macrocephaly with multiple epiphyseal dysplasia and distinctive facies.Legg-Calvé-Perthes disease (LCPD) is one of a group of disorders known as the osteochondroses. The Osteochondroses typically are characterized by degeneration (avascular necrosis) and subsequent regeneration of the growing end or ‘head’ of a long bone (epiphyses). In Legg-Calvé-Perthes disease, the growing end (epiphysis) of the upper portion (capital) of the thigh bone (femur) is affected. Researchers believe that an unexplained interruption of the blood supply (ischemia) to the capital femoral epiphysis results in degeneration (avascular necrosis) and deformity of the thigh bone in this area. Symptoms may include a limp with or without pain in the hip, knee, thigh, and/or groin; muscle spasms; delayed maturation of the femur; mild short stature; and/or limited movements of the affected hip. The disease process seems to be self-limiting as new blood supplies are established (revascularization) and new healthy bone forms (reossifies) in the affected area. Most cases of Legg-Calvé-Perthes disease occur randomly for no apparent reason (sporadically). (For more information on this disorder, choose “Legg-Calvé-Perthes disease” as your search term in the Rare Disease Database.)Meyer dysplasia is a rare condition that primarily affects the epiphyses of the thigh bone (femur) in young children. Meyer dysplasia may not cause any symptoms (asymptomatic), but can result in pain in both hips and cause young children to limp. Affected children may have limited range of motion in the hips and a waddling gait. In most cases, both hips are affected. The disorder usually begins during the second year of life and often resolves without treatment by the age of six. During this time the epiphyses continue to grow and unify. It is important to distinguish Meyer dysplasia from more serious causes of hip dysplasia. Many cases do not require treatment. In some cases, flattening of the epiphyses of the femur (femoral head) occurs and may possibly represent a mild form of multiple epiphyseal dysplasia.
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Related disorders of Recessive Multiple Epiphyseal Dysplasia. Symptoms of the following disorders can be similar to those of recessive multiple epiphyseal dysplasia. Comparisons may be useful for a differential diagnosis.Skeletal dysplasias (osteochondrodysplasias) are a general term for a group of disorders characterized by abnormal growth or development or cartilage and bone. Some forms cause life-threatening complications shortly after birth, while others are only may or may not cause life-threatening complications. Some forms do not cause life-threatening complications early in life. Skeletal dysplasias can be associated with short-limbed short stature or with more proportional shortening of the trunk and limbs. Various additional abnormalities or malformations may be present depending upon the specific disorder. There are approximately 500 types of skeletal dysplasias with more than 300 causative genes.Autosomal dominant multiple epiphyseal dysplasia refers to group of disorders characterized by skeletal malformations (dysplasia) including those affecting bones of the hands, feet, and knees. There is significant overlap between the signs of autosomal dominant forms of multiple epiphyseal dysplasia and the autosomal recessive form (type 4). The dominant forms are usually not associated with additional findings such as clubfoot, clinodactyly, cleft palate and double patella. These disorders are due to mutations in specific genes; they are inherited as autosomal dominant traits. (For more information on this disorder, choose “multiple epiphyseal dysplasia” as your search term in the Rare Disease Database.)Multiple epiphyseal dysplasia can occur as part of a larger syndrome characterized by additional specific symptoms. Several extremely rare genetic disorders, which are inherited as autosomal recessive traits, have multiple epiphyseal dysplasia as a characteristic symptoms. These disorders include Wolcott-Rallison syndrome, Lowry-Wood syndrome, Hunter-MacDonald syndrome, and macrocephaly with multiple epiphyseal dysplasia and distinctive facies.Legg-Calvé-Perthes disease (LCPD) is one of a group of disorders known as the osteochondroses. The Osteochondroses typically are characterized by degeneration (avascular necrosis) and subsequent regeneration of the growing end or ‘head’ of a long bone (epiphyses). In Legg-Calvé-Perthes disease, the growing end (epiphysis) of the upper portion (capital) of the thigh bone (femur) is affected. Researchers believe that an unexplained interruption of the blood supply (ischemia) to the capital femoral epiphysis results in degeneration (avascular necrosis) and deformity of the thigh bone in this area. Symptoms may include a limp with or without pain in the hip, knee, thigh, and/or groin; muscle spasms; delayed maturation of the femur; mild short stature; and/or limited movements of the affected hip. The disease process seems to be self-limiting as new blood supplies are established (revascularization) and new healthy bone forms (reossifies) in the affected area. Most cases of Legg-Calvé-Perthes disease occur randomly for no apparent reason (sporadically). (For more information on this disorder, choose “Legg-Calvé-Perthes disease” as your search term in the Rare Disease Database.)Meyer dysplasia is a rare condition that primarily affects the epiphyses of the thigh bone (femur) in young children. Meyer dysplasia may not cause any symptoms (asymptomatic), but can result in pain in both hips and cause young children to limp. Affected children may have limited range of motion in the hips and a waddling gait. In most cases, both hips are affected. The disorder usually begins during the second year of life and often resolves without treatment by the age of six. During this time the epiphyses continue to grow and unify. It is important to distinguish Meyer dysplasia from more serious causes of hip dysplasia. Many cases do not require treatment. In some cases, flattening of the epiphyses of the femur (femoral head) occurs and may possibly represent a mild form of multiple epiphyseal dysplasia.
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Recessive Multiple Epiphyseal Dysplasia
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Diagnosis of Recessive Multiple Epiphyseal Dysplasia
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A diagnosis of recessive multiple epiphyseal dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The disorder may be suspected in individuals with joint pain, particularly in the hips and knees, skeletal malformation of the hands, feet and knees, and scoliosis.Clinical Testing and WorkupBasic x-rays (radiographs) can help to establish a diagnosis of rMED by revealing abnormal epiphyses, brachydactyly, and a double patella.
Molecular genetic testing can support a diagnosis of multiple epiphyseal dysplasia. Molecular genetic testing can detect mutations in the SLC26A gene known to cause the disorder, but it is only available as a diagnostic service at specialized laboratories. The test is often expensive and often not necessary to confirm a diagnosis of rMED.
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Diagnosis of Recessive Multiple Epiphyseal Dysplasia. A diagnosis of recessive multiple epiphyseal dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The disorder may be suspected in individuals with joint pain, particularly in the hips and knees, skeletal malformation of the hands, feet and knees, and scoliosis.Clinical Testing and WorkupBasic x-rays (radiographs) can help to establish a diagnosis of rMED by revealing abnormal epiphyses, brachydactyly, and a double patella.
Molecular genetic testing can support a diagnosis of multiple epiphyseal dysplasia. Molecular genetic testing can detect mutations in the SLC26A gene known to cause the disorder, but it is only available as a diagnostic service at specialized laboratories. The test is often expensive and often not necessary to confirm a diagnosis of rMED.
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Recessive Multiple Epiphyseal Dysplasia
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Therapies of Recessive Multiple Epiphyseal Dysplasia
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TreatmentThe treatment of rMED is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, geneticists, orthopedic surgeons, rheumatologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families.Standard physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), is beneficial. Pain management can be challenging. Cautious use of pain (analgesic) medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) is recommended.In some cases, surgery may be necessary to achieve better positioning and to increase the range of motion in certain joints. Surgery may be necessary to treat malformation of the hips and, in some cases, total hip replacement surgery may be necessary. Surgical procedures may be recommended to correct clubfoot or abnormalities of the knee.
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Therapies of Recessive Multiple Epiphyseal Dysplasia. TreatmentThe treatment of rMED is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, geneticists, orthopedic surgeons, rheumatologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families.Standard physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), is beneficial. Pain management can be challenging. Cautious use of pain (analgesic) medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) is recommended.In some cases, surgery may be necessary to achieve better positioning and to increase the range of motion in certain joints. Surgery may be necessary to treat malformation of the hips and, in some cases, total hip replacement surgery may be necessary. Surgical procedures may be recommended to correct clubfoot or abnormalities of the knee.
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Recessive Multiple Epiphyseal Dysplasia
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nord_1055_0
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Overview of Recurrent Pericarditis
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SummaryRecurrent pericarditis is a disease characterized by recurrent episodes of inflammation of the pericardium, which is the sac containing the heart. The main symptom associated with an episode of pericarditis is chest pain that is typically sharp and worse when taking a deep breath (pleuritic). Shortness of breath (dyspnea) also occurs frequently. Recurrent pericarditis can develop in individuals of any age. The first-line therapy for pericarditis, including for recurrent cases, is a combination of colchicine and either aspirin or non-steroidal anti-inflammatory drugs such as ibuprofen. Although recurrent pericarditis can significantly affect quality of life, it is typically not life threatening or associated with serious illness, and patients are usually well between episodes. IntroductionAs discussed below, there are numerous causes (etiologies) of pericarditis. Most cases of recurrent pericarditis are idiopathic, that is, the specific cause is not known. Pericarditis is often classified based on the timing of symptoms. A new-onset episode of pericarditis is called acute pericarditis. Episodes lasting more than 4 to 6 weeks but less than 3 months are called incessant pericarditis, while episodes lasting more than 3 months are known as chronic pericarditis. Recurrent pericarditis is defined as an episode of acute pericarditis that occurs at least 4 to 6 weeks after the resolution of a prior episode. Recurrences can occur months or even years after an initial episode.
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Overview of Recurrent Pericarditis. SummaryRecurrent pericarditis is a disease characterized by recurrent episodes of inflammation of the pericardium, which is the sac containing the heart. The main symptom associated with an episode of pericarditis is chest pain that is typically sharp and worse when taking a deep breath (pleuritic). Shortness of breath (dyspnea) also occurs frequently. Recurrent pericarditis can develop in individuals of any age. The first-line therapy for pericarditis, including for recurrent cases, is a combination of colchicine and either aspirin or non-steroidal anti-inflammatory drugs such as ibuprofen. Although recurrent pericarditis can significantly affect quality of life, it is typically not life threatening or associated with serious illness, and patients are usually well between episodes. IntroductionAs discussed below, there are numerous causes (etiologies) of pericarditis. Most cases of recurrent pericarditis are idiopathic, that is, the specific cause is not known. Pericarditis is often classified based on the timing of symptoms. A new-onset episode of pericarditis is called acute pericarditis. Episodes lasting more than 4 to 6 weeks but less than 3 months are called incessant pericarditis, while episodes lasting more than 3 months are known as chronic pericarditis. Recurrent pericarditis is defined as an episode of acute pericarditis that occurs at least 4 to 6 weeks after the resolution of a prior episode. Recurrences can occur months or even years after an initial episode.
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Recurrent Pericarditis
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Symptoms of Recurrent Pericarditis
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The main symptom of pericarditis is chest pain, which is present in the vast majority of affected individuals. Typically, the pain is described as sharp and worse when coughing or taking a deep breath (pleuritic). The typical pain seen in pericarditis is also worse when lying down and is partially relieved when leaning forward. It can radiate to the neck, upper back or shoulders. Other symptoms that are associated with pericarditis include shortness of breath (dyspnea), fever, fatigue, malaise and the sensation of an irregular heartbeat (palpitations). Another feature frequently seen in pericarditis is accumulation of fluid in the space between the heart and the pericardium (pericardial sac), which is known as a pericardial effusion. The symptoms seen with a second or subsequent episode of recurrent pericarditis are often similar to the first event, although they tend to be less severe with recurrences. An episode of pericarditis can last days to weeks or longer. Although the symptoms of pericarditis can significantly affect quality of life, affected individuals typically have no symptoms between episodes. The number of episodes of recurrent pericarditis varies greatly between patients.The two most serious complications of pericarditis are an effusion causing cardiac tamponade and constrictive pericarditis. Cardiac tamponade occurs when a pericardial effusion becomes large enough to impair contraction of the heart. Symptoms of cardiac tamponade include dyspnea, chest discomfort, fatigue, fluid accumulation in the body (edema), and low blood pressure (hypotension). In severe cases, cardiac tamponade can impair cardiac function to the point where it compromises delivery of blood and oxygen to the organs (cardiogenic shock). Constrictive pericarditis is a consequence of chronic pericardial inflammation and is characterized by scarring (fibrosis) and loss of elasticity of the pericardium. The main symptoms of constrictive pericarditis are dyspnea, edema, shortness of breath when lying flat (orthopnea) and chest pain. Fortunately, both cardiac tamponade and constrictive pericarditis are very rare complications of recurrent idiopathic pericarditis, although the risk of constrictive pericarditis is higher with certain other causes of pericarditis (see the “Causes” section below for more details). Overall, most patients can live a productive life with a very low risk of mortality related to recurrent pericarditis.
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Symptoms of Recurrent Pericarditis. The main symptom of pericarditis is chest pain, which is present in the vast majority of affected individuals. Typically, the pain is described as sharp and worse when coughing or taking a deep breath (pleuritic). The typical pain seen in pericarditis is also worse when lying down and is partially relieved when leaning forward. It can radiate to the neck, upper back or shoulders. Other symptoms that are associated with pericarditis include shortness of breath (dyspnea), fever, fatigue, malaise and the sensation of an irregular heartbeat (palpitations). Another feature frequently seen in pericarditis is accumulation of fluid in the space between the heart and the pericardium (pericardial sac), which is known as a pericardial effusion. The symptoms seen with a second or subsequent episode of recurrent pericarditis are often similar to the first event, although they tend to be less severe with recurrences. An episode of pericarditis can last days to weeks or longer. Although the symptoms of pericarditis can significantly affect quality of life, affected individuals typically have no symptoms between episodes. The number of episodes of recurrent pericarditis varies greatly between patients.The two most serious complications of pericarditis are an effusion causing cardiac tamponade and constrictive pericarditis. Cardiac tamponade occurs when a pericardial effusion becomes large enough to impair contraction of the heart. Symptoms of cardiac tamponade include dyspnea, chest discomfort, fatigue, fluid accumulation in the body (edema), and low blood pressure (hypotension). In severe cases, cardiac tamponade can impair cardiac function to the point where it compromises delivery of blood and oxygen to the organs (cardiogenic shock). Constrictive pericarditis is a consequence of chronic pericardial inflammation and is characterized by scarring (fibrosis) and loss of elasticity of the pericardium. The main symptoms of constrictive pericarditis are dyspnea, edema, shortness of breath when lying flat (orthopnea) and chest pain. Fortunately, both cardiac tamponade and constrictive pericarditis are very rare complications of recurrent idiopathic pericarditis, although the risk of constrictive pericarditis is higher with certain other causes of pericarditis (see the “Causes” section below for more details). Overall, most patients can live a productive life with a very low risk of mortality related to recurrent pericarditis.
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Recurrent Pericarditis
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Causes of Recurrent Pericarditis
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The causes of pericarditis can be divided in two major categories: those that lead to isolated pericarditis and systemic diseases that can involve the pericardium as one of their manifestations. Most cases of isolated pericarditis are idiopathic. Viral infections have been considered to initiate first episodes of idiopathic pericarditis, but it is not clear how often this is actually the case. Dysfunction of the immune system is thought to play a role in recurrent cases of idiopathic pericarditis. Bacteria (notably tuberculosis), parasites and fungi can also be implicated more rarely, but it is unusual for these non-viral infections to be limited to the pericardium. Pericarditis can also occur after a heart attack (peri-infarction pericarditis and Dressler syndrome) or after cardiac surgery (post-pericardiotomy syndrome) and other types of invasive cardiac procedures. These types of pericarditis are known collectively as post-cardiac injury pericarditis.Numerous systemic diseases have pericardial involvement as one of their possible manifestations. These include metabolic disturbances such as kidney failure (uremia) and certain medications which cause an immune response affecting the pericardium. Invasion of the pericardium by metastatic cancer (neoplastic pericarditis) is not rare.Most of systemic disorders that cause pericarditis are characterized by either an immune system that mistakenly attack one’s own body (autoimmune diseases) or by uncontrolled inflammation (autoinflammatory syndromes). Examples of autoimmune diseases associated with pericarditis include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Behçet’s disease. Autoinflammatory syndromes are rare and usually inherited. The most common in which pericarditis occurs is familial Mediterranean fever (FMF). The underlying cause of pericarditis is the strongest predictor of the risk of developing constrictive pericarditis, although this complication remains rare overall. The highest risk is seen with bacterial pericarditis, especially tuberculosis, intermediate risk is seen with immune-mediated and neoplastic pericarditis and the risk is low in viral and post-cardiac injury pericarditis. Idiopathic recurrent pericarditis does not seem to confer a significant risk of developing constrictive pericarditis.
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Causes of Recurrent Pericarditis. The causes of pericarditis can be divided in two major categories: those that lead to isolated pericarditis and systemic diseases that can involve the pericardium as one of their manifestations. Most cases of isolated pericarditis are idiopathic. Viral infections have been considered to initiate first episodes of idiopathic pericarditis, but it is not clear how often this is actually the case. Dysfunction of the immune system is thought to play a role in recurrent cases of idiopathic pericarditis. Bacteria (notably tuberculosis), parasites and fungi can also be implicated more rarely, but it is unusual for these non-viral infections to be limited to the pericardium. Pericarditis can also occur after a heart attack (peri-infarction pericarditis and Dressler syndrome) or after cardiac surgery (post-pericardiotomy syndrome) and other types of invasive cardiac procedures. These types of pericarditis are known collectively as post-cardiac injury pericarditis.Numerous systemic diseases have pericardial involvement as one of their possible manifestations. These include metabolic disturbances such as kidney failure (uremia) and certain medications which cause an immune response affecting the pericardium. Invasion of the pericardium by metastatic cancer (neoplastic pericarditis) is not rare.Most of systemic disorders that cause pericarditis are characterized by either an immune system that mistakenly attack one’s own body (autoimmune diseases) or by uncontrolled inflammation (autoinflammatory syndromes). Examples of autoimmune diseases associated with pericarditis include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Behçet’s disease. Autoinflammatory syndromes are rare and usually inherited. The most common in which pericarditis occurs is familial Mediterranean fever (FMF). The underlying cause of pericarditis is the strongest predictor of the risk of developing constrictive pericarditis, although this complication remains rare overall. The highest risk is seen with bacterial pericarditis, especially tuberculosis, intermediate risk is seen with immune-mediated and neoplastic pericarditis and the risk is low in viral and post-cardiac injury pericarditis. Idiopathic recurrent pericarditis does not seem to confer a significant risk of developing constrictive pericarditis.
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Recurrent Pericarditis
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Affects of Recurrent Pericarditis
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Pericarditis is estimated to affect about 28 individuals per 100,000 in the general population every year. Apart from individuals with predisposing conditions, the most frequently affected group are men between the ages of 20 and 50. However, the disease can occur in people of any demographic, including children. It is estimated that about 15 to 30% of individuals that have an initial episode of idiopathic pericarditis will develop recurrent pericarditis.
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Affects of Recurrent Pericarditis. Pericarditis is estimated to affect about 28 individuals per 100,000 in the general population every year. Apart from individuals with predisposing conditions, the most frequently affected group are men between the ages of 20 and 50. However, the disease can occur in people of any demographic, including children. It is estimated that about 15 to 30% of individuals that have an initial episode of idiopathic pericarditis will develop recurrent pericarditis.
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Recurrent Pericarditis
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Related disorders of Recurrent Pericarditis
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Symptoms of the following disorders can resemble or be confused with those of pericarditis.Angina is a condition caused by a limitation of blood flow to the heart. It is usually caused by partial obstruction of the arteries that feed the heart (coronary arteries) or by a fatty plaque (atheroma), but can rarely be caused by spasms of the arteries (vasospastic angina). Angina is usually triggered by exercise or stress and is relieved by rest, except in the case of vasospastic angina, which occurs at rest. The main symptom of angina is chest pain, which patients usually describe as a squeezing, pressure or tightness. It is often accompanied by dyspnea, sweating (diaphoresis), nausea and anxiety. Angina that occurs at rest, lasts longer than usual, becomes more frequent or becomes more intense is called unstable angina.Acute myocardial infarction (MI) also called heart attack, often progresses from angina and is characterized by a total or almost total obstruction of a coronary artery, most commonly by a blood clot (thrombus) that forms after rupture of a fatty plaque. The main symptoms of myocardial infarction are crushing chest pain, dyspnea, diaphoresis, nausea and anxiety.Myocarditis is a rare cause of cardiovascular disease that can be manifest as sudden death, abnormal heart rhythms, chest pain or heart failure. The symptoms of myocarditis are not specific to the disease and are similar to symptoms of more common heart disorders. A sensation of tightness or squeezing in the chest that is present with rest and with exertion is common. The cause of myocarditis is an inflammation of the heart muscle, most often following a viral infection. Myocarditis can occur concurrently with pericarditis, a condition known as myopericarditis. (For more information choose “myocarditis” as your search term in the Rare Disease Database.)In addition to these conditions, chest pain that can mimic pericarditis is seen in a wide range of conditions including gastric inflammation (gastritis) or ulcers, esophageal inflammation (esophagitis) and gastroesophageal reflux disease (GERD), clots in the arteries of the lung (pulmonary embolism), inflammation of the lining of the lungs (pleuritis), chest wall trauma and a number of other diseases.
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Related disorders of Recurrent Pericarditis. Symptoms of the following disorders can resemble or be confused with those of pericarditis.Angina is a condition caused by a limitation of blood flow to the heart. It is usually caused by partial obstruction of the arteries that feed the heart (coronary arteries) or by a fatty plaque (atheroma), but can rarely be caused by spasms of the arteries (vasospastic angina). Angina is usually triggered by exercise or stress and is relieved by rest, except in the case of vasospastic angina, which occurs at rest. The main symptom of angina is chest pain, which patients usually describe as a squeezing, pressure or tightness. It is often accompanied by dyspnea, sweating (diaphoresis), nausea and anxiety. Angina that occurs at rest, lasts longer than usual, becomes more frequent or becomes more intense is called unstable angina.Acute myocardial infarction (MI) also called heart attack, often progresses from angina and is characterized by a total or almost total obstruction of a coronary artery, most commonly by a blood clot (thrombus) that forms after rupture of a fatty plaque. The main symptoms of myocardial infarction are crushing chest pain, dyspnea, diaphoresis, nausea and anxiety.Myocarditis is a rare cause of cardiovascular disease that can be manifest as sudden death, abnormal heart rhythms, chest pain or heart failure. The symptoms of myocarditis are not specific to the disease and are similar to symptoms of more common heart disorders. A sensation of tightness or squeezing in the chest that is present with rest and with exertion is common. The cause of myocarditis is an inflammation of the heart muscle, most often following a viral infection. Myocarditis can occur concurrently with pericarditis, a condition known as myopericarditis. (For more information choose “myocarditis” as your search term in the Rare Disease Database.)In addition to these conditions, chest pain that can mimic pericarditis is seen in a wide range of conditions including gastric inflammation (gastritis) or ulcers, esophageal inflammation (esophagitis) and gastroesophageal reflux disease (GERD), clots in the arteries of the lung (pulmonary embolism), inflammation of the lining of the lungs (pleuritis), chest wall trauma and a number of other diseases.
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Diagnosis of Recurrent Pericarditis
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The diagnostic evaluation of a patient with suspected pericarditis begins with a complete patient history and physical examination in order to evaluate risk factors, signs and symptoms of the disease, and features that could suggest an alternative diagnosis. An essential part of the physical examination is auscultation of the heart using a stethoscope; in some patients, a characteristic scratching sound, known as a pericardial friction rub, may be heard. The physical exam can also show signs of cardiac tamponade or constrictive pericarditis, such as dyspnea, distended neck veins, edema, or low blood pressure. After gathering a complete history and performing an appropriate physical examination, certain tests will be performed in all patients with suspected pericarditis. An electrocardiogram, which measures electrical activity of the heart, might show characteristic changes associated with pericarditis and can help rule out other cardiac causes of chest pain. Blood levels of troponin, a protein that is released into the blood following damage to cardiac muscle, are also useful to differentiate pericarditis from other heart conditions. Troponin levels are usually normal in isolated pericarditis but are elevated in myopericarditis, myocarditis and myocardial infarction. Other routine laboratory tests include a complete blood count, which can show an increase in white blood cells due to inflammation, and certain inflammatory markers, namely, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Routine imaging tests include a chest X-ray, which is usually normal in pericarditis but can show signs of an alternative diagnosis or a pericardial effusion if it is large. An echocardiogram, an imaging method that uses sound waves to evaluate the anatomy and function of the heart and pericardium, is also routinely performed in patients with suspected pericarditis.Certain tests are only performed in a subset of patients. For instance, if the diagnosis of pericarditis is not confirmed with routine tests, advanced imaging studies can be performed, notably computed tomography (CT) or magnetic resonance imaging (MRI) of the heart. If a bacterial or neoplastic pericarditis is suspected and a significant pericardial effusion is present, pericardial fluid can be removed for analysis. This is done during a procedure known as pericardiocentesis, where a needle is inserted into the pericardial space to drain the effusion. Very rarely, a sample of pericardial tissue can be harvested for analysis (pericardial biopsy). Additional laboratory tests that might be performed depending on the clinical scenario include blood cultures if bacterial pericarditis is suspected, specific tests (e.g., antinuclear antibody levels) if an autoimmune disease is suspected or a tuberculin skin test if tuberculosis is suspected. The findings of routine or more advanced tests may also determine the need for additional testing if necessary.
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Diagnosis of Recurrent Pericarditis. The diagnostic evaluation of a patient with suspected pericarditis begins with a complete patient history and physical examination in order to evaluate risk factors, signs and symptoms of the disease, and features that could suggest an alternative diagnosis. An essential part of the physical examination is auscultation of the heart using a stethoscope; in some patients, a characteristic scratching sound, known as a pericardial friction rub, may be heard. The physical exam can also show signs of cardiac tamponade or constrictive pericarditis, such as dyspnea, distended neck veins, edema, or low blood pressure. After gathering a complete history and performing an appropriate physical examination, certain tests will be performed in all patients with suspected pericarditis. An electrocardiogram, which measures electrical activity of the heart, might show characteristic changes associated with pericarditis and can help rule out other cardiac causes of chest pain. Blood levels of troponin, a protein that is released into the blood following damage to cardiac muscle, are also useful to differentiate pericarditis from other heart conditions. Troponin levels are usually normal in isolated pericarditis but are elevated in myopericarditis, myocarditis and myocardial infarction. Other routine laboratory tests include a complete blood count, which can show an increase in white blood cells due to inflammation, and certain inflammatory markers, namely, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Routine imaging tests include a chest X-ray, which is usually normal in pericarditis but can show signs of an alternative diagnosis or a pericardial effusion if it is large. An echocardiogram, an imaging method that uses sound waves to evaluate the anatomy and function of the heart and pericardium, is also routinely performed in patients with suspected pericarditis.Certain tests are only performed in a subset of patients. For instance, if the diagnosis of pericarditis is not confirmed with routine tests, advanced imaging studies can be performed, notably computed tomography (CT) or magnetic resonance imaging (MRI) of the heart. If a bacterial or neoplastic pericarditis is suspected and a significant pericardial effusion is present, pericardial fluid can be removed for analysis. This is done during a procedure known as pericardiocentesis, where a needle is inserted into the pericardial space to drain the effusion. Very rarely, a sample of pericardial tissue can be harvested for analysis (pericardial biopsy). Additional laboratory tests that might be performed depending on the clinical scenario include blood cultures if bacterial pericarditis is suspected, specific tests (e.g., antinuclear antibody levels) if an autoimmune disease is suspected or a tuberculin skin test if tuberculosis is suspected. The findings of routine or more advanced tests may also determine the need for additional testing if necessary.
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Therapies of Recurrent Pericarditis
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In every patient with pericarditis, restriction of physical activity is recommended until symptoms have resolved and inflammatory markers have normalized. If a systemic disease is identified as the cause of pericarditis, therapy should be focused on treating the underlying condition. For instance, antibiotics will be required for a patient with tuberculosis, and chemotherapy or other treatments will be required in a patient with neoplastic pericarditis. Another important consideration is whether the affected individual needs to be admitted to the hospital or can be treated as an outpatient. Although most patients can be treated outside the hospital, patients with high-risk features are usually admitted. These features include fever, a slow (subacute) onset of disease without sudden onset of chest pain, presence of a large pericardial effusion, use of immunosuppressant medications or blood thinners (anticoagulants) or high troponin levels (which suggests myopericarditis).Patients with viral or idiopathic pericarditis are treated with a combination of colchicine and either aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen or indomethacin. This medication combination is also the first line of treatment in most patients with recurrent pericarditis. These medications are continued at least until symptoms have resolved and inflammatory markers have normalized. In patients with contraindications to NSAIDs or no improvement with first-line therapy, NSAIDs can be replaced with prednisone, a corticosteroid drug with powerful anti-inflammatory properties. Patients who still have symptoms despite treatment with colchicine and prednisone may benefit from addition or continuation of a NSAID. In refractory cases, other therapies may be used, although their efficacy has yet to be confirmed in controlled clinical trials. These therapies inhibit the immune system to decrease inflammation and include azathioprine, methotrexate and intravenous immune globulins (IVIG). None of these have been tested in controlled clinical trials.Most recently, drugs that block the effects of a specific immune pathway known as interleukin-1 (IL-1) have been used with great success in patients with refractory, recurrent idiopathic and post-cardiac injury pericarditis. These drugs are so-called “biologics”, which are proteins that selectively block this pathway and must be injected under the skin (subcutaneously). The two IL-1 antagonists that have been employed to date are anakinra and rilonacept.In 2021, Arcalyst (rilonacept) was approved by the U.S. Food and Drug Administration (FDA) to treat recurrent pericarditis and reduce the risk of recurrence in adults and children 12 years and older. As a last resort, surgery where the pericardium is removed can be performed (pericardiotomy). Pericardiotomy might also be performed if constrictive pericarditis has developed. In the rare cases where cardiac tamponade develops, pericardiocentesis or surgical drainage of the pericardial effusion might have to be performed.
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Therapies of Recurrent Pericarditis. In every patient with pericarditis, restriction of physical activity is recommended until symptoms have resolved and inflammatory markers have normalized. If a systemic disease is identified as the cause of pericarditis, therapy should be focused on treating the underlying condition. For instance, antibiotics will be required for a patient with tuberculosis, and chemotherapy or other treatments will be required in a patient with neoplastic pericarditis. Another important consideration is whether the affected individual needs to be admitted to the hospital or can be treated as an outpatient. Although most patients can be treated outside the hospital, patients with high-risk features are usually admitted. These features include fever, a slow (subacute) onset of disease without sudden onset of chest pain, presence of a large pericardial effusion, use of immunosuppressant medications or blood thinners (anticoagulants) or high troponin levels (which suggests myopericarditis).Patients with viral or idiopathic pericarditis are treated with a combination of colchicine and either aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen or indomethacin. This medication combination is also the first line of treatment in most patients with recurrent pericarditis. These medications are continued at least until symptoms have resolved and inflammatory markers have normalized. In patients with contraindications to NSAIDs or no improvement with first-line therapy, NSAIDs can be replaced with prednisone, a corticosteroid drug with powerful anti-inflammatory properties. Patients who still have symptoms despite treatment with colchicine and prednisone may benefit from addition or continuation of a NSAID. In refractory cases, other therapies may be used, although their efficacy has yet to be confirmed in controlled clinical trials. These therapies inhibit the immune system to decrease inflammation and include azathioprine, methotrexate and intravenous immune globulins (IVIG). None of these have been tested in controlled clinical trials.Most recently, drugs that block the effects of a specific immune pathway known as interleukin-1 (IL-1) have been used with great success in patients with refractory, recurrent idiopathic and post-cardiac injury pericarditis. These drugs are so-called “biologics”, which are proteins that selectively block this pathway and must be injected under the skin (subcutaneously). The two IL-1 antagonists that have been employed to date are anakinra and rilonacept.In 2021, Arcalyst (rilonacept) was approved by the U.S. Food and Drug Administration (FDA) to treat recurrent pericarditis and reduce the risk of recurrence in adults and children 12 years and older. As a last resort, surgery where the pericardium is removed can be performed (pericardiotomy). Pericardiotomy might also be performed if constrictive pericarditis has developed. In the rare cases where cardiac tamponade develops, pericardiocentesis or surgical drainage of the pericardial effusion might have to be performed.
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Recurrent Pericarditis
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Overview of Recurrent Respiratory Papillomatosis
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SummaryRecurrent respiratory papillomatosis (RRP) is a rare disorder characterized by the development of small, wart-like growths (papillomas) in the respiratory tract. The respiratory tract is the system of organs within the body that allows individuals to breathe. The respiratory tract includes the nose, mouth, throat (pharynx), voice box (larynx), windpipe (trachea), various airway passages (bronchi) and lungs. Papillomas can develop anywhere along the respiratory tract, but most often affect the larynx and the vocal cords (laryngeal papillomatosis). Less often, the disorder affects the area within the mouth (oral cavity), trachea and bronchi. Only in rare cases do these growths spread to affect the lungs. Papillomas are noncancerous (benign), but in extremely rare cases can undergo cancerous (malignant) transformation. Although benign, papillomas can cause severe, even life-threatening airway obstruction and respiratory complications. In RRP, papillomas tend to grow back after they have been removed. RRP can affect children, adolescents or adults and is caused by infection with human papillomavirus (HPV), although exposure to the virus alone may be insufficient to cause the disease.IntroductionRRP is generally broken down into two subtypes – the juvenile-onset form and the adult-onset form. Juvenile cases develop before the age of 12 and are generally more aggressive and recurring. Children tend to need surgical treatment more often than adults. The disorder tends to improve in late childhood. Although aggressive disease is more common in children, adults can still potentially develop an aggressive form of the disorder.
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Overview of Recurrent Respiratory Papillomatosis. SummaryRecurrent respiratory papillomatosis (RRP) is a rare disorder characterized by the development of small, wart-like growths (papillomas) in the respiratory tract. The respiratory tract is the system of organs within the body that allows individuals to breathe. The respiratory tract includes the nose, mouth, throat (pharynx), voice box (larynx), windpipe (trachea), various airway passages (bronchi) and lungs. Papillomas can develop anywhere along the respiratory tract, but most often affect the larynx and the vocal cords (laryngeal papillomatosis). Less often, the disorder affects the area within the mouth (oral cavity), trachea and bronchi. Only in rare cases do these growths spread to affect the lungs. Papillomas are noncancerous (benign), but in extremely rare cases can undergo cancerous (malignant) transformation. Although benign, papillomas can cause severe, even life-threatening airway obstruction and respiratory complications. In RRP, papillomas tend to grow back after they have been removed. RRP can affect children, adolescents or adults and is caused by infection with human papillomavirus (HPV), although exposure to the virus alone may be insufficient to cause the disease.IntroductionRRP is generally broken down into two subtypes – the juvenile-onset form and the adult-onset form. Juvenile cases develop before the age of 12 and are generally more aggressive and recurring. Children tend to need surgical treatment more often than adults. The disorder tends to improve in late childhood. Although aggressive disease is more common in children, adults can still potentially develop an aggressive form of the disorder.
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Symptoms of Recurrent Respiratory Papillomatosis
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The specific symptoms, course of the disease, and severity of RRP can vary greatly from one person to another. In some people, the disease may resolve without treatment (spontaneous remissions) or it may remain stable requiring only periodic intervention (e.g. only a few surgeries during their lifetime). In other peoople, the disease may be aggressive requiring frequent medical intervention and potentially more than 100 surgeries during a person’s lifetime.The most common presenting symptom of RRP is hoarseness. Hoarseness may become progressively worse, and the voice of an affected individual may be weak, raspy or sound low in pitch or strained. The severity of voice problems can vary from one person to another due, in part, to the size and specific locations of papillomas. Affected individuals may develop labored, noisy breathing (stridor) due to obstruction of the airway. Initially, stridor may occur when breathing in (inspiratory stridor), but eventually occurs both when breathing in and out (biphasic stridor). Some individuals may exhibit difficulty speaking (dysphonia) or lose their voice entirely (aphonia). Affected infants may also have a weak cry, episodes of choking and fail to grow and gain weight at the expected rate (failure to thrive).Additional symptoms that can develop include a chronic cough, difficulty swallowing (dysphagia), shortness of breath or difficulty breathing (dyspnea), the sensation of a foreign body in the throat, and choking episodes.Left untreated, papillomas can eventually compromise the airways, resulting in life-threatening breathing difficulties (acute respiratory distress). If RRP spreads to the lungs, affected individuals can potentially experience recurrent pneumonia, chronic lung disease (bronchiectasis) and, ultimately, progressive pulmonary failure. In extremely rare cases (i.e., less than 1% of cases), papillomas can become cancerous (malignant transformation) developing into squamous cell carcinoma.
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Symptoms of Recurrent Respiratory Papillomatosis. The specific symptoms, course of the disease, and severity of RRP can vary greatly from one person to another. In some people, the disease may resolve without treatment (spontaneous remissions) or it may remain stable requiring only periodic intervention (e.g. only a few surgeries during their lifetime). In other peoople, the disease may be aggressive requiring frequent medical intervention and potentially more than 100 surgeries during a person’s lifetime.The most common presenting symptom of RRP is hoarseness. Hoarseness may become progressively worse, and the voice of an affected individual may be weak, raspy or sound low in pitch or strained. The severity of voice problems can vary from one person to another due, in part, to the size and specific locations of papillomas. Affected individuals may develop labored, noisy breathing (stridor) due to obstruction of the airway. Initially, stridor may occur when breathing in (inspiratory stridor), but eventually occurs both when breathing in and out (biphasic stridor). Some individuals may exhibit difficulty speaking (dysphonia) or lose their voice entirely (aphonia). Affected infants may also have a weak cry, episodes of choking and fail to grow and gain weight at the expected rate (failure to thrive).Additional symptoms that can develop include a chronic cough, difficulty swallowing (dysphagia), shortness of breath or difficulty breathing (dyspnea), the sensation of a foreign body in the throat, and choking episodes.Left untreated, papillomas can eventually compromise the airways, resulting in life-threatening breathing difficulties (acute respiratory distress). If RRP spreads to the lungs, affected individuals can potentially experience recurrent pneumonia, chronic lung disease (bronchiectasis) and, ultimately, progressive pulmonary failure. In extremely rare cases (i.e., less than 1% of cases), papillomas can become cancerous (malignant transformation) developing into squamous cell carcinoma.
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Causes of Recurrent Respiratory Papillomatosis
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Recurrent respiratory papillomatosis is caused by the human papillomavirus (HPV). This virus is common in human beings with some studies estimating that as many as 75%-80% of men and women will be affected by HPV at some point during their lives if they are not vaccinated against the virus. HPV is passed through genital contact, most often during sex. Most individuals who are infected with HPV never develop any symptoms. There are more than 150 different subtypes of HPV and approximately 40 of these subtypes can affect the genital tract. Two specific subtypes, HPV 6 and HPV 11, account for more than 90% of cases of RRP. These two subtypes are the same HPV subtypes most often identified in genital warts (anogenital condyloma). HPV subtypes 16 and 18 account for most of the remaining cases. Together, these four subtypes are responsible for about 70% of cases of cervical cancer.In children, the most likely cause of the transmission of HPV is passage from an affected mother to the child during labor as the child passes through the birth canal. However, this may not account for all cases of juvenile onset RPP and other mechanisms for HPV infection may exist. Some cases appear to have developed before birth (in utero).Most children born to women with HPV do not develop RRP. In addition, many individuals with HPV in the tissues of the respiratory tract never develop papillomas. This suggests that additional factors, such as immunologic or genetic ones, are necessary for the development of RRP in individuals with HPV. Other factors such as timing, length and volume of exposure to the HPV may play a role.Certain risk factors have been identified for the development of RRP. Risk factors are variables that are associated with an increased risk of disease or infection. Three risk factors for juvenile-onset recurrent respiratory papillomatosis are being a firstborn child, having a vaginal delivery with a prolonged labor, and the mother being under 20 years of age. If the mother has active genital warts, the risk of passing on HPV is approximately 1 in 250-400. These risk factors do not apply to adult-onset recurrent respiratory papillomatosis.In adults, the mode of transmission is less clear. Some cases may represent infection during infancy as described above, but that remains latent until being triggered for unknown reasons in adulthood. Some circumstantial evidence suggests that RRP can develop after HPV is transmitted through oral sexual contact.Adult-onset recurrent respiratory papillomatosis may be worsened by tobacco exposure, gastroesophageal reflux, or radiation therapy.
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Causes of Recurrent Respiratory Papillomatosis. Recurrent respiratory papillomatosis is caused by the human papillomavirus (HPV). This virus is common in human beings with some studies estimating that as many as 75%-80% of men and women will be affected by HPV at some point during their lives if they are not vaccinated against the virus. HPV is passed through genital contact, most often during sex. Most individuals who are infected with HPV never develop any symptoms. There are more than 150 different subtypes of HPV and approximately 40 of these subtypes can affect the genital tract. Two specific subtypes, HPV 6 and HPV 11, account for more than 90% of cases of RRP. These two subtypes are the same HPV subtypes most often identified in genital warts (anogenital condyloma). HPV subtypes 16 and 18 account for most of the remaining cases. Together, these four subtypes are responsible for about 70% of cases of cervical cancer.In children, the most likely cause of the transmission of HPV is passage from an affected mother to the child during labor as the child passes through the birth canal. However, this may not account for all cases of juvenile onset RPP and other mechanisms for HPV infection may exist. Some cases appear to have developed before birth (in utero).Most children born to women with HPV do not develop RRP. In addition, many individuals with HPV in the tissues of the respiratory tract never develop papillomas. This suggests that additional factors, such as immunologic or genetic ones, are necessary for the development of RRP in individuals with HPV. Other factors such as timing, length and volume of exposure to the HPV may play a role.Certain risk factors have been identified for the development of RRP. Risk factors are variables that are associated with an increased risk of disease or infection. Three risk factors for juvenile-onset recurrent respiratory papillomatosis are being a firstborn child, having a vaginal delivery with a prolonged labor, and the mother being under 20 years of age. If the mother has active genital warts, the risk of passing on HPV is approximately 1 in 250-400. These risk factors do not apply to adult-onset recurrent respiratory papillomatosis.In adults, the mode of transmission is less clear. Some cases may represent infection during infancy as described above, but that remains latent until being triggered for unknown reasons in adulthood. Some circumstantial evidence suggests that RRP can develop after HPV is transmitted through oral sexual contact.Adult-onset recurrent respiratory papillomatosis may be worsened by tobacco exposure, gastroesophageal reflux, or radiation therapy.
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Affects of Recurrent Respiratory Papillomatosis
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The juvenile form of recurrent respiratory papillomatosis affects males and females in equal numbers. The adult form affects males slightly more often than females. In the United States, the incidence of RRP was previously estimated to be approximately 2 per 100,000 adults and 4 per 100,000 children with approximately 1,000 new pediatric cases in the United States each year. With the increased uptake of the HPV vaccine, these numbers are dropping precipitously. In children, JORRP is most often diagnosed between the ages of 2-4. In adults, the disorder occurs most often in the third or fourth decade though a second peak around age 60 has recently been noted.
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Affects of Recurrent Respiratory Papillomatosis. The juvenile form of recurrent respiratory papillomatosis affects males and females in equal numbers. The adult form affects males slightly more often than females. In the United States, the incidence of RRP was previously estimated to be approximately 2 per 100,000 adults and 4 per 100,000 children with approximately 1,000 new pediatric cases in the United States each year. With the increased uptake of the HPV vaccine, these numbers are dropping precipitously. In children, JORRP is most often diagnosed between the ages of 2-4. In adults, the disorder occurs most often in the third or fourth decade though a second peak around age 60 has recently been noted.
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Related disorders of Recurrent Respiratory Papillomatosis
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A variety of conditions can produce signs and symptoms that are similar to those seen in RRP. Such conditions include asthma, allergies, chronic bronchitis, croup, vocal nodules and gastroesophageal reflux. Comparisons may be useful for a differential diagnosis.
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Related disorders of Recurrent Respiratory Papillomatosis. A variety of conditions can produce signs and symptoms that are similar to those seen in RRP. Such conditions include asthma, allergies, chronic bronchitis, croup, vocal nodules and gastroesophageal reflux. Comparisons may be useful for a differential diagnosis.
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Diagnosis of Recurrent Respiratory Papillomatosis
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Diagnosis of Recurrent Respiratory Papillomatosis.
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Therapies of Recurrent Respiratory Papillomatosis
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Treatment
There is currently no “cure” for RPP. Treatment is directed toward removing papillomas, decreasing the spread of disease, creating a safe and patent airway, preserving nearby anatomical structures, improving voice quality if necessary and increasing the time between surgical procedures. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, internists, ear-nose-throat specialists that focus on children (pediatric otorhinolaryngologists) or on airway abnormalities (laryngologists), anesthesiologists, speech pathologists and other healthcare professionals may need to systematically and comprehensively plan an RRP patient’s treatment.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as frequency of disease recurrences; specific location and spread of the disease; papilloma size; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference and other appropriate factors.None of the various treatment options for RRP have proven consistently effective. Additionally, most treatment recommendations are based on case reports or small case series. Large scale clinical trials for treating RRP are required to determine the best therapeutic options, which ultimately may vary from one person to another.The mainstay of treatment is surgical removal of papillomas. However, like warts on the hands and feet, these growths often return necessitating more surgery. The recurrence of papillomas is unpredictable. Some individuals may require surgery every few weeks while others may only require surgery twice a year or only a few times during their life. Surgical techniques used to treat individuals with RRP include “cold” excision, microdebridement, various pulsed dye lasers, or carbon dioxide lasers. Cold excision, sometimes referred to as “cold steel,” is the use of sharp surgical equipment to remove papillomas. Cold excision may be beneficial for the initial removal (debulking) of papillomas and for papillomas located in certain areas. Microdebridement is an increasingly popular procedure for use in children with RRP in which suction is applied to affected tissue which is then cut away (debrided) by miniature shavers. Pulsed dye lasers use various light frequencies focused into a single beam to destroy the blood vessels that supply the papillomas. Laser ablation generates a laser beam by passing electricity through a mixture of several different gases including carbon dioxide (CO2). The CO2 laser is used to directly destroy papillomas in the voicebox and can also be used through a bronchoscope to effectively remove papillomas in the trachea (windpipe).In severe cases where tumor growth is aggressive, an affected individual may need a tracheostomy to keep the breathing airways open. A tracheostomy involves surgically inserting a tube into the windpipe (trachea). A tracheostomy is used only as a method of last resort because the procedure may allow for spread of the disease further into the respiratory tract.In the past, some individuals received certain medications designed to slow the regrowth of papillomas and increase the time between surgeries (adjuvant therapy). Medications that have been used include antivirals such as acyclovir, ribavirin or cidofovir (see below), interferon, and indole 3-carbinol (I3-C). Interferon is a drug that is a synthetic form of certain proteins produced by the immune system. I3-C is an anticancer compound that is found in cruciferous vegetables such as cabbage, cauliflower, and broccoli. Adjuvant therapy is usually recommended based upon specific indications: undergoing more than four surgeries in one year, rapid regrowth of papillomas causing airway compromise, or spread of the disease down the throat and into the lungs.Some physicians recommend that affected individuals take medications for gastroesophageal reflux (GERD) as this condition has been known to worsen RRP.
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Therapies of Recurrent Respiratory Papillomatosis. Treatment
There is currently no “cure” for RPP. Treatment is directed toward removing papillomas, decreasing the spread of disease, creating a safe and patent airway, preserving nearby anatomical structures, improving voice quality if necessary and increasing the time between surgical procedures. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, internists, ear-nose-throat specialists that focus on children (pediatric otorhinolaryngologists) or on airway abnormalities (laryngologists), anesthesiologists, speech pathologists and other healthcare professionals may need to systematically and comprehensively plan an RRP patient’s treatment.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as frequency of disease recurrences; specific location and spread of the disease; papilloma size; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference and other appropriate factors.None of the various treatment options for RRP have proven consistently effective. Additionally, most treatment recommendations are based on case reports or small case series. Large scale clinical trials for treating RRP are required to determine the best therapeutic options, which ultimately may vary from one person to another.The mainstay of treatment is surgical removal of papillomas. However, like warts on the hands and feet, these growths often return necessitating more surgery. The recurrence of papillomas is unpredictable. Some individuals may require surgery every few weeks while others may only require surgery twice a year or only a few times during their life. Surgical techniques used to treat individuals with RRP include “cold” excision, microdebridement, various pulsed dye lasers, or carbon dioxide lasers. Cold excision, sometimes referred to as “cold steel,” is the use of sharp surgical equipment to remove papillomas. Cold excision may be beneficial for the initial removal (debulking) of papillomas and for papillomas located in certain areas. Microdebridement is an increasingly popular procedure for use in children with RRP in which suction is applied to affected tissue which is then cut away (debrided) by miniature shavers. Pulsed dye lasers use various light frequencies focused into a single beam to destroy the blood vessels that supply the papillomas. Laser ablation generates a laser beam by passing electricity through a mixture of several different gases including carbon dioxide (CO2). The CO2 laser is used to directly destroy papillomas in the voicebox and can also be used through a bronchoscope to effectively remove papillomas in the trachea (windpipe).In severe cases where tumor growth is aggressive, an affected individual may need a tracheostomy to keep the breathing airways open. A tracheostomy involves surgically inserting a tube into the windpipe (trachea). A tracheostomy is used only as a method of last resort because the procedure may allow for spread of the disease further into the respiratory tract.In the past, some individuals received certain medications designed to slow the regrowth of papillomas and increase the time between surgeries (adjuvant therapy). Medications that have been used include antivirals such as acyclovir, ribavirin or cidofovir (see below), interferon, and indole 3-carbinol (I3-C). Interferon is a drug that is a synthetic form of certain proteins produced by the immune system. I3-C is an anticancer compound that is found in cruciferous vegetables such as cabbage, cauliflower, and broccoli. Adjuvant therapy is usually recommended based upon specific indications: undergoing more than four surgeries in one year, rapid regrowth of papillomas causing airway compromise, or spread of the disease down the throat and into the lungs.Some physicians recommend that affected individuals take medications for gastroesophageal reflux (GERD) as this condition has been known to worsen RRP.
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Recurrent Respiratory Papillomatosis
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nord_1057_0
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Overview of Refractory Celiac Disease
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Refractory celiac disease (RCD) is a complex autoimmune disorder much like the more common celiac disease but, unlike celiac disease, it is resistant or unresponsive to at least 12 months of treatment with a strict gluten-free diet. Gliadin, a component of the wheat storage protein gluten, together with similar proteins in barley and rye, are the villains that trigger the immune reaction in celiac disease. The diagnosis of RCD is made by exclusion, especially of any other disorder that can affect the huge number of thread-like projections that line the interior of the intestine (intestinal villi), such as intestinal lymphoma, Crohn's disease, small intestinal bacterial overgrowth or hypogammaglobulinemia.The intestinal villi are the means by which the gut absorbs fluids and nutrients. In celiac disease and refractory celiac disease, these villi shrink and shrivel (atrophy) affecting the absorption of nutrients via the intestines. In celiac disease, treatment by means of a strict gluten-free diet is usually sufficient to overcome the disorder. However, refractory celiac disease is just that: refractory or stubbornly resistant to treatment. Only a small percentage (1-2%) of the people with celiac disease will develop RCD, and these patients are almost always 50 years of age or older. However, as yet, it is impossible to predict which of the tiny (1.5%) minority of patient of those with celiac disease will develop RCD.
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Overview of Refractory Celiac Disease. Refractory celiac disease (RCD) is a complex autoimmune disorder much like the more common celiac disease but, unlike celiac disease, it is resistant or unresponsive to at least 12 months of treatment with a strict gluten-free diet. Gliadin, a component of the wheat storage protein gluten, together with similar proteins in barley and rye, are the villains that trigger the immune reaction in celiac disease. The diagnosis of RCD is made by exclusion, especially of any other disorder that can affect the huge number of thread-like projections that line the interior of the intestine (intestinal villi), such as intestinal lymphoma, Crohn's disease, small intestinal bacterial overgrowth or hypogammaglobulinemia.The intestinal villi are the means by which the gut absorbs fluids and nutrients. In celiac disease and refractory celiac disease, these villi shrink and shrivel (atrophy) affecting the absorption of nutrients via the intestines. In celiac disease, treatment by means of a strict gluten-free diet is usually sufficient to overcome the disorder. However, refractory celiac disease is just that: refractory or stubbornly resistant to treatment. Only a small percentage (1-2%) of the people with celiac disease will develop RCD, and these patients are almost always 50 years of age or older. However, as yet, it is impossible to predict which of the tiny (1.5%) minority of patient of those with celiac disease will develop RCD.
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Refractory Celiac Disease
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