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nord_857_1
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Symptoms of N-Acetylglutamate Synthetase Deficiency
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NAGS deficiency may be associated with complete or partial absence of the NAGS enzyme. Complete lack of the NAGS enzyme results in the severe form of the disorder, in which symptoms occur shortly after birth (neonatal period). Partial lack of the NAGS enzyme results in a milder form of the disorder that occurs later during infancy or childhood or even adulthood in some cases. Specific symptoms can vary from one person to another.The symptoms of NAGS deficiency are caused by the accumulation of ammonia in the blood. In the most severe cases, the symptoms of NAGS deficiency occur within 24-72 hours after birth. Affected infants may exhibit refusal to eat and poor feeding habits, progressive lethargy, recurrent vomiting, diarrhea, irritability and an abnormally enlarged liver (hepatomegaly). More severe complications can also develop including seizures, confusion, respiratory distress, and the abnormal accumulation of fluid in the brain (cerebral edema).In some cases, the symptoms of NAGS deficiency may progress to coma due to high levels of ammonia in the blood (hyperammonemic coma). In such cases, the disorder may potentially result in neurological abnormalities including developmental delays, learning disabilities and intellectual disability. The severity of such neurological abnormalities is greater in infants who are in hyperammonemic coma for more than three days. If left untreated, the disorder will result in life-threatening complications.Some individuals with NAGS deficiency may not exhibit symptoms until later during infancy or childhood or even adulthood because of a partial deficiency of the NAGS enzyme. Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), poor growth, avoidance of protein from the diet, inability to coordinate voluntary movements (ataxia), lethargy, vomiting, and/or diminished muscle tone (hypotonia). Infants and children with the mild form of NAGS deficiency can still experience hyperammonemic coma and life-threatening complications.
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Symptoms of N-Acetylglutamate Synthetase Deficiency. NAGS deficiency may be associated with complete or partial absence of the NAGS enzyme. Complete lack of the NAGS enzyme results in the severe form of the disorder, in which symptoms occur shortly after birth (neonatal period). Partial lack of the NAGS enzyme results in a milder form of the disorder that occurs later during infancy or childhood or even adulthood in some cases. Specific symptoms can vary from one person to another.The symptoms of NAGS deficiency are caused by the accumulation of ammonia in the blood. In the most severe cases, the symptoms of NAGS deficiency occur within 24-72 hours after birth. Affected infants may exhibit refusal to eat and poor feeding habits, progressive lethargy, recurrent vomiting, diarrhea, irritability and an abnormally enlarged liver (hepatomegaly). More severe complications can also develop including seizures, confusion, respiratory distress, and the abnormal accumulation of fluid in the brain (cerebral edema).In some cases, the symptoms of NAGS deficiency may progress to coma due to high levels of ammonia in the blood (hyperammonemic coma). In such cases, the disorder may potentially result in neurological abnormalities including developmental delays, learning disabilities and intellectual disability. The severity of such neurological abnormalities is greater in infants who are in hyperammonemic coma for more than three days. If left untreated, the disorder will result in life-threatening complications.Some individuals with NAGS deficiency may not exhibit symptoms until later during infancy or childhood or even adulthood because of a partial deficiency of the NAGS enzyme. Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), poor growth, avoidance of protein from the diet, inability to coordinate voluntary movements (ataxia), lethargy, vomiting, and/or diminished muscle tone (hypotonia). Infants and children with the mild form of NAGS deficiency can still experience hyperammonemic coma and life-threatening complications.
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N-Acetylglutamate Synthetase Deficiency
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nord_857_2
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Causes of N-Acetylglutamate Synthetase Deficiency
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NAGS deficiency is an autosomal recessive genetic disorder caused by mutations of the NAGS gene. Mutations in the NAGS gene results in deficiency of the enzyme N-acetylglutamate synthetase. The symptoms of NAGS deficiency develop due to the lack of this enzyme which is needed to break down nitrogen in the body. Failure to properly break down nitrogen leads to the abnormal accumulation of nitrogen, in the form of ammonia, in the blood (hyperammonemia). Specifically, the NAGS enzyme is an activator of another enzyme of the urea cycle known as carbamyl phosphate synthetase (CPS).Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. 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 N-Acetylglutamate Synthetase Deficiency. NAGS deficiency is an autosomal recessive genetic disorder caused by mutations of the NAGS gene. Mutations in the NAGS gene results in deficiency of the enzyme N-acetylglutamate synthetase. The symptoms of NAGS deficiency develop due to the lack of this enzyme which is needed to break down nitrogen in the body. Failure to properly break down nitrogen leads to the abnormal accumulation of nitrogen, in the form of ammonia, in the blood (hyperammonemia). Specifically, the NAGS enzyme is an activator of another enzyme of the urea cycle known as carbamyl phosphate synthetase (CPS).Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. 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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N-Acetylglutamate Synthetase Deficiency
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nord_857_3
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Affects of N-Acetylglutamate Synthetase Deficiency
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NAGS deficiency is a rare disorder that affects males and females in equal numbers. In most cases, onset of symptoms occurs at, or shortly following, birth. The estimated frequency of urea cycle disorders collectively is one in 30,000 births. However, because urea cycle disorders like NAGS deficiency often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population.
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Affects of N-Acetylglutamate Synthetase Deficiency. NAGS deficiency is a rare disorder that affects males and females in equal numbers. In most cases, onset of symptoms occurs at, or shortly following, birth. The estimated frequency of urea cycle disorders collectively is one in 30,000 births. However, because urea cycle disorders like NAGS deficiency often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population.
| 857 |
N-Acetylglutamate Synthetase Deficiency
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nord_857_4
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Related disorders of N-Acetylglutamate Synthetase Deficiency
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Symptoms of the following disorders may be similar to those of NAGS deficiency. Comparisons may be useful for a differential diagnosis:The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly) in some cases. In severe cases, life-threatening complications may result. In addition to NAGS deficiency, the other urea cycle disorders are: argininosuccinate synthetase deficiency (citrullinemia); argininosuccinase acid lyase deficiency; ornithine transcarbamylase (OTC) deficiency; arginase deficiency and carbamylphosphate synthetase (CPS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)Reye syndrome is a rare childhood disorder characterized by liver failure, abnormal brain function (encephalopathy), abnormally low levels of glucose (hypoglycemia), and high levels of ammonia in the blood. This disorder usually follows a viral infection. It may be triggered by the use of aspirin in children recovering from chicken pox or influenza. Deficiencies of the urea cycle enzymes are thought to play a role in the development of Reye syndrome. Symptoms include vomiting, diarrhea, rapid breathing, irritability, fatigue, and behavioral changes. Neurological symptoms may be life-threatening and include seizures, stupor, and coma. (For more information on this disorder, choose “Reye” as your search term in the Rare Disease Database.)Organic acidemias are a rare group of inherited metabolic disorders characterized by deficiency of certain enzymes that are necessary to break down (metabolize) chemical “building blocks” (amino acids) of certain proteins. Failure to break down amino acids results in the excessive accumulation of acids in the blood. Symptoms may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, lethargy, and seizures. If left untreated, organic acidemias may progress to coma and life-threatening complications. These disorders are of a genetic origin and affect the urea cycle as a secondary phenomenon.
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Related disorders of N-Acetylglutamate Synthetase Deficiency. Symptoms of the following disorders may be similar to those of NAGS deficiency. Comparisons may be useful for a differential diagnosis:The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly) in some cases. In severe cases, life-threatening complications may result. In addition to NAGS deficiency, the other urea cycle disorders are: argininosuccinate synthetase deficiency (citrullinemia); argininosuccinase acid lyase deficiency; ornithine transcarbamylase (OTC) deficiency; arginase deficiency and carbamylphosphate synthetase (CPS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)Reye syndrome is a rare childhood disorder characterized by liver failure, abnormal brain function (encephalopathy), abnormally low levels of glucose (hypoglycemia), and high levels of ammonia in the blood. This disorder usually follows a viral infection. It may be triggered by the use of aspirin in children recovering from chicken pox or influenza. Deficiencies of the urea cycle enzymes are thought to play a role in the development of Reye syndrome. Symptoms include vomiting, diarrhea, rapid breathing, irritability, fatigue, and behavioral changes. Neurological symptoms may be life-threatening and include seizures, stupor, and coma. (For more information on this disorder, choose “Reye” as your search term in the Rare Disease Database.)Organic acidemias are a rare group of inherited metabolic disorders characterized by deficiency of certain enzymes that are necessary to break down (metabolize) chemical “building blocks” (amino acids) of certain proteins. Failure to break down amino acids results in the excessive accumulation of acids in the blood. Symptoms may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, lethargy, and seizures. If left untreated, organic acidemias may progress to coma and life-threatening complications. These disorders are of a genetic origin and affect the urea cycle as a secondary phenomenon.
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N-Acetylglutamate Synthetase Deficiency
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nord_857_5
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Diagnosis of N-Acetylglutamate Synthetase Deficiency
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A diagnosis of NAGS deficiency (or any urea cycle disorder) should be considered in any newborn that has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability.A diagnosis of NAGS deficiency can be made following a detailed patient/family history, identification of characteristic findings, and a variety of specialized tests. Blood tests may reveal excessive amounts of ammonia in the blood, the characteristic finding of urea cycles disorders. However, high levels of ammonia in the blood may characterize other disorders such as the organic acidemias, congenital lactic acidosis, and fatty acid oxidation disorders. Urea cycles disorders can be differentiated from these disorders through the examination of urine for elevated levels of or abnormal organic acids. In urea cycle disorders, urinary organic acids are normal.A diagnosis of NAGS deficiency can be confirmed through molecular genetic testing that reveals a mutation of the NAGS gene that characterizes this disorder.
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Diagnosis of N-Acetylglutamate Synthetase Deficiency. A diagnosis of NAGS deficiency (or any urea cycle disorder) should be considered in any newborn that has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability.A diagnosis of NAGS deficiency can be made following a detailed patient/family history, identification of characteristic findings, and a variety of specialized tests. Blood tests may reveal excessive amounts of ammonia in the blood, the characteristic finding of urea cycles disorders. However, high levels of ammonia in the blood may characterize other disorders such as the organic acidemias, congenital lactic acidosis, and fatty acid oxidation disorders. Urea cycles disorders can be differentiated from these disorders through the examination of urine for elevated levels of or abnormal organic acids. In urea cycle disorders, urinary organic acids are normal.A diagnosis of NAGS deficiency can be confirmed through molecular genetic testing that reveals a mutation of the NAGS gene that characterizes this disorder.
| 857 |
N-Acetylglutamate Synthetase Deficiency
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nord_857_6
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Therapies of N-Acetylglutamate Synthetase Deficiency
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TreatmentTreatment of an individual with NAGS deficiency may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticists, dieticians, and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech language, and physical therapists may be needed to treat children with developmental disabilities.The treatment of NAGS deficiency is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy for NAGS deficiency had combined dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).In 2010, the U.S. Food and Drug Administration (FDA) approved the use of Carbaglu® (carbamylglutamate) tablets to reduce blood ammonia levels in patients with NAGS deficiency. Carbaglu is manufactured by Orphan Europe. Some individuals who take carbamylglutamic acid may still need to follow dietary restrictions and receive supplemental arginine.Dietary restrictions in individuals with NAGS deficiency are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants with NAGS deficiency are placed a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow's milk formula, an essential amino acid formula (, and a calorie supplement without protein is often used. These are manufactured by a variety of specialty companies or infant formula manufacturers and their use should be supervised by a trained metabolic dietician. The nitrogen scavenger drugs sodium phenylacetate and sodium benzoate provide an alternative pathway for removing excess nitrogen. Intravenous forms of these medications are available (Ammonul). Phenylbutyrate (Buphenyl) an oral form of phenylacetate has a less offensive odor and is available. Ravicti is a form of phenylbutyrate that is less irritating to the gastrointestinal track. These medications are often administered via a tube that is placed in the stomach through the abdominal wall (gastrostomy tube) or a narrow tube that reaches the stomach via the nose (nasogastric tube) in young children.Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). The advent of carbaglu therapy has reduced the vulnerability to these episodes. Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some cases, especially those with complete enzyme deficiency, prompt treatment may not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.Aggressive treatment is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may be hospitalized and protein may be completely eliminated from the diet for 24 hours. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate (Ammonul. Non-protein calories may be also provided as glucose. Carbaglu should be continued or given, if the patient is not already on it.In the past, in individuals where there was no improvement or where hyperammonemic coma developed, the removal of wastes by filtering an affected individual's blood through a machine (hemodialysis) may have been be necessary. However, hemodialysis may be less frequently needed or not needed at all in individuals on carbaglu therapy. Hemodialysis is also used to treat infants, children, and adults who are first diagnosed with NAGS deficiency during hyperammonemic coma.Preventive Care
After diagnosis of NAGS deficiency every effort should be made to take and administer carbaglu. Steps can be taken to anticipate the onset of a hyperammonemic episode. Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. In addition, elevated levels of an amino acid (glutamine) in the blood often precede the development of hyperammonemia by days or weeks. Affected individuals should receive periodic tests to measure the amount of amino acids such as glutamine in the blood. Detection of elevated levels of ammonia or glutamine may allow treatment before clinical symptoms appear.Genetic counseling may be of benefit for individuals with NAGS deficiency and their families.
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Therapies of N-Acetylglutamate Synthetase Deficiency. TreatmentTreatment of an individual with NAGS deficiency may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticists, dieticians, and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech language, and physical therapists may be needed to treat children with developmental disabilities.The treatment of NAGS deficiency is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy for NAGS deficiency had combined dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).In 2010, the U.S. Food and Drug Administration (FDA) approved the use of Carbaglu® (carbamylglutamate) tablets to reduce blood ammonia levels in patients with NAGS deficiency. Carbaglu is manufactured by Orphan Europe. Some individuals who take carbamylglutamic acid may still need to follow dietary restrictions and receive supplemental arginine.Dietary restrictions in individuals with NAGS deficiency are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants with NAGS deficiency are placed a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow's milk formula, an essential amino acid formula (, and a calorie supplement without protein is often used. These are manufactured by a variety of specialty companies or infant formula manufacturers and their use should be supervised by a trained metabolic dietician. The nitrogen scavenger drugs sodium phenylacetate and sodium benzoate provide an alternative pathway for removing excess nitrogen. Intravenous forms of these medications are available (Ammonul). Phenylbutyrate (Buphenyl) an oral form of phenylacetate has a less offensive odor and is available. Ravicti is a form of phenylbutyrate that is less irritating to the gastrointestinal track. These medications are often administered via a tube that is placed in the stomach through the abdominal wall (gastrostomy tube) or a narrow tube that reaches the stomach via the nose (nasogastric tube) in young children.Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). The advent of carbaglu therapy has reduced the vulnerability to these episodes. Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some cases, especially those with complete enzyme deficiency, prompt treatment may not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.Aggressive treatment is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may be hospitalized and protein may be completely eliminated from the diet for 24 hours. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate (Ammonul. Non-protein calories may be also provided as glucose. Carbaglu should be continued or given, if the patient is not already on it.In the past, in individuals where there was no improvement or where hyperammonemic coma developed, the removal of wastes by filtering an affected individual's blood through a machine (hemodialysis) may have been be necessary. However, hemodialysis may be less frequently needed or not needed at all in individuals on carbaglu therapy. Hemodialysis is also used to treat infants, children, and adults who are first diagnosed with NAGS deficiency during hyperammonemic coma.Preventive Care
After diagnosis of NAGS deficiency every effort should be made to take and administer carbaglu. Steps can be taken to anticipate the onset of a hyperammonemic episode. Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. In addition, elevated levels of an amino acid (glutamine) in the blood often precede the development of hyperammonemia by days or weeks. Affected individuals should receive periodic tests to measure the amount of amino acids such as glutamine in the blood. Detection of elevated levels of ammonia or glutamine may allow treatment before clinical symptoms appear.Genetic counseling may be of benefit for individuals with NAGS deficiency and their families.
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N-Acetylglutamate Synthetase Deficiency
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nord_858_0
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Overview of Nager Syndrome
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SummaryNager syndrome is a rare inherited disorder characterized by craniofacial malformations occurring in association with abnormalities of the thumb and forearm. Craniofacial malformations include underdevelopment of the cheekbones (malar hypoplasia) resulting in downward slanting palpebral fissures; incomplete development of the lower jaw (mandibular hypoplasia), causing the jaw to appear abnormally small (micrognathia); and small (microtia) and/or malformed (dysplastic) external ears (pinnae), often with a blind ending or absent external ear canals, resulting in hearing impairment (conductive hearing loss). Nager syndrome is distinguished from other forms of acrofacial dysostosis by the limb abnormalities, which are primarily on the thumb (radial) side of the hand and forearm including underdevelopment or absence of the thumbs and the radius bone in the forearm, and abnormal fusion of bones in the forearms (radioulnar synostosis). The fingers and the feet are usually normal. Intelligence is usually not affected. Nager syndrome is typically inherited in an autosomal dominant pattern and is caused by changes (mutations) in the SF3B4 gene. Although an individual with Nager syndrome can transmit the condition to his/her children, many cases occur randomly (sporadic) as a new gene change (de novo mutation) in the family.IntroductionNager syndrome was first described in the medical literature in 1948 by doctors Nager and De Reynier. Nager syndrome belongs to a group of disorders collectively known as acrofacial dysostoses or AFDs. These disorders are characterized by craniofacial and limb abnormalities. AFDs are generally broken down into preaxial and postaxial types. Nager syndrome is a preaxial form; the term preaxial refers to the bones of the arms and legs that are on the thumb and big toe sides of the body.
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Overview of Nager Syndrome. SummaryNager syndrome is a rare inherited disorder characterized by craniofacial malformations occurring in association with abnormalities of the thumb and forearm. Craniofacial malformations include underdevelopment of the cheekbones (malar hypoplasia) resulting in downward slanting palpebral fissures; incomplete development of the lower jaw (mandibular hypoplasia), causing the jaw to appear abnormally small (micrognathia); and small (microtia) and/or malformed (dysplastic) external ears (pinnae), often with a blind ending or absent external ear canals, resulting in hearing impairment (conductive hearing loss). Nager syndrome is distinguished from other forms of acrofacial dysostosis by the limb abnormalities, which are primarily on the thumb (radial) side of the hand and forearm including underdevelopment or absence of the thumbs and the radius bone in the forearm, and abnormal fusion of bones in the forearms (radioulnar synostosis). The fingers and the feet are usually normal. Intelligence is usually not affected. Nager syndrome is typically inherited in an autosomal dominant pattern and is caused by changes (mutations) in the SF3B4 gene. Although an individual with Nager syndrome can transmit the condition to his/her children, many cases occur randomly (sporadic) as a new gene change (de novo mutation) in the family.IntroductionNager syndrome was first described in the medical literature in 1948 by doctors Nager and De Reynier. Nager syndrome belongs to a group of disorders collectively known as acrofacial dysostoses or AFDs. These disorders are characterized by craniofacial and limb abnormalities. AFDs are generally broken down into preaxial and postaxial types. Nager syndrome is a preaxial form; the term preaxial refers to the bones of the arms and legs that are on the thumb and big toe sides of the body.
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Nager Syndrome
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nord_858_1
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Symptoms of Nager Syndrome
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The specific symptoms that occur may vary from one person to another, even among members of the same family. Affected individuals may develop a variety of craniofacial and limb abnormalities which usually are noticeable at birth (congenital).Common craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate) and/or velopharyngeal insufficiency, in which the soft palate of the mouth does not close properly during speech; narrowing of the back of the nasal cavity (choanal atresia); malformation of the internal or external ears that can range from mild abnormality to absence of the external portion of the ear. Additional craniofacial findings in or around the eyes include downward-slanting palpebral fissures (which means that opening between the upper and lower lids slants downward), absence of tissue (colobomas) from the lower eyelids, partial or total absence of the eyelashes of the lower eyelids, and droopy or sagging of the upper eyelids (ptosis). In some patients, scalp hair may extend onto the cheek.Micrognathia is caused by underdevelopment (hypoplasia) of the lower jaw bone (mandible). Severe mandibular hypoplasia along with cleft palate and choanal atresia can result in feeding difficulties and/or severe breathing difficulties during infancy. In some cases, if left untreated, breathing difficulties can cause life-threatening complications. Affected individuals may have temporomandibular joint dysfunction (TMJD); the temporomandibular joint connects the jaws to the side of the head. TMJD can cause pain of the jaw, face and neck, stiff jaw muscles, and upper and lower teeth that do not meet properly when closing the mouth (malocclusion).Malformation of the ears can contribute to affected individuals developing conductive hearing loss. Conductive hearing loss occurs due to lack of conduction of sound from the outer or middle ear to the inner ear. Degree of hearing loss can vary. Hearing impairment may cause speech development to be delayed.Individuals with Nager syndrome also have abnormalities affecting the arms and hands including underdevelopment or absence of the thumbs, the presence of an extra (third) copy of a bone known as the phalange within the thumb (triphalangeal thumbs), and underdevelopment of the forearm bone on the thumb side of the arm (radius). Less often, webbing (syndactyly) of the fingers may occur, or certain fingers may be fixed or stuck in a bent position (camptodactyly). The formation of an abnormal bone or soft tissue connection between the ulna and the radius, two main bones of the forearm (radioulnar synostosis) may also occur. Because of these abnormalities, the forearms may appear abnormally short. Some individuals may have difficulty fully straightening their arms because the range of motion of the elbow is limited. A few very severely affected individuals have severely shortened upper limbs (phocomelia).Although abnormalities of the hands and forearms are more common, some affected individuals have abnormalities affecting the feet and lower legs including underdeveloped or absent toes, webbing of the toes, clubfeet, and the abnormal turning inward of the big toe towards the index toe (hallux valgus).While most individuals with Nager syndrome are healthy, a few severely affected individuals have serious internal malformations involving the kidney and/or the heart. Additional rare symptoms that have been reported in the medical literature include diaphragmatic hernia (an abnormal connection between the chest and abdomen), and underdevelopment of the larynx which can contribute to respiratory problems, as well as additional skeletal abnormalities such as underdevelopment of the first rib, abnormal curvature of the spine (scoliosis), or dislocation of the hip.
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Symptoms of Nager Syndrome. The specific symptoms that occur may vary from one person to another, even among members of the same family. Affected individuals may develop a variety of craniofacial and limb abnormalities which usually are noticeable at birth (congenital).Common craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate) and/or velopharyngeal insufficiency, in which the soft palate of the mouth does not close properly during speech; narrowing of the back of the nasal cavity (choanal atresia); malformation of the internal or external ears that can range from mild abnormality to absence of the external portion of the ear. Additional craniofacial findings in or around the eyes include downward-slanting palpebral fissures (which means that opening between the upper and lower lids slants downward), absence of tissue (colobomas) from the lower eyelids, partial or total absence of the eyelashes of the lower eyelids, and droopy or sagging of the upper eyelids (ptosis). In some patients, scalp hair may extend onto the cheek.Micrognathia is caused by underdevelopment (hypoplasia) of the lower jaw bone (mandible). Severe mandibular hypoplasia along with cleft palate and choanal atresia can result in feeding difficulties and/or severe breathing difficulties during infancy. In some cases, if left untreated, breathing difficulties can cause life-threatening complications. Affected individuals may have temporomandibular joint dysfunction (TMJD); the temporomandibular joint connects the jaws to the side of the head. TMJD can cause pain of the jaw, face and neck, stiff jaw muscles, and upper and lower teeth that do not meet properly when closing the mouth (malocclusion).Malformation of the ears can contribute to affected individuals developing conductive hearing loss. Conductive hearing loss occurs due to lack of conduction of sound from the outer or middle ear to the inner ear. Degree of hearing loss can vary. Hearing impairment may cause speech development to be delayed.Individuals with Nager syndrome also have abnormalities affecting the arms and hands including underdevelopment or absence of the thumbs, the presence of an extra (third) copy of a bone known as the phalange within the thumb (triphalangeal thumbs), and underdevelopment of the forearm bone on the thumb side of the arm (radius). Less often, webbing (syndactyly) of the fingers may occur, or certain fingers may be fixed or stuck in a bent position (camptodactyly). The formation of an abnormal bone or soft tissue connection between the ulna and the radius, two main bones of the forearm (radioulnar synostosis) may also occur. Because of these abnormalities, the forearms may appear abnormally short. Some individuals may have difficulty fully straightening their arms because the range of motion of the elbow is limited. A few very severely affected individuals have severely shortened upper limbs (phocomelia).Although abnormalities of the hands and forearms are more common, some affected individuals have abnormalities affecting the feet and lower legs including underdeveloped or absent toes, webbing of the toes, clubfeet, and the abnormal turning inward of the big toe towards the index toe (hallux valgus).While most individuals with Nager syndrome are healthy, a few severely affected individuals have serious internal malformations involving the kidney and/or the heart. Additional rare symptoms that have been reported in the medical literature include diaphragmatic hernia (an abnormal connection between the chest and abdomen), and underdevelopment of the larynx which can contribute to respiratory problems, as well as additional skeletal abnormalities such as underdevelopment of the first rib, abnormal curvature of the spine (scoliosis), or dislocation of the hip.
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Nager Syndrome
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nord_858_2
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Causes of Nager Syndrome
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Most cases of Nager syndrome are cause by mutations in the SF3B4 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.Because individuals with Nager syndrome have a change in only 1 copy of the SF3B4 gene we know that Nager syndrome is inherited as an autosomal dominant condition. Most cases occur as a new (sporadic or de novo) mutation at the time of the formation of the egg or sperm for that child only, and no other family members are affected. An individual who is the first one in the family to have Nager syndrome does, however, still have a 50% risk to transmit it to his or her children. Previous reports of siblings with Nager syndrome born to apparently unaffected parents could represent a different recessive form of Nager syndrome, but are more likely due to failure to recognize the condition in a mildly affected parent or to a parent having a gene change only in the ovary or testis (gonadal mosaicism).
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Causes of Nager Syndrome. Most cases of Nager syndrome are cause by mutations in the SF3B4 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.Because individuals with Nager syndrome have a change in only 1 copy of the SF3B4 gene we know that Nager syndrome is inherited as an autosomal dominant condition. Most cases occur as a new (sporadic or de novo) mutation at the time of the formation of the egg or sperm for that child only, and no other family members are affected. An individual who is the first one in the family to have Nager syndrome does, however, still have a 50% risk to transmit it to his or her children. Previous reports of siblings with Nager syndrome born to apparently unaffected parents could represent a different recessive form of Nager syndrome, but are more likely due to failure to recognize the condition in a mildly affected parent or to a parent having a gene change only in the ovary or testis (gonadal mosaicism).
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Nager Syndrome
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Affects of Nager Syndrome
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Nager syndrome affects males and females in equal numbers. The exact incidence and prevalence in the general population is unknown. Many cases go misdiagnosed or undiagnosed, making it difficult to determine the true frequency in the general population. More than 100 cases have been reported in the medical literature. Although rare, Nager syndrome is the most common form of acrofacial dysostosis.
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Affects of Nager Syndrome. Nager syndrome affects males and females in equal numbers. The exact incidence and prevalence in the general population is unknown. Many cases go misdiagnosed or undiagnosed, making it difficult to determine the true frequency in the general population. More than 100 cases have been reported in the medical literature. Although rare, Nager syndrome is the most common form of acrofacial dysostosis.
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Nager Syndrome
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Related disorders of Nager Syndrome
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Symptoms of the following disorders can be similar to those of Nager syndrome. Comparisons may be useful for a differential diagnosis.Miller syndrome, also known as postaxial acrofacial dysostosis, is a rare genetic disorder characterized by craniofacial malformations occurring along with abnormalities of the arms, hands and/or feet which usually involve the post-axial (little finger or little toe) side. Craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate); small, protruding, “cup-shaped” ears; and/or absence of tissue (colobomas) from the lower eyelids. Limb abnormalities may include incomplete development, webbing (syndactyly), and/or closure or absence of certain fingers and/or toes; and/or improper development and/or abnormal fusion of bones in the forearms (radioulnar synostosis), causing the forearms to appear unusually short. Additional physical abnormalities can occur in some cases. Intelligence is not affected. Miller syndrome is inherited as an autosomal recessive trait caused by mutations in the DHODH gene. (For more information on this disorder, choose “Miller” as your search term in the Rare Disease Database.)Treacher Collins syndrome (TCS) is a rare genetic disorder characterized by distinctive abnormalities of the head and face area resulting from underdevelopment (hypoplasia) of certain facial structures including the jaw, cheekbones and nearby structures (zygomatic complex) which differs from Nager syndrome in that the limbs are usually normal. Craniofacial abnormalities tend to involve the cheekbones, jaws, mouth, ears, and/or eyes. In addition to the various facial abnormalities, affected individuals may have malformations of the external ears and middle ear structures and eye (ocular) abnormalities including an abnormal downward slant to the opening between the upper and lower eyelids (palpebral fissures). Affected individuals may develop hearing loss and breathing (respiratory) difficulties. Furthermore, brain and behavioral anomalies such as microcephaly and psychomotor delay have also been occasionally reported as part of the condition. The specific symptoms and physical characteristics associated with TCS can vary greatly from one individual to another. Some individuals may have mild symptoms and go undiagnosed, while others may develop serious, life-threatening respiratory complications. TCS is caused by a mutation in the TCOF1, POLR1C or POLR1D genes. In the case of TCOF1 or POLR1D, the mode of inheritance is autosomal dominant, while in the case of POLR1C it is autosomal recessive. (For more information on this disorder, choose “Treacher Collins” as your search term in the Rare Disease Database.)Rodriguez syndrome, also known as acrofacial dysostosis syndrome of Rodriguez, is an extremely rare disorder. There is considerable overlap in both craniofacial and limb abnormalities in Nager and Rodriguez syndromes. Some researchers believe that certain cases of Rodriguez syndrome may represent a more severe expression of Nager syndrome. In addition to physical findings commonly found with Nager syndrome, individuals with Rodriguez syndrome may also have underdevelopment of the fibula, the outer and narrower long bone of the leg (fibular hypoplasia), eleven ribs, underdevelopment of the shoulder and pelvic girdle, and heart, central nervous system and urogenital abnormalities. Babies with Rodriguez syndrome are usually stillborn or die in the immediate newborn period due to severe airway problems. The disorder was believed to be inherited as an autosomal recessive trait, but a child with Rodriguez syndrome was recently found to have a de novo mutation in the just one copy of the SF3B4 gene just as in Nager syndrome.A variety of rare disorders include postaxial acrofacial dysostosis as a finding including Weyers acrofacial dysostosis, Catania acrofacial dysostosis, and Palagonia acrofacial dysostosis. Other disorders that may have symptoms or physical findings that overlap with Nager syndrome include ophthalmo-acromelic syndrome, Pallister-Hall syndrome, mandibulofacial dysostosis type Guion-Almeida, Burn-McKeown syndrome, and oculo-auriculo-vertebral syndrome.
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Related disorders of Nager Syndrome. Symptoms of the following disorders can be similar to those of Nager syndrome. Comparisons may be useful for a differential diagnosis.Miller syndrome, also known as postaxial acrofacial dysostosis, is a rare genetic disorder characterized by craniofacial malformations occurring along with abnormalities of the arms, hands and/or feet which usually involve the post-axial (little finger or little toe) side. Craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia); an abnormally small lower jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate); small, protruding, “cup-shaped” ears; and/or absence of tissue (colobomas) from the lower eyelids. Limb abnormalities may include incomplete development, webbing (syndactyly), and/or closure or absence of certain fingers and/or toes; and/or improper development and/or abnormal fusion of bones in the forearms (radioulnar synostosis), causing the forearms to appear unusually short. Additional physical abnormalities can occur in some cases. Intelligence is not affected. Miller syndrome is inherited as an autosomal recessive trait caused by mutations in the DHODH gene. (For more information on this disorder, choose “Miller” as your search term in the Rare Disease Database.)Treacher Collins syndrome (TCS) is a rare genetic disorder characterized by distinctive abnormalities of the head and face area resulting from underdevelopment (hypoplasia) of certain facial structures including the jaw, cheekbones and nearby structures (zygomatic complex) which differs from Nager syndrome in that the limbs are usually normal. Craniofacial abnormalities tend to involve the cheekbones, jaws, mouth, ears, and/or eyes. In addition to the various facial abnormalities, affected individuals may have malformations of the external ears and middle ear structures and eye (ocular) abnormalities including an abnormal downward slant to the opening between the upper and lower eyelids (palpebral fissures). Affected individuals may develop hearing loss and breathing (respiratory) difficulties. Furthermore, brain and behavioral anomalies such as microcephaly and psychomotor delay have also been occasionally reported as part of the condition. The specific symptoms and physical characteristics associated with TCS can vary greatly from one individual to another. Some individuals may have mild symptoms and go undiagnosed, while others may develop serious, life-threatening respiratory complications. TCS is caused by a mutation in the TCOF1, POLR1C or POLR1D genes. In the case of TCOF1 or POLR1D, the mode of inheritance is autosomal dominant, while in the case of POLR1C it is autosomal recessive. (For more information on this disorder, choose “Treacher Collins” as your search term in the Rare Disease Database.)Rodriguez syndrome, also known as acrofacial dysostosis syndrome of Rodriguez, is an extremely rare disorder. There is considerable overlap in both craniofacial and limb abnormalities in Nager and Rodriguez syndromes. Some researchers believe that certain cases of Rodriguez syndrome may represent a more severe expression of Nager syndrome. In addition to physical findings commonly found with Nager syndrome, individuals with Rodriguez syndrome may also have underdevelopment of the fibula, the outer and narrower long bone of the leg (fibular hypoplasia), eleven ribs, underdevelopment of the shoulder and pelvic girdle, and heart, central nervous system and urogenital abnormalities. Babies with Rodriguez syndrome are usually stillborn or die in the immediate newborn period due to severe airway problems. The disorder was believed to be inherited as an autosomal recessive trait, but a child with Rodriguez syndrome was recently found to have a de novo mutation in the just one copy of the SF3B4 gene just as in Nager syndrome.A variety of rare disorders include postaxial acrofacial dysostosis as a finding including Weyers acrofacial dysostosis, Catania acrofacial dysostosis, and Palagonia acrofacial dysostosis. Other disorders that may have symptoms or physical findings that overlap with Nager syndrome include ophthalmo-acromelic syndrome, Pallister-Hall syndrome, mandibulofacial dysostosis type Guion-Almeida, Burn-McKeown syndrome, and oculo-auriculo-vertebral syndrome.
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Nager Syndrome
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Diagnosis of Nager Syndrome
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A diagnosis of Nager syndrome is based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic physical findings. Most of the associated abnormalities are present at birth (congenital).Molecular genetic testing can confirm a diagnosis of Nager syndrome. Molecular genetic testing can detect a mutation the SF3B4 gene, but is available only as a diagnostic service at specialized laboratories.Clinical Testing and Workup
Specialized x-ray studies will confirm the presence and/or extent of certain observed craniofacial abnormalities. For example, such imaging tests show the abnormally small jaw (micrognathia) due to underdevelopment of the lower jaw bone (mandibular hypoplasia) as well as the underdeveloped cheekbone (malar hypoplasia).
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Diagnosis of Nager Syndrome. A diagnosis of Nager syndrome is based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic physical findings. Most of the associated abnormalities are present at birth (congenital).Molecular genetic testing can confirm a diagnosis of Nager syndrome. Molecular genetic testing can detect a mutation the SF3B4 gene, but is available only as a diagnostic service at specialized laboratories.Clinical Testing and Workup
Specialized x-ray studies will confirm the presence and/or extent of certain observed craniofacial abnormalities. For example, such imaging tests show the abnormally small jaw (micrognathia) due to underdevelopment of the lower jaw bone (mandibular hypoplasia) as well as the underdeveloped cheekbone (malar hypoplasia).
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Nager Syndrome
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Therapies of Nager Syndrome
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Treatment
The treatment of Nager syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, oral surgeons, plastic surgeons, pediatric ear, nose and throat specialists (pediatric otolaryngologists), specialists in diagnosing and treating eye disorders (ophthalmologists), specialists in diagnosing and treating ear disorders (otologists), specialists in treating hearing loss (audiologists), psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Affected individuals may benefit from referral to a craniofacial center.Specific treatment may consist of surgery to create a small opening in the throat, through which a small tube is inserted to assist with breathing (tracheostomy). Surgery may also be necessary to create a small opening in the stomach to allow the insertion of a feeding tube in infants experiencing difficulty eating in order to maintain proper nutrition.Surgery may be required to correct abnormalities of the jaws, limbs, and eyes. Surgery and/or speech therapy may be necessary when cleft palate or cleft lip is present. Skeletal malformations such as rib abnormalities, limited range of motion of the elbows, and scoliosis may require surgical intervention. Congenital heart defects often require surgery.Early intervention with appropriate physical, occupational, and speech therapy services is important in ensuring that affected children reach their full potential. Physical and occupational therapy may be necessary to aid in walking and using one’s hands. Speech therapy may be of benefit for individuals with speech development delays due to hearing loss. Hearing loss may require tubes to be implanted in the ears or the use of a hearing aid.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
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Therapies of Nager Syndrome. Treatment
The treatment of Nager syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, oral surgeons, plastic surgeons, pediatric ear, nose and throat specialists (pediatric otolaryngologists), specialists in diagnosing and treating eye disorders (ophthalmologists), specialists in diagnosing and treating ear disorders (otologists), specialists in treating hearing loss (audiologists), psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Affected individuals may benefit from referral to a craniofacial center.Specific treatment may consist of surgery to create a small opening in the throat, through which a small tube is inserted to assist with breathing (tracheostomy). Surgery may also be necessary to create a small opening in the stomach to allow the insertion of a feeding tube in infants experiencing difficulty eating in order to maintain proper nutrition.Surgery may be required to correct abnormalities of the jaws, limbs, and eyes. Surgery and/or speech therapy may be necessary when cleft palate or cleft lip is present. Skeletal malformations such as rib abnormalities, limited range of motion of the elbows, and scoliosis may require surgical intervention. Congenital heart defects often require surgery.Early intervention with appropriate physical, occupational, and speech therapy services is important in ensuring that affected children reach their full potential. Physical and occupational therapy may be necessary to aid in walking and using one’s hands. Speech therapy may be of benefit for individuals with speech development delays due to hearing loss. Hearing loss may require tubes to be implanted in the ears or the use of a hearing aid.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
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Nager Syndrome
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nord_859_0
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Overview of Nail Patella Syndrome
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SummaryNail-patella syndrome (NPS) is a rare genetic disorder that is usually apparent at birth or during early childhood. Although the symptoms and physical characteristics associated with NPS may vary greatly in range and severity, characteristic abnormalities include improper development (dysplasia) of the fingernails and toenails; absence (aplasia) and/or underdevelopment (hypoplasia) of the knee caps (patellae) which may easily dislocate; limited movement of the elbow including extension and rotation caused by underdevelopment or dislocation of the radius (a forearm bone that is part of the elbow) and/or webbing of skin at the bend of the elbow(s); and/or abnormal projections of bone from the upper (superior) portion of both sides of the hipbone (bilateral iliac horns).In addition, some individuals with NPS may have abnormally increased fluid pressure of the eyes (glaucoma). The condition results due to progressive blockage of the outflow of fluid (aqueous humor) from the front chamber of the eyes (open-angle glaucoma). Without appropriate treatment, the gradual increase in fluid pressure may cause increased narrowing of visual fields and eventual blindness. Another common eye (ocular) difference associated with NPS is an abnormally dark (hyperpigmented) and “cloverleaf” shape discoloration around the inner margin (pupillary margin) of the colored portion of the eyes (irides). This is known as (Lester’s sign) and does not cause any problems with vision.Approximately 30 -50% of individuals with NPS may also develop abnormalities in kidney function (nephropathy) during childhood or later in life. Kidney failure may occur in up to 5% of all NPS patients.NPS is an autosomal dominant genetic condition. This means any individual with NPS, regardless of gender, has a 50% chance of passing this condition on to each of his/her offspring. It is estimated that almost 90% of individuals with NPS have inherited it from an affected parent with the remaining 10% being the first affected person in their family.Introduction* Another name for nail patella syndrome (NPS) is Fong disease, named after Capt. E.E. Fong. Dr. Fong described in 1946 the horn-like structures on the back of iliac bones in a patient with NPS. Though he did not associate iliac horns with NPS, his name became connected to this condition. Turner and Keiser published earlier descriptions of the iliac horns in patients with NPS in 1933 and 1939, respectively.
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Overview of Nail Patella Syndrome. SummaryNail-patella syndrome (NPS) is a rare genetic disorder that is usually apparent at birth or during early childhood. Although the symptoms and physical characteristics associated with NPS may vary greatly in range and severity, characteristic abnormalities include improper development (dysplasia) of the fingernails and toenails; absence (aplasia) and/or underdevelopment (hypoplasia) of the knee caps (patellae) which may easily dislocate; limited movement of the elbow including extension and rotation caused by underdevelopment or dislocation of the radius (a forearm bone that is part of the elbow) and/or webbing of skin at the bend of the elbow(s); and/or abnormal projections of bone from the upper (superior) portion of both sides of the hipbone (bilateral iliac horns).In addition, some individuals with NPS may have abnormally increased fluid pressure of the eyes (glaucoma). The condition results due to progressive blockage of the outflow of fluid (aqueous humor) from the front chamber of the eyes (open-angle glaucoma). Without appropriate treatment, the gradual increase in fluid pressure may cause increased narrowing of visual fields and eventual blindness. Another common eye (ocular) difference associated with NPS is an abnormally dark (hyperpigmented) and “cloverleaf” shape discoloration around the inner margin (pupillary margin) of the colored portion of the eyes (irides). This is known as (Lester’s sign) and does not cause any problems with vision.Approximately 30 -50% of individuals with NPS may also develop abnormalities in kidney function (nephropathy) during childhood or later in life. Kidney failure may occur in up to 5% of all NPS patients.NPS is an autosomal dominant genetic condition. This means any individual with NPS, regardless of gender, has a 50% chance of passing this condition on to each of his/her offspring. It is estimated that almost 90% of individuals with NPS have inherited it from an affected parent with the remaining 10% being the first affected person in their family.Introduction* Another name for nail patella syndrome (NPS) is Fong disease, named after Capt. E.E. Fong. Dr. Fong described in 1946 the horn-like structures on the back of iliac bones in a patient with NPS. Though he did not associate iliac horns with NPS, his name became connected to this condition. Turner and Keiser published earlier descriptions of the iliac horns in patients with NPS in 1933 and 1939, respectively.
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Nail Patella Syndrome
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Symptoms of Nail Patella Syndrome
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Nail changes are the most constant feature of NPS (98%). In most individuals with NPS, improper development (dysplasia) of the nails is apparent at birth or early infancy. While the thumbnails are almost always affected, the other fingernails may be more mildly affected or not at all. Typically the severity of the nail dysplasia decreases from the thumb toward the 5th digit. The nails may be abnormally small and narrow (i.e., one half to one third of normal size), split, abnormally thickened, depressed, and/or discolored. In addition, in most people, the crescent-shaped pale area at the base of the nail (lunula) is malformed and/or triangular. Improper development (dysplasia) of the toenails is usually less common than the fingernails; if the toenails are involved, it is often the little toenail that is affected.Most individuals with NPS also have abnormalities of certain bones. In most people, one or both knee caps (patellae) may be abnormally small, underdeveloped (hypoplastic), and misshaped (e.g., tripartite, polygonal). In other people, one or both knee caps may be absent. In addition, affected individuals may also demonstrate underdevelopment (hypoplasia) of the two bones that create the outer part of the knee (the top of the fibula in the lower part of the leg and/or the lower, rounded projection of the femur in the upper part of the leg). Due to such abnormalities, individuals with NPS often exhibit partial dislocation (subluxation) of the patella and a limited range of movements of the knee(s), a deformity in which one or both legs bend outward at the knee (“bow-leg” or genu varum), and/or progressive degeneration, stiffness, tenderness, and pain of the knee(s) (osteoarthritis). In severe cases, osteoarthritis may eventually limit use of the knee(s).Most people with NPS also have abnormalities of the elbows. The portions of bone that meet at the elbow(s) (i.e.capitellum, head of radius) may be abnormally small and underdeveloped (hypoplastic). In addition, some affected individuals may have abnormal webbing of skin at the bend of the elbow(s) (antecubital pterygium). Due to such abnormalities, affected individuals may be unable to completely extend the arms, rotate the arms inward toward the body with the palms facing down (pronation), or rotate the arms outward with the palms facing upward (supination). Some affected individuals may experience partial dislocation of the elbows (subluxation). Individuals with NPS may also develop progressive osteoarthritis of the elbows that, in severe cases, may eventually limit elbow function.The majority of individuals with NPS also have abnormal projections of bone from the upper (superior) portion of both sides of the hipbone (bilateral iliac horns). In some cases, additional skeletal abnormalities may be present. These may include underdevelopment (hypoplasia) of the shoulder blades (scapulae) and/or abnormal sideways curvature of the spine (scoliosis).Some affected individuals within particular families may also have a condition in which fluid pressure of the eyes becomes abnormally increased (glaucoma). The condition results due to progressive blockage of the outflow of fluid (aqueous humor) from the front chamber of the eyes (open-angle glaucoma). Initially, affected individuals may have no apparent symptoms (asymptomatic). As fluid pressure increases, some individuals with the condition may develop mild headaches, blurred vision, and/or the appearance of “halos” around certain lights. Since glaucoma may be asymptomatic, annual screening for this condition should be performed in all patients with NPS. Without appropriate treatment, elevated fluid pressure may lead to gradual loss of peripheral vision, increased narrowing of visual fields, and eventual blindness.Other eye (ocular) abnormalities may also be associated with NPS. In approximately 45 percent of affected individuals, the inner margin (pupillary margin) of the colored portion of the eyes (irides) may appear abnormally dark (hyperpigmentation) and “cloverleaf shaped” (Lester’s sign). Some individuals may also have abnormal clouding of the lenses of the eyes (cataracts) and/or unusually small corneas (microcornea). The cornea is the front, clear portion of the eye through which light passes. The degree of associated visual impairment depends upon the severity and/or combination of eye abnormalities present.Approximately 30-50% of individuals with NPS may also experience abnormalities in kidney function (nephropathy) that may be apparent during childhood or later in life. Such kidney disease may be due to abnormal degeneration of the tiny tubes (renal tubules) that collect, conduct, and secrete urine (nephrotic kidney disease) and/or inflammation and degeneration of the clusters of capillaries (renal glomeruli) that filter the blood passing through the kidneys (glomerular kidney disease).In most affected individuals, the first apparent signs of nephropathy include the presence of small amounts of blood in the urine (microhematuria); high blood pressure (hypertension); and/or an abnormal accumulation of fluid between layers of tissue under the skin (edema). In most people, the nephropathy may be relatively benign. However, in about 5% of those affected, progressive kidney failure may result, causing potentially life-threatening complications.For example, some affected individuals with nephropathy may begin to exhibit a variety of symptoms (nephrotic syndrome) including anemia, edema, and/or other characteristic, abnormal laboratory findings (see “Standard Therapies, Diagnosis” for more information). In some people, the kidneys may eventually lose their ability to excrete waste products through the urine, to regulate the balance of salt and water in the body, and to perform their other vital functions (renal failure), resulting in potentially life-threatening complications. Progression to renal failure is rare in patients with NPS, usually in adults if it occurs.
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Symptoms of Nail Patella Syndrome. Nail changes are the most constant feature of NPS (98%). In most individuals with NPS, improper development (dysplasia) of the nails is apparent at birth or early infancy. While the thumbnails are almost always affected, the other fingernails may be more mildly affected or not at all. Typically the severity of the nail dysplasia decreases from the thumb toward the 5th digit. The nails may be abnormally small and narrow (i.e., one half to one third of normal size), split, abnormally thickened, depressed, and/or discolored. In addition, in most people, the crescent-shaped pale area at the base of the nail (lunula) is malformed and/or triangular. Improper development (dysplasia) of the toenails is usually less common than the fingernails; if the toenails are involved, it is often the little toenail that is affected.Most individuals with NPS also have abnormalities of certain bones. In most people, one or both knee caps (patellae) may be abnormally small, underdeveloped (hypoplastic), and misshaped (e.g., tripartite, polygonal). In other people, one or both knee caps may be absent. In addition, affected individuals may also demonstrate underdevelopment (hypoplasia) of the two bones that create the outer part of the knee (the top of the fibula in the lower part of the leg and/or the lower, rounded projection of the femur in the upper part of the leg). Due to such abnormalities, individuals with NPS often exhibit partial dislocation (subluxation) of the patella and a limited range of movements of the knee(s), a deformity in which one or both legs bend outward at the knee (“bow-leg” or genu varum), and/or progressive degeneration, stiffness, tenderness, and pain of the knee(s) (osteoarthritis). In severe cases, osteoarthritis may eventually limit use of the knee(s).Most people with NPS also have abnormalities of the elbows. The portions of bone that meet at the elbow(s) (i.e.capitellum, head of radius) may be abnormally small and underdeveloped (hypoplastic). In addition, some affected individuals may have abnormal webbing of skin at the bend of the elbow(s) (antecubital pterygium). Due to such abnormalities, affected individuals may be unable to completely extend the arms, rotate the arms inward toward the body with the palms facing down (pronation), or rotate the arms outward with the palms facing upward (supination). Some affected individuals may experience partial dislocation of the elbows (subluxation). Individuals with NPS may also develop progressive osteoarthritis of the elbows that, in severe cases, may eventually limit elbow function.The majority of individuals with NPS also have abnormal projections of bone from the upper (superior) portion of both sides of the hipbone (bilateral iliac horns). In some cases, additional skeletal abnormalities may be present. These may include underdevelopment (hypoplasia) of the shoulder blades (scapulae) and/or abnormal sideways curvature of the spine (scoliosis).Some affected individuals within particular families may also have a condition in which fluid pressure of the eyes becomes abnormally increased (glaucoma). The condition results due to progressive blockage of the outflow of fluid (aqueous humor) from the front chamber of the eyes (open-angle glaucoma). Initially, affected individuals may have no apparent symptoms (asymptomatic). As fluid pressure increases, some individuals with the condition may develop mild headaches, blurred vision, and/or the appearance of “halos” around certain lights. Since glaucoma may be asymptomatic, annual screening for this condition should be performed in all patients with NPS. Without appropriate treatment, elevated fluid pressure may lead to gradual loss of peripheral vision, increased narrowing of visual fields, and eventual blindness.Other eye (ocular) abnormalities may also be associated with NPS. In approximately 45 percent of affected individuals, the inner margin (pupillary margin) of the colored portion of the eyes (irides) may appear abnormally dark (hyperpigmentation) and “cloverleaf shaped” (Lester’s sign). Some individuals may also have abnormal clouding of the lenses of the eyes (cataracts) and/or unusually small corneas (microcornea). The cornea is the front, clear portion of the eye through which light passes. The degree of associated visual impairment depends upon the severity and/or combination of eye abnormalities present.Approximately 30-50% of individuals with NPS may also experience abnormalities in kidney function (nephropathy) that may be apparent during childhood or later in life. Such kidney disease may be due to abnormal degeneration of the tiny tubes (renal tubules) that collect, conduct, and secrete urine (nephrotic kidney disease) and/or inflammation and degeneration of the clusters of capillaries (renal glomeruli) that filter the blood passing through the kidneys (glomerular kidney disease).In most affected individuals, the first apparent signs of nephropathy include the presence of small amounts of blood in the urine (microhematuria); high blood pressure (hypertension); and/or an abnormal accumulation of fluid between layers of tissue under the skin (edema). In most people, the nephropathy may be relatively benign. However, in about 5% of those affected, progressive kidney failure may result, causing potentially life-threatening complications.For example, some affected individuals with nephropathy may begin to exhibit a variety of symptoms (nephrotic syndrome) including anemia, edema, and/or other characteristic, abnormal laboratory findings (see “Standard Therapies, Diagnosis” for more information). In some people, the kidneys may eventually lose their ability to excrete waste products through the urine, to regulate the balance of salt and water in the body, and to perform their other vital functions (renal failure), resulting in potentially life-threatening complications. Progression to renal failure is rare in patients with NPS, usually in adults if it occurs.
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Nail Patella Syndrome
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Causes of Nail Patella Syndrome
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NPS is an autosomal dominant genetic condition. Human traits, including the classic genetic diseases, are the product of the interaction of two copies of every gene. One copy is received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected individual to each offspring is 50% for each pregnancy. The risk is the same for males and females. Approximately 90% of people with NPS have an affected parent and, therefore, 10% develop the condition as the result of a new mutation.LMX1B is the only gene currently known to cause NPS. However, it is likely that one or more genes will be found in the future to cause NPS because there are rare families with all the classic features of NPS lacking a mutation in the LMX1B gene. The LMX1B gene regulates production of a protein that controls the direction the embryonic structures that become the arms and legs (limb buds) and grow relative to the trunk. Mutations of the LMX1B gene result in skeletal defects, including impaired development of the knee caps and elbows, nail dysplasia, and kidney abnormalities.Many different mutations of the LMX1B gene have been identified in people with NPS. There does not appear to be a correlation between specific LMX1B gene mutations and the range and severity of the condition. However, mutations in one small region of this gene have been found in people with isolated kidney disease. More research is needed to learn more about this unique presentation.
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Causes of Nail Patella Syndrome. NPS is an autosomal dominant genetic condition. Human traits, including the classic genetic diseases, are the product of the interaction of two copies of every gene. One copy is received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected individual to each offspring is 50% for each pregnancy. The risk is the same for males and females. Approximately 90% of people with NPS have an affected parent and, therefore, 10% develop the condition as the result of a new mutation.LMX1B is the only gene currently known to cause NPS. However, it is likely that one or more genes will be found in the future to cause NPS because there are rare families with all the classic features of NPS lacking a mutation in the LMX1B gene. The LMX1B gene regulates production of a protein that controls the direction the embryonic structures that become the arms and legs (limb buds) and grow relative to the trunk. Mutations of the LMX1B gene result in skeletal defects, including impaired development of the knee caps and elbows, nail dysplasia, and kidney abnormalities.Many different mutations of the LMX1B gene have been identified in people with NPS. There does not appear to be a correlation between specific LMX1B gene mutations and the range and severity of the condition. However, mutations in one small region of this gene have been found in people with isolated kidney disease. More research is needed to learn more about this unique presentation.
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Affects of Nail Patella Syndrome
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NPS affects males and females in equal numbers and is thought to affect approximately one in 50,000 people. The true prevalence may be higher since mildly affected people may be undiagnosed.
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Affects of Nail Patella Syndrome. NPS affects males and females in equal numbers and is thought to affect approximately one in 50,000 people. The true prevalence may be higher since mildly affected people may be undiagnosed.
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Related disorders of Nail Patella Syndrome
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Symptoms of the following disorders can be similar to those of Nail-Patella syndrome. Comparisons may be useful for a differential diagnosis:Small patella syndrome is also known as ischiopatellar dysplasia or Scott-Taor syndrome. It is also a dominant condition and is caused by mutations in TBX4. It is characterized by absent or small patella, abnormal ossification (not fused) of the ischiopubic junction and a characteristic “axe-cut” notch below the acetabulum which can be seen by radiographs. Patients with small patella syndrome do not have abnormalities of their nails, elbows, eyes or kidneys.DOOR syndrome is a rare genetic disorder that may be recognized shortly after birth. “DOOR,” an acronym for characteristic abnormalities associated with the syndrome, stands for (D)eafness due to a defect of the inner ear or auditory nerve (sensorineural hearing loss); (O)nychodystrophy or malformation of the nails; (O)steodystrophy, meaning malformation of certain bones; and mild to profound mental (R)etardation. In addition, in some cases, affected infants may have sudden episodes of uncontrolled electrical activity in the brain (seizures). Distinctive nail abnormalities may include underdeveloped, misshapen, or absent fingernails and/or toenails, while characteristic bone malformations may consist of an extra small bone in the thumbs and/or great toes (triphalangy) and/or underdevelopment (hypoplasia) of bones in other fingers and/or toes. DOOR syndrome is inherited as an autosomal recessive condition by mutations in the TBC1D24 gene. (For more information on this condition, search for “DOOR syndrome” in the Rare Disease Database.)Coffin-Siris syndrome (CSS) is a rare genetic disorder that may be evident at birth (congenital). The disorder is characterized by abnormalities of the head and facial (craniofacial) area, resulting in a coarse facial appearance. Craniofacial malformations may include an abnormally small head (microcephaly); a wide nose with a low nasal bridge; a wide mouth with thick, prominent lips; thick eyebrows and eyelashes (hypertrichosis); and sparse scalp hair. In addition, affected infants and children typically have short fifth fingers (“pinkies”) and toes with underdeveloped (hypoplastic) or absent nails; other malformations of the fingers and toes; and eye abnormalities. Feeding difficulties and frequent respiratory infections during infancy, diminished muscle tone (hypotonia), abnormal looseness (laxity) of the joints, delayed bone age, developmental delays, hearing loss, and intellectual disability may also be present. The specific symptoms and severity can vary among affected individuals. Treatment is directed towards the symptoms that are present in an individual with CSS. Mutations in six different genes, ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1 and SOX11, have been found to cause CSS. Researchers believe the disease can be transmitted genetically as an autosomal dominant trait but most cases appear to be the result of a new mutation. (For more information on this condition, search for “Coffin-Siris syndrome” in the Rare Disease Database.)Meier-Gorlin syndrome is another recessive condition caused by mutations in several different recessive genes including ORC1, ORC4, ORC6, GMNN, CDT1, MCM5, CDC6 and CDC45. This condition is marked also by absent patellae and radial head/elbow dislocation, but also extremely small ears (microtia), short stature with delayed bone age, and microcephaly. There are additional disorders that may be characterized by nail dysplasia, skeletal malformations, and/or renal abnormalities similar to those potentially associated NPS. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Nail Patella Syndrome. Symptoms of the following disorders can be similar to those of Nail-Patella syndrome. Comparisons may be useful for a differential diagnosis:Small patella syndrome is also known as ischiopatellar dysplasia or Scott-Taor syndrome. It is also a dominant condition and is caused by mutations in TBX4. It is characterized by absent or small patella, abnormal ossification (not fused) of the ischiopubic junction and a characteristic “axe-cut” notch below the acetabulum which can be seen by radiographs. Patients with small patella syndrome do not have abnormalities of their nails, elbows, eyes or kidneys.DOOR syndrome is a rare genetic disorder that may be recognized shortly after birth. “DOOR,” an acronym for characteristic abnormalities associated with the syndrome, stands for (D)eafness due to a defect of the inner ear or auditory nerve (sensorineural hearing loss); (O)nychodystrophy or malformation of the nails; (O)steodystrophy, meaning malformation of certain bones; and mild to profound mental (R)etardation. In addition, in some cases, affected infants may have sudden episodes of uncontrolled electrical activity in the brain (seizures). Distinctive nail abnormalities may include underdeveloped, misshapen, or absent fingernails and/or toenails, while characteristic bone malformations may consist of an extra small bone in the thumbs and/or great toes (triphalangy) and/or underdevelopment (hypoplasia) of bones in other fingers and/or toes. DOOR syndrome is inherited as an autosomal recessive condition by mutations in the TBC1D24 gene. (For more information on this condition, search for “DOOR syndrome” in the Rare Disease Database.)Coffin-Siris syndrome (CSS) is a rare genetic disorder that may be evident at birth (congenital). The disorder is characterized by abnormalities of the head and facial (craniofacial) area, resulting in a coarse facial appearance. Craniofacial malformations may include an abnormally small head (microcephaly); a wide nose with a low nasal bridge; a wide mouth with thick, prominent lips; thick eyebrows and eyelashes (hypertrichosis); and sparse scalp hair. In addition, affected infants and children typically have short fifth fingers (“pinkies”) and toes with underdeveloped (hypoplastic) or absent nails; other malformations of the fingers and toes; and eye abnormalities. Feeding difficulties and frequent respiratory infections during infancy, diminished muscle tone (hypotonia), abnormal looseness (laxity) of the joints, delayed bone age, developmental delays, hearing loss, and intellectual disability may also be present. The specific symptoms and severity can vary among affected individuals. Treatment is directed towards the symptoms that are present in an individual with CSS. Mutations in six different genes, ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1 and SOX11, have been found to cause CSS. Researchers believe the disease can be transmitted genetically as an autosomal dominant trait but most cases appear to be the result of a new mutation. (For more information on this condition, search for “Coffin-Siris syndrome” in the Rare Disease Database.)Meier-Gorlin syndrome is another recessive condition caused by mutations in several different recessive genes including ORC1, ORC4, ORC6, GMNN, CDT1, MCM5, CDC6 and CDC45. This condition is marked also by absent patellae and radial head/elbow dislocation, but also extremely small ears (microtia), short stature with delayed bone age, and microcephaly. There are additional disorders that may be characterized by nail dysplasia, skeletal malformations, and/or renal abnormalities similar to those potentially associated NPS. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Diagnosis of Nail Patella Syndrome
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NPS may be suspected at birth or early childhood based upon the identification of certain characteristic findings (e.g., nail dysplasia, hypoplastic or absent patellae, antecubital pterygium, bilateral symmetrical iliac spurs/horns). However, in others, the disorder may not be suspected until later in life. NPS may be confirmed based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient and family history, advanced imaging techniques, and laboratory testing.Specialized imaging techniques such as x-ray studies, computerized tomography (CT) scanning, and/or magnetic resonance imaging (MRI) may confirm the presence and/or extent of certain bone abnormalities characteristically associated with NPS (e.g., patellae hypoplasia and/or aplasia, hypoplastic capitellum and head of radius, bilateral iliac spurs, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structure. During MRI, a magnetic field and radio waves are used to create cross-sectional images.Molecular genetic testing for mutations in the LMX1B gene is available to confirm the diagnosis.
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Diagnosis of Nail Patella Syndrome. NPS may be suspected at birth or early childhood based upon the identification of certain characteristic findings (e.g., nail dysplasia, hypoplastic or absent patellae, antecubital pterygium, bilateral symmetrical iliac spurs/horns). However, in others, the disorder may not be suspected until later in life. NPS may be confirmed based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient and family history, advanced imaging techniques, and laboratory testing.Specialized imaging techniques such as x-ray studies, computerized tomography (CT) scanning, and/or magnetic resonance imaging (MRI) may confirm the presence and/or extent of certain bone abnormalities characteristically associated with NPS (e.g., patellae hypoplasia and/or aplasia, hypoplastic capitellum and head of radius, bilateral iliac spurs, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structure. During MRI, a magnetic field and radio waves are used to create cross-sectional images.Molecular genetic testing for mutations in the LMX1B gene is available to confirm the diagnosis.
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Therapies of Nail Patella Syndrome
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TreatmentThe treatment of NPS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who diagnose and treat abnormalities of the bones (orthopedists), specialists who diagnose and treat disorders of the kidneys (nephrologists), eye specialists (ophthalmologists), physical therapists, dietitians, and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.Specific therapies for the treatment of NPS are symptomatic and supportive. In some cases, treatment for associated bone abnormalities may include surgical stabilization or replacement of knee caps with artificial devices (prosthetics) and/or correction and/or reconstruction of hypoplastic bones within the knee and/or elbow areas. Abnormal webbing at the bend of the elbow (antecubital pterygium) may also be surgically released to help improve arm extension. However, further surgical manipulation of the elbows may be quite difficult because the internal elbow structures may be misplaced due to its abnormal embryologic development. For this reason, magnetic resonance imaging is recommended prior to undertaking surgery on the elbow (or knee, for that matter). Scoliosis may be treated with a combination of exercises and physical therapy, other supportive techniques, braces, casts, and/or corrective surgery.In individuals with open-angle glaucoma, treatment measures may include the use of medicated eye drops to help reduce fluid pressure in the eyes, certain medications by mouth, and/or surgery. In affected children with other ocular abnormalities associated with NPS, corrective glasses, contact lenses, and/or surgery may be used in some cases to help improve vision. There are no differences in treatment of glaucoma in patients with NPS versus those who do not have this condition.Affected individuals with nephropathy, particularly those who have been diagnosed with nephrotic syndrome, should be referred to physicians who specialize in diseases affecting the kidneys (nephrologists). Blood pressure and kidney function must be screened annually. For those with abnormal renal function, he/she must be followed more closely by the nephrologist to determine when/if treatment is indicated. Early intervention is important to ensure that children with NPS reach their potential. Special services that may be beneficial to affected children may include physical therapy, special social support, and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. Family members of individuals with NPS should also receive thorough clinical examinations and other appropriate tests to detect certain abnormalities potentially associated with the disorder. Other treatment for this disorder is symptomatic and supportive.Clinical Testing and Work-UpChildren and adolescents with NPS should be carefully monitored for abnormal sideways curvature of the spine (scoliosis) to ensure prompt detection and appropriate preventive and/or corrective treatment. Affected individuals should also receive thorough eye examinations to confirm and/or detect the presence of certain ocular abnormalities that may be associated with NPS (e.g., open-angle glaucoma, microcornea, cataracts). For example, in many cases, open-angle glaucoma may initially cause no apparent symptoms and therefore may only be detected during an eye examination, including specialized testing to measure eye pressure. Early detection of glaucoma is important in ensuring prompt treatment to reduce eye fluid pressure and prevent progressive visual impairment.In addition, physicians may closely monitor individuals with NPS beginning in early infancy to ensure prompt detection of abnormal kidney function and implementation of immediate, appropriate treatment measures to help prevent potential progressive kidney dysfunction. Laboratory tests may confirm certain findings that may indicate renal insufficiency, such as blood tests to check BUN and creatinine levels. Screening for nephropathy may include urinary analysis which may reveal small traces of blood (hematuria) and/or abnormally high levels of protein (proteinuria), specifically albumin (albuminuria), in the urine. Additional laboratory studies may reveal unusually low levels of albumin in an affected individual’s blood (hypoalbuminemia). Such findings, occurring in association with anemia and edema, may indicate a diagnosis of nephrotic syndrome in some individuals with NPS.Microscopic examination (e.g., immunofluorescence and electron microscopy) of samples of kidney tissue (renal biopsy) may reveal certain characteristic structural abnormalities that may be present even in some individuals with NPS who may not exhibit observable symptoms or clinical findings indicating renal involvement. For example, in many affected individuals both with and without apparent clinical renal involvement, microscopic examination may reveal certain abnormal changes of the clusters of capillaries (renal glomeruli) that filter blood passing through the kidneys. Such changes may include an increased number of cells (hypercellularity), abnormal thickening of the capillary walls, abnormal deposits of the protein collagen, and/or replacement of normal tissue with scar tissue (focal and segmental sclerosis). In some cases, confirmation of certain glomerular changes may reveal impairment of the glomeruli’s filtering ability and may help to confirm a diagnosis of nephrotic syndrome.
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Therapies of Nail Patella Syndrome. TreatmentThe treatment of NPS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who diagnose and treat abnormalities of the bones (orthopedists), specialists who diagnose and treat disorders of the kidneys (nephrologists), eye specialists (ophthalmologists), physical therapists, dietitians, and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.Specific therapies for the treatment of NPS are symptomatic and supportive. In some cases, treatment for associated bone abnormalities may include surgical stabilization or replacement of knee caps with artificial devices (prosthetics) and/or correction and/or reconstruction of hypoplastic bones within the knee and/or elbow areas. Abnormal webbing at the bend of the elbow (antecubital pterygium) may also be surgically released to help improve arm extension. However, further surgical manipulation of the elbows may be quite difficult because the internal elbow structures may be misplaced due to its abnormal embryologic development. For this reason, magnetic resonance imaging is recommended prior to undertaking surgery on the elbow (or knee, for that matter). Scoliosis may be treated with a combination of exercises and physical therapy, other supportive techniques, braces, casts, and/or corrective surgery.In individuals with open-angle glaucoma, treatment measures may include the use of medicated eye drops to help reduce fluid pressure in the eyes, certain medications by mouth, and/or surgery. In affected children with other ocular abnormalities associated with NPS, corrective glasses, contact lenses, and/or surgery may be used in some cases to help improve vision. There are no differences in treatment of glaucoma in patients with NPS versus those who do not have this condition.Affected individuals with nephropathy, particularly those who have been diagnosed with nephrotic syndrome, should be referred to physicians who specialize in diseases affecting the kidneys (nephrologists). Blood pressure and kidney function must be screened annually. For those with abnormal renal function, he/she must be followed more closely by the nephrologist to determine when/if treatment is indicated. Early intervention is important to ensure that children with NPS reach their potential. Special services that may be beneficial to affected children may include physical therapy, special social support, and other medical, social, and/or vocational services.Genetic counseling is recommended for affected individuals and their families. Family members of individuals with NPS should also receive thorough clinical examinations and other appropriate tests to detect certain abnormalities potentially associated with the disorder. Other treatment for this disorder is symptomatic and supportive.Clinical Testing and Work-UpChildren and adolescents with NPS should be carefully monitored for abnormal sideways curvature of the spine (scoliosis) to ensure prompt detection and appropriate preventive and/or corrective treatment. Affected individuals should also receive thorough eye examinations to confirm and/or detect the presence of certain ocular abnormalities that may be associated with NPS (e.g., open-angle glaucoma, microcornea, cataracts). For example, in many cases, open-angle glaucoma may initially cause no apparent symptoms and therefore may only be detected during an eye examination, including specialized testing to measure eye pressure. Early detection of glaucoma is important in ensuring prompt treatment to reduce eye fluid pressure and prevent progressive visual impairment.In addition, physicians may closely monitor individuals with NPS beginning in early infancy to ensure prompt detection of abnormal kidney function and implementation of immediate, appropriate treatment measures to help prevent potential progressive kidney dysfunction. Laboratory tests may confirm certain findings that may indicate renal insufficiency, such as blood tests to check BUN and creatinine levels. Screening for nephropathy may include urinary analysis which may reveal small traces of blood (hematuria) and/or abnormally high levels of protein (proteinuria), specifically albumin (albuminuria), in the urine. Additional laboratory studies may reveal unusually low levels of albumin in an affected individual’s blood (hypoalbuminemia). Such findings, occurring in association with anemia and edema, may indicate a diagnosis of nephrotic syndrome in some individuals with NPS.Microscopic examination (e.g., immunofluorescence and electron microscopy) of samples of kidney tissue (renal biopsy) may reveal certain characteristic structural abnormalities that may be present even in some individuals with NPS who may not exhibit observable symptoms or clinical findings indicating renal involvement. For example, in many affected individuals both with and without apparent clinical renal involvement, microscopic examination may reveal certain abnormal changes of the clusters of capillaries (renal glomeruli) that filter blood passing through the kidneys. Such changes may include an increased number of cells (hypercellularity), abnormal thickening of the capillary walls, abnormal deposits of the protein collagen, and/or replacement of normal tissue with scar tissue (focal and segmental sclerosis). In some cases, confirmation of certain glomerular changes may reveal impairment of the glomeruli’s filtering ability and may help to confirm a diagnosis of nephrotic syndrome.
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Overview of Nance-Horan Syndrome
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Nance-Horan syndrome is a rare genetic disorder that may be evident at birth (congenital). It is primarily characterized by abnormalities of the teeth and clouding of the lens of the eyes (congenital cataracts), resulting in poor vision. Additional eye (ocular) abnormalities are also often present, such as unusual smallness of the front, clear portion of the eye through which light passes (microcornea) and involuntary, rapid, rhythmic eye movements (nystagmus). In some affected individuals, the disorder may also be associated with additional physical abnormalities and/or intellectual impairment. The range and severity of symptoms may vary greatly from one person to another, including among affected members of the same family.Nance-Horan syndrome is inherited as an X-linked trait that it is usually fully expressed in males only. However, females who carry a single copy of the disease gene (heterozygotes) may manifest some of the symptoms and findings associated with the disorder. These may include microcornea and/or clouding of the lens of the eyes (posterior sutural cataract). Symptoms are less severe than those of affected males, potentially causing only slightly decreased clearness or clarity of vision (visual acuity). In some patients, abnormalities of the teeth may also be present. Intellectual impairment rarely occurs in females.
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Overview of Nance-Horan Syndrome. Nance-Horan syndrome is a rare genetic disorder that may be evident at birth (congenital). It is primarily characterized by abnormalities of the teeth and clouding of the lens of the eyes (congenital cataracts), resulting in poor vision. Additional eye (ocular) abnormalities are also often present, such as unusual smallness of the front, clear portion of the eye through which light passes (microcornea) and involuntary, rapid, rhythmic eye movements (nystagmus). In some affected individuals, the disorder may also be associated with additional physical abnormalities and/or intellectual impairment. The range and severity of symptoms may vary greatly from one person to another, including among affected members of the same family.Nance-Horan syndrome is inherited as an X-linked trait that it is usually fully expressed in males only. However, females who carry a single copy of the disease gene (heterozygotes) may manifest some of the symptoms and findings associated with the disorder. These may include microcornea and/or clouding of the lens of the eyes (posterior sutural cataract). Symptoms are less severe than those of affected males, potentially causing only slightly decreased clearness or clarity of vision (visual acuity). In some patients, abnormalities of the teeth may also be present. Intellectual impairment rarely occurs in females.
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Symptoms of Nance-Horan Syndrome
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In affected males, the primary physical characteristic associated with Nance-Horan syndrome is the presence of dense clouding (opacities) of the lens of both eyes at birth (congenital bilateral nuclear cataracts).The lens of an eye is the small transparent flattened and elongated ball located behind the iris through which light passes. The light focuses on the retina, the thin nerve-rich membrane that lining the back of the eye. The retina converts the light into nerve impulses and relays the information along the optic nerve to the brain. Cataracts affect both eyes (bilateral) and usually result in blurred vision and severely decreased clearness or clarity of vision (visual acuity). Vision loss can potentially be profound.Males with Nance-Horan syndrome may have additional eye abnormalities. The front (anterior), clear portion of the eye through which light passes (cornea) may be unusually small (microcornea). In addition, affected males with poor vision may have recurrent, involuntary, “to-and-fro” movements of the eyes (pendular nystagmus) and/or misalignment of the eyes (strabismus). In some cases, the entire eye may be abnormally small (microphthalmia) and/or the upper eyelid may droop (ptosis).Males with Nance-Horan syndrome may also have several dental abnormalities such as unusually shaped, extra (supernumerary) teeth, absence of some teeth (dental agenesis), impacted teeth or unusually wide spaces (diastema) between some of the teeth. Front teeth (incisors) are tapered and “screwdriver-shaped” or are similar in appearance to a tooth abnormality often associated with congenital syphilis (i.e., Hutchinson’s teeth). Posterior teeth may be conical, rounded, cylindrical or with extra cusps (small bumps at the surface of the molar teeth). Some affected males may have an extra (supernumerary), centrally located front tooth in the upper jaw (mesiodens). The tooth may be “cone-shaped” with an abnormally short root. Such supernumerary incisors may prevent or disrupt the normal eruption of permanent incisors in some cases. Both the baby (deciduous) and permanent teeth are involved.In many males with Nance-Horan syndrome, other physical findings may also occur. Distinctive facial features may be present, but may be subtle. The ears may be flared forward (anteverted) and unusually prominent, with folded lobes. Affected males may have a large, prominent nose with a high, narrow nasal bridge; a narrow prominent jaw (prognathism); and a long sometimes narrow face.Some males with Nance-Horan syndrome may also experience delays in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation). In addition, some reports suggest that approximately 20 to 30 percent of affected males may have varying levels of intellectual dysfunction. Intellectual dysfunction is usually mild or moderate, but in some cases can be severe. Autism spectrum disorder symptoms have also been observed in a few patients.As mentioned above, females who carry a single copy of the disease gene for Nance-Horan syndrome (heterozygotes) may develop some symptoms of the disorder. Such symptoms are usually milder and more variable than those associated with the fully expressed disorder. Affected females may have abnormally small corneas (microcornea) and/or Y-shaped clouding (opacities) in the back portion of the lens of the eyes at birth (congenital posterior sutural cataracts). Vision may be normal, or there may be slightly decreased clearness or clarity of vision (visual acuity). Without appropriate treatment, posterior sutural cataracts may progress to total clouding of the lens of the eyes (total cataracts) later in life. Heterozygous females often have some dental abnormalities, such as abnormally-shaped front teeth (incisors) and/or unusually wide spaces (irregular diastema) between some of the teeth. Affected females usually do not develop intellectual impairment.
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Symptoms of Nance-Horan Syndrome. In affected males, the primary physical characteristic associated with Nance-Horan syndrome is the presence of dense clouding (opacities) of the lens of both eyes at birth (congenital bilateral nuclear cataracts).The lens of an eye is the small transparent flattened and elongated ball located behind the iris through which light passes. The light focuses on the retina, the thin nerve-rich membrane that lining the back of the eye. The retina converts the light into nerve impulses and relays the information along the optic nerve to the brain. Cataracts affect both eyes (bilateral) and usually result in blurred vision and severely decreased clearness or clarity of vision (visual acuity). Vision loss can potentially be profound.Males with Nance-Horan syndrome may have additional eye abnormalities. The front (anterior), clear portion of the eye through which light passes (cornea) may be unusually small (microcornea). In addition, affected males with poor vision may have recurrent, involuntary, “to-and-fro” movements of the eyes (pendular nystagmus) and/or misalignment of the eyes (strabismus). In some cases, the entire eye may be abnormally small (microphthalmia) and/or the upper eyelid may droop (ptosis).Males with Nance-Horan syndrome may also have several dental abnormalities such as unusually shaped, extra (supernumerary) teeth, absence of some teeth (dental agenesis), impacted teeth or unusually wide spaces (diastema) between some of the teeth. Front teeth (incisors) are tapered and “screwdriver-shaped” or are similar in appearance to a tooth abnormality often associated with congenital syphilis (i.e., Hutchinson’s teeth). Posterior teeth may be conical, rounded, cylindrical or with extra cusps (small bumps at the surface of the molar teeth). Some affected males may have an extra (supernumerary), centrally located front tooth in the upper jaw (mesiodens). The tooth may be “cone-shaped” with an abnormally short root. Such supernumerary incisors may prevent or disrupt the normal eruption of permanent incisors in some cases. Both the baby (deciduous) and permanent teeth are involved.In many males with Nance-Horan syndrome, other physical findings may also occur. Distinctive facial features may be present, but may be subtle. The ears may be flared forward (anteverted) and unusually prominent, with folded lobes. Affected males may have a large, prominent nose with a high, narrow nasal bridge; a narrow prominent jaw (prognathism); and a long sometimes narrow face.Some males with Nance-Horan syndrome may also experience delays in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation). In addition, some reports suggest that approximately 20 to 30 percent of affected males may have varying levels of intellectual dysfunction. Intellectual dysfunction is usually mild or moderate, but in some cases can be severe. Autism spectrum disorder symptoms have also been observed in a few patients.As mentioned above, females who carry a single copy of the disease gene for Nance-Horan syndrome (heterozygotes) may develop some symptoms of the disorder. Such symptoms are usually milder and more variable than those associated with the fully expressed disorder. Affected females may have abnormally small corneas (microcornea) and/or Y-shaped clouding (opacities) in the back portion of the lens of the eyes at birth (congenital posterior sutural cataracts). Vision may be normal, or there may be slightly decreased clearness or clarity of vision (visual acuity). Without appropriate treatment, posterior sutural cataracts may progress to total clouding of the lens of the eyes (total cataracts) later in life. Heterozygous females often have some dental abnormalities, such as abnormally-shaped front teeth (incisors) and/or unusually wide spaces (irregular diastema) between some of the teeth. Affected females usually do not develop intellectual impairment.
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Causes of Nance-Horan Syndrome
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Nance-Horan syndrome is caused by mutations of the NHS gene, which is located on the X chromosome. The function of this gene is not fully understood. Nance-Horan syndrome is inherited as an X-linked trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.X-linked disorders are conditions that result from changes (mutations) of a gene on an X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. In females, disease traits resulting from the abnormal copy of a gene on one X chromosome can be “masked” by the normal copy of the gene on the other X chromosome. (For more, see below.) In the opposite, since males only have one X chromosome, if they inherit an abnormal copy of a gene for a disease present on the X, it will likely be fully expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters and a 50 percent risk of transmitting the disease to their sons.As mentioned above, in females who carry a copy of a disease gene for an X-linked trait, disease traits on the X chromosome may essentially be “masked” by the normal gene on the other X chromosome. More specifically, because only one functioning X chromosome is required in males and females, one of the X chromosomes in each cell of a female is essentially “turned off”, usually in a random pattern (random X chromosome inactivation). Therefore, if the X chromosome with the gene mutation is activated in some cells, female carriers may manifest certain, typically more variable or mild features of the disorder as previously discussed (see Symptoms section above).
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Causes of Nance-Horan Syndrome. Nance-Horan syndrome is caused by mutations of the NHS gene, which is located on the X chromosome. The function of this gene is not fully understood. Nance-Horan syndrome is inherited as an X-linked trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.X-linked disorders are conditions that result from changes (mutations) of a gene on an X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. In females, disease traits resulting from the abnormal copy of a gene on one X chromosome can be “masked” by the normal copy of the gene on the other X chromosome. (For more, see below.) In the opposite, since males only have one X chromosome, if they inherit an abnormal copy of a gene for a disease present on the X, it will likely be fully expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters and a 50 percent risk of transmitting the disease to their sons.As mentioned above, in females who carry a copy of a disease gene for an X-linked trait, disease traits on the X chromosome may essentially be “masked” by the normal gene on the other X chromosome. More specifically, because only one functioning X chromosome is required in males and females, one of the X chromosomes in each cell of a female is essentially “turned off”, usually in a random pattern (random X chromosome inactivation). Therefore, if the X chromosome with the gene mutation is activated in some cells, female carriers may manifest certain, typically more variable or mild features of the disorder as previously discussed (see Symptoms section above).
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Affects of Nance-Horan Syndrome
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As discussed above, Nance-Horan syndrome is usually fully expressed in males only, although females who carry a single copy of the disease gene (heterozygotes) may develop certain features. The disorder is present at birth (congenital). Nance-Horan syndrome was described in 1974 by two research teams independent of each other. Fewer than 50 families (kindreds) have been described in the medical literature. The exact incidence of the disorder is unknown. Researchers believe that affected individuals may go unrecognized or misdiagnosed, making it difficult to determine the true frequency of Nance-Horan syndrome in the general population.
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Affects of Nance-Horan Syndrome. As discussed above, Nance-Horan syndrome is usually fully expressed in males only, although females who carry a single copy of the disease gene (heterozygotes) may develop certain features. The disorder is present at birth (congenital). Nance-Horan syndrome was described in 1974 by two research teams independent of each other. Fewer than 50 families (kindreds) have been described in the medical literature. The exact incidence of the disorder is unknown. Researchers believe that affected individuals may go unrecognized or misdiagnosed, making it difficult to determine the true frequency of Nance-Horan syndrome in the general population.
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Related disorders of Nance-Horan Syndrome
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Symptoms of the following disorders may be similar to those of Nance-Horan syndrome. Comparisons may be useful for a differential diagnosis:There are several other rare inherited disorders in which clouding of the lens of the eyes at or shortly after birth (congenital or postnatal cataracts) occurs in association with other abnormalities of the eye. In some cases, the front (anterior), clear portion of the eye through which light passes (cornea) may be unusually small and/or the entire eye may be smaller than normal (microphthalmia). In addition, affected individuals may exhibit rapid, involuntary movements of the eyes (nystagmus); nearsightedness (myopia); misaligned eyes (strabismus); and/or other abnormalities of the eyes. Visual impairment may range from slight to severe, depending upon the extent of cataracts and/or any additional eye abnormalities that are present. These rare cataract disorders are typically isolated and/or may be inherited as autosomal dominant, autosomal recessive, and/or X-linked genetic traits, depending upon the disorder in question. Such disorders include isolated microphthalmia with cataract; cataract-microcornea syndrome; X-linked congenital cataract (total congenital cataract with posterior sutural opacities in heterozygotes; and X-linked congenital cataract with microcornea. The latter two disorders are caused by mutations in the same gene that causes Nance-Horan syndrome (allelic disorders). Some researchers believe that these three disorders represent different expressions of one disorder.Lenz microphthalmia syndrome is an extremely rare inherited disorder characterized by abnormal smallness of one or both eyes (unilateral or bilateral microphthalmia) and/or droopy eyelids (blepharoptosis), resulting in visual impairment. In rare cases, affected infants may exhibit complete absence or rudimentary (vestigial) portions of the eyes (anophthalmia). Most affected infants also exhibit developmental disability, ranging from mild to severe, as well as intellectual disability. Additional physical abnormalities associated with this disorder may include an unusually small head (microcephaly); teeth that are widely spaced or abnormally crowded; ears that flare forward (anteverted) and/or are underdeveloped (hypoplastic); and/or malformations of the fingers and/or toes (digits). Some affected individuals may also exhibit incomplete closure of the roof of the mouth (cleft palate); a vertical groove in the upper lip (cleft lip); a sideways and front-to-back curvature of the spine (kyphoscoliosis); and/or abnormalities of the reproductive and urinary (genitourinary) tract, such as failure of the testes to descend into the scrotum in males (cryptorchidism) and/or underdevelopment (hypoplasia) or absence of a kidney (renal agenesis). Lenz microphthalmia syndrome, which is inherited as an X-linked genetic trait, is fully expressed in males only. However, females who carry one copy of the disease gene (heterozygotes) may exhibit some of the signs associated with the disorder, such as an abnormally small head (microcephaly) and/or malformations of the fingers and/or toes. (For more information on this disorder, choose “Lenz Microphthalmia” as your search term in the Rare Disease Database.)
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Related disorders of Nance-Horan Syndrome. Symptoms of the following disorders may be similar to those of Nance-Horan syndrome. Comparisons may be useful for a differential diagnosis:There are several other rare inherited disorders in which clouding of the lens of the eyes at or shortly after birth (congenital or postnatal cataracts) occurs in association with other abnormalities of the eye. In some cases, the front (anterior), clear portion of the eye through which light passes (cornea) may be unusually small and/or the entire eye may be smaller than normal (microphthalmia). In addition, affected individuals may exhibit rapid, involuntary movements of the eyes (nystagmus); nearsightedness (myopia); misaligned eyes (strabismus); and/or other abnormalities of the eyes. Visual impairment may range from slight to severe, depending upon the extent of cataracts and/or any additional eye abnormalities that are present. These rare cataract disorders are typically isolated and/or may be inherited as autosomal dominant, autosomal recessive, and/or X-linked genetic traits, depending upon the disorder in question. Such disorders include isolated microphthalmia with cataract; cataract-microcornea syndrome; X-linked congenital cataract (total congenital cataract with posterior sutural opacities in heterozygotes; and X-linked congenital cataract with microcornea. The latter two disorders are caused by mutations in the same gene that causes Nance-Horan syndrome (allelic disorders). Some researchers believe that these three disorders represent different expressions of one disorder.Lenz microphthalmia syndrome is an extremely rare inherited disorder characterized by abnormal smallness of one or both eyes (unilateral or bilateral microphthalmia) and/or droopy eyelids (blepharoptosis), resulting in visual impairment. In rare cases, affected infants may exhibit complete absence or rudimentary (vestigial) portions of the eyes (anophthalmia). Most affected infants also exhibit developmental disability, ranging from mild to severe, as well as intellectual disability. Additional physical abnormalities associated with this disorder may include an unusually small head (microcephaly); teeth that are widely spaced or abnormally crowded; ears that flare forward (anteverted) and/or are underdeveloped (hypoplastic); and/or malformations of the fingers and/or toes (digits). Some affected individuals may also exhibit incomplete closure of the roof of the mouth (cleft palate); a vertical groove in the upper lip (cleft lip); a sideways and front-to-back curvature of the spine (kyphoscoliosis); and/or abnormalities of the reproductive and urinary (genitourinary) tract, such as failure of the testes to descend into the scrotum in males (cryptorchidism) and/or underdevelopment (hypoplasia) or absence of a kidney (renal agenesis). Lenz microphthalmia syndrome, which is inherited as an X-linked genetic trait, is fully expressed in males only. However, females who carry one copy of the disease gene (heterozygotes) may exhibit some of the signs associated with the disorder, such as an abnormally small head (microcephaly) and/or malformations of the fingers and/or toes. (For more information on this disorder, choose “Lenz Microphthalmia” as your search term in the Rare Disease Database.)
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Diagnosis of Nance-Horan Syndrome
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Nance-Horan syndrome may be diagnosed based upon a thorough clinical evaluation, detection of characteristic physical findings such as congenital cataracts and dental abnormalities, and specialized testing, including the use of an illuminated microscope to examine the interior of the eyes (slit-lamp examination) and dental x-ray series. Molecular genetic testing for the NHS gene is available to confirm the diagnosis. When the specific mutation is identified, it is possible to test the at-risk females, who would like to know their genetic status before having children. Prenatal diagnosis is feasible when the mutation is identified in a particular family.
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Diagnosis of Nance-Horan Syndrome. Nance-Horan syndrome may be diagnosed based upon a thorough clinical evaluation, detection of characteristic physical findings such as congenital cataracts and dental abnormalities, and specialized testing, including the use of an illuminated microscope to examine the interior of the eyes (slit-lamp examination) and dental x-ray series. Molecular genetic testing for the NHS gene is available to confirm the diagnosis. When the specific mutation is identified, it is possible to test the at-risk females, who would like to know their genetic status before having children. Prenatal diagnosis is feasible when the mutation is identified in a particular family.
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Therapies of Nance-Horan Syndrome
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TreatmentThe treatment of Nance-Horan syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists, such as pediatricians; physicians who diagnose and treat diseases of the eye (ophthalmologists); dental specialists who diagnose, prevent, and/or correct misalignment (malocclusion) and other abnormalities of the teeth (orthodontists); and other health care professionals.A variety of methods may be used to treat, prevent, and/or correct eye defects associated with Nance-Horan syndrome, depending upon the specific combination of abnormalities present, their severity, and/or other factors. In affected males with cataracts, surgery may be recommended to remove the cataracts and, in some cases, to implant artificial lenses. Significant vision loss may still occur despite surgical removal of cataracts. In addition, corrective glasses, contact lenses, and/or other measures may be used to help improve vision.Approximately 50 percent of males with Nance-Horan syndrome develop glaucoma, which results from cataract surgery during infancy. Glaucoma is a condition marked by a rise in the pressure within the eyeball preventing the normal drainage of fluid from the eye and potentially causing characteristic damage to the optic nerve, which relays nerve impulses from the retina to the brain. Glaucoma may be treated medically or surgically.Carrier females and at-risk females should receive regular examinations from an ophthalmologist to ensure early detection of eye abnormalities potentially associated with the disorder. Infrequently, cataract surgery may be recommended to improve or preserve visual acuity.In affected individuals with extra front teeth (supernumerary incisors), surgery may be advised to remove the additional incisors. Braces, dental surgery, and/or other corrective procedures may also be undertaken to correct other dental abnormalities, such as unusually wide spaces (diastema) between some of the teeth.Early intervention is important in ensuring that affected children reach their potential. Special services that may be beneficial may include special remedial education and other medical, social, and/or vocational services. Affected individuals may need to attend a school for the visually impaired.Genetic counseling will be of benefit for affected individuals, at-risk females, and their families. Family members of affected individuals should also receive regular clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with Nance-Horan syndrome or heterozygosity for the disorder.
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Therapies of Nance-Horan Syndrome. TreatmentThe treatment of Nance-Horan syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists, such as pediatricians; physicians who diagnose and treat diseases of the eye (ophthalmologists); dental specialists who diagnose, prevent, and/or correct misalignment (malocclusion) and other abnormalities of the teeth (orthodontists); and other health care professionals.A variety of methods may be used to treat, prevent, and/or correct eye defects associated with Nance-Horan syndrome, depending upon the specific combination of abnormalities present, their severity, and/or other factors. In affected males with cataracts, surgery may be recommended to remove the cataracts and, in some cases, to implant artificial lenses. Significant vision loss may still occur despite surgical removal of cataracts. In addition, corrective glasses, contact lenses, and/or other measures may be used to help improve vision.Approximately 50 percent of males with Nance-Horan syndrome develop glaucoma, which results from cataract surgery during infancy. Glaucoma is a condition marked by a rise in the pressure within the eyeball preventing the normal drainage of fluid from the eye and potentially causing characteristic damage to the optic nerve, which relays nerve impulses from the retina to the brain. Glaucoma may be treated medically or surgically.Carrier females and at-risk females should receive regular examinations from an ophthalmologist to ensure early detection of eye abnormalities potentially associated with the disorder. Infrequently, cataract surgery may be recommended to improve or preserve visual acuity.In affected individuals with extra front teeth (supernumerary incisors), surgery may be advised to remove the additional incisors. Braces, dental surgery, and/or other corrective procedures may also be undertaken to correct other dental abnormalities, such as unusually wide spaces (diastema) between some of the teeth.Early intervention is important in ensuring that affected children reach their potential. Special services that may be beneficial may include special remedial education and other medical, social, and/or vocational services. Affected individuals may need to attend a school for the visually impaired.Genetic counseling will be of benefit for affected individuals, at-risk females, and their families. Family members of affected individuals should also receive regular clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with Nance-Horan syndrome or heterozygosity for the disorder.
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Overview of Narcolepsy
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SummaryNarcolepsy is a neurological sleep disorder characterized by chronic, excessive attacks of drowsiness during the day, sometimes called excessive daytime sleepiness (EDS). Attacks of drowsiness may persist for only a few seconds or several minutes. These episodes vary in frequency from a few incidents to several during a single day. Nighttime (nocturnal) sleep patterns may also be disrupted. Three additional symptoms often associated with narcolepsy are sudden extreme muscle weakness (cataplexy), a specific type of hallucination that occurs just before falling asleep or upon awakening, and brief episodes of paralysis while waking up. Narcolepsy also may be associated with “automatic behavior”, i.e. doing something automatically without any memory afterward. The incidence of narcolepsy is approximately 1 in 2,000 and most researchers believe that the disorder remains undiagnosed or misdiagnosed in many affected individuals. There is increasing evidence that narcolepsy is an autoimmune disorder. Autoimmune disorders are caused when the body's immune system mistakenly attacks healthy tissue or cells. In narcolepsy, the immune system destroys certain brain cells that produce a peptide called hypocretin. Hypocretin impacts on many brain functions, but the details of its actions are not yet understood. Why the immune system attacks healthy cells in narcolepsy is unknown and additional environmental and genetic factors may play a role in the development of the disorder.
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Overview of Narcolepsy. SummaryNarcolepsy is a neurological sleep disorder characterized by chronic, excessive attacks of drowsiness during the day, sometimes called excessive daytime sleepiness (EDS). Attacks of drowsiness may persist for only a few seconds or several minutes. These episodes vary in frequency from a few incidents to several during a single day. Nighttime (nocturnal) sleep patterns may also be disrupted. Three additional symptoms often associated with narcolepsy are sudden extreme muscle weakness (cataplexy), a specific type of hallucination that occurs just before falling asleep or upon awakening, and brief episodes of paralysis while waking up. Narcolepsy also may be associated with “automatic behavior”, i.e. doing something automatically without any memory afterward. The incidence of narcolepsy is approximately 1 in 2,000 and most researchers believe that the disorder remains undiagnosed or misdiagnosed in many affected individuals. There is increasing evidence that narcolepsy is an autoimmune disorder. Autoimmune disorders are caused when the body's immune system mistakenly attacks healthy tissue or cells. In narcolepsy, the immune system destroys certain brain cells that produce a peptide called hypocretin. Hypocretin impacts on many brain functions, but the details of its actions are not yet understood. Why the immune system attacks healthy cells in narcolepsy is unknown and additional environmental and genetic factors may play a role in the development of the disorder.
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Narcolepsy
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Symptoms of Narcolepsy
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The development and severity of symptoms associated with narcolepsy vary greatly from one person to another. The onset of symptoms initially occurs one at a time; appearance of new symptoms may be separated by years, with sleepiness generally preceding cataplexy. Narcolepsy usually begins in an adolescent whose initial symptoms are mild but worsen with age. Sometimes symptoms do not change for months, while at other times symptoms may change very quickly. Depending upon the severity of the disorder, narcolepsy can dramatically affect a person’s daily routine, disrupting all aspects of a person’s life.Excessive daytime sleepiness (EDS) is usually the first symptom of narcolepsy. People with narcolepsy typically experience periods of drowsiness, tiredness, lack of energy, an irresistible urge to sleep (“sleep attack”), and/or an inability to resist sleep. This susceptibility to unending drowsiness and/or falling asleep may occur every day but the severity varies from day to day and throughout each day. These episodes are more likely to occur during monotonous, boring activities such as watching television. However, the episodes can occur at any time even when a person is walking, talking, eating or driving a car. Consequently, narcolepsy can profoundly disrupt a person’s life. Affected individuals may fall asleep for brief periods ranging from a few seconds to several minutes. A characteristic finding of narcolepsy is that affected individuals often feel dramatically more awake and alert following short naps.Narcolepsy can also disrupt nighttime sleeping patterns. Affected individuals may frequently awaken during the night and may be wide awake for significant periods during the night. Despite disrupted sleep patterns, the total sleep time for people with narcolepsy in every 24 hour period is generally normal because they sleep repeatedly for short periods during the day and night.Many individuals with narcolepsy experience weakness and the sudden loss of voluntary muscle tone (cataplexy). This often occurs during times of intense emotions such as laughter, anger, elation, and/or surprise. Episodes of cataplexy may occur as short periods of partial muscle weakness and can vary in duration and severity. In some cases, a cataplectic attack may be barely noticeable. Affected individuals may experience very brief, mild episodes that may cause the knees to buckle, the jaws to sage, the eyelids to droop or the head to drop. Occasionally in severe cases, there may be an almost complete loss of muscle control that lasts for several minutes. During a severe cataplectic attack, speech and movement may become difficult or impossible although there is no loss of consciousness. Cataplexy may improve as affected individuals grow older.Some people with narcolepsy do not have cataplexy, and cataplexy is not necessary for a diagnosis of narcolepsy. Cataplexy usually develops approximately several weeks to months after the development of excessive daytime sleepiness. In rare cases, cataplexy may precede the development of difficulties in maintaining alertness.Some individuals with narcolepsy may experience hallucinations that may occur at the beginning or at the end of a sleep period. These are often vivid and frightening. Examples of hallucinations may include hearing a phone ring or a person walking nearby, seeing people or animals that aren’t there, or having an out of body experience. When the hallucinations occur upon awakening, they are called hypnopompic hallucinations; when they occur when falling asleep, they are called hypnagogic hallucinations. Hallucinations often occur in conjunction with sleep paralysis.People with narcolepsy may experience temporary “sleep paralysis”. They may be briefly unable to move their limbs or heads or speak. Episodes of sleep paralysis are very short and typically coincide with falling asleep or waking up. Affected individuals regain all movements after these brief episodes.Some affected individuals may also experience additional symptoms including fatigue, depression, difficulty concentrating, and memory problems. Periodic leg movements and sleep apnea have also been reported in individuals with narcolepsy.
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Symptoms of Narcolepsy. The development and severity of symptoms associated with narcolepsy vary greatly from one person to another. The onset of symptoms initially occurs one at a time; appearance of new symptoms may be separated by years, with sleepiness generally preceding cataplexy. Narcolepsy usually begins in an adolescent whose initial symptoms are mild but worsen with age. Sometimes symptoms do not change for months, while at other times symptoms may change very quickly. Depending upon the severity of the disorder, narcolepsy can dramatically affect a person’s daily routine, disrupting all aspects of a person’s life.Excessive daytime sleepiness (EDS) is usually the first symptom of narcolepsy. People with narcolepsy typically experience periods of drowsiness, tiredness, lack of energy, an irresistible urge to sleep (“sleep attack”), and/or an inability to resist sleep. This susceptibility to unending drowsiness and/or falling asleep may occur every day but the severity varies from day to day and throughout each day. These episodes are more likely to occur during monotonous, boring activities such as watching television. However, the episodes can occur at any time even when a person is walking, talking, eating or driving a car. Consequently, narcolepsy can profoundly disrupt a person’s life. Affected individuals may fall asleep for brief periods ranging from a few seconds to several minutes. A characteristic finding of narcolepsy is that affected individuals often feel dramatically more awake and alert following short naps.Narcolepsy can also disrupt nighttime sleeping patterns. Affected individuals may frequently awaken during the night and may be wide awake for significant periods during the night. Despite disrupted sleep patterns, the total sleep time for people with narcolepsy in every 24 hour period is generally normal because they sleep repeatedly for short periods during the day and night.Many individuals with narcolepsy experience weakness and the sudden loss of voluntary muscle tone (cataplexy). This often occurs during times of intense emotions such as laughter, anger, elation, and/or surprise. Episodes of cataplexy may occur as short periods of partial muscle weakness and can vary in duration and severity. In some cases, a cataplectic attack may be barely noticeable. Affected individuals may experience very brief, mild episodes that may cause the knees to buckle, the jaws to sage, the eyelids to droop or the head to drop. Occasionally in severe cases, there may be an almost complete loss of muscle control that lasts for several minutes. During a severe cataplectic attack, speech and movement may become difficult or impossible although there is no loss of consciousness. Cataplexy may improve as affected individuals grow older.Some people with narcolepsy do not have cataplexy, and cataplexy is not necessary for a diagnosis of narcolepsy. Cataplexy usually develops approximately several weeks to months after the development of excessive daytime sleepiness. In rare cases, cataplexy may precede the development of difficulties in maintaining alertness.Some individuals with narcolepsy may experience hallucinations that may occur at the beginning or at the end of a sleep period. These are often vivid and frightening. Examples of hallucinations may include hearing a phone ring or a person walking nearby, seeing people or animals that aren’t there, or having an out of body experience. When the hallucinations occur upon awakening, they are called hypnopompic hallucinations; when they occur when falling asleep, they are called hypnagogic hallucinations. Hallucinations often occur in conjunction with sleep paralysis.People with narcolepsy may experience temporary “sleep paralysis”. They may be briefly unable to move their limbs or heads or speak. Episodes of sleep paralysis are very short and typically coincide with falling asleep or waking up. Affected individuals regain all movements after these brief episodes.Some affected individuals may also experience additional symptoms including fatigue, depression, difficulty concentrating, and memory problems. Periodic leg movements and sleep apnea have also been reported in individuals with narcolepsy.
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Narcolepsy
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Causes of Narcolepsy
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Narcolepsy with cataplexy (type 1) has been linked to low levels of a specific brain chemical called hypocretin (also known as orexin). This chemical plays an important role in regulating sleep and other functions. Hypocretin also functions as a neurotransmitter, a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. Researchers have determined that the number of neurons that produce hypocretin is significantly reduced in individuals with narcolepsy. Hypocretin-producing neurons are found in the hypothalamus, the area of the brain that regulates many functions including sleep, appetite and body temperature. In some individuals as many as 80-90 percent of hypocretin-producing neurons in the hypothalamus are lost. Individuals who have narcolepsy with cataplexy have the lowest levels of hypocretin.In 2009, researchers discovered that individuals with narcolepsy have changes in a gene known as a T cell receptor gene. (T cells are specialized immune cells that play a role in all immune system responses). This variant T cell receptor gives individuals a genetic predisposition to developing narcolepsy. A genetic predisposition means that a person carries a gene or genes for a disease, but that it may not be expressed unless other additional factors are present. The genetic factors associated with narcolepsy are insufficient to cause the disorder by themselves.Many cases of narcolepsy are strongly associated with a group of genes known as the human leukocyte antigen (HLA) complex located on human chromosome 6. These genes play a role in regulating the proper function of the immune system. Affected individuals often have variants of some of these genes. The exact role and significance of these HLAs in narcolepsy are not fully understood. Most disorders associated with the HLA complex have an immunological component to the disorder, either through autoimmunity or because of an improper immune system response to a foreign substance. Researchers believe that HLA and the variant T cell found in individuals with narcolepsy interact in a manner that causes the destruction of brain cells that produce hypocretin.The exact cause of narcolepsy without cataplexy (type 2) is unknown.
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Causes of Narcolepsy. Narcolepsy with cataplexy (type 1) has been linked to low levels of a specific brain chemical called hypocretin (also known as orexin). This chemical plays an important role in regulating sleep and other functions. Hypocretin also functions as a neurotransmitter, a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. Researchers have determined that the number of neurons that produce hypocretin is significantly reduced in individuals with narcolepsy. Hypocretin-producing neurons are found in the hypothalamus, the area of the brain that regulates many functions including sleep, appetite and body temperature. In some individuals as many as 80-90 percent of hypocretin-producing neurons in the hypothalamus are lost. Individuals who have narcolepsy with cataplexy have the lowest levels of hypocretin.In 2009, researchers discovered that individuals with narcolepsy have changes in a gene known as a T cell receptor gene. (T cells are specialized immune cells that play a role in all immune system responses). This variant T cell receptor gives individuals a genetic predisposition to developing narcolepsy. A genetic predisposition means that a person carries a gene or genes for a disease, but that it may not be expressed unless other additional factors are present. The genetic factors associated with narcolepsy are insufficient to cause the disorder by themselves.Many cases of narcolepsy are strongly associated with a group of genes known as the human leukocyte antigen (HLA) complex located on human chromosome 6. These genes play a role in regulating the proper function of the immune system. Affected individuals often have variants of some of these genes. The exact role and significance of these HLAs in narcolepsy are not fully understood. Most disorders associated with the HLA complex have an immunological component to the disorder, either through autoimmunity or because of an improper immune system response to a foreign substance. Researchers believe that HLA and the variant T cell found in individuals with narcolepsy interact in a manner that causes the destruction of brain cells that produce hypocretin.The exact cause of narcolepsy without cataplexy (type 2) is unknown.
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Narcolepsy
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Affects of Narcolepsy
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The exact number of people with narcolepsy in the United States is unknown. One estimate places the prevalence at .03 percent to .16 percent of the general population in various ethnic groups worldwide. One U.S. study placed the incidence of new cases of narcolepsy at .74 per 100,000 person-years in the general population in the United States. The disorder has also been estimated to affect 1 in 2,000 people in the general population. However, because narcolepsy often goes unrecognized or misdiagnosed, determining its true frequency in the general population is difficult.The onset of narcolepsy can occur anytime between early childhood and 50 years of age. Two peak time periods have been identified; one around 15 years of age and another around 36 years of age. Some researchers believe that narcolepsy is under-diagnosed in children. Narcolepsy tends to remain a lifelong condition. Although the nature and severity of symptoms experienced by an affected person may varying over time, the disorder is not progressive.Narcolepsy was first described in the medical literature in 1880 by Gelineau and in 1887 by Westphal.
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Affects of Narcolepsy. The exact number of people with narcolepsy in the United States is unknown. One estimate places the prevalence at .03 percent to .16 percent of the general population in various ethnic groups worldwide. One U.S. study placed the incidence of new cases of narcolepsy at .74 per 100,000 person-years in the general population in the United States. The disorder has also been estimated to affect 1 in 2,000 people in the general population. However, because narcolepsy often goes unrecognized or misdiagnosed, determining its true frequency in the general population is difficult.The onset of narcolepsy can occur anytime between early childhood and 50 years of age. Two peak time periods have been identified; one around 15 years of age and another around 36 years of age. Some researchers believe that narcolepsy is under-diagnosed in children. Narcolepsy tends to remain a lifelong condition. Although the nature and severity of symptoms experienced by an affected person may varying over time, the disorder is not progressive.Narcolepsy was first described in the medical literature in 1880 by Gelineau and in 1887 by Westphal.
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Related disorders of Narcolepsy
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Symptoms of the following disorders can be similar to those of narcolepsy. Comparisons may be useful for a differential diagnosis:Idiopathic hypersomnia is a rare condition characterized by episodes or extreme sleepiness that occur for no identifiable reason (idiopathic). Episodes may be chronic or constant. The disorder differs from narcolepsy in that affected individuals do not experience sudden sleep episodes or develop cataplexy. In addition, affected individuals do not feel refreshed after a nap. Some individuals with idiopathic hypersomnia sleep for long periods (e.g., more than 10 hours); others sleep for shorter periods (e.g., fewer than 10 hours). Idiopathic hypersomnia can disrupt many aspects of life. Behavioral modification and certain medications are used to treat the disorder.Sleep apnea is a common sleep disorder characterized by temporary, recurrent interruptions of breathing during sleep. Symptoms of the disorder include frequent interruptions of sleep during the night, excessive sleepiness during the day, loud snoring, irritability, poor concentration and/or cognition. Obesity, including neck obesity and narrow airways in the neck are commonly associated with sleep apnea. In obstructive sleep apnea syndrome, the most common form of sleep apnea, labored breathing is interrupted by airway collapse. Partial awakening may then occur and the person may gasp for air. Sleep is resumed as breathing begins again. Untreated sleep apnea may be associated with high blood pressure, irregular heartbeats, and increased risks for heart attack, heart failure, stroke and diabetes.Kleine-Levin syndrome is a rare disorder characterized by the need for excessive amounts of sleep (hypersomnolence), (i.e., up to 20 hours a day); excessive food intake (compulsive hyperphagia); and behavioral changes such as an abnormally uninhibited sexual drive. When awake, affected individuals may exhibit irritability, lack of energy (lethargy), and/or lack of emotions (apathy). They may also appear confused (disoriented) and experience hallucinations. Symptoms of Kleine-Levin syndrome are cyclical. An affected individual may go for weeks or months without experiencing symptoms. When present, symptoms may persist for days to weeks. In some cases, the symptoms associated with Kleine-Levin syndrome eventually disappear with advancing age. However, episodes may recur later during life. The exact cause of Kleine-Levin syndrome is not known. (For more information, choose “Kleine-Levin” as your search term in the Rare Disease Database.)Symptoms resembling those of narcolepsy may also occur after brain tumors (intracranial), head trauma, hardening of the arteries in the brain (cerebral arteriosclerosis), psychosis, and/or excessive amounts of protein in the blood due to kidney failure (uremia). Hypothyroidism, delayed sleep phase syndrome, periodic limb movement disorder, depression, hypoglycemia and other conditions can also cause excessive daytime sleepiness.
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Related disorders of Narcolepsy. Symptoms of the following disorders can be similar to those of narcolepsy. Comparisons may be useful for a differential diagnosis:Idiopathic hypersomnia is a rare condition characterized by episodes or extreme sleepiness that occur for no identifiable reason (idiopathic). Episodes may be chronic or constant. The disorder differs from narcolepsy in that affected individuals do not experience sudden sleep episodes or develop cataplexy. In addition, affected individuals do not feel refreshed after a nap. Some individuals with idiopathic hypersomnia sleep for long periods (e.g., more than 10 hours); others sleep for shorter periods (e.g., fewer than 10 hours). Idiopathic hypersomnia can disrupt many aspects of life. Behavioral modification and certain medications are used to treat the disorder.Sleep apnea is a common sleep disorder characterized by temporary, recurrent interruptions of breathing during sleep. Symptoms of the disorder include frequent interruptions of sleep during the night, excessive sleepiness during the day, loud snoring, irritability, poor concentration and/or cognition. Obesity, including neck obesity and narrow airways in the neck are commonly associated with sleep apnea. In obstructive sleep apnea syndrome, the most common form of sleep apnea, labored breathing is interrupted by airway collapse. Partial awakening may then occur and the person may gasp for air. Sleep is resumed as breathing begins again. Untreated sleep apnea may be associated with high blood pressure, irregular heartbeats, and increased risks for heart attack, heart failure, stroke and diabetes.Kleine-Levin syndrome is a rare disorder characterized by the need for excessive amounts of sleep (hypersomnolence), (i.e., up to 20 hours a day); excessive food intake (compulsive hyperphagia); and behavioral changes such as an abnormally uninhibited sexual drive. When awake, affected individuals may exhibit irritability, lack of energy (lethargy), and/or lack of emotions (apathy). They may also appear confused (disoriented) and experience hallucinations. Symptoms of Kleine-Levin syndrome are cyclical. An affected individual may go for weeks or months without experiencing symptoms. When present, symptoms may persist for days to weeks. In some cases, the symptoms associated with Kleine-Levin syndrome eventually disappear with advancing age. However, episodes may recur later during life. The exact cause of Kleine-Levin syndrome is not known. (For more information, choose “Kleine-Levin” as your search term in the Rare Disease Database.)Symptoms resembling those of narcolepsy may also occur after brain tumors (intracranial), head trauma, hardening of the arteries in the brain (cerebral arteriosclerosis), psychosis, and/or excessive amounts of protein in the blood due to kidney failure (uremia). Hypothyroidism, delayed sleep phase syndrome, periodic limb movement disorder, depression, hypoglycemia and other conditions can also cause excessive daytime sleepiness.
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Narcolepsy
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Diagnosis of Narcolepsy
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Narcolepsy is diagnosed based upon a thorough clinical evaluation; a careful patient and family history; objective verification of characteristic symptoms (i.e., excessive daytime drowsiness, potentially in association with cataplexy, hypnagogic hallucinations, and/or sleep paralysis); and specialized sleep studies.Two main tests used to diagnose narcolepsy are an overnight polysomnogram (PSG) followed by a multiple sleep latency test (MSLT). A PSG is a test done during sleep and continually measures a variety of things including brain wave changes, heart rate, eye movements, limb movements, muscle tone and respiration. A PSG is usually followed by a MSLT, which measures how quickly someone falls asleep for a nap every two hours during the day (4 or 5 nap opportunities). Individuals with narcolepsy fall asleep during the day more easily than people without narcolepsy. In addition, they will enter dreaming sleep (rapid eye movement sleep) even during a brief nap; something a healthy well-slept individual will not do.Individuals with narcolepsy often have extremely low levels of hypocretin in their cerebrospinal fluid. Testing cerebrospinal fluid for hypocretin levels may be able to assist in a diagnosis of narcolepsy.
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Diagnosis of Narcolepsy. Narcolepsy is diagnosed based upon a thorough clinical evaluation; a careful patient and family history; objective verification of characteristic symptoms (i.e., excessive daytime drowsiness, potentially in association with cataplexy, hypnagogic hallucinations, and/or sleep paralysis); and specialized sleep studies.Two main tests used to diagnose narcolepsy are an overnight polysomnogram (PSG) followed by a multiple sleep latency test (MSLT). A PSG is a test done during sleep and continually measures a variety of things including brain wave changes, heart rate, eye movements, limb movements, muscle tone and respiration. A PSG is usually followed by a MSLT, which measures how quickly someone falls asleep for a nap every two hours during the day (4 or 5 nap opportunities). Individuals with narcolepsy fall asleep during the day more easily than people without narcolepsy. In addition, they will enter dreaming sleep (rapid eye movement sleep) even during a brief nap; something a healthy well-slept individual will not do.Individuals with narcolepsy often have extremely low levels of hypocretin in their cerebrospinal fluid. Testing cerebrospinal fluid for hypocretin levels may be able to assist in a diagnosis of narcolepsy.
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Narcolepsy
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Therapies of Narcolepsy
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TreatmentThe treatment of narcolepsy is directed toward the specific symptoms that are present in each individual. Various medications may help to alleviate certain symptoms associated with narcolepsy.For individuals who experience excessive daytime sleepiness and sleep attacks, therapy may include administration of certain stimulants, such as modafinil (Provigil). Modafinil was approved by the Food and Drug and Administration (FDA) for the treatment of excessive daytime sleepiness in narcolepsy in 1999. Modafinil is now the most widely prescribed drug for excessive daytime sleepiness. The drug’s mechanism of action appears to differ from that of other stimulants and does not appear to affect alertness or memory. In addition, evidence suggests that modafinil therapy is not associated with dependency or symptoms of withdrawal and therefore may be an effective alternative to other treatments for excessive daytime sleepiness. Modafinil is generally associated with fewer side effects than previous drugs used to treat this condition.Previous drugs that have been used to treat excessive daytime sleepiness in narcolepsy include methylphenidate (Ritalin, Methylin), methamphetamine, or dextroamphetamine. These drugs stimulate the central nervous system and are still used when modafinil is unsuccessful. Because such medications may be associated with certain side effects, including nervousness, insomnia, or irritability, careful monitoring by physicians is required to ensure appropriate dosage adjustments and effectiveness of such therapy. In addition, close monitoring and long-term follow-up by physicians may be required if therapy is withdrawn.Additional stimulants that have been used to treat excessive daytime sleepiness and narcolepsy include manzindol, selegiline, and pemoline.A variety of drugs have been used to treat cataplexy. The orphan drug Xyrem, manufactured by Jazz Pharmaceuticals, has been approved by the FDA to treat cataplexy, the sudden loss of muscular control and weakness that is associated with narcolepsy. Xyrem has also been effective in improving nighttime sleep in individuals with narcolepsy. Some individuals with narcolepsy treated with high doses of the drug showed improved of daytime sleepiness. However, Xyrem is potentially associated with serious side effects. The generic name for Xyrem is sodium oxybate and it is also known as gamma hydroxybutyrate or GHB.Individuals with cataplexy, sleep paralysis and/or hypnagogic hallucinations may be treated with certain antidepressants. Specifically, doctors often prescribe selective serotonin reuptake inhibitors, which suppress rapid eye movement sleep, to help alleviate these symptoms. These drugs include for example, fluoxetine (Prozac, Serafem, others), sertraline (Zoloft), atomoxetine (Strattera) and venlafaxine (Effexor). The most common side effects are decreased sexual desire and delayed orgasm. Other side effects can include digestive problems, restlessness, headache and insomnia. Older tricyclic antidepressants such as imipramine, desimipramine, protriptyline, and clomipramine may also be effective in reducing cataplexy, sleep paralysis and/or hallucinations, but many people are bothered by side effects, including dry mouth and constipation. Close monitoring by a physician is necessary for those taking antidepressant medications and is also required if such therapy is withdrawn.In addition to drug therapy, many individuals have benefited from behavioral modification. Regular sleep habits are important for individuals with narcolepsy, including ensuring regular bedtime hours and preventing sleep interruptions. If possible, taking regular naps during the day may help to control excessive daytime sleepiness. Regular exercise is also recommended. Affected individuals should consider speaking with their physicians concerning the establishment of appropriate sleep schedules.
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Therapies of Narcolepsy. TreatmentThe treatment of narcolepsy is directed toward the specific symptoms that are present in each individual. Various medications may help to alleviate certain symptoms associated with narcolepsy.For individuals who experience excessive daytime sleepiness and sleep attacks, therapy may include administration of certain stimulants, such as modafinil (Provigil). Modafinil was approved by the Food and Drug and Administration (FDA) for the treatment of excessive daytime sleepiness in narcolepsy in 1999. Modafinil is now the most widely prescribed drug for excessive daytime sleepiness. The drug’s mechanism of action appears to differ from that of other stimulants and does not appear to affect alertness or memory. In addition, evidence suggests that modafinil therapy is not associated with dependency or symptoms of withdrawal and therefore may be an effective alternative to other treatments for excessive daytime sleepiness. Modafinil is generally associated with fewer side effects than previous drugs used to treat this condition.Previous drugs that have been used to treat excessive daytime sleepiness in narcolepsy include methylphenidate (Ritalin, Methylin), methamphetamine, or dextroamphetamine. These drugs stimulate the central nervous system and are still used when modafinil is unsuccessful. Because such medications may be associated with certain side effects, including nervousness, insomnia, or irritability, careful monitoring by physicians is required to ensure appropriate dosage adjustments and effectiveness of such therapy. In addition, close monitoring and long-term follow-up by physicians may be required if therapy is withdrawn.Additional stimulants that have been used to treat excessive daytime sleepiness and narcolepsy include manzindol, selegiline, and pemoline.A variety of drugs have been used to treat cataplexy. The orphan drug Xyrem, manufactured by Jazz Pharmaceuticals, has been approved by the FDA to treat cataplexy, the sudden loss of muscular control and weakness that is associated with narcolepsy. Xyrem has also been effective in improving nighttime sleep in individuals with narcolepsy. Some individuals with narcolepsy treated with high doses of the drug showed improved of daytime sleepiness. However, Xyrem is potentially associated with serious side effects. The generic name for Xyrem is sodium oxybate and it is also known as gamma hydroxybutyrate or GHB.Individuals with cataplexy, sleep paralysis and/or hypnagogic hallucinations may be treated with certain antidepressants. Specifically, doctors often prescribe selective serotonin reuptake inhibitors, which suppress rapid eye movement sleep, to help alleviate these symptoms. These drugs include for example, fluoxetine (Prozac, Serafem, others), sertraline (Zoloft), atomoxetine (Strattera) and venlafaxine (Effexor). The most common side effects are decreased sexual desire and delayed orgasm. Other side effects can include digestive problems, restlessness, headache and insomnia. Older tricyclic antidepressants such as imipramine, desimipramine, protriptyline, and clomipramine may also be effective in reducing cataplexy, sleep paralysis and/or hallucinations, but many people are bothered by side effects, including dry mouth and constipation. Close monitoring by a physician is necessary for those taking antidepressant medications and is also required if such therapy is withdrawn.In addition to drug therapy, many individuals have benefited from behavioral modification. Regular sleep habits are important for individuals with narcolepsy, including ensuring regular bedtime hours and preventing sleep interruptions. If possible, taking regular naps during the day may help to control excessive daytime sleepiness. Regular exercise is also recommended. Affected individuals should consider speaking with their physicians concerning the establishment of appropriate sleep schedules.
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Narcolepsy
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Overview of Necrotizing Enterocolitis
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Necrotizing enterocolitis, abbreviated NEC, is a devastating disease that affects a newborn’s intestines. It typically occurs in premature infants, born less than 37 weeks, and is characterized by severe inflammation of a baby’s small or large intestines, which may progress to tissue death (necrosis). NEC occurs in about 1 case per 1000 live births [1]. NEC can occur in full term babies but it is much more common in very premature infants, especially very low birth weight babies — incidence ranges from 3% in infants with birth weight of 1251 to 1500 grams (2 pounds 12.13 ounces to 3 pounds 4.91 ounces) to 11% for infants born weighing less than 750 grams (1 pounds 10.46 ounces) [2]. NEC typically occurs when a newborn is several weeks old and on enteral feeds. Initially babies present with vomiting, large distended belly, bloody stools, long pauses in their breathing, and decreased activity. This can further progress to bowel necrosis and perforation. Medical treatment involves discontinuation of enteral feeds (the delivery of nutritionally complete feeds directly into the stomach), initiation of broad-spectrum antibiotics and supportive care [3]. Surgical intervention is indicated when there is evidence of bowel perforation and necrotic bowel. This serious gastrointestinal disease is associated with significant morbidity (complications associated with the disease) and mortality. Despite treatment, about 15% of babies who develop NEC die and some babies that survive suffer from numerous complications such as short bowel syndrome, poor growth, and long-term neurodevelopmental impairments [4]. The exact mechanism of this disease, while not fully understood, is believed to be multifactorial and related to a premature intestine, abnormal gut microbial colonization, and intestinal inflammation.NEC remains a leading cause of morbidity and mortality in the neonatal intensive care unit despite significant advances in the care being provided to premature infants [5;6]. It remains primarily a disease of prematurity. Term infants with risk factors such as congenital heart disease, sepsis, or hypotension (low blood pressure) can also develop NEC [7]. Bell’s classification was introduced in 1978 and is still widely used to clinically stage NEC based on disease severity: stage I being suspected NEC, stage II being confirmed NEC, and stage III being confirmed NEC with intestinal perforation and/or multi-system involvement [8]. More recently, the terminology of acquired neonatal intestinal diseases (ANIDs) was introduced by Gordon et al. to further classify NEC into subgroups based on associated clinical factors: these include NEC in term infants, NEC associated with red blood cell transfusions, NEC associated with cow’s milk intolerance, NEC associated with contagion and/or lymphocytosis, NEC associated with extreme prematurity, and NEC-like diseases [9].
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Overview of Necrotizing Enterocolitis. Necrotizing enterocolitis, abbreviated NEC, is a devastating disease that affects a newborn’s intestines. It typically occurs in premature infants, born less than 37 weeks, and is characterized by severe inflammation of a baby’s small or large intestines, which may progress to tissue death (necrosis). NEC occurs in about 1 case per 1000 live births [1]. NEC can occur in full term babies but it is much more common in very premature infants, especially very low birth weight babies — incidence ranges from 3% in infants with birth weight of 1251 to 1500 grams (2 pounds 12.13 ounces to 3 pounds 4.91 ounces) to 11% for infants born weighing less than 750 grams (1 pounds 10.46 ounces) [2]. NEC typically occurs when a newborn is several weeks old and on enteral feeds. Initially babies present with vomiting, large distended belly, bloody stools, long pauses in their breathing, and decreased activity. This can further progress to bowel necrosis and perforation. Medical treatment involves discontinuation of enteral feeds (the delivery of nutritionally complete feeds directly into the stomach), initiation of broad-spectrum antibiotics and supportive care [3]. Surgical intervention is indicated when there is evidence of bowel perforation and necrotic bowel. This serious gastrointestinal disease is associated with significant morbidity (complications associated with the disease) and mortality. Despite treatment, about 15% of babies who develop NEC die and some babies that survive suffer from numerous complications such as short bowel syndrome, poor growth, and long-term neurodevelopmental impairments [4]. The exact mechanism of this disease, while not fully understood, is believed to be multifactorial and related to a premature intestine, abnormal gut microbial colonization, and intestinal inflammation.NEC remains a leading cause of morbidity and mortality in the neonatal intensive care unit despite significant advances in the care being provided to premature infants [5;6]. It remains primarily a disease of prematurity. Term infants with risk factors such as congenital heart disease, sepsis, or hypotension (low blood pressure) can also develop NEC [7]. Bell’s classification was introduced in 1978 and is still widely used to clinically stage NEC based on disease severity: stage I being suspected NEC, stage II being confirmed NEC, and stage III being confirmed NEC with intestinal perforation and/or multi-system involvement [8]. More recently, the terminology of acquired neonatal intestinal diseases (ANIDs) was introduced by Gordon et al. to further classify NEC into subgroups based on associated clinical factors: these include NEC in term infants, NEC associated with red blood cell transfusions, NEC associated with cow’s milk intolerance, NEC associated with contagion and/or lymphocytosis, NEC associated with extreme prematurity, and NEC-like diseases [9].
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Necrotizing Enterocolitis
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Symptoms of Necrotizing Enterocolitis
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Onset of NEC is typically during the first several weeks after birth when feeds have been started, and the age of onset inversely related to gestational age at birth. Early in the disease process, neonates can exhibit signs of feeding intolerance with vomiting, increased gastric aspirates, bile-tinged (green) gastric aspirates, or decreased bowel sounds with abdominal distention and tenderness. Gross or occult blood can be present in stools indicating mucosal injury. Many of these signs are non-specific and can occur with other disorders. Progression of NEC results in systemic signs such as lethargy, long pauses in breathing called apnea, temperature instability, and poor perfusion (pumping of fluid through an organ or tissue.) Ultimately this can lead to respiratory failure and cardiovascular collapse requiring mechanical ventilation and vasopressors. A palpable mass and erythema (abnormal redness of the skin due to capillary congestion, as in inflammation) of the abdominal wall is indicative of a more advanced disease process.
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Symptoms of Necrotizing Enterocolitis. Onset of NEC is typically during the first several weeks after birth when feeds have been started, and the age of onset inversely related to gestational age at birth. Early in the disease process, neonates can exhibit signs of feeding intolerance with vomiting, increased gastric aspirates, bile-tinged (green) gastric aspirates, or decreased bowel sounds with abdominal distention and tenderness. Gross or occult blood can be present in stools indicating mucosal injury. Many of these signs are non-specific and can occur with other disorders. Progression of NEC results in systemic signs such as lethargy, long pauses in breathing called apnea, temperature instability, and poor perfusion (pumping of fluid through an organ or tissue.) Ultimately this can lead to respiratory failure and cardiovascular collapse requiring mechanical ventilation and vasopressors. A palpable mass and erythema (abnormal redness of the skin due to capillary congestion, as in inflammation) of the abdominal wall is indicative of a more advanced disease process.
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Necrotizing Enterocolitis
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Causes of Necrotizing Enterocolitis
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After many years of research and clinical observation, the etiology and pathogenesis of NEC remain elusive. Some key risk factors have been consistently identified as important prerequisites for initiation of intestinal injury leading to NEC. These include prematurity, formula feeding, abnormal microbial intestinal colonization, and ischemia (when blood vessels to the intestines become narrowed or blocked, reducing blood flow.) [3;10;11].Prematurity remains the main important risk factor associated with NEC. The immaturity of intestinal epithelial cell barrier and immune system appear to contribute to the pathogenesis. Before birth, the fetus has a sterile intestinal environment and becomes colonized rapidly with bacteria after birth. Inappropriate colonization with predominance of gram negative bacteria can lead to disruption of normal intestinal epithelium, bacterial translocation, and trigger an excessive inflammatory response [10;12-14]. The hallmark histologic findings seen in NEC are inflammation and coagulation necrosis [11] (a pattern of tissue death.) Ischemia is another important pathophysiologic factor in the development of NEC. Decreased oxygen supply to intestinal cells can lead to cellular injury and necrosis.
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Causes of Necrotizing Enterocolitis. After many years of research and clinical observation, the etiology and pathogenesis of NEC remain elusive. Some key risk factors have been consistently identified as important prerequisites for initiation of intestinal injury leading to NEC. These include prematurity, formula feeding, abnormal microbial intestinal colonization, and ischemia (when blood vessels to the intestines become narrowed or blocked, reducing blood flow.) [3;10;11].Prematurity remains the main important risk factor associated with NEC. The immaturity of intestinal epithelial cell barrier and immune system appear to contribute to the pathogenesis. Before birth, the fetus has a sterile intestinal environment and becomes colonized rapidly with bacteria after birth. Inappropriate colonization with predominance of gram negative bacteria can lead to disruption of normal intestinal epithelium, bacterial translocation, and trigger an excessive inflammatory response [10;12-14]. The hallmark histologic findings seen in NEC are inflammation and coagulation necrosis [11] (a pattern of tissue death.) Ischemia is another important pathophysiologic factor in the development of NEC. Decreased oxygen supply to intestinal cells can lead to cellular injury and necrosis.
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Necrotizing Enterocolitis
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Affects of Necrotizing Enterocolitis
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NEC affects 5 to 10% of premature infants born weighing less than 1500 g. Among the risk factors defined for NEC, prematurity and birth weight remain inversely related to risk for NEC. Term infants who develop NEC usually have specific risk factors such as congenital heart disease, sepsis, and low blood pressure.
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Affects of Necrotizing Enterocolitis. NEC affects 5 to 10% of premature infants born weighing less than 1500 g. Among the risk factors defined for NEC, prematurity and birth weight remain inversely related to risk for NEC. Term infants who develop NEC usually have specific risk factors such as congenital heart disease, sepsis, and low blood pressure.
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Necrotizing Enterocolitis
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Related disorders of Necrotizing Enterocolitis
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Many other gastrointestinal diseases can mimic NEC, so when evaluating a patient it is important to consider and treat alternative etiologies. Sepsis can cause an ileus with abdominal distention and feeding intolerance. Premature infants, especially those on indomethacin or steroids can also present with spontaneous intestinal perforation (SIP). SIP is characterized by isolated perforation of the distal small bowel. Other causes of severe abdominal distention in neonates include bowel obstruction from Hirshsprung’s disease, small bowel atresia, meconium ileus, and malrotation with volvulus. NEC can also be mistaken for allergic enterocolitis secondary to cow’s milk protein allergy.
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Related disorders of Necrotizing Enterocolitis. Many other gastrointestinal diseases can mimic NEC, so when evaluating a patient it is important to consider and treat alternative etiologies. Sepsis can cause an ileus with abdominal distention and feeding intolerance. Premature infants, especially those on indomethacin or steroids can also present with spontaneous intestinal perforation (SIP). SIP is characterized by isolated perforation of the distal small bowel. Other causes of severe abdominal distention in neonates include bowel obstruction from Hirshsprung’s disease, small bowel atresia, meconium ileus, and malrotation with volvulus. NEC can also be mistaken for allergic enterocolitis secondary to cow’s milk protein allergy.
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Necrotizing Enterocolitis
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Diagnosis of Necrotizing Enterocolitis
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NEC is diagnosed clinically and radiographically. Once clinical suspicion arises, an abdominal X-ray is performed as an initial evaluation. This is repeated serially depending on acuity and clinical course to assess disease progression. Characteristic findings on NEC process on abdominal radiographs include pneumatosis intestinalis (air in the intestinal wall), abnormal persistent dilated loops, thickened bowel wall, pneumoperitoneum and portal vein gas. Pneumoperitoneum defined as abdominal free air is a surgical emergency indicating bowel perforation and usually requires intervention. Abdominal ultrasonography can also be used to evaluate for free fluid in the abdominal cavity or abscess formation. Addition laboratory studies to evaluate severity of NEC include a blood culture, coagulation studies and complete blood count with manual differential to assess for leukocytosis with bandemia, neutropenia, anemia and thrombocytopenia. Blood gases are checked serially to assess severity of acidosis and need for respiratory support or to assist with fluid management.
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Diagnosis of Necrotizing Enterocolitis. NEC is diagnosed clinically and radiographically. Once clinical suspicion arises, an abdominal X-ray is performed as an initial evaluation. This is repeated serially depending on acuity and clinical course to assess disease progression. Characteristic findings on NEC process on abdominal radiographs include pneumatosis intestinalis (air in the intestinal wall), abnormal persistent dilated loops, thickened bowel wall, pneumoperitoneum and portal vein gas. Pneumoperitoneum defined as abdominal free air is a surgical emergency indicating bowel perforation and usually requires intervention. Abdominal ultrasonography can also be used to evaluate for free fluid in the abdominal cavity or abscess formation. Addition laboratory studies to evaluate severity of NEC include a blood culture, coagulation studies and complete blood count with manual differential to assess for leukocytosis with bandemia, neutropenia, anemia and thrombocytopenia. Blood gases are checked serially to assess severity of acidosis and need for respiratory support or to assist with fluid management.
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Necrotizing Enterocolitis
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Therapies of Necrotizing Enterocolitis
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Treatment of NEC depends on the clinical staging. In cases of suspected NEC, stage I, initial treatment consists of bowel rest with discontinuation of enteral feeds, nasogastric decompression, cultures of blood, and initiation of broad-spectrum antibiotics. While infant remains NPO, “nothing by mouth”, intravenous parenteral nutrition is initiated. Close observation with serial examinations and radiographs is essential. Surgical consultation is obtained once NEC is confirmed, stage II or III. Supportive care includes respiratory support, inotropic (cardiac function) support, fluid resuscitation and correction of acid-base imbalance. Patients with NEC can develop disseminated intravascular coagulation (DIC) (a condition that prevents blood from clotting normally) from consumption of clotting factors and require blood product transfusions. The principal indication for surgical intervention in NEC is a perforated or necrotic intestine. Other indications include clinical deterioration and severe abdominal distention causing abdominal compartment syndrome (organ dysfunction or failure due to a severe increase in the pressure within the abdomen.) Two surgical approaches are usually done depending on clinical presentation, laparotomy with resection (removal) of necrotic bowel or primary peritoneal drainage (the procedure of inserting a Penrose drain into the space within the abdomen that contains the intestines, the stomach, and the liver).Prevention of NEC has the greatest potential to reduce adverse outcomes related with NEC. Currently, breast milk has been clearly shown to be protective against NEC compared with formula feeding [15;16]. Establishment of a standardized feeding protocol with objective criteria for withholding feeds has also been shown to reduce the risk of NEC [17]. Probiotics have the potential to prevent NEC by restoring gut microbial flora but it still requires further investigation as to optimum dosage and duration of treatment [18].
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Therapies of Necrotizing Enterocolitis. Treatment of NEC depends on the clinical staging. In cases of suspected NEC, stage I, initial treatment consists of bowel rest with discontinuation of enteral feeds, nasogastric decompression, cultures of blood, and initiation of broad-spectrum antibiotics. While infant remains NPO, “nothing by mouth”, intravenous parenteral nutrition is initiated. Close observation with serial examinations and radiographs is essential. Surgical consultation is obtained once NEC is confirmed, stage II or III. Supportive care includes respiratory support, inotropic (cardiac function) support, fluid resuscitation and correction of acid-base imbalance. Patients with NEC can develop disseminated intravascular coagulation (DIC) (a condition that prevents blood from clotting normally) from consumption of clotting factors and require blood product transfusions. The principal indication for surgical intervention in NEC is a perforated or necrotic intestine. Other indications include clinical deterioration and severe abdominal distention causing abdominal compartment syndrome (organ dysfunction or failure due to a severe increase in the pressure within the abdomen.) Two surgical approaches are usually done depending on clinical presentation, laparotomy with resection (removal) of necrotic bowel or primary peritoneal drainage (the procedure of inserting a Penrose drain into the space within the abdomen that contains the intestines, the stomach, and the liver).Prevention of NEC has the greatest potential to reduce adverse outcomes related with NEC. Currently, breast milk has been clearly shown to be protective against NEC compared with formula feeding [15;16]. Establishment of a standardized feeding protocol with objective criteria for withholding feeds has also been shown to reduce the risk of NEC [17]. Probiotics have the potential to prevent NEC by restoring gut microbial flora but it still requires further investigation as to optimum dosage and duration of treatment [18].
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Necrotizing Enterocolitis
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nord_863_0
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Overview of Necrotizing Fasciitis
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Necrotizing fasciitis (NF) is a rare infection that means “decaying infection of the fascia,” which is the soft tissue that is part of the connective tissue system that runs throughout the body. NF is caused by one or more bacteria that attacks the skin, the tissue just beneath the skin (subcutaneous tissue) and the fascia causing these tissues to die (necrosis). These infections can be sudden, vicious, and fast spreading. If not treated quickly with antibiotics and/or debridement of the infected tissue, the patient may develop toxic shock syndrome or toxic shock-like syndrome, which may lead to multiple organ failure and death.
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Overview of Necrotizing Fasciitis. Necrotizing fasciitis (NF) is a rare infection that means “decaying infection of the fascia,” which is the soft tissue that is part of the connective tissue system that runs throughout the body. NF is caused by one or more bacteria that attacks the skin, the tissue just beneath the skin (subcutaneous tissue) and the fascia causing these tissues to die (necrosis). These infections can be sudden, vicious, and fast spreading. If not treated quickly with antibiotics and/or debridement of the infected tissue, the patient may develop toxic shock syndrome or toxic shock-like syndrome, which may lead to multiple organ failure and death.
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Necrotizing Fasciitis
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Symptoms of Necrotizing Fasciitis
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Early symptoms of NF are often mistaken for the flu or local skin irritation. They include high fever, sore throat, stomachache, nausea, diarrhea, chills and general body aches. Around the same time, patients may notice redness (erythema) and pain or tenderness around the red area. The red area often occurs at the infection point, which may include surgical sites, a cut, scratch, bruise, boil, pimple, site of medication or drug injection or any small injury that could have occurred during daily life. The affected area may also spread from the infection point quickly, sometimes spreading at a rate as fast as an inch an hour.If NF progresses to show advanced symptoms, the patient will continue to have a very high fever (over 102 degrees Fahrenheit) or may become hypothermic (low temperature) and become dehydrated. The pain in the infected area becomes constant and piercing, often extending beyond the area that is red. The pain can be much more severe than expected based on the original injury. The infected area may appear bright red, shiny, swollen and very hot to the touch. As the infection progresses, the affected area will continue to swell, become purple or mottled (blotches of black, purple, and red) and may be accompanied by a rash of blisters and this is a sign of skin necrosis. The affected area may become hard due to the swelling/inflammation caused by the infection (induration). Although the pain becomes excruciating over the initial 24-48 hours, a very late sign of infection is sudden improvement in pain or lack of sensation in the affected area. This may occur as the nerves in the area begin to die and often occurs at the same time that the skin starts to turn purple/black. The patient may have extremely low blood pressure (hypotension) and a faint, rapid heartbeat (tachycardia), which results in dizziness, weakness and confusion.If NF progresses to show critical symptoms, the patient’s confusion and weakness will become pronounced and the patient may become delirious. They may repeatedly lose bowel/bladder control or consciousness and the infected area will swell to several times the normal size. On occasion, the swollen area may split open and release large amounts of thin, cloudy drainage fluid, although this is not common. Large blisters (bullae) filled with a bloody or yellowish fluid and blackened necrotic lesions appear, causing the skin to break open. The pain slowly subsides as nerves are destroyed, causing a lack of sensation (anesthesia). Urine output ceases (anuria), blood pressure drops severely, heart rate continues to be rapid and breathing becomes rapid and shallow (tachypnea). Eventually, the patient’s vital organs (kidneys, liver, lungs, etc.) shut down due to toxic shock. The skin and other tissues continue to blacken as they die and may shed from the body. Death is imminent.
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Symptoms of Necrotizing Fasciitis. Early symptoms of NF are often mistaken for the flu or local skin irritation. They include high fever, sore throat, stomachache, nausea, diarrhea, chills and general body aches. Around the same time, patients may notice redness (erythema) and pain or tenderness around the red area. The red area often occurs at the infection point, which may include surgical sites, a cut, scratch, bruise, boil, pimple, site of medication or drug injection or any small injury that could have occurred during daily life. The affected area may also spread from the infection point quickly, sometimes spreading at a rate as fast as an inch an hour.If NF progresses to show advanced symptoms, the patient will continue to have a very high fever (over 102 degrees Fahrenheit) or may become hypothermic (low temperature) and become dehydrated. The pain in the infected area becomes constant and piercing, often extending beyond the area that is red. The pain can be much more severe than expected based on the original injury. The infected area may appear bright red, shiny, swollen and very hot to the touch. As the infection progresses, the affected area will continue to swell, become purple or mottled (blotches of black, purple, and red) and may be accompanied by a rash of blisters and this is a sign of skin necrosis. The affected area may become hard due to the swelling/inflammation caused by the infection (induration). Although the pain becomes excruciating over the initial 24-48 hours, a very late sign of infection is sudden improvement in pain or lack of sensation in the affected area. This may occur as the nerves in the area begin to die and often occurs at the same time that the skin starts to turn purple/black. The patient may have extremely low blood pressure (hypotension) and a faint, rapid heartbeat (tachycardia), which results in dizziness, weakness and confusion.If NF progresses to show critical symptoms, the patient’s confusion and weakness will become pronounced and the patient may become delirious. They may repeatedly lose bowel/bladder control or consciousness and the infected area will swell to several times the normal size. On occasion, the swollen area may split open and release large amounts of thin, cloudy drainage fluid, although this is not common. Large blisters (bullae) filled with a bloody or yellowish fluid and blackened necrotic lesions appear, causing the skin to break open. The pain slowly subsides as nerves are destroyed, causing a lack of sensation (anesthesia). Urine output ceases (anuria), blood pressure drops severely, heart rate continues to be rapid and breathing becomes rapid and shallow (tachypnea). Eventually, the patient’s vital organs (kidneys, liver, lungs, etc.) shut down due to toxic shock. The skin and other tissues continue to blacken as they die and may shed from the body. Death is imminent.
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Causes of Necrotizing Fasciitis
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NF is caused by a bacterium (monomicrobial NF) or several bacteria (polymicrobial NF) infecting the tissue just beneath the skin (subcutaneous tissue). The bacteria or bacterium enter the body either via an external injury (surgical sites, a cut, scratch, bruise, boil or any small injury) or via direct spread from a punctured / perforated internal organ (particularly the colon, rectum or anus) or sexual organ. Upon infection, the bacteria or bacterium spreads via the fascia, producing endo-toxins (toxins released as the bacteria die and break apart or are lysed) and exo-toxins (toxins released by bacteria as waste) that restricts blood supply to tissue (tissue ischemia), digestion of cells by enzymes resulting in a lesion consisting of pus and the fluid remains of dead tissue, and often systemic illness (disease of any major organ system or any condition that ultimately affects the whole body). Because blood supply to these tissues becomes impaired, neither antibiotics nor the body’s own mechanisms to fight infection can reach these tissues. As such, treatment requires surgical debridement (surgical removal of dead and infected tissue).Given the prevalence of all the bacteria that cause NF, it is important to ensure external wounds are kept clean to minimize infection. This can be done with simple soap and water.The rest of this section highlights the different bacteria known to cause NF.Group A Streptococci (Streptococcus pyogenes)
Group A strep bacteria are among the most common causes of NF. These Gram-positive bacteria are commonly carried by humans in the nose, throat, and skin without showing any symptoms. There are over 100 types (serotypes) of group A strep. Strep is the bacteria that causes strep throat. However, when it penetrates the body, it can cause necrotizing fasciitis. When group A strep causes NF, it can occur together with streptococcal toxic shock syndrome (STSS), which accelerates the speed and deadliness of the infection.Staphylococcus aureus
Staphylococcus aureus bacteria are becoming a more common cause of NF. Similar to Strep, these gram-positive bacteria are commonly carried by humans on our skin or noses without showing any symptoms. Staph bacteria can cause boils and food poisoning. Methicillin-resistant staphylococcus aureus (MRSA) is a strain of these bacteria that is a major source of hospital-acquired infections but has become increasingly common in the community over the last decade. It is also frequently found in communal areas such as locker rooms, dormitories, and nursing homes. Its resistance to antibiotics presents a concern during treatment, but specific antibiotics are available to treat MRSA.Klebsiella
Klebsiella are gram-negative bacteria commonly found in nature. They are known to cause pneumonia, urinary tract infections as well as NF.Escherichia coli
Escherichia coli are gram-negative bacteria often found in the large intestine. Most are harmless but have been known to cause food poisoning. Most strains are helpful for humans when confined to our large intestine (colon), as they provide vitamin K and prevent harmful bacteria from establishing in the intestines. However, E. coli outside of the intestine can cause infection, including NF.Bacteroides
Bacteroides are anaerobic (can survive without oxygen) gram-negative bacteria that are normally found in the mouth, intestines and genitals. These bacteria usually benefit humans by preventing serious pathogens from colonizing the gut. However, when bacteroides infect the fascia (e.g., via a perforated bowel), NF can result.Clostridium
Clostridium are anaerobic gram-positive bacteria that are commonly found in soil, as well as the intestines of humans and animals. Clostridium botulinum is a bacterium that causes botulism, but there are many other types of Clostridia, including Clostridium perfringens, Clostridium histolylicum, Clostridium septicum and Clostridium sordellii. These bacteria are not as common causes of NF but have been known to cause NF and gas gangrene.Pseudomonas
Pseudomonas are gram-negative bacteria that are widespread in nature. They cause many infections, including skin infections and pneumonia. NF infections caused by Pseudomonas usually occur in patients with compromised immune systems.Prevotella
Prevotella are gram-negative bacteria that exist throughout the body, usually without causing symptoms. NF infections caused by Prevotella often occur together with other bacteria and usually target the mouth, jaw, neck and face.
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Causes of Necrotizing Fasciitis. NF is caused by a bacterium (monomicrobial NF) or several bacteria (polymicrobial NF) infecting the tissue just beneath the skin (subcutaneous tissue). The bacteria or bacterium enter the body either via an external injury (surgical sites, a cut, scratch, bruise, boil or any small injury) or via direct spread from a punctured / perforated internal organ (particularly the colon, rectum or anus) or sexual organ. Upon infection, the bacteria or bacterium spreads via the fascia, producing endo-toxins (toxins released as the bacteria die and break apart or are lysed) and exo-toxins (toxins released by bacteria as waste) that restricts blood supply to tissue (tissue ischemia), digestion of cells by enzymes resulting in a lesion consisting of pus and the fluid remains of dead tissue, and often systemic illness (disease of any major organ system or any condition that ultimately affects the whole body). Because blood supply to these tissues becomes impaired, neither antibiotics nor the body’s own mechanisms to fight infection can reach these tissues. As such, treatment requires surgical debridement (surgical removal of dead and infected tissue).Given the prevalence of all the bacteria that cause NF, it is important to ensure external wounds are kept clean to minimize infection. This can be done with simple soap and water.The rest of this section highlights the different bacteria known to cause NF.Group A Streptococci (Streptococcus pyogenes)
Group A strep bacteria are among the most common causes of NF. These Gram-positive bacteria are commonly carried by humans in the nose, throat, and skin without showing any symptoms. There are over 100 types (serotypes) of group A strep. Strep is the bacteria that causes strep throat. However, when it penetrates the body, it can cause necrotizing fasciitis. When group A strep causes NF, it can occur together with streptococcal toxic shock syndrome (STSS), which accelerates the speed and deadliness of the infection.Staphylococcus aureus
Staphylococcus aureus bacteria are becoming a more common cause of NF. Similar to Strep, these gram-positive bacteria are commonly carried by humans on our skin or noses without showing any symptoms. Staph bacteria can cause boils and food poisoning. Methicillin-resistant staphylococcus aureus (MRSA) is a strain of these bacteria that is a major source of hospital-acquired infections but has become increasingly common in the community over the last decade. It is also frequently found in communal areas such as locker rooms, dormitories, and nursing homes. Its resistance to antibiotics presents a concern during treatment, but specific antibiotics are available to treat MRSA.Klebsiella
Klebsiella are gram-negative bacteria commonly found in nature. They are known to cause pneumonia, urinary tract infections as well as NF.Escherichia coli
Escherichia coli are gram-negative bacteria often found in the large intestine. Most are harmless but have been known to cause food poisoning. Most strains are helpful for humans when confined to our large intestine (colon), as they provide vitamin K and prevent harmful bacteria from establishing in the intestines. However, E. coli outside of the intestine can cause infection, including NF.Bacteroides
Bacteroides are anaerobic (can survive without oxygen) gram-negative bacteria that are normally found in the mouth, intestines and genitals. These bacteria usually benefit humans by preventing serious pathogens from colonizing the gut. However, when bacteroides infect the fascia (e.g., via a perforated bowel), NF can result.Clostridium
Clostridium are anaerobic gram-positive bacteria that are commonly found in soil, as well as the intestines of humans and animals. Clostridium botulinum is a bacterium that causes botulism, but there are many other types of Clostridia, including Clostridium perfringens, Clostridium histolylicum, Clostridium septicum and Clostridium sordellii. These bacteria are not as common causes of NF but have been known to cause NF and gas gangrene.Pseudomonas
Pseudomonas are gram-negative bacteria that are widespread in nature. They cause many infections, including skin infections and pneumonia. NF infections caused by Pseudomonas usually occur in patients with compromised immune systems.Prevotella
Prevotella are gram-negative bacteria that exist throughout the body, usually without causing symptoms. NF infections caused by Prevotella often occur together with other bacteria and usually target the mouth, jaw, neck and face.
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Affects of Necrotizing Fasciitis
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Conditions and behaviors that increase the prevalence of poly-microbial NF include obesity, poorly controlled or untreated diabetes, chronic kidney failure, HIV, immunosuppression (for example steroid, monoclonal antibody, or chemotherapy use), alcohol abuse, undrained abscesses, IV drug use, penetrating trauma, insect bites, surgical incisions, indwelling catheters, chicken pox, vesicles and (rarely) perforation of the gastrointestinal tract (Sarani et al). However, everybody is susceptible to NF.
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Affects of Necrotizing Fasciitis. Conditions and behaviors that increase the prevalence of poly-microbial NF include obesity, poorly controlled or untreated diabetes, chronic kidney failure, HIV, immunosuppression (for example steroid, monoclonal antibody, or chemotherapy use), alcohol abuse, undrained abscesses, IV drug use, penetrating trauma, insect bites, surgical incisions, indwelling catheters, chicken pox, vesicles and (rarely) perforation of the gastrointestinal tract (Sarani et al). However, everybody is susceptible to NF.
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Related disorders of Necrotizing Fasciitis
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Necrotizing Soft Tissue Infection (NSTI)
NF is a type of NSTI. NSTIs encompass all forms of diseases that involve necrotizing infection of soft tissue. This terminology is being encouraged by doctors since all NSTIs require a similar approach to diagnosis and treatment regardless of location or depth of infection on the body. Diseases that fall under NSTI include necrotizing adipositis or necrotizing cellulitis, necrotizing fasciitis and necrotizing myositis.NSTI Caused by Vibrio Vulnificus (VV)
VV causes symptoms similar to other NSTIs. It is classified by some experts as an NSTI, although this is not universally agreed upon. VV is a bacterium found in warm sea water and can infect people in a similar fashion to other bacteria (through wounds). Aside from exposure to marine life, people with moderate to severe liver disease (particularly chronic hepatitis B infection) are at risk for infection by VV. If not caught and treated early, multi-system organ failure can develop within 24 hours, followed by death. VV is the most severe aggressive form of NSTI and usually starts in the legs.Toxic Shock Syndrome (TSS) and Streptococcal TSS or Toxic Shock-Like Syndrome (TSLS)
TSS and TSLS occurs when a patient is infected with a bacterium (often staphylococcus aureus or streptococcus pyogenes) and succumbs to the exo-toxins and endotoxins released by the bacteria. It is a complication of NSTIs and needs to be treated quickly with antibiotics, fluid management, and when needed, vasopressors. TSS or TSLS is diagnosed based on strict criteria defined by the Centers for Disease Control and Prevention (CDC). Symptoms typically include high fever, low blood pressure, rashes, vomiting, diarrhea, kidney failure, low platelet counts and confusion.Mucormycosis
Mucormycosis is an infection caused by mucorales fungi, which are found in bread and fruit mold. It rarely infects humans, but can infect those who are immunocompromised (e.g., severe burn victims or those suffering complications from diabetes, HIV, chemotherapy, high dose steroids or leukemia). Symptoms of mucormycosis mimic those of NF, including rapid spread of soft tissue necrosis and blisters. Similar to NF, mucormycosis requires prompt diagnosis and similar treatment to save patients. It is known to affect the sinuses and soft palate, and can spread very quickly to the brain, often with fatal results. Standard antibiotics have no activity against mucormycosis because this organism responds to antifungal agents only.Brown Recluse Spider Bite
Bites from the brown recluse spider (also known as the fiddle back or loxosceles reclusa) can be confused with NF. The bites are rarely fatal but cause severe pain and localized skin and soft tissue necrosis, rashes, lethargy, fever and chills, similar to NF symptoms. Treatment for these bites requires antibiotic therapy and wound care.
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Related disorders of Necrotizing Fasciitis. Necrotizing Soft Tissue Infection (NSTI)
NF is a type of NSTI. NSTIs encompass all forms of diseases that involve necrotizing infection of soft tissue. This terminology is being encouraged by doctors since all NSTIs require a similar approach to diagnosis and treatment regardless of location or depth of infection on the body. Diseases that fall under NSTI include necrotizing adipositis or necrotizing cellulitis, necrotizing fasciitis and necrotizing myositis.NSTI Caused by Vibrio Vulnificus (VV)
VV causes symptoms similar to other NSTIs. It is classified by some experts as an NSTI, although this is not universally agreed upon. VV is a bacterium found in warm sea water and can infect people in a similar fashion to other bacteria (through wounds). Aside from exposure to marine life, people with moderate to severe liver disease (particularly chronic hepatitis B infection) are at risk for infection by VV. If not caught and treated early, multi-system organ failure can develop within 24 hours, followed by death. VV is the most severe aggressive form of NSTI and usually starts in the legs.Toxic Shock Syndrome (TSS) and Streptococcal TSS or Toxic Shock-Like Syndrome (TSLS)
TSS and TSLS occurs when a patient is infected with a bacterium (often staphylococcus aureus or streptococcus pyogenes) and succumbs to the exo-toxins and endotoxins released by the bacteria. It is a complication of NSTIs and needs to be treated quickly with antibiotics, fluid management, and when needed, vasopressors. TSS or TSLS is diagnosed based on strict criteria defined by the Centers for Disease Control and Prevention (CDC). Symptoms typically include high fever, low blood pressure, rashes, vomiting, diarrhea, kidney failure, low platelet counts and confusion.Mucormycosis
Mucormycosis is an infection caused by mucorales fungi, which are found in bread and fruit mold. It rarely infects humans, but can infect those who are immunocompromised (e.g., severe burn victims or those suffering complications from diabetes, HIV, chemotherapy, high dose steroids or leukemia). Symptoms of mucormycosis mimic those of NF, including rapid spread of soft tissue necrosis and blisters. Similar to NF, mucormycosis requires prompt diagnosis and similar treatment to save patients. It is known to affect the sinuses and soft palate, and can spread very quickly to the brain, often with fatal results. Standard antibiotics have no activity against mucormycosis because this organism responds to antifungal agents only.Brown Recluse Spider Bite
Bites from the brown recluse spider (also known as the fiddle back or loxosceles reclusa) can be confused with NF. The bites are rarely fatal but cause severe pain and localized skin and soft tissue necrosis, rashes, lethargy, fever and chills, similar to NF symptoms. Treatment for these bites requires antibiotic therapy and wound care.
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Diagnosis of Necrotizing Fasciitis
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Diagnosing NF early and quickly is vital to improving survival. However, studies have shown that since it is so rare (on average, doctors see two cases of NF during their lifetime), misdiagnosis is common. As such, patients and doctors should have a high index of suspicion and ask to eliminate NF as a diagnosis as soon as possible.Once at the hospital, patients will have laboratory testing performed. Often, patients will have white blood cell counts greater than 15,400 cells/mm3 or a sodium level lower than 135 mmol/L. While doctors and scientists have tried to develop laboratory risk indicators for necrotizing fasciitis score to predict if a patient has NF, this scoring tool has yet to be validated in large scale studies.Apart from clinical diagnosis based on presenting symptoms (i.e., doctor’s initial opinion based on his/her experience and observations), doctors have two options to help diagnose NF. The first is radiographic testing (e.g., X-ray, CT scans and MRIs). X-rays tend to be a poor choice of diagnostic testing as it only shows air trapped under the skin (subcutaneous emphysema), which is only present in a small proportion of NF patients. CT scans are readily available and do a good job of helping doctors diagnose NF because it can show inflammatory changes, such as accumulation of fluid (edema), thickening or collection of pus (abscesses) in the fascia, in addition to gas formation. MRIs are less available and often difficult to administer to patients in critical or unstable condition, often leading to a delay in diagnosis. However, they also effectively help doctors diagnose NF by showing soft-tissue or fascial thickening.The second option is the gold standard in diagnosing NF i.e., exploratory surgery where it is common to find “dishwater” or foul-smelling discharge, necrosis or lack of bleeding, and loss of the normal resistance of the fascia to finger dissection. Intra-operative biopsy with gram stain can be used in some cases but not necessary as findings from the exploratory surgery are often definitive.Upon diagnosing NF, doctors will often perform tissue cultures on the infected tissue to determine the bacteria that is causing the infection. However, beginning NF treatment before the results of the cultures are available (often ~3 days after culture) is essential.
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Diagnosis of Necrotizing Fasciitis. Diagnosing NF early and quickly is vital to improving survival. However, studies have shown that since it is so rare (on average, doctors see two cases of NF during their lifetime), misdiagnosis is common. As such, patients and doctors should have a high index of suspicion and ask to eliminate NF as a diagnosis as soon as possible.Once at the hospital, patients will have laboratory testing performed. Often, patients will have white blood cell counts greater than 15,400 cells/mm3 or a sodium level lower than 135 mmol/L. While doctors and scientists have tried to develop laboratory risk indicators for necrotizing fasciitis score to predict if a patient has NF, this scoring tool has yet to be validated in large scale studies.Apart from clinical diagnosis based on presenting symptoms (i.e., doctor’s initial opinion based on his/her experience and observations), doctors have two options to help diagnose NF. The first is radiographic testing (e.g., X-ray, CT scans and MRIs). X-rays tend to be a poor choice of diagnostic testing as it only shows air trapped under the skin (subcutaneous emphysema), which is only present in a small proportion of NF patients. CT scans are readily available and do a good job of helping doctors diagnose NF because it can show inflammatory changes, such as accumulation of fluid (edema), thickening or collection of pus (abscesses) in the fascia, in addition to gas formation. MRIs are less available and often difficult to administer to patients in critical or unstable condition, often leading to a delay in diagnosis. However, they also effectively help doctors diagnose NF by showing soft-tissue or fascial thickening.The second option is the gold standard in diagnosing NF i.e., exploratory surgery where it is common to find “dishwater” or foul-smelling discharge, necrosis or lack of bleeding, and loss of the normal resistance of the fascia to finger dissection. Intra-operative biopsy with gram stain can be used in some cases but not necessary as findings from the exploratory surgery are often definitive.Upon diagnosing NF, doctors will often perform tissue cultures on the infected tissue to determine the bacteria that is causing the infection. However, beginning NF treatment before the results of the cultures are available (often ~3 days after culture) is essential.
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Therapies of Necrotizing Fasciitis
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Treatment
Upon arriving at the hospital, it is important for doctors to assess the situation and determine which treatments to begin first to best suit the patient. Discussing treatments for additional complications (like toxic shock syndrome) from NF is beyond the scope of this document. This section will focus on describing therapies to treat NF specifically: surgical debridement, antibiotic therapy, hyperbaric oxygen therapy and IV immune globulin (IVIg) therapy.Surgical Debridement
Surgical debridement is the cornerstone of treatment for NF. It is the removal of dead, damaged or infected tissue to allow the remaining healthy tissue to heal more effectively. Many studies have shown that the timing and adequacy of the initial debridement has the biggest impact on mortality. Multiple debridements are often needed as the infection is rarely eliminated after a single surgery. On average, three debridements spaced 12 to 36 hours apart are needed to control the infection. Often, entire muscle groups are infected and must be removed by the surgeon. The surgeon must remove all tissues and structures that are dead or infected to control the infection and prevent spread of the infection to vital organs (usually in the torso), sometimes resulting in removal of significant amounts of tissue or even limbs.After surgery, the wounds should be left open and treated with wet-to-dry dressings (or “packing”). There is little evidence that using enzymatic debriding agents or caustic solutions, such as dilute sodium hypochlorite (bleach), iodine solutions (e.g., Betadine), or antibiotic solutions have any use in post-surgery care. Recently, there have been some studies suggesting that using a system that continuously instills and suctions out salt solutions or low-grade enzymatic solutions in a wound may help speed up control of the infection after debridement. Vacuum-assisted closure devices may be useful in treating large wounds once infection is controlled, but there have not been significant studies in NF patients showing improvement in wound management or healing from use of these devices. Upon confirmation that no more surgeries are required, skin grafts and/or plastic surgery may be required to fully close the wounds.Antibiotic Therapy
Since antibiotics cannot penetrate the necrotic infected tissue, surgical debridement is the first priority of treatment. However, simultaneous antibiotic therapy is essential in helping to control sepsis and prevent the further spread of the infection. The recommended initial course of treatment is the use of vancomycin or daptomycin to treat MRSA and gram-positive bacteria, an agent to treat anaerobic bacteria (e.g., clindamycin or metronidazole), and an agent to treat gram-negative bacteria. Alternatively, anaerobic and gram-negative bacteria can be treated with one drug that covers both.While there is increasing resistance to clindamycin, it should still be used as it inhibits production of bacterial endo- and exo-toxins. Quinolones, as well as piperacillin / tazobactam or meropenem are often used to cover gram-negative organisms also.Although there have been no studies to determine the appropriate length of antibiotic therapy, current best practices continue antibiotic treatment until no additional surgical debridement is needed and the patient is no longer showing signs of systemic inflammation.
Common combinations of antibiotic therapies include:
1. Vancomycin or Daptomycin, Clindamycin and Piperacillin/ tazobactam
2. Vancomycin or Daptomycin, Clindamycin and Levofloxacin if the patient has a severe penicillin allergyClindamycin is recommended because of its ability to inhibit toxin production in Streptococcal (gram positive) infections.Hyperbaric Oxygen (HBO) Therapy
Use of HBO is controversial to treat NF and has not been proven using adequate large-scale clinical studies in humans. Use of HBO therapy for NF is based on animal and human studies showing that hyperbaric conditions inhibit infection and exo-toxin production by clostridia. Animal studies have shown mortality reductions with HBO in clostridial NF. While HBO may be an effective treatment for NF in conjunction with antibiotics and surgical debridement, it should be used with careful consideration of the risk-benefit for the patient. Some considerations include the fact that Clostridial NF is not common, and use of HBO means moving a patient out of intensive care where emergency intervention can be provided safely and quickly (this is not the case during HBO therapy).IV Immune Globulin (IVIg) Therapy
Immune globulins are antibodies (proteins) that are found in blood or other bodily fluids of animals. They are used by the immune system to fight foreign objects like bacteria and viruses. IVIg therapy is not an FDA approved therapy for NF and its use and effectiveness are controversial. Use of IVIg therapy is based on the theory that IVIg can bind to exo-toxins released by staphylococci and streptococci, limiting damage by these toxins. This has been confirmed in some small clinical trials, but these trials have not been extensively done in large populations. If used, IV immune globulin should be restricted to critically ill patients with either staphylococcal or streptococcal NF whose exo-toxins IVIg therapy may control.
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Therapies of Necrotizing Fasciitis. Treatment
Upon arriving at the hospital, it is important for doctors to assess the situation and determine which treatments to begin first to best suit the patient. Discussing treatments for additional complications (like toxic shock syndrome) from NF is beyond the scope of this document. This section will focus on describing therapies to treat NF specifically: surgical debridement, antibiotic therapy, hyperbaric oxygen therapy and IV immune globulin (IVIg) therapy.Surgical Debridement
Surgical debridement is the cornerstone of treatment for NF. It is the removal of dead, damaged or infected tissue to allow the remaining healthy tissue to heal more effectively. Many studies have shown that the timing and adequacy of the initial debridement has the biggest impact on mortality. Multiple debridements are often needed as the infection is rarely eliminated after a single surgery. On average, three debridements spaced 12 to 36 hours apart are needed to control the infection. Often, entire muscle groups are infected and must be removed by the surgeon. The surgeon must remove all tissues and structures that are dead or infected to control the infection and prevent spread of the infection to vital organs (usually in the torso), sometimes resulting in removal of significant amounts of tissue or even limbs.After surgery, the wounds should be left open and treated with wet-to-dry dressings (or “packing”). There is little evidence that using enzymatic debriding agents or caustic solutions, such as dilute sodium hypochlorite (bleach), iodine solutions (e.g., Betadine), or antibiotic solutions have any use in post-surgery care. Recently, there have been some studies suggesting that using a system that continuously instills and suctions out salt solutions or low-grade enzymatic solutions in a wound may help speed up control of the infection after debridement. Vacuum-assisted closure devices may be useful in treating large wounds once infection is controlled, but there have not been significant studies in NF patients showing improvement in wound management or healing from use of these devices. Upon confirmation that no more surgeries are required, skin grafts and/or plastic surgery may be required to fully close the wounds.Antibiotic Therapy
Since antibiotics cannot penetrate the necrotic infected tissue, surgical debridement is the first priority of treatment. However, simultaneous antibiotic therapy is essential in helping to control sepsis and prevent the further spread of the infection. The recommended initial course of treatment is the use of vancomycin or daptomycin to treat MRSA and gram-positive bacteria, an agent to treat anaerobic bacteria (e.g., clindamycin or metronidazole), and an agent to treat gram-negative bacteria. Alternatively, anaerobic and gram-negative bacteria can be treated with one drug that covers both.While there is increasing resistance to clindamycin, it should still be used as it inhibits production of bacterial endo- and exo-toxins. Quinolones, as well as piperacillin / tazobactam or meropenem are often used to cover gram-negative organisms also.Although there have been no studies to determine the appropriate length of antibiotic therapy, current best practices continue antibiotic treatment until no additional surgical debridement is needed and the patient is no longer showing signs of systemic inflammation.
Common combinations of antibiotic therapies include:
1. Vancomycin or Daptomycin, Clindamycin and Piperacillin/ tazobactam
2. Vancomycin or Daptomycin, Clindamycin and Levofloxacin if the patient has a severe penicillin allergyClindamycin is recommended because of its ability to inhibit toxin production in Streptococcal (gram positive) infections.Hyperbaric Oxygen (HBO) Therapy
Use of HBO is controversial to treat NF and has not been proven using adequate large-scale clinical studies in humans. Use of HBO therapy for NF is based on animal and human studies showing that hyperbaric conditions inhibit infection and exo-toxin production by clostridia. Animal studies have shown mortality reductions with HBO in clostridial NF. While HBO may be an effective treatment for NF in conjunction with antibiotics and surgical debridement, it should be used with careful consideration of the risk-benefit for the patient. Some considerations include the fact that Clostridial NF is not common, and use of HBO means moving a patient out of intensive care where emergency intervention can be provided safely and quickly (this is not the case during HBO therapy).IV Immune Globulin (IVIg) Therapy
Immune globulins are antibodies (proteins) that are found in blood or other bodily fluids of animals. They are used by the immune system to fight foreign objects like bacteria and viruses. IVIg therapy is not an FDA approved therapy for NF and its use and effectiveness are controversial. Use of IVIg therapy is based on the theory that IVIg can bind to exo-toxins released by staphylococci and streptococci, limiting damage by these toxins. This has been confirmed in some small clinical trials, but these trials have not been extensively done in large populations. If used, IV immune globulin should be restricted to critically ill patients with either staphylococcal or streptococcal NF whose exo-toxins IVIg therapy may control.
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Overview of Nelson Syndrome
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Nelson syndrome is a disorder characterized by abnormal hormone secretion, enlargement of the pituitary gland (hypophysis), and the development of large and invasive growths known as adenomas. It occurs in an estimated 15 to 25 percent of people who undergo surgical removal of the adrenal glands for Cushing disease. Symptoms associated with Nelson syndrome include intense skin discoloration (hyperpigmentation), headaches, vision impairment, and the cessation of menstrual periods in women.
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Overview of Nelson Syndrome. Nelson syndrome is a disorder characterized by abnormal hormone secretion, enlargement of the pituitary gland (hypophysis), and the development of large and invasive growths known as adenomas. It occurs in an estimated 15 to 25 percent of people who undergo surgical removal of the adrenal glands for Cushing disease. Symptoms associated with Nelson syndrome include intense skin discoloration (hyperpigmentation), headaches, vision impairment, and the cessation of menstrual periods in women.
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Nelson Syndrome
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Symptoms of Nelson Syndrome
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Symptoms of Nelson syndrome include intense skin pigmentation, headaches, visual field disturbances and the cessation of menstrual periods in females. Blood levels of the pituitary hormones adrenocorticotrope hormone (ACTH) and beta-melanocyte stimulating hormone (beta-MSH) are abnormally high. The pituitary gland gets abnormally large in Nelson syndrome, causing headaches and visceral symptoms.
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Symptoms of Nelson Syndrome. Symptoms of Nelson syndrome include intense skin pigmentation, headaches, visual field disturbances and the cessation of menstrual periods in females. Blood levels of the pituitary hormones adrenocorticotrope hormone (ACTH) and beta-melanocyte stimulating hormone (beta-MSH) are abnormally high. The pituitary gland gets abnormally large in Nelson syndrome, causing headaches and visceral symptoms.
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Causes of Nelson Syndrome
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Nelson syndrome can be caused by surgical removal of the adrenal glands on both sides of the body (bilateral adrenalectomy). Removal of the adrenal glands is a treatment for Cushing disease. Cushing disease is the name given to a condition in which Cushing syndrome, an endocrine disorder, occurs because of the presence of benign (non-cancerous) tumors on the pituitary gland. Following removal of these adrenal glands, some people will develop Nelson syndrome. Growth of a pre-existing or a concealed (occult) tumor of the pituitary gland may also cause this disorder.
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Causes of Nelson Syndrome. Nelson syndrome can be caused by surgical removal of the adrenal glands on both sides of the body (bilateral adrenalectomy). Removal of the adrenal glands is a treatment for Cushing disease. Cushing disease is the name given to a condition in which Cushing syndrome, an endocrine disorder, occurs because of the presence of benign (non-cancerous) tumors on the pituitary gland. Following removal of these adrenal glands, some people will develop Nelson syndrome. Growth of a pre-existing or a concealed (occult) tumor of the pituitary gland may also cause this disorder.
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Affects of Nelson Syndrome
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Nelson syndrome affects approximately 15 to 25% of people who have undergone surgical removal of their adrenal glands. It affects males and females in equal numbers. Cases caused by tumors are very rare.
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Affects of Nelson Syndrome. Nelson syndrome affects approximately 15 to 25% of people who have undergone surgical removal of their adrenal glands. It affects males and females in equal numbers. Cases caused by tumors are very rare.
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Related disorders of Nelson Syndrome
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Related disorders of Nelson Syndrome.
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Diagnosis of Nelson Syndrome
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When Nelson syndrome is suspected, blood samples are analyzed for the presence or absence of cortisol and/or aldosterone. Imaging studies such as CAT scans or magnetic resonance imaging may also be used.
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Diagnosis of Nelson Syndrome. When Nelson syndrome is suspected, blood samples are analyzed for the presence or absence of cortisol and/or aldosterone. Imaging studies such as CAT scans or magnetic resonance imaging may also be used.
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Therapies of Nelson Syndrome
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TreatmentTreatment for Nelson syndrome consists of radiation to limit abnormal growth of the pituitary gland. If the pituitary gland increases so much in size that it encroaches on surrounding brain structures, it may be surgically removed.Microsurgical removal of Nelson syndrome adenomas through the bone at the base of the skull (transsphenoidal) may be recommended.
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Therapies of Nelson Syndrome. TreatmentTreatment for Nelson syndrome consists of radiation to limit abnormal growth of the pituitary gland. If the pituitary gland increases so much in size that it encroaches on surrounding brain structures, it may be surgically removed.Microsurgical removal of Nelson syndrome adenomas through the bone at the base of the skull (transsphenoidal) may be recommended.
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Overview of Nemaline Myopathy
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SummaryNemaline myopathy is a rare genetic muscle disorder. Six different clinical subtypes of nemaline myopathy have been identified based on disease severity and age of onset, ranging from a severe congenital-onset (at birth) form that is usually lethal in the first few months of life, through to less severe forms with onset in childhood or adulthood. Most affected individuals have a milder form of the disorder known as typical congenital nemaline myopathy and are able to walk and lead active lives. The inheritance pattern is variable depending on the underlying genetic cause. Characteristic symptoms of all forms of nemaline myopathy include muscle weakness, diminished muscle tone (hypotonia), and reduced or absent reflexes. In most people, muscle weakness is static (nonprogressive) over time. Weakness of the muscles of breathing and swallowing are the major cause of morbidity and mortality.IntroductionNemaline myopathy is defined by muscle weakness and the presence of fine, thread-like or rod-like structures called “nemaline bodies”, when muscle biopsies are viewed under the microscope. The prefix “nema-” is derived from Greek and means “thread-like.” Nemaline bodies consist of accumulations of muscle proteins due to mutations in genes which encode proteins components of the muscle thin filament.
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Overview of Nemaline Myopathy. SummaryNemaline myopathy is a rare genetic muscle disorder. Six different clinical subtypes of nemaline myopathy have been identified based on disease severity and age of onset, ranging from a severe congenital-onset (at birth) form that is usually lethal in the first few months of life, through to less severe forms with onset in childhood or adulthood. Most affected individuals have a milder form of the disorder known as typical congenital nemaline myopathy and are able to walk and lead active lives. The inheritance pattern is variable depending on the underlying genetic cause. Characteristic symptoms of all forms of nemaline myopathy include muscle weakness, diminished muscle tone (hypotonia), and reduced or absent reflexes. In most people, muscle weakness is static (nonprogressive) over time. Weakness of the muscles of breathing and swallowing are the major cause of morbidity and mortality.IntroductionNemaline myopathy is defined by muscle weakness and the presence of fine, thread-like or rod-like structures called “nemaline bodies”, when muscle biopsies are viewed under the microscope. The prefix “nema-” is derived from Greek and means “thread-like.” Nemaline bodies consist of accumulations of muscle proteins due to mutations in genes which encode proteins components of the muscle thin filament.
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Symptoms of Nemaline Myopathy
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The age of onset and severity of symptoms and signs associated with nemaline myopathy vary greatly from patient to patient. Some patients with nemaline myopathy present at or shortly after birth (congenital onset). Less often, the disorder may develop during childhood or even more uncommonly in adulthood. The major clinical features of nemaline myopathy are muscle weakness, hypotonia and reduced or absent reflexes. Muscle weakness is usually most severe in muscles of the face, neck and proximal muscles. The proximal muscles are the muscles that are closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Because facial muscles are involved, affected individuals may develop distinctive facial features including an elongated face, a displaced jaw that is farther back than normal (retrognathia), and a highly-arched roof of the mouth (palate). Muscle weakness may also cause difficulty speaking (dysarthria) and swallowing resulting in feeding difficulties. Some infants with nemaline myopathy may require a feeding tube. Breathing (respiratory) difficulties may also occur because of muscle weakness. Affected infants often experience delays in attaining motor milestones such as head control, sitting up or standing. Most infants do not have other developmental issues and intelligence is usually unaffected. As affected individuals age they may develop abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers cause deformity and restrict the movement of an affected area (contractures), a sunken chest (pectus excavatum), abnormal side-to-side-curvature of the spine (scoliosis) or abnormal rigidity of the spine. Six different clinical presentations of nemaline myopathy have been identified. Typical Congenital Nemaline Myopathy
This is the most common form of nemaline myopathy accounting for approximately half of all cases. This form is present at or shortly after birth or sometime during the first year of life. Affected infants may exhibit muscle weakness, hypotonia leading to abnormal “floppiness”, and feeding difficulties. Muscle weakness is less severe in the typical congenital form than in the severe congenital or intermediate congenital forms. Some infants with this form may have significant muscle weakness at birth that improves with age. Weakness of respiratory muscles is common and may cause breathing difficulties, and nocturnal hypoventilation, a condition in which inadequate breathing during sleep results in increased levels of carbon dioxide in the blood (hypercarbia). Some infants may have an abnormal waddling walk (gait), swallowing difficulties (dysphagia), speech difficulties (dysarthria), and a nasal tone to the voice. Affected infants may also experience delays attaining gross motor milestones such as holding one's head up, sitting or standing. In rare cases, delayed attainment of motor milestones may be the first sign of the disorder. Muscle weakness in infants with the typical congenital form of nemaline myopathy usually affects the proximal muscles, but, in rare cases, may spread to affect the distal muscles, which are the muscles farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet. The muscle weakness associated with the typical form does not usually progress. However, during growth spurts associated with puberty, some individuals have experienced progressive worsening of muscle weakness that ultimately may require the use of a wheelchair. Most individuals who have typical congenital nemaline myopathy are eventually able to walk independently. Severe Congenital (Neonatal) Nemaline Myopathy
This form of nemaline myopathy is apparent at birth and accounts for approximately 16 percent of cases. Affected infants have profound muscle weakness and severe hypotonia. Infants with this form of nemaline myopathy experience difficulty sucking and swallowing leading to feeding difficulties, show little spontaneous movement, and exhibit respiratory insufficiency. Some infants may experience the passage or backflow (reflux) of the contents of the stomach or small intestines into the esophagus (gastroesophageal reflux). In rare cases, this form of nemaline myopathy has been associated with disease of the heart muscle (cardiomyopathy) and the presence of multiple contractures (arthrogryposis multiplex congenita). Fractures may also occur. The severe involvement of respiratory muscles often leads to life-threatening respiratory failure and weakness of the bulbar (swallowing) muscles increases the risk of aspiration pneumonia (in which liquid or food is inhaled into the lungs). Intermediate Congenital Nemaline Myopathy
This form of nemaline myopathy is less severe than the severe congenital form and more severe than the typical congenital form. It accounts for approximately 20 percent of cases. The early development of contractures is characteristic of this form of nemaline myopathy. As affected infants age, they often experience delays in attaining motor milestones or may not be able to sit up or walk independently. Children with intermediate congenital nemaline myopathy often require a wheelchair or ongoing breathing (ventilatory) support during childhhood. Childhood-Onset Nemaline Myopathy
This form of nemaline myopathy usually becomes apparent between 10-20 years of age and accounts for approximately 13 percent of cases. The development of early motor skills is usually unaffected. Sometime during the late teens or early twenties, affected individuals develop slowly progressive muscle weakness. Affected individuals may be unable to bend the foot upward toward the leg (foot drop). Eventually the entire ankle and lower legs muscles are involved. In one family with this form of nemaline myopathy, two members required wheelchairs by age 40. Adult-Onset Nemaline Myopathy
The onset and severity of this form of nemaline myopathy varies. It is extremely rare accounting for only 4 percent of cases. It occurs in individuals between the ages of 20-50 who develop generalized muscle weakness that may progress rapidly. Muscle pain (myalgia) may also occur. Involvement of certain neck muscles may make it difficult to hold one's head up and cause the head to drop. Although uncommon, some individuals may develop respiratory or cardiac complications often in conjunction with increasing muscle weakness. This form of nemaline myopathy may be distinct form the genetic or inherited forms of the disorder.Amish Nemaline Myopathy
This form of myopathy was identified in several related families within an Amish community. Onset is shortly after birth and affected infants may have hypotonia, multiple contractures, and tremors, which usually diminish over the first few months of life. Affected infants have progressive muscle weakness, a severely deformed chest with a prominent sternum (pectus carinatum), muscle wasting (atrophy) and life-threatening respiratory insufficiency.
Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita (joint contractures, which are permanent shortening of a muscle) often lead to death in the second year of life.
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Symptoms of Nemaline Myopathy. The age of onset and severity of symptoms and signs associated with nemaline myopathy vary greatly from patient to patient. Some patients with nemaline myopathy present at or shortly after birth (congenital onset). Less often, the disorder may develop during childhood or even more uncommonly in adulthood. The major clinical features of nemaline myopathy are muscle weakness, hypotonia and reduced or absent reflexes. Muscle weakness is usually most severe in muscles of the face, neck and proximal muscles. The proximal muscles are the muscles that are closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Because facial muscles are involved, affected individuals may develop distinctive facial features including an elongated face, a displaced jaw that is farther back than normal (retrognathia), and a highly-arched roof of the mouth (palate). Muscle weakness may also cause difficulty speaking (dysarthria) and swallowing resulting in feeding difficulties. Some infants with nemaline myopathy may require a feeding tube. Breathing (respiratory) difficulties may also occur because of muscle weakness. Affected infants often experience delays in attaining motor milestones such as head control, sitting up or standing. Most infants do not have other developmental issues and intelligence is usually unaffected. As affected individuals age they may develop abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers cause deformity and restrict the movement of an affected area (contractures), a sunken chest (pectus excavatum), abnormal side-to-side-curvature of the spine (scoliosis) or abnormal rigidity of the spine. Six different clinical presentations of nemaline myopathy have been identified. Typical Congenital Nemaline Myopathy
This is the most common form of nemaline myopathy accounting for approximately half of all cases. This form is present at or shortly after birth or sometime during the first year of life. Affected infants may exhibit muscle weakness, hypotonia leading to abnormal “floppiness”, and feeding difficulties. Muscle weakness is less severe in the typical congenital form than in the severe congenital or intermediate congenital forms. Some infants with this form may have significant muscle weakness at birth that improves with age. Weakness of respiratory muscles is common and may cause breathing difficulties, and nocturnal hypoventilation, a condition in which inadequate breathing during sleep results in increased levels of carbon dioxide in the blood (hypercarbia). Some infants may have an abnormal waddling walk (gait), swallowing difficulties (dysphagia), speech difficulties (dysarthria), and a nasal tone to the voice. Affected infants may also experience delays attaining gross motor milestones such as holding one's head up, sitting or standing. In rare cases, delayed attainment of motor milestones may be the first sign of the disorder. Muscle weakness in infants with the typical congenital form of nemaline myopathy usually affects the proximal muscles, but, in rare cases, may spread to affect the distal muscles, which are the muscles farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet. The muscle weakness associated with the typical form does not usually progress. However, during growth spurts associated with puberty, some individuals have experienced progressive worsening of muscle weakness that ultimately may require the use of a wheelchair. Most individuals who have typical congenital nemaline myopathy are eventually able to walk independently. Severe Congenital (Neonatal) Nemaline Myopathy
This form of nemaline myopathy is apparent at birth and accounts for approximately 16 percent of cases. Affected infants have profound muscle weakness and severe hypotonia. Infants with this form of nemaline myopathy experience difficulty sucking and swallowing leading to feeding difficulties, show little spontaneous movement, and exhibit respiratory insufficiency. Some infants may experience the passage or backflow (reflux) of the contents of the stomach or small intestines into the esophagus (gastroesophageal reflux). In rare cases, this form of nemaline myopathy has been associated with disease of the heart muscle (cardiomyopathy) and the presence of multiple contractures (arthrogryposis multiplex congenita). Fractures may also occur. The severe involvement of respiratory muscles often leads to life-threatening respiratory failure and weakness of the bulbar (swallowing) muscles increases the risk of aspiration pneumonia (in which liquid or food is inhaled into the lungs). Intermediate Congenital Nemaline Myopathy
This form of nemaline myopathy is less severe than the severe congenital form and more severe than the typical congenital form. It accounts for approximately 20 percent of cases. The early development of contractures is characteristic of this form of nemaline myopathy. As affected infants age, they often experience delays in attaining motor milestones or may not be able to sit up or walk independently. Children with intermediate congenital nemaline myopathy often require a wheelchair or ongoing breathing (ventilatory) support during childhhood. Childhood-Onset Nemaline Myopathy
This form of nemaline myopathy usually becomes apparent between 10-20 years of age and accounts for approximately 13 percent of cases. The development of early motor skills is usually unaffected. Sometime during the late teens or early twenties, affected individuals develop slowly progressive muscle weakness. Affected individuals may be unable to bend the foot upward toward the leg (foot drop). Eventually the entire ankle and lower legs muscles are involved. In one family with this form of nemaline myopathy, two members required wheelchairs by age 40. Adult-Onset Nemaline Myopathy
The onset and severity of this form of nemaline myopathy varies. It is extremely rare accounting for only 4 percent of cases. It occurs in individuals between the ages of 20-50 who develop generalized muscle weakness that may progress rapidly. Muscle pain (myalgia) may also occur. Involvement of certain neck muscles may make it difficult to hold one's head up and cause the head to drop. Although uncommon, some individuals may develop respiratory or cardiac complications often in conjunction with increasing muscle weakness. This form of nemaline myopathy may be distinct form the genetic or inherited forms of the disorder.Amish Nemaline Myopathy
This form of myopathy was identified in several related families within an Amish community. Onset is shortly after birth and affected infants may have hypotonia, multiple contractures, and tremors, which usually diminish over the first few months of life. Affected infants have progressive muscle weakness, a severely deformed chest with a prominent sternum (pectus carinatum), muscle wasting (atrophy) and life-threatening respiratory insufficiency.
Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita (joint contractures, which are permanent shortening of a muscle) often lead to death in the second year of life.
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Causes of Nemaline Myopathy
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Ten genes have been found to cause nemaline myopathy. Nemaline myopathy can be inherited as an autosomal recessive or dominant trait. At least 50% of cases of nemaline myopathy follow autosomal recessive inheritance, and the remainder are inherited in an autosomal dominant manner or are sporadic (new dominant cases – the first occurrence in the family).
Genetic disorders 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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
Mutations in the ACTA1 gene have been found to cause approximately 15-25 percent of nemaline myopathy. Most ACTA1 mutations are a spontaneous (de novo) genetic change (new mutation) and not inherited. However, some cases have resulted from autosomal dominant and, more rarely, autosomal recessive inheritance. Mutations of the ACTA1 gene may cause the severe, intermediate or typical congenital forms of nemaline myopathy. Mutations in the NEB gene have been identified as a cause of about 50% of nemaline myopathy. Mutations in this gene can cause any form of the disorder, but most individuals with a NEB mutation have the typical congenital form. Mutations of the NEB gene are inherited as an autosomal recessive trait. Mutations in the TPM2, TPM3, TNNT1, CFL2, KBTBD13, KLHL40, KLHL41 and LMOD3 genes are rarer causes of nemaline myopathy, with only smaller numbers of affected families reported to date. The genes involved in nemaline myopathy contain instructions for creating (encoding) certain proteins that play an essential role in the normal structure and function of the contractile apparatus of skeletal muscle. Mutations to these genes result in deficiency or dysfunction of these proteins. These proteins are work together to form structures known as thin filaments, which are basically long chains of proteins. Thin filaments are found in the sarcomere, the basic structural and functional unit of striated muscle, and they play a role in the formation and contractile function of skeletal muscle fibers. Therefore, if these proteins are deficient or defective, the strength of muscle contraction and in some cases the development of normal muscle structure is impaired.
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Causes of Nemaline Myopathy. Ten genes have been found to cause nemaline myopathy. Nemaline myopathy can be inherited as an autosomal recessive or dominant trait. At least 50% of cases of nemaline myopathy follow autosomal recessive inheritance, and the remainder are inherited in an autosomal dominant manner or are sporadic (new dominant cases – the first occurrence in the family).
Genetic disorders 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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
Mutations in the ACTA1 gene have been found to cause approximately 15-25 percent of nemaline myopathy. Most ACTA1 mutations are a spontaneous (de novo) genetic change (new mutation) and not inherited. However, some cases have resulted from autosomal dominant and, more rarely, autosomal recessive inheritance. Mutations of the ACTA1 gene may cause the severe, intermediate or typical congenital forms of nemaline myopathy. Mutations in the NEB gene have been identified as a cause of about 50% of nemaline myopathy. Mutations in this gene can cause any form of the disorder, but most individuals with a NEB mutation have the typical congenital form. Mutations of the NEB gene are inherited as an autosomal recessive trait. Mutations in the TPM2, TPM3, TNNT1, CFL2, KBTBD13, KLHL40, KLHL41 and LMOD3 genes are rarer causes of nemaline myopathy, with only smaller numbers of affected families reported to date. The genes involved in nemaline myopathy contain instructions for creating (encoding) certain proteins that play an essential role in the normal structure and function of the contractile apparatus of skeletal muscle. Mutations to these genes result in deficiency or dysfunction of these proteins. These proteins are work together to form structures known as thin filaments, which are basically long chains of proteins. Thin filaments are found in the sarcomere, the basic structural and functional unit of striated muscle, and they play a role in the formation and contractile function of skeletal muscle fibers. Therefore, if these proteins are deficient or defective, the strength of muscle contraction and in some cases the development of normal muscle structure is impaired.
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Affects of Nemaline Myopathy
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Nemaline myopathy is a rare disorder that affects males and females. The incidence is unknown although two studies (one in Finland and one in an American Ashkenazi Jewish population) estimated the incidence to be 1 in 50,000 live births. An incidence of 1/500 has been reported in the Amish community.
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Affects of Nemaline Myopathy. Nemaline myopathy is a rare disorder that affects males and females. The incidence is unknown although two studies (one in Finland and one in an American Ashkenazi Jewish population) estimated the incidence to be 1 in 50,000 live births. An incidence of 1/500 has been reported in the Amish community.
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Related disorders of Nemaline Myopathy
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Congenital myopathy is a general term for a group of muscle disorders (myopathies) that are present at birth (congenital). These disorders are characterized by muscle weakness, hypotonia, diminished reflexes, and delays in reaching motor milestones (e.g., walking). In some disorders, muscle weakness is progressive and may result in life-threatening complications. This group of disorders includes central core disease, centronuclear myopathy, congenital fiber type disproportion, and minimulticore myopathy. Congenital myopathies are usually apparent in the newborn (neonatal) period, but may present much later in life even in adulthood. In most cases, inheritance of these disorders is either autosomal recessive or autosomal dominant. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) Secondary nemaline myopathy refers to instances in which the nemaline bodies that characterize the muscle fibers of individuals with nemaline myopathy have been seen in other disorders. Such disorders include mitochondrial myopathies, myotonic dystrophy type I, and Hodgkin's 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 Nemaline Myopathy. Congenital myopathy is a general term for a group of muscle disorders (myopathies) that are present at birth (congenital). These disorders are characterized by muscle weakness, hypotonia, diminished reflexes, and delays in reaching motor milestones (e.g., walking). In some disorders, muscle weakness is progressive and may result in life-threatening complications. This group of disorders includes central core disease, centronuclear myopathy, congenital fiber type disproportion, and minimulticore myopathy. Congenital myopathies are usually apparent in the newborn (neonatal) period, but may present much later in life even in adulthood. In most cases, inheritance of these disorders is either autosomal recessive or autosomal dominant. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) Secondary nemaline myopathy refers to instances in which the nemaline bodies that characterize the muscle fibers of individuals with nemaline myopathy have been seen in other disorders. Such disorders include mitochondrial myopathies, myotonic dystrophy type I, and Hodgkin's 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 Nemaline Myopathy
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A diagnosis of nemaline myopathy is suspected based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic findings. A diagnosis of nemaline myopathy is suspected based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic findings. A diagnosis may be confirmed by the presence of thread- or rod-like structures (nemaline bodies) on muscle biopsy when stained with Gomori trichrome. A biopsy is the surgical removal and microscopic evaluation of affected tissue. Increasingly the diagnosis is made or confirmed by molecular genetic testing for mutations in the genes known to cause nemaline myopathy.
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Diagnosis of Nemaline Myopathy. A diagnosis of nemaline myopathy is suspected based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic findings. A diagnosis of nemaline myopathy is suspected based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic findings. A diagnosis may be confirmed by the presence of thread- or rod-like structures (nemaline bodies) on muscle biopsy when stained with Gomori trichrome. A biopsy is the surgical removal and microscopic evaluation of affected tissue. Increasingly the diagnosis is made or confirmed by molecular genetic testing for mutations in the genes known to cause nemaline myopathy.
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Therapies of Nemaline Myopathy
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Treatment No specific treatment exists for nemaline myopathy. Treatment is supportive and directed toward the specific symptoms that are apparent in each individual. Infants with nemaline myopathy may benefit from a program involving mild-to-moderate, low-impact exercise, massage, and stretching techniques. Such therapy is aimed at preserving muscle strength and function and to prevent the development of contractures. In addition, respiratory support may be necessary, potentially including mechanical ventilation to prevent nocturnal hypoventilation. Careful monitoring of breathing is essential because even individuals with minimal muscle weakness in the arms and legs can have impaired breathing especially during sleep. Lower respiratory infections must be promptly and aggressively treated to avoid complications. Since some affected individuals may experience feeding difficulties, tube-feeding may be required to ensure proper caloric and nutritional intake. Speech therapy may be necessary for individuals with difficulty speaking or nasally speech. In some cases, various orthopedic techniques, such as the use of special braces, other devices, and/or surgical measures, may be recommended to help prevent and/or treat certain musculoskeletal abnormalities such as scoliosis and joint contractures. Individuals with significant muscle weakness in the legs may eventually require a wheelchair. Affected individuals should receive an assessment of heart function because a risk for cardiac abnormalities does exist, although it is a rare complication.
Genetic counseling is recommended for affected individuals and their families.
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Therapies of Nemaline Myopathy. Treatment No specific treatment exists for nemaline myopathy. Treatment is supportive and directed toward the specific symptoms that are apparent in each individual. Infants with nemaline myopathy may benefit from a program involving mild-to-moderate, low-impact exercise, massage, and stretching techniques. Such therapy is aimed at preserving muscle strength and function and to prevent the development of contractures. In addition, respiratory support may be necessary, potentially including mechanical ventilation to prevent nocturnal hypoventilation. Careful monitoring of breathing is essential because even individuals with minimal muscle weakness in the arms and legs can have impaired breathing especially during sleep. Lower respiratory infections must be promptly and aggressively treated to avoid complications. Since some affected individuals may experience feeding difficulties, tube-feeding may be required to ensure proper caloric and nutritional intake. Speech therapy may be necessary for individuals with difficulty speaking or nasally speech. In some cases, various orthopedic techniques, such as the use of special braces, other devices, and/or surgical measures, may be recommended to help prevent and/or treat certain musculoskeletal abnormalities such as scoliosis and joint contractures. Individuals with significant muscle weakness in the legs may eventually require a wheelchair. Affected individuals should receive an assessment of heart function because a risk for cardiac abnormalities does exist, although it is a rare complication.
Genetic counseling is recommended for affected individuals and their families.
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Overview of Neonatal Cholestasis
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Neonatal cholestasis refers to impaired flow of bile at any point from the liver cells into the intestine of a newborn.Neonatal cholestasis may be caused by viruses, metabolic disease or genetic disorders, as well as other rare diseases that affect or impair the function of the liver. In a small percent of patients, the cause of liver injury is unknown – these cases are referred to as idiopathic neonatal hepatitis (INH). The incidence of neonatal cholestasis is estimated to be ~1:2500 live births worldwide, and 25% to 50% are now known to be associated with changes (mutations) in specific genes.The symptoms of neonatal cholestasis may vary from one individual to another. Symptoms of liver disease include yellowing of the whites of the eyes and the skin (jaundice), enlargement of the liver (hepatomegaly), unusually dark urine, and poor growth. Some individuals with neonatal cholestasis fully recover from the condition (sporadic or transient forms); however, some will progress to chronic liver disease (persistent or progressive forms).
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Overview of Neonatal Cholestasis. Neonatal cholestasis refers to impaired flow of bile at any point from the liver cells into the intestine of a newborn.Neonatal cholestasis may be caused by viruses, metabolic disease or genetic disorders, as well as other rare diseases that affect or impair the function of the liver. In a small percent of patients, the cause of liver injury is unknown – these cases are referred to as idiopathic neonatal hepatitis (INH). The incidence of neonatal cholestasis is estimated to be ~1:2500 live births worldwide, and 25% to 50% are now known to be associated with changes (mutations) in specific genes.The symptoms of neonatal cholestasis may vary from one individual to another. Symptoms of liver disease include yellowing of the whites of the eyes and the skin (jaundice), enlargement of the liver (hepatomegaly), unusually dark urine, and poor growth. Some individuals with neonatal cholestasis fully recover from the condition (sporadic or transient forms); however, some will progress to chronic liver disease (persistent or progressive forms).
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Neonatal Cholestasis
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Symptoms of Neonatal Cholestasis
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The liver is located on the right side of the abdominal cavity just under the rib cage. The liver has many different functions including filtering harmful substances (toxins, including bilirubin) out of the bloodstream, synthesizing proteins, storing essential vitamins, helping to breakdown (metabolize) food to use as energy, creating components that help the blood form clots in response to injury, and producing bile, a liquid that plays an essential role in breaking down fats in the small intestine.The disorder can range from a mild, temporary (transient) disease that improves without treatment to more serious forms that cause additional complications. The common symptoms of liver disease may appear anytime during the first few weeks of life. By the age of 2 to 3 months, it becomes clear that an infant with neonatal cholestasis is not gaining weight and is growing at a slower than normal rate (failure to thrive). The infant may be irritable because of excessively itchy skin (pruritus). Other symptoms may include enlargement of the spleen (splenomegaly).In more serious forms of neonatal cholestasis additional symptoms can occur including easy bruising, prolonged bleeding, infection (sepsis) and/or the accumulation of body fluids within the abdomen (ascites) in the later stages of chronic liver injury. Liver (hepatic) failure may eventually develop in some individuals with severe forms of neonatal cholestasis
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Symptoms of Neonatal Cholestasis. The liver is located on the right side of the abdominal cavity just under the rib cage. The liver has many different functions including filtering harmful substances (toxins, including bilirubin) out of the bloodstream, synthesizing proteins, storing essential vitamins, helping to breakdown (metabolize) food to use as energy, creating components that help the blood form clots in response to injury, and producing bile, a liquid that plays an essential role in breaking down fats in the small intestine.The disorder can range from a mild, temporary (transient) disease that improves without treatment to more serious forms that cause additional complications. The common symptoms of liver disease may appear anytime during the first few weeks of life. By the age of 2 to 3 months, it becomes clear that an infant with neonatal cholestasis is not gaining weight and is growing at a slower than normal rate (failure to thrive). The infant may be irritable because of excessively itchy skin (pruritus). Other symptoms may include enlargement of the spleen (splenomegaly).In more serious forms of neonatal cholestasis additional symptoms can occur including easy bruising, prolonged bleeding, infection (sepsis) and/or the accumulation of body fluids within the abdomen (ascites) in the later stages of chronic liver injury. Liver (hepatic) failure may eventually develop in some individuals with severe forms of neonatal cholestasis
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Neonatal Cholestasis
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Causes of Neonatal Cholestasis
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Neonatal cholestasis, in general, has many different causes including several viruses including cytomegalovirus and the herpes viruses; various metabolic liver diseases or genetic disorders such as alpha-1-antitrypsin deficiency and Alagille syndrome. Other rare disorders may also impair the function of the liver. All of these disorders are usually diagnosed promptly. According to the medical literature, 15-20% of cases of neonatal cholestasis run in families (familial form) – and in recent years multiple studies have shown that genetic factors play a role in its development.
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Causes of Neonatal Cholestasis. Neonatal cholestasis, in general, has many different causes including several viruses including cytomegalovirus and the herpes viruses; various metabolic liver diseases or genetic disorders such as alpha-1-antitrypsin deficiency and Alagille syndrome. Other rare disorders may also impair the function of the liver. All of these disorders are usually diagnosed promptly. According to the medical literature, 15-20% of cases of neonatal cholestasis run in families (familial form) – and in recent years multiple studies have shown that genetic factors play a role in its development.
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Neonatal Cholestasis
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Affects of Neonatal Cholestasis
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The incidence of neonatal cholestasis in the general population is unknown. The proportion of cases classified as “idiopathic” has diminished as advanced diagnostic techniques and a better molecular understanding of cholestatic diseases in general have allowed physicians to diagnose many infants as being affected with specific syndromes. In the past, these infants would have been included as having idiopathic neonatal hepatitis.
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Affects of Neonatal Cholestasis. The incidence of neonatal cholestasis in the general population is unknown. The proportion of cases classified as “idiopathic” has diminished as advanced diagnostic techniques and a better molecular understanding of cholestatic diseases in general have allowed physicians to diagnose many infants as being affected with specific syndromes. In the past, these infants would have been included as having idiopathic neonatal hepatitis.
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Neonatal Cholestasis
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Related disorders of Neonatal Cholestasis
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Symptoms of the following disorders can be similar to those of neonatal cholestasis:Biliary atresia is a rare disorder characterized by destruction or absence of all or a portion of the bile duct system, a series of tubes that allow the passage of bile from the liver into the gall bladder and, eventually, the small intestine. In patients with biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants may have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (cirrhosis). Additional symptoms may include itching, enlargement of the liver (hepatomegaly), pale, gray stools, and a swollen abdomen (ascites). In some cases, additional abnormalities may be present, including heart defects and kidney and spleen malformations. The exact cause of biliary atresia is unknown. (For more information on this disorder, choose “biliary atresia” as your search term in the Rare Disease Database.)
Metabolic liver diseases are a mixed group of disorders in which certain enzymes required to “metabolize” or breakdown various substances in the body (e.g., carbohydrates, proteins, fats) are missing or reduced. Certain of these enzymes are crucial in the production of energy. Absence or deficiency of critical enzymes causes substances to build up in the body, potentially damaging various organs. A variety of metabolic diseases are associated with liver dysfunction similar to that found in neonatal cholestasis. These disorders include alpha-1-antitrypsin deficiency, cystic fibrosis, fatty acid oxidation disorders, galactosemia, tyrosinemia, Zellweger syndrome, hereditary fructose intolerance and bile acid synthesis defects. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Neonatal cholestasis may result from a variety of different viral infections that are present at birth (congenital viral infections). Such infections include cytomegalovirus infection, the herpes viruses, enteroviruses, and rubella (measles). Certain nonviral infections can cause neonatal cholestasis including congenital syphilis and toxoplasmosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Certain rare genetic disorders may affect the liver and cause neonatal cholestasis. These disorders include Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC) subtypes, and benign recurrent intrahepatic cholestasis (BRIC). Alagille syndrome is a genetic liver disorder characterized by insufficient excretion of bile due to a lower than normal number of bile ducts inside the liver. PFIC is a group of rare genetic disorders that affect the liver; these are characterized by interruption or suppression of the flow of bile from the liver (cholestasis). In PFIC, cholestasis occurs due to defects within the liver (intrahepatic). (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 Neonatal Cholestasis. Symptoms of the following disorders can be similar to those of neonatal cholestasis:Biliary atresia is a rare disorder characterized by destruction or absence of all or a portion of the bile duct system, a series of tubes that allow the passage of bile from the liver into the gall bladder and, eventually, the small intestine. In patients with biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants may have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (cirrhosis). Additional symptoms may include itching, enlargement of the liver (hepatomegaly), pale, gray stools, and a swollen abdomen (ascites). In some cases, additional abnormalities may be present, including heart defects and kidney and spleen malformations. The exact cause of biliary atresia is unknown. (For more information on this disorder, choose “biliary atresia” as your search term in the Rare Disease Database.)
Metabolic liver diseases are a mixed group of disorders in which certain enzymes required to “metabolize” or breakdown various substances in the body (e.g., carbohydrates, proteins, fats) are missing or reduced. Certain of these enzymes are crucial in the production of energy. Absence or deficiency of critical enzymes causes substances to build up in the body, potentially damaging various organs. A variety of metabolic diseases are associated with liver dysfunction similar to that found in neonatal cholestasis. These disorders include alpha-1-antitrypsin deficiency, cystic fibrosis, fatty acid oxidation disorders, galactosemia, tyrosinemia, Zellweger syndrome, hereditary fructose intolerance and bile acid synthesis defects. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Neonatal cholestasis may result from a variety of different viral infections that are present at birth (congenital viral infections). Such infections include cytomegalovirus infection, the herpes viruses, enteroviruses, and rubella (measles). Certain nonviral infections can cause neonatal cholestasis including congenital syphilis and toxoplasmosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Certain rare genetic disorders may affect the liver and cause neonatal cholestasis. These disorders include Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC) subtypes, and benign recurrent intrahepatic cholestasis (BRIC). Alagille syndrome is a genetic liver disorder characterized by insufficient excretion of bile due to a lower than normal number of bile ducts inside the liver. PFIC is a group of rare genetic disorders that affect the liver; these are characterized by interruption or suppression of the flow of bile from the liver (cholestasis). In PFIC, cholestasis occurs due to defects within the liver (intrahepatic). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Neonatal Cholestasis
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Diagnosis of Neonatal Cholestasis
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The key to diagnosis is early recognition of neonatal jaundice (elevated levels of conjugated bilirubin in the blood – hyperbilirubinemia).This allows the timely initiation of a diagnostic evaluation, the goals of which are to identify treatable disorders. Therefore, any infant jaundiced beyond 14 days of life should have blood tests done to determine if the jaundice is due to cholestasis (elevated conjugated bilirubin levels) or is associated with elevated unconjugated bilirubin levels. The latter is normal (“physiologic jaundice”) or related to breast milk feedingNeonatal cholestasis is a diagnosis attained by excluding other conditions.The structure of the liver and the surrounding ducts and blood vessels can be examined by ultrasonography. In some patients, a liver biopsy may be necessary. During a biopsy, a needle and syringe are used to remove a small piece of liver tissue. This sample is studied under a microscope. A liver biopsy may be able to rule out other liver disorders such as those that affect the inside of the liver (intrahepatic disorders) and extrahepatic disease (biliary atresia).The current gold standard for the diagnosis of inherited syndromes of neonatal cholestasis is genetic testing. Typically, patients with otherwise unexplained cholestasis despite extensive diagnostic work-up (laboratory assessment and liver biopsy) undergo a search for mutations in genes associated with liver disease
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Diagnosis of Neonatal Cholestasis. The key to diagnosis is early recognition of neonatal jaundice (elevated levels of conjugated bilirubin in the blood – hyperbilirubinemia).This allows the timely initiation of a diagnostic evaluation, the goals of which are to identify treatable disorders. Therefore, any infant jaundiced beyond 14 days of life should have blood tests done to determine if the jaundice is due to cholestasis (elevated conjugated bilirubin levels) or is associated with elevated unconjugated bilirubin levels. The latter is normal (“physiologic jaundice”) or related to breast milk feedingNeonatal cholestasis is a diagnosis attained by excluding other conditions.The structure of the liver and the surrounding ducts and blood vessels can be examined by ultrasonography. In some patients, a liver biopsy may be necessary. During a biopsy, a needle and syringe are used to remove a small piece of liver tissue. This sample is studied under a microscope. A liver biopsy may be able to rule out other liver disorders such as those that affect the inside of the liver (intrahepatic disorders) and extrahepatic disease (biliary atresia).The current gold standard for the diagnosis of inherited syndromes of neonatal cholestasis is genetic testing. Typically, patients with otherwise unexplained cholestasis despite extensive diagnostic work-up (laboratory assessment and liver biopsy) undergo a search for mutations in genes associated with liver disease
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Neonatal Cholestasis
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Therapies of Neonatal Cholestasis
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TreatmentCareful attention to nutritional needs and diet are essential for infants with this disorder. Special supplements (i.e., fat-soluble vitamins), formulas, and/or dietary restrictions may be suggested by the physician. Special infant formulas may be prescribed, for example, malabsorption of long-chain triglycerides may be corrected with formulas that contain medium-chain triglycerides.There is no specific treatment available for infants with neonatal cholestasis. Treatment is directed toward the specific symptoms that are apparent in each individual.If itching (pruritus) becomes a problem, a drug that has been used to treat itching associated with liver disease is ursodeoxycholic acid.A surgical choice of last resort for infants who develop end-stage liver disease is a liver transplantation.
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Therapies of Neonatal Cholestasis. TreatmentCareful attention to nutritional needs and diet are essential for infants with this disorder. Special supplements (i.e., fat-soluble vitamins), formulas, and/or dietary restrictions may be suggested by the physician. Special infant formulas may be prescribed, for example, malabsorption of long-chain triglycerides may be corrected with formulas that contain medium-chain triglycerides.There is no specific treatment available for infants with neonatal cholestasis. Treatment is directed toward the specific symptoms that are apparent in each individual.If itching (pruritus) becomes a problem, a drug that has been used to treat itching associated with liver disease is ursodeoxycholic acid.A surgical choice of last resort for infants who develop end-stage liver disease is a liver transplantation.
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Neonatal Cholestasis
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Overview of Neonatal Hemochromatosis
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Neonatal hemochromatosis is a disorder affecting fetuses and newborns. It is characterized by liver disease associated with the accumulation of excess iron in the liver and other areas of the body. Neonatal hemochromatosis is caused by severe fetal liver disease (see below). Some severe cases result in stillbirth, while live born infants with neonatal hemochromatosis typically show signs within 48 hours of birth. Neonatal hemochromatosis often produces life-threatening complications such as liver failure. However, some infants are less severely affected than others. There is a high risk of recurrence in subsequent pregnancies of women who have had a child with neonatal hemochromatosis. Although the exact cause of the disorder is not fully understood, researchers believe most cases of neonatal hemochromatosis result from maternal fetal alloimmunity, a condition in which antibodies from the mother travel over the placenta and mistakenly attack the fetus.
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Overview of Neonatal Hemochromatosis. Neonatal hemochromatosis is a disorder affecting fetuses and newborns. It is characterized by liver disease associated with the accumulation of excess iron in the liver and other areas of the body. Neonatal hemochromatosis is caused by severe fetal liver disease (see below). Some severe cases result in stillbirth, while live born infants with neonatal hemochromatosis typically show signs within 48 hours of birth. Neonatal hemochromatosis often produces life-threatening complications such as liver failure. However, some infants are less severely affected than others. There is a high risk of recurrence in subsequent pregnancies of women who have had a child with neonatal hemochromatosis. Although the exact cause of the disorder is not fully understood, researchers believe most cases of neonatal hemochromatosis result from maternal fetal alloimmunity, a condition in which antibodies from the mother travel over the placenta and mistakenly attack the fetus.
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Neonatal Hemochromatosis
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Symptoms of Neonatal Hemochromatosis
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Neonatal hemochromatosis is characterized by liver disease that is present in the fetus or at birth (congenital). Damage to the liver occurs during pregnancy, ultimately leading to the abnormal accumulation of iron within tissue. Iron accumulation occurs while the fetus is developing in the womb and fetal loss late in pregnancy is common in families with a history of neonatal hemochromatosis. Growth delays within the womb (intrauterine growth deficiencies) are also common and many newborns are born prematurely.Liver disease is usually apparent shortly after birth, although in rare cases it may not become apparent until days or weeks later. Symptoms of liver disease include low blood sugar (hypoglycemia), abnormalities in blood clotting (coagulopathy), yellowing of the skin and whites of the eyes (jaundice), decreased or absent urine production (oligouria) and swelling or puffiness due to fluid accumulation (edema), which may or may not occur in the abdomen (ascites). In many cases, scarring (cirrhosis), end stage liver disease and liver failure occur, sometimes within hours of birth. Iron accumulation may also occur in other organs including the pancreas, heart, thyroid, and salivary glands.Neonatal hemochromatosis is considered a spectrum of disease with both severely affected and less severely affected infants. Some researchers speculate that some infants with neonatal hemochromatosis have no symptoms and the disorder may go undetected in such cases. In the medical literature, twins have developed neonatal hemochromatosis and one twin is severely affected while the other is only mildly affected.
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Symptoms of Neonatal Hemochromatosis. Neonatal hemochromatosis is characterized by liver disease that is present in the fetus or at birth (congenital). Damage to the liver occurs during pregnancy, ultimately leading to the abnormal accumulation of iron within tissue. Iron accumulation occurs while the fetus is developing in the womb and fetal loss late in pregnancy is common in families with a history of neonatal hemochromatosis. Growth delays within the womb (intrauterine growth deficiencies) are also common and many newborns are born prematurely.Liver disease is usually apparent shortly after birth, although in rare cases it may not become apparent until days or weeks later. Symptoms of liver disease include low blood sugar (hypoglycemia), abnormalities in blood clotting (coagulopathy), yellowing of the skin and whites of the eyes (jaundice), decreased or absent urine production (oligouria) and swelling or puffiness due to fluid accumulation (edema), which may or may not occur in the abdomen (ascites). In many cases, scarring (cirrhosis), end stage liver disease and liver failure occur, sometimes within hours of birth. Iron accumulation may also occur in other organs including the pancreas, heart, thyroid, and salivary glands.Neonatal hemochromatosis is considered a spectrum of disease with both severely affected and less severely affected infants. Some researchers speculate that some infants with neonatal hemochromatosis have no symptoms and the disorder may go undetected in such cases. In the medical literature, twins have developed neonatal hemochromatosis and one twin is severely affected while the other is only mildly affected.
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Neonatal Hemochromatosis
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Causes of Neonatal Hemochromatosis
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The cause of neonatal hemochromatosis is not fully understood. A woman who has a child with neonatal hemochromatosis has approximately an 80 percent chance of having another child with the disorder. This pattern of recurrence cannot be explained by normal inheritance patterns. Thus, neonatal hemochromatosis appears to be congenital and familial, but not inherited.Significant evidence indicates that most cases of neonatal hemochromatosis result from fetal liver disease due to maternal fetal alloimmunity, a condition termed gestational alloimmune liver disease. A developing fetus is protected from foreign material (e.g., bacteria) by antibodies from its mother, which travel from the mother to the fetus through the placenta. Antibodies are specialized proteins that react against foreign material in the body bringing about their destruction. However, in materno-fetal alloimmune diseases, certain maternal antibodies mistakenly recognize some fetal cells or proteins, causing fetal injury. In gestational alloimmune liver disease, the fetal liver is targeted. Liver cells (hepatocytes) are damaged or killed by the antibody, and damage to the liver ultimately results in the abnormal accumulation of excess iron in the body and the symptoms of neonatal hemochromatosis.Maternal fetal alloimmunity would explain the high recurrence rate of neonatal hemochromatosis in children of women who have already had a child with the disorder. Also, some women have had multiple children with neonatal hemochromatosis despite the children having different fathers, which would also be explained by maternal fetal alloimmunity.Although maternal fetal alloimmunity would explain the majority of cases of neonatal hemochromatosis, rare cases may have a different cause. Neonatal hemochromatosis has been seen in association with genetic diseases including mitochondrial disease (DGUOK gene mutations), metabolic disease (bile acid synthetic defect) and chromosomal abnormalities (trisomy 21). More research is necessary to determine all of the causes and internal mechanisms that result in the development of neonatal hemochromatosis.
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Causes of Neonatal Hemochromatosis. The cause of neonatal hemochromatosis is not fully understood. A woman who has a child with neonatal hemochromatosis has approximately an 80 percent chance of having another child with the disorder. This pattern of recurrence cannot be explained by normal inheritance patterns. Thus, neonatal hemochromatosis appears to be congenital and familial, but not inherited.Significant evidence indicates that most cases of neonatal hemochromatosis result from fetal liver disease due to maternal fetal alloimmunity, a condition termed gestational alloimmune liver disease. A developing fetus is protected from foreign material (e.g., bacteria) by antibodies from its mother, which travel from the mother to the fetus through the placenta. Antibodies are specialized proteins that react against foreign material in the body bringing about their destruction. However, in materno-fetal alloimmune diseases, certain maternal antibodies mistakenly recognize some fetal cells or proteins, causing fetal injury. In gestational alloimmune liver disease, the fetal liver is targeted. Liver cells (hepatocytes) are damaged or killed by the antibody, and damage to the liver ultimately results in the abnormal accumulation of excess iron in the body and the symptoms of neonatal hemochromatosis.Maternal fetal alloimmunity would explain the high recurrence rate of neonatal hemochromatosis in children of women who have already had a child with the disorder. Also, some women have had multiple children with neonatal hemochromatosis despite the children having different fathers, which would also be explained by maternal fetal alloimmunity.Although maternal fetal alloimmunity would explain the majority of cases of neonatal hemochromatosis, rare cases may have a different cause. Neonatal hemochromatosis has been seen in association with genetic diseases including mitochondrial disease (DGUOK gene mutations), metabolic disease (bile acid synthetic defect) and chromosomal abnormalities (trisomy 21). More research is necessary to determine all of the causes and internal mechanisms that result in the development of neonatal hemochromatosis.
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Neonatal Hemochromatosis
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Affects of Neonatal Hemochromatosis
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Neonatal hemochromatosis is a disorder that affects males and females in equal numbers. The exact incidence of the disorder is unknown. Neonatal hemochromatosis is the most common cause of liver failure in newborns and the most common reason for a liver transplant in newborns. Neonatal hemochromatosis was first reported in the medical literature in 1957.
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Affects of Neonatal Hemochromatosis. Neonatal hemochromatosis is a disorder that affects males and females in equal numbers. The exact incidence of the disorder is unknown. Neonatal hemochromatosis is the most common cause of liver failure in newborns and the most common reason for a liver transplant in newborns. Neonatal hemochromatosis was first reported in the medical literature in 1957.
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Neonatal Hemochromatosis
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Related disorders of Neonatal Hemochromatosis
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Symptoms of the following disorders can be similar to those of neonatal hemochromatosis. Comparisons may be useful for a differential diagnosis.Neonatal hepatitis is a general term for inflammation of the liver (hepatitis) that occurs shortly after birth in newborns. Neonatal hepatitis may be caused by viruses, certain metabolic disorders, and other rare diseases that affect or impair the function of the liver. In some children, the cause of liver inflammation is unknown. These cases are referred to as idiopathic neonatal hepatitis (INH). The symptoms of idiopathic neonatal hepatitis may vary greatly from one individual to another. Symptoms common to liver disease often occur including yellowing of the whites of the eyes and the skin (jaundice), enlargement of the liver (hepatomegaly) and unusually dark urine. Approximately 80 percent of individuals with idiopathic neonatal hepatitis fully recover from the condition. (For more information on this disorder, choose (neonatal hepatitis) as your search term in the Rare Disease Database.)Metabolic disorders are a group of disorders in which certain enzymes required to metabolize or breakdown various substances in the body (e.g., carbohydrates, proteins, fats) are missing or reduced. Some of these enzymes are crucial in the production of energy. The absence or deficiency of critical enzymes cause substances to build up in the body potentially damaging various organs A variety of metabolic diseases are associated with liver dysfunction. These disorders include alpha-1-antitrypsin deficiency, cystic fibrosis, fatty acid oxidation disorders, galactosemia, tyrosinemia, Zellweger syndrome, hereditary fructose intolerance and bile acid synthesis defects. (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 Neonatal Hemochromatosis. Symptoms of the following disorders can be similar to those of neonatal hemochromatosis. Comparisons may be useful for a differential diagnosis.Neonatal hepatitis is a general term for inflammation of the liver (hepatitis) that occurs shortly after birth in newborns. Neonatal hepatitis may be caused by viruses, certain metabolic disorders, and other rare diseases that affect or impair the function of the liver. In some children, the cause of liver inflammation is unknown. These cases are referred to as idiopathic neonatal hepatitis (INH). The symptoms of idiopathic neonatal hepatitis may vary greatly from one individual to another. Symptoms common to liver disease often occur including yellowing of the whites of the eyes and the skin (jaundice), enlargement of the liver (hepatomegaly) and unusually dark urine. Approximately 80 percent of individuals with idiopathic neonatal hepatitis fully recover from the condition. (For more information on this disorder, choose (neonatal hepatitis) as your search term in the Rare Disease Database.)Metabolic disorders are a group of disorders in which certain enzymes required to metabolize or breakdown various substances in the body (e.g., carbohydrates, proteins, fats) are missing or reduced. Some of these enzymes are crucial in the production of energy. The absence or deficiency of critical enzymes cause substances to build up in the body potentially damaging various organs A variety of metabolic diseases are associated with liver dysfunction. These disorders include alpha-1-antitrypsin deficiency, cystic fibrosis, fatty acid oxidation disorders, galactosemia, tyrosinemia, Zellweger syndrome, hereditary fructose intolerance and bile acid synthesis defects. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Neonatal Hemochromatosis
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Diagnosis of Neonatal Hemochromatosis
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A diagnosis of neonatal hemochromatosis should be suspected in any infants demonstrating liver disease before birth (antenatally) or shortly after birth. Blood tests may reveal elevated levels of ferritin in the blood serum, which may be indicative of liver disease and iron accumulation. Ferritin is an iron compound that is used as an indicator of the body's iron stores.A diagnosis of neonatal hemochromatosis may be confirmed based upon a thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests that can demonstrate the presence of excess iron in tissue outside the liver (extrahepatic siderosis). Surgical removal and microscopic evaluation of tissue (biopsy) can reveal excess iron. Magnetic resonance imaging (MRI), which uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, can also be used to detect excess iron in tissue.
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Diagnosis of Neonatal Hemochromatosis. A diagnosis of neonatal hemochromatosis should be suspected in any infants demonstrating liver disease before birth (antenatally) or shortly after birth. Blood tests may reveal elevated levels of ferritin in the blood serum, which may be indicative of liver disease and iron accumulation. Ferritin is an iron compound that is used as an indicator of the body's iron stores.A diagnosis of neonatal hemochromatosis may be confirmed based upon a thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests that can demonstrate the presence of excess iron in tissue outside the liver (extrahepatic siderosis). Surgical removal and microscopic evaluation of tissue (biopsy) can reveal excess iron. Magnetic resonance imaging (MRI), which uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, can also be used to detect excess iron in tissue.
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Neonatal Hemochromatosis
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Therapies of Neonatal Hemochromatosis
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TreatmentThe treatment of neonatal hemochromatosis is controversial. Recent evidence suggests that interfering with the alloimmune liver injury by treating affected babies with double-volume blood exchange transfusion and high-dose intravenous immunoglobulin can significantly improve survival. Other treatment options include liver transplantation. Therapy with a combination of certain drugs and antioxidants has proven ineffective. The results of these treatments have varied. Regardless of the treatment option, early diagnosis and prompt treatment are essential for achieving a positive outcome.Neonatal hemochromatosis is the most common cause of liver transplantation in newborns and the procedure has achieved long-term survival in some cases. However, there are numerous risks involved with liver transplant (e.g., cancer risk due to immunosuppressant medications) and additional complications in infants with neonatal hemochromatosis (prematurity, small size for gestational age, potential damage to other organs).In rare cases, some infants with neonatal hemochromatosis have improved without any treatment outside of standard supportive intensive care (spontaneous resolution). Therapy aimed at preventing neonatal hemochromatosis before it occurs has proven very effective. Researchers treated pregnant women (all of whom previously have had a child with neonatal hemochromatosis) with high-dose IVIG during pregnancy, with greater than 95% successful outcome. IVIG therapy modifies the activity of the immune system (immunomodulation). IVIG is a solution containing antibodies donated from healthy individuals and administered directly to a vein. Any woman who has had a baby affected with NH should consider this therapy in subsequent pregnancies.
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Therapies of Neonatal Hemochromatosis. TreatmentThe treatment of neonatal hemochromatosis is controversial. Recent evidence suggests that interfering with the alloimmune liver injury by treating affected babies with double-volume blood exchange transfusion and high-dose intravenous immunoglobulin can significantly improve survival. Other treatment options include liver transplantation. Therapy with a combination of certain drugs and antioxidants has proven ineffective. The results of these treatments have varied. Regardless of the treatment option, early diagnosis and prompt treatment are essential for achieving a positive outcome.Neonatal hemochromatosis is the most common cause of liver transplantation in newborns and the procedure has achieved long-term survival in some cases. However, there are numerous risks involved with liver transplant (e.g., cancer risk due to immunosuppressant medications) and additional complications in infants with neonatal hemochromatosis (prematurity, small size for gestational age, potential damage to other organs).In rare cases, some infants with neonatal hemochromatosis have improved without any treatment outside of standard supportive intensive care (spontaneous resolution). Therapy aimed at preventing neonatal hemochromatosis before it occurs has proven very effective. Researchers treated pregnant women (all of whom previously have had a child with neonatal hemochromatosis) with high-dose IVIG during pregnancy, with greater than 95% successful outcome. IVIG therapy modifies the activity of the immune system (immunomodulation). IVIG is a solution containing antibodies donated from healthy individuals and administered directly to a vein. Any woman who has had a baby affected with NH should consider this therapy in subsequent pregnancies.
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Neonatal Hemochromatosis
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Overview of Neonatal Lupus
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SummaryNeonatal lupus is a rare acquired autoimmune disorder that is present at birth (congenital). Affected infants often develop a characteristic red rash or skin eruption. The most significant potential complication is a heart condition known as congenital heart block. Congenital heart block does not resolve within the first several months of life and infants may ultimately require a pacemaker. Some infants develop only skin symptoms, some infants develop only heart symptoms, and, less often, some infants develop both. Less common findings include liver disease, an abnormally large head circumference (macrocephaly), and/or low numbers of circulating blood platelets that assist in blood clotting functions (thrombocytopenia), white blood cells that help fight infection (neutropenia), and red blood cells that help deliver oxygen to the body (anemia). Neonatal lupus results from specific autoantibodies that travel across the placenta from a pregnant woman to her developing fetus. These autoantibodies damage specific fetal tissue through a process that is not fully understood.IntroductionNeonatal lupus is not the infant form of lupus (systemic lupus erythematosus); the name was given to this disorder because the skin rash resembles the one associated with lupus. The affected infant or child does not have systemic lupus erythematosus and often the mother does not either (often this is miscommunicated to the mother but she is at about a 20% risk of later developing lupus). Neonatal lupus is a distinct, separate disorder.
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Overview of Neonatal Lupus. SummaryNeonatal lupus is a rare acquired autoimmune disorder that is present at birth (congenital). Affected infants often develop a characteristic red rash or skin eruption. The most significant potential complication is a heart condition known as congenital heart block. Congenital heart block does not resolve within the first several months of life and infants may ultimately require a pacemaker. Some infants develop only skin symptoms, some infants develop only heart symptoms, and, less often, some infants develop both. Less common findings include liver disease, an abnormally large head circumference (macrocephaly), and/or low numbers of circulating blood platelets that assist in blood clotting functions (thrombocytopenia), white blood cells that help fight infection (neutropenia), and red blood cells that help deliver oxygen to the body (anemia). Neonatal lupus results from specific autoantibodies that travel across the placenta from a pregnant woman to her developing fetus. These autoantibodies damage specific fetal tissue through a process that is not fully understood.IntroductionNeonatal lupus is not the infant form of lupus (systemic lupus erythematosus); the name was given to this disorder because the skin rash resembles the one associated with lupus. The affected infant or child does not have systemic lupus erythematosus and often the mother does not either (often this is miscommunicated to the mother but she is at about a 20% risk of later developing lupus). Neonatal lupus is a distinct, separate disorder.
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Neonatal Lupus
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Symptoms of Neonatal Lupus
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The most common symptom associated with neonatal lupus is a rash that consists of reddish, ring-like skin lesions and resembles the rash associated with systemic lupus erythematosus. The rash is temporary (transient), usually developing during the first few weeks of life and clearing up at some point during the next several months. In rare cases, skin lesions may persist into childhood. The face and scalp are most commonly affected. The raccoon eye patter is a big clue to this diagnosis when it is present. Less often the rash can occur on the trunk, arms and legs. Some affected infants may also exhibit an abnormal sensitivity to sunlight (photosensitivity), which may initially trigger the development of the rash. Although the most common timing for the rash is about 6 weeks after birth, sometimes the rash may not develop until 2-3 months later. Of note breast feeding is not associated with an increased chance of rash. The most serious complication of neonatal lupus is a heart condition known as congenital heart block. The occurrence of congenital heart block in infants may be as common as the skin rash, it is not known. It is the most serious complication and when the block is complete it is a permanent condition and can potentially be life-threatening. Congenital heart block is characterized by an interference with the transfer of the heart beat from the top to the middle (conduction system) that controls the rate that the heart beats. The severity of such conduction abnormalities may vary among affected infants meaning there can be first, second, or third degree blocks, the latter most serious.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. In the mild form of heart block, the two upper chambers of the heart (atria) beat normally and there is a slight lag time to trigger the lower chambers (ventricles) but this has no clinical significance. In the more moderate forms some beats get through (second degree block which does slow the heart rate a little) and the most severe form, there is no beat that gets through. This severe form is complete heart block in which the atria beat at a normal rate but the ventricles beat slowly. In some cases, heart block may lead to blackouts (syncope), breathlessness, and/or irregular heartbeats (arrhythmias). Some infants may also develop disease of the heart muscle (cardiomyopathy), which can occur in association with thickening within the muscular lining of the heart chambers due to an increase in the amount of supporting connective tissue and elastic fibers (endocardial fibroelastosis). Less often, additional cardiac abnormalities have been reported including inflammation of the myocardium, which is the middle layer of the heart wall, a condition known as myocarditis. In severe cases, life-threatening complications such as heart failure or sudden cardiac arrest can potentially develop. There can also be abnormalities of the mitral and triscuspid valves.Infants with neonatal lupus may also have low numbers of special red blood cells (platelets) that assist in blood clotting functions (thrombocytopenia), low levels of other circulating red blood cells (anemia), low levels of certain white blood cells (neutropenia), and abnormally large spleen (splenomegaly), an abnormally large liver (hepatomegaly), and a form of liver (hepatic) disease known as cholestatic hepatitis. Cholestatic hepatitis is a rare condition characterized by stoppage or reduced flow of bile from the liver (cholestasis), inflammation of the liver (hepatitis), and yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Fortunately, anything more than transient elevation of the liver enzymes with no associated symptoms is the most common of the liver abnormalities. Again, most of these non-cardiac abnormalities resolve themselves within the first six months of an affected infant’s life when the maternal antibodies are cleared from the infant’s circulation.Although extremely rare, some infants with neonatal lupus may have an abnormally large head (macrocephaly). Macrocephaly is defined as a condition in which the circumference of the head is larger than would be expected based upon a child’s age and gender. Some of these infants and children may also develop hydrocephalus, a condition characterized by excessive accumulation of cerebrospinal fluid in the skull that can cause pressure on the tissues of the brain.
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Symptoms of Neonatal Lupus. The most common symptom associated with neonatal lupus is a rash that consists of reddish, ring-like skin lesions and resembles the rash associated with systemic lupus erythematosus. The rash is temporary (transient), usually developing during the first few weeks of life and clearing up at some point during the next several months. In rare cases, skin lesions may persist into childhood. The face and scalp are most commonly affected. The raccoon eye patter is a big clue to this diagnosis when it is present. Less often the rash can occur on the trunk, arms and legs. Some affected infants may also exhibit an abnormal sensitivity to sunlight (photosensitivity), which may initially trigger the development of the rash. Although the most common timing for the rash is about 6 weeks after birth, sometimes the rash may not develop until 2-3 months later. Of note breast feeding is not associated with an increased chance of rash. The most serious complication of neonatal lupus is a heart condition known as congenital heart block. The occurrence of congenital heart block in infants may be as common as the skin rash, it is not known. It is the most serious complication and when the block is complete it is a permanent condition and can potentially be life-threatening. Congenital heart block is characterized by an interference with the transfer of the heart beat from the top to the middle (conduction system) that controls the rate that the heart beats. The severity of such conduction abnormalities may vary among affected infants meaning there can be first, second, or third degree blocks, the latter most serious.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. In the mild form of heart block, the two upper chambers of the heart (atria) beat normally and there is a slight lag time to trigger the lower chambers (ventricles) but this has no clinical significance. In the more moderate forms some beats get through (second degree block which does slow the heart rate a little) and the most severe form, there is no beat that gets through. This severe form is complete heart block in which the atria beat at a normal rate but the ventricles beat slowly. In some cases, heart block may lead to blackouts (syncope), breathlessness, and/or irregular heartbeats (arrhythmias). Some infants may also develop disease of the heart muscle (cardiomyopathy), which can occur in association with thickening within the muscular lining of the heart chambers due to an increase in the amount of supporting connective tissue and elastic fibers (endocardial fibroelastosis). Less often, additional cardiac abnormalities have been reported including inflammation of the myocardium, which is the middle layer of the heart wall, a condition known as myocarditis. In severe cases, life-threatening complications such as heart failure or sudden cardiac arrest can potentially develop. There can also be abnormalities of the mitral and triscuspid valves.Infants with neonatal lupus may also have low numbers of special red blood cells (platelets) that assist in blood clotting functions (thrombocytopenia), low levels of other circulating red blood cells (anemia), low levels of certain white blood cells (neutropenia), and abnormally large spleen (splenomegaly), an abnormally large liver (hepatomegaly), and a form of liver (hepatic) disease known as cholestatic hepatitis. Cholestatic hepatitis is a rare condition characterized by stoppage or reduced flow of bile from the liver (cholestasis), inflammation of the liver (hepatitis), and yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Fortunately, anything more than transient elevation of the liver enzymes with no associated symptoms is the most common of the liver abnormalities. Again, most of these non-cardiac abnormalities resolve themselves within the first six months of an affected infant’s life when the maternal antibodies are cleared from the infant’s circulation.Although extremely rare, some infants with neonatal lupus may have an abnormally large head (macrocephaly). Macrocephaly is defined as a condition in which the circumference of the head is larger than would be expected based upon a child’s age and gender. Some of these infants and children may also develop hydrocephalus, a condition characterized by excessive accumulation of cerebrospinal fluid in the skull that can cause pressure on the tissues of the brain.
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Neonatal Lupus
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Causes of Neonatal Lupus
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Neonatal lupus is a rare acquired disorder that occurs when specific antibodies are passed from a pregnant woman to the developing fetus via the placenta. In most cases, it is the anti-Ro/SSA antibody, the anti-La/SSB antibody, or both. In rare cases, the skin rash associated with neonatal lupus has been associated with another autoantibody that reacts against another type of ribonucleoprotein (the test is called anti-RNP). Other symptoms such as congenital heart block are not thought to occur with anti-RNP but a few isolated cases have been recently published, the importance of which is not yet clear.Antibodies are produced by the body’s immune system to fight foreign substances, known as antigens, in the body. Antigens include microorganisms that may potentially cause disease, toxins, and other such substances. During pregnancy, antibodies travel across the placenta from the mother to the bloodstream of the developing fetus. This is a normal, important process because the fetus cannot make antibodies on its own. In neonatal lupus, certain antibodies known as autoantibodies also cross over the placenta. Autoantibodies are antibodies that mistakenly damage healthy tissue (autoantigens). Autoantibodies are produced in individuals with autoimmune disorders such as lupus, Sjogren’s syndrome, and other such disorders. These autoantibodies attack healthy fetal tissue, resulting in the various symptoms associated with neonatal lupus. The exact underlying process by which maternal autoantibodies affect the fetus is not fully understood. Mothers of infants with neonatal lupus do not necessarily have lupus themselves. Women who have the anti-Ro or anti-La antibodies may have a different rheumatic disorder such as Sjogren’s syndrome or rheumatoid arthritis. In many cases, women with these antibodies may not have any symptoms of rheumatic disease (asymptomatic) or only vague symptoms such as photosensitivity or color changes of their fingers in cold weather (Raynauds) suggesting rheumatic disease or may be diagnosed with an autoimmune disorder only after a diagnosis of neonatal lupus in their child. Again it is important to keep in mind that many mothers are clinically healthy with no disease, just autoantibodies. In considering the risk of congenital heart block, it is not related to whether a mother has lupus or SS but only the autoantibodies. The risk is about 2% (one in fifty). However, again regardless of maternal health status, if a prior pregnancy has resulted in a child with heart block, the changes of having another child with this disease is about 18%. If a mother has had a child with a skin rash, the chance of another child with a skin rash approaches 30% but heart block is about 13%. Pregnant women with the anti-Ro or anti-La antibodies all do pass the antibody on to a developing fetus but, as stated above, only one in 50 offspring will develop neonatal lupus syndrome. Because the majority of women with these disorders have children who do not develop neonatal lupus, researchers believe that other factors, most likely genetic or environmental ones, are necessary for the development of the disorder.
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Causes of Neonatal Lupus. Neonatal lupus is a rare acquired disorder that occurs when specific antibodies are passed from a pregnant woman to the developing fetus via the placenta. In most cases, it is the anti-Ro/SSA antibody, the anti-La/SSB antibody, or both. In rare cases, the skin rash associated with neonatal lupus has been associated with another autoantibody that reacts against another type of ribonucleoprotein (the test is called anti-RNP). Other symptoms such as congenital heart block are not thought to occur with anti-RNP but a few isolated cases have been recently published, the importance of which is not yet clear.Antibodies are produced by the body’s immune system to fight foreign substances, known as antigens, in the body. Antigens include microorganisms that may potentially cause disease, toxins, and other such substances. During pregnancy, antibodies travel across the placenta from the mother to the bloodstream of the developing fetus. This is a normal, important process because the fetus cannot make antibodies on its own. In neonatal lupus, certain antibodies known as autoantibodies also cross over the placenta. Autoantibodies are antibodies that mistakenly damage healthy tissue (autoantigens). Autoantibodies are produced in individuals with autoimmune disorders such as lupus, Sjogren’s syndrome, and other such disorders. These autoantibodies attack healthy fetal tissue, resulting in the various symptoms associated with neonatal lupus. The exact underlying process by which maternal autoantibodies affect the fetus is not fully understood. Mothers of infants with neonatal lupus do not necessarily have lupus themselves. Women who have the anti-Ro or anti-La antibodies may have a different rheumatic disorder such as Sjogren’s syndrome or rheumatoid arthritis. In many cases, women with these antibodies may not have any symptoms of rheumatic disease (asymptomatic) or only vague symptoms such as photosensitivity or color changes of their fingers in cold weather (Raynauds) suggesting rheumatic disease or may be diagnosed with an autoimmune disorder only after a diagnosis of neonatal lupus in their child. Again it is important to keep in mind that many mothers are clinically healthy with no disease, just autoantibodies. In considering the risk of congenital heart block, it is not related to whether a mother has lupus or SS but only the autoantibodies. The risk is about 2% (one in fifty). However, again regardless of maternal health status, if a prior pregnancy has resulted in a child with heart block, the changes of having another child with this disease is about 18%. If a mother has had a child with a skin rash, the chance of another child with a skin rash approaches 30% but heart block is about 13%. Pregnant women with the anti-Ro or anti-La antibodies all do pass the antibody on to a developing fetus but, as stated above, only one in 50 offspring will develop neonatal lupus syndrome. Because the majority of women with these disorders have children who do not develop neonatal lupus, researchers believe that other factors, most likely genetic or environmental ones, are necessary for the development of the disorder.
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Neonatal Lupus
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Affects of Neonatal Lupus
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Neonatal lupus is a rare condition that has occurred slightly more in female than male infants but is far less female gender dominant than systemic lupus erythematosus. Most symptoms of the disorder, except congenital heart block, are temporary (transient), usually resolving themselves within several months. The exact incidence is unknown, but congenital heart block is estimated to occur in 1 in 15,000 live births. In general, the heart block associated with maternal autoantibodies occurs in the absence of any structural abnormalities of the heart.
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Affects of Neonatal Lupus. Neonatal lupus is a rare condition that has occurred slightly more in female than male infants but is far less female gender dominant than systemic lupus erythematosus. Most symptoms of the disorder, except congenital heart block, are temporary (transient), usually resolving themselves within several months. The exact incidence is unknown, but congenital heart block is estimated to occur in 1 in 15,000 live births. In general, the heart block associated with maternal autoantibodies occurs in the absence of any structural abnormalities of the heart.
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Neonatal Lupus
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Related disorders of Neonatal Lupus
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Symptoms of the following disorders can be similar to those of neonatal lupus. Comparisons may be useful for a differential diagnosis:There are several syndromes that are characterized by a skin rash that is present at birth (congenital) including Bloom syndrome, Rothmund-Thompson syndrome, Langerhans cell histiocytosis, granuloma annulare, juvenile dermatomyositis, tinea, corporis, erythema multiforme, atopic dermatitis, seborrheic dermatitis, and psoriasis. There are several infections that can occur the weeks just before or after birth (perinatally) including congenital rubella, congenital syphilis, cytomegalovirus, and group B Streptococcus. These disorders usually have additional findings that distinguish them from neonatal lupus. (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 Neonatal Lupus. Symptoms of the following disorders can be similar to those of neonatal lupus. Comparisons may be useful for a differential diagnosis:There are several syndromes that are characterized by a skin rash that is present at birth (congenital) including Bloom syndrome, Rothmund-Thompson syndrome, Langerhans cell histiocytosis, granuloma annulare, juvenile dermatomyositis, tinea, corporis, erythema multiforme, atopic dermatitis, seborrheic dermatitis, and psoriasis. There are several infections that can occur the weeks just before or after birth (perinatally) including congenital rubella, congenital syphilis, cytomegalovirus, and group B Streptococcus. These disorders usually have additional findings that distinguish them from neonatal lupus. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Neonatal Lupus
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Diagnosis of Neonatal Lupus
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The diagnosis depends of course on the manifestation. If during pregnancy, a fetal heart beat is found to be slow, then an echocardiogram is ordered. Echocardiography is an exam that uses reflected sound waves to create a picture of the heart and is required to assess the function of the heart and diagnose heart block. The mother should be immediately tested for anti-Ro and La antibodies. The diagnosis of the skin rash is based upon a thorough clinical evaluation. It may not always be necessary to test the infant for the antibodies as the mother’s blood test tells the story.
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Diagnosis of Neonatal Lupus. The diagnosis depends of course on the manifestation. If during pregnancy, a fetal heart beat is found to be slow, then an echocardiogram is ordered. Echocardiography is an exam that uses reflected sound waves to create a picture of the heart and is required to assess the function of the heart and diagnose heart block. The mother should be immediately tested for anti-Ro and La antibodies. The diagnosis of the skin rash is based upon a thorough clinical evaluation. It may not always be necessary to test the infant for the antibodies as the mother’s blood test tells the story.
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Neonatal Lupus
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Therapies of Neonatal Lupus
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Treatment
The treatment of neonatal lupus is directed toward the specific symptoms that are apparent in each individual. Cutaneous symptoms generally resolve without treatment (spontaneously) during the first several months of life. Infants diagnosed with neonatal lupus should receive a thorough evaluation to determine whether blood (hematological) or liver (hepatic) complications are also present.Protection from sunlight (e.g. sunscreen and protective clothing) is recommended for infants initially. Mild topical steroids may be used to treat skin symptoms but in most cases no treatment is needed and this should be discussed with the pediatrician. The rash may be merely cosmetic and not require any treatment.Infants with the rash should have an EKG done. However, if there have been no signs of a heart problem during pregnancy or at birth, those with other manifestations of neonatal lupus do not require continuous cardiac evaluation. For infants with congenital heart block, many will require a pacemaker to be implanted. In infants with less severe heart disease, periodic monitoring of heart function should be performed in case a pacemaker is needed later during childhood. Other treatment is symptomatic and supportive.
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Therapies of Neonatal Lupus. Treatment
The treatment of neonatal lupus is directed toward the specific symptoms that are apparent in each individual. Cutaneous symptoms generally resolve without treatment (spontaneously) during the first several months of life. Infants diagnosed with neonatal lupus should receive a thorough evaluation to determine whether blood (hematological) or liver (hepatic) complications are also present.Protection from sunlight (e.g. sunscreen and protective clothing) is recommended for infants initially. Mild topical steroids may be used to treat skin symptoms but in most cases no treatment is needed and this should be discussed with the pediatrician. The rash may be merely cosmetic and not require any treatment.Infants with the rash should have an EKG done. However, if there have been no signs of a heart problem during pregnancy or at birth, those with other manifestations of neonatal lupus do not require continuous cardiac evaluation. For infants with congenital heart block, many will require a pacemaker to be implanted. In infants with less severe heart disease, periodic monitoring of heart function should be performed in case a pacemaker is needed later during childhood. Other treatment is symptomatic and supportive.
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Neonatal Lupus
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Overview of Neonatal-Onset Multisystem Inflammatory Disease
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Summary Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome, is a rare, systemic, inflammatory condition characterized by fever, rash, joint symptoms, and central nervous system (CNS) symptoms. The hallmark of NOMID is onset during early infancy, usually before six months of age. The severity of NOMID varies from child to child. Early diagnosis and prompt treatment with specific medications is important for preventing severe complications of the disease and improving life expectancy. Introduction NOMID is the least common and most severe form of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene. All of these syndromes are characterized by fever, rash, and musculoskeletal pain.
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Overview of Neonatal-Onset Multisystem Inflammatory Disease. Summary Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome, is a rare, systemic, inflammatory condition characterized by fever, rash, joint symptoms, and central nervous system (CNS) symptoms. The hallmark of NOMID is onset during early infancy, usually before six months of age. The severity of NOMID varies from child to child. Early diagnosis and prompt treatment with specific medications is important for preventing severe complications of the disease and improving life expectancy. Introduction NOMID is the least common and most severe form of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene. All of these syndromes are characterized by fever, rash, and musculoskeletal pain.
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Neonatal-Onset Multisystem Inflammatory Disease
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Symptoms of Neonatal-Onset Multisystem Inflammatory Disease
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In addition to fever, symptoms of NOMID involve the skin, CNS and joints. Skin rashes occur in all patients within the first six weeks of life and persist throughout their lives. CNS symptoms include inflammation around the brain (chronic aseptic meningitis), cognitive/mental deficits/learning disabilities, and seizures and sensory organ dysfunction, which can result in vision and hearing loss. Joint inflammation and joint and bone deformities range in severity. Enlargement of the bones around the knee is also characteristic of NOMID.Other clinical features include stunted growth, enlargement of the liver and spleen, an abnormal increase in the number of white blood cells, an elevation in blood levels of the protein amyloid A, C-reactive protein, and erythrocyte sedimentation rate (blood tests used to measure elevations of these markers can detect or grade inflammation). In addition, abnormal facial features, narrowed smaller teeth and other dental abnormalities can sometimes be seen.NOMID shares symptoms, and should not be confused, with juvenile idiopathic arthritis (JIA). High recurrent fevers, joint pain, deforming joint disease and rash are symptoms of both NOMID and JIA. However, NOMID is differentiated by the onset of skin disease at birth and a persistent rash. In addition, many patients with NOMID have nonspecific joint pain and enlargement of the knees, while patients with JIA present with inflamed synovial joints, such as the shoulder or knee, increased production of fluid in the synovial joints and warm, swollen, stiff joints.NOMID patients suffer from frequent, almost daily flare-up episodes which cause great discomfort, can be very debilitating, and may require medical assistance during the episodes. Some patients are unable to walk or bear weight on their legs due to joint damage and/or pain. Many children with NOMID have cognitive and mental deficits and/or learning disabilities as well as vision and hearing loss.
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Symptoms of Neonatal-Onset Multisystem Inflammatory Disease. In addition to fever, symptoms of NOMID involve the skin, CNS and joints. Skin rashes occur in all patients within the first six weeks of life and persist throughout their lives. CNS symptoms include inflammation around the brain (chronic aseptic meningitis), cognitive/mental deficits/learning disabilities, and seizures and sensory organ dysfunction, which can result in vision and hearing loss. Joint inflammation and joint and bone deformities range in severity. Enlargement of the bones around the knee is also characteristic of NOMID.Other clinical features include stunted growth, enlargement of the liver and spleen, an abnormal increase in the number of white blood cells, an elevation in blood levels of the protein amyloid A, C-reactive protein, and erythrocyte sedimentation rate (blood tests used to measure elevations of these markers can detect or grade inflammation). In addition, abnormal facial features, narrowed smaller teeth and other dental abnormalities can sometimes be seen.NOMID shares symptoms, and should not be confused, with juvenile idiopathic arthritis (JIA). High recurrent fevers, joint pain, deforming joint disease and rash are symptoms of both NOMID and JIA. However, NOMID is differentiated by the onset of skin disease at birth and a persistent rash. In addition, many patients with NOMID have nonspecific joint pain and enlargement of the knees, while patients with JIA present with inflamed synovial joints, such as the shoulder or knee, increased production of fluid in the synovial joints and warm, swollen, stiff joints.NOMID patients suffer from frequent, almost daily flare-up episodes which cause great discomfort, can be very debilitating, and may require medical assistance during the episodes. Some patients are unable to walk or bear weight on their legs due to joint damage and/or pain. Many children with NOMID have cognitive and mental deficits and/or learning disabilities as well as vision and hearing loss.
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Neonatal-Onset Multisystem Inflammatory Disease
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Causes of Neonatal-Onset Multisystem Inflammatory Disease
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About 50-60 percent of those who are diagnosed with NOMID have an alteration (mutation) in the CIAS1/NLRP3 gene that codes for the protein cryopyrin (NALP3). Most of the NOMID patients originally described without identifiable mutations were later found to be have somatic mutations a small percentage of their white blood cells (somatic mosaics). Mutations in this gene result in increased activity of a protein complex containing cryopyrin known as the inflammasome, which regulates inflammation in the body. Increased inflammasome activity leads to an increased release of a protein known as interleukin (IL-1ß), which leads to symptoms of inflammation such as fever and joint pain.NOMID follows an autosomal dominant inheritance pattern. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the altered gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Neonatal-Onset Multisystem Inflammatory Disease. About 50-60 percent of those who are diagnosed with NOMID have an alteration (mutation) in the CIAS1/NLRP3 gene that codes for the protein cryopyrin (NALP3). Most of the NOMID patients originally described without identifiable mutations were later found to be have somatic mutations a small percentage of their white blood cells (somatic mosaics). Mutations in this gene result in increased activity of a protein complex containing cryopyrin known as the inflammasome, which regulates inflammation in the body. Increased inflammasome activity leads to an increased release of a protein known as interleukin (IL-1ß), which leads to symptoms of inflammation such as fever and joint pain.NOMID follows an autosomal dominant inheritance pattern. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the altered gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Neonatal-Onset Multisystem Inflammatory Disease
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Affects of Neonatal-Onset Multisystem Inflammatory Disease
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NOMID is a very rare disorder; approximately 100 affected individuals with different ethnic backgrounds have been widely reported. Males and females are equally affected.
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Affects of Neonatal-Onset Multisystem Inflammatory Disease. NOMID is a very rare disorder; approximately 100 affected individuals with different ethnic backgrounds have been widely reported. Males and females are equally affected.
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Neonatal-Onset Multisystem Inflammatory Disease
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Related disorders of Neonatal-Onset Multisystem Inflammatory Disease
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Symptoms of the following disorders can be similar to those of NOMID, and there is significant phenotypic overlap. Comparisons may be useful for a differential diagnosis.Familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria, is another condition in the CAPS category, caused by mutations in the CIAS1/NLRP3 gene. It is a rare, inherited inflammatory disorder characterized by intermittent episodes of a similar rash, fever, chills, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. Onset of FCAS presents during infancy and early childhood and persists throughout the patient’s life. (For more information on this condition, chose “FCAS” as your search term in the Rare Disease Database.)Muckle-Wells syndrome (MWS) is another condition in the CAPS category, caused by mutations in the CIAS1/NLRP3 gene. Individuals with MWS often have episodic fever, chills, and painful joints. Sometimes these symptoms are exacerbated by cold similar to the related condition FCAS, but can also be triggered by other stimuli or have no apparent cause. Most MWS patients develop progressive hearing loss. In some MWS patients, amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient’s tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated. (For more information on this condition, chose “Muckle-Wells” as your search term in the Rare Disease Database.)
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Related disorders of Neonatal-Onset Multisystem Inflammatory Disease. Symptoms of the following disorders can be similar to those of NOMID, and there is significant phenotypic overlap. Comparisons may be useful for a differential diagnosis.Familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria, is another condition in the CAPS category, caused by mutations in the CIAS1/NLRP3 gene. It is a rare, inherited inflammatory disorder characterized by intermittent episodes of a similar rash, fever, chills, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. Onset of FCAS presents during infancy and early childhood and persists throughout the patient’s life. (For more information on this condition, chose “FCAS” as your search term in the Rare Disease Database.)Muckle-Wells syndrome (MWS) is another condition in the CAPS category, caused by mutations in the CIAS1/NLRP3 gene. Individuals with MWS often have episodic fever, chills, and painful joints. Sometimes these symptoms are exacerbated by cold similar to the related condition FCAS, but can also be triggered by other stimuli or have no apparent cause. Most MWS patients develop progressive hearing loss. In some MWS patients, amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient’s tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated. (For more information on this condition, chose “Muckle-Wells” as your search term in the Rare Disease Database.)
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Neonatal-Onset Multisystem Inflammatory Disease
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Diagnosis of Neonatal-Onset Multisystem Inflammatory Disease
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Diagnosis of NOMID is determined through an evaluation of a patient’s symptoms and medical history. Diagnosis includes: skin biopsy, eye exam, hearing test, brain MRI, joint x-rays and cerebrospinal fluid test (detects aseptic meningitis or high white blood counts in the spinal fluid). The diagnosis can be confirmed through genetic testing, but almost half of all NOMID patients do not have an easily identifiable mutation in the CIAS1/NLRP3 gene.
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Diagnosis of Neonatal-Onset Multisystem Inflammatory Disease. Diagnosis of NOMID is determined through an evaluation of a patient’s symptoms and medical history. Diagnosis includes: skin biopsy, eye exam, hearing test, brain MRI, joint x-rays and cerebrospinal fluid test (detects aseptic meningitis or high white blood counts in the spinal fluid). The diagnosis can be confirmed through genetic testing, but almost half of all NOMID patients do not have an easily identifiable mutation in the CIAS1/NLRP3 gene.
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Therapies of Neonatal-Onset Multisystem Inflammatory Disease
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Treatment
Therapies that suppress inflammation, including high-dose corticosteroids and disease-modifying antirheumatic drugs have been used to treat NOMID.Anakinra (Kineret) marketed by Sobi, Inc. was approved by the U.S. Food and Drug Administration (FDA) in 2013 to treat patients with NOMID, and is the only medication that is FDA approved to treat these patients.Canakinumab (Ilaris) by Novartis Pharmaceuticals, a monoclonal antibody to interleukin-1 beta, was approved by the FDA in 2009 as a treatment for adults and children 4 years and older with familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). Ilaris has been used to successfully treat NOMID patients and is approved in Europe, although higher than standard doses are often required and it is not FDA approved for NOMID at this time.Rilonacept (Arcalyst) by Regeneron Pharmaceuticals, an interleukin-1 blocker, was approved by the FDA in 2008 for the treatment of CAPS, including FCAS and MWS, in adults and children 12 years and older, but it is not approved for NOMID and there is limited clinical experience in NOMID patients.
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Therapies of Neonatal-Onset Multisystem Inflammatory Disease. Treatment
Therapies that suppress inflammation, including high-dose corticosteroids and disease-modifying antirheumatic drugs have been used to treat NOMID.Anakinra (Kineret) marketed by Sobi, Inc. was approved by the U.S. Food and Drug Administration (FDA) in 2013 to treat patients with NOMID, and is the only medication that is FDA approved to treat these patients.Canakinumab (Ilaris) by Novartis Pharmaceuticals, a monoclonal antibody to interleukin-1 beta, was approved by the FDA in 2009 as a treatment for adults and children 4 years and older with familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). Ilaris has been used to successfully treat NOMID patients and is approved in Europe, although higher than standard doses are often required and it is not FDA approved for NOMID at this time.Rilonacept (Arcalyst) by Regeneron Pharmaceuticals, an interleukin-1 blocker, was approved by the FDA in 2008 for the treatment of CAPS, including FCAS and MWS, in adults and children 12 years and older, but it is not approved for NOMID and there is limited clinical experience in NOMID patients.
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Overview of Nephrogenic Diabetes Insipidus
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SummaryNephrogenic diabetes insipidus (NDI) is a rare kidney disorder that may be inherited or acquired. NDI is not related to the more common diabetes mellitus (sugar diabetes), in which the body does not produce or properly use insulin. NDI is a distinct disorder caused by complete or partial resistance of the kidneys to arginine vasopressin (AVP). Vasopressin is an antidiuretic hormone used by the kidney to manage water balance in the body. NDI causes chronic excessive urine production (polyuria). Patients must drink as much water as they excrete, leading to excessive thirst (polydipsia). Failure to do so can result in severe dehydration. If left untreated, repeated episodes of severe dehydration may develop, eventually resulting in serious complications including cognitive impairment. Most cases of hereditary NDI are due to changes (mutations or variants) in the AVPR2 gene and are inherited in an X-linked pattern. Rare cases are due to variants in the AQP2 gene and are inherited in an autosomal recessive or dominant pattern. NDI may also be acquired during life due to drugs (e.g., lithium therapy), kidney disease, obstruction of the tubes that carry urine from the kidneys to the bladder (ureters) and prolonged metabolic imbalances such as low levels of potassium in the blood (hypokalemia) or high levels of calcium in the blood (hypercalcemia). NDI may also be a temporary complication associated with pregnancy.IntroductionThe term nephrogenic diabetes insipidus was first used in the medical literature in 1947. In the past, the term diabetes insipidus renalis was used to denote this disorder. NDI is different from central diabetes insipidus, which is a rare disorder characterized by the inability of the body to produce vasopressin (rather than vasopressin resistance as in NDI).
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Overview of Nephrogenic Diabetes Insipidus. SummaryNephrogenic diabetes insipidus (NDI) is a rare kidney disorder that may be inherited or acquired. NDI is not related to the more common diabetes mellitus (sugar diabetes), in which the body does not produce or properly use insulin. NDI is a distinct disorder caused by complete or partial resistance of the kidneys to arginine vasopressin (AVP). Vasopressin is an antidiuretic hormone used by the kidney to manage water balance in the body. NDI causes chronic excessive urine production (polyuria). Patients must drink as much water as they excrete, leading to excessive thirst (polydipsia). Failure to do so can result in severe dehydration. If left untreated, repeated episodes of severe dehydration may develop, eventually resulting in serious complications including cognitive impairment. Most cases of hereditary NDI are due to changes (mutations or variants) in the AVPR2 gene and are inherited in an X-linked pattern. Rare cases are due to variants in the AQP2 gene and are inherited in an autosomal recessive or dominant pattern. NDI may also be acquired during life due to drugs (e.g., lithium therapy), kidney disease, obstruction of the tubes that carry urine from the kidneys to the bladder (ureters) and prolonged metabolic imbalances such as low levels of potassium in the blood (hypokalemia) or high levels of calcium in the blood (hypercalcemia). NDI may also be a temporary complication associated with pregnancy.IntroductionThe term nephrogenic diabetes insipidus was first used in the medical literature in 1947. In the past, the term diabetes insipidus renalis was used to denote this disorder. NDI is different from central diabetes insipidus, which is a rare disorder characterized by the inability of the body to produce vasopressin (rather than vasopressin resistance as in NDI).
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Symptoms of Nephrogenic Diabetes Insipidus
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The symptoms of NDI can vary from one person to another. Some individuals may be more severely affected than others. The acquired form is almost always less severe than the hereditary forms. In hereditary X-linked NDI, symptoms usually appear shortly after birth and most children are diagnosed within the first year of life. In autosomal dominant NDI, symptoms tend to appear later in life, sometimes not until adulthood. The acquired form of NDI most often occurs in adults and the onset of symptoms may be slow.The two main symptoms of NDI are chronic excessive urine production (polyuria) leading to excessive thirst (polydipsia). Excessive urination at night (nocturia) also occurs. Some infants may present with vomiting, retching, unexplained fevers, lethargy and irritability. Constipation, diarrhea and poor feeding may also occur. As a result, some infants may fail to grow or gain weight at the expected rate (failure to thrive). In some patients, these symptoms may be mild and underappreciated.Infants and adults with NDI may rapidly develop dehydration following low water intake, a hot environment or concurrent illness. Infants with NDI may experience repeated episodes of dehydration, which can result in weakness, confusion, dry mucous membranes, dry skin and weight loss. If left untreated, severe dehydration may develop. Repeated episodes of severe dehydration may result in significant abnormalities including seizures, brain damage, developmental delays and physical and intellectual disability. However, with proper diagnosis and prompt treatment, intelligence and development are usually normal.Because of the chronic excretion of large amounts of urine, additional symptoms may develop as affected individuals age including bedwetting at night (nocturnal enuresis), abnormal accumulation of urine in the kidneys (hydronephrosis), swelling (distention) of the ureters with urine due to blockage (hydroureter) and an abnormally large bladder (megacystis). Some individuals develop widening (dilatation) of the urinary tract.Adults with NDI may also develop orthostatic hypotension, a condition in which there is a dramatic decrease in blood pressure upon standing or sitting. Orthostatic hypotension can result in dizziness or momentary loss of consciousness (syncope).Many individuals with NDI attain an adult height that is just below normal or where would be expected otherwise. This may result from unsuccessful management or inadequate nutrition during childhood (e.g., failure to thrive).
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Symptoms of Nephrogenic Diabetes Insipidus. The symptoms of NDI can vary from one person to another. Some individuals may be more severely affected than others. The acquired form is almost always less severe than the hereditary forms. In hereditary X-linked NDI, symptoms usually appear shortly after birth and most children are diagnosed within the first year of life. In autosomal dominant NDI, symptoms tend to appear later in life, sometimes not until adulthood. The acquired form of NDI most often occurs in adults and the onset of symptoms may be slow.The two main symptoms of NDI are chronic excessive urine production (polyuria) leading to excessive thirst (polydipsia). Excessive urination at night (nocturia) also occurs. Some infants may present with vomiting, retching, unexplained fevers, lethargy and irritability. Constipation, diarrhea and poor feeding may also occur. As a result, some infants may fail to grow or gain weight at the expected rate (failure to thrive). In some patients, these symptoms may be mild and underappreciated.Infants and adults with NDI may rapidly develop dehydration following low water intake, a hot environment or concurrent illness. Infants with NDI may experience repeated episodes of dehydration, which can result in weakness, confusion, dry mucous membranes, dry skin and weight loss. If left untreated, severe dehydration may develop. Repeated episodes of severe dehydration may result in significant abnormalities including seizures, brain damage, developmental delays and physical and intellectual disability. However, with proper diagnosis and prompt treatment, intelligence and development are usually normal.Because of the chronic excretion of large amounts of urine, additional symptoms may develop as affected individuals age including bedwetting at night (nocturnal enuresis), abnormal accumulation of urine in the kidneys (hydronephrosis), swelling (distention) of the ureters with urine due to blockage (hydroureter) and an abnormally large bladder (megacystis). Some individuals develop widening (dilatation) of the urinary tract.Adults with NDI may also develop orthostatic hypotension, a condition in which there is a dramatic decrease in blood pressure upon standing or sitting. Orthostatic hypotension can result in dizziness or momentary loss of consciousness (syncope).Many individuals with NDI attain an adult height that is just below normal or where would be expected otherwise. This may result from unsuccessful management or inadequate nutrition during childhood (e.g., failure to thrive).
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Causes of Nephrogenic Diabetes Insipidus
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A variety of factors can cause acquired NDI. A common cause is chronic use of the drug lithium. Less common causes include protein malnutrition, a variety of kidney diseases, obstruction of the urinary tract and prolonged metabolic imbalances, specifically low levels of potassium in the blood (hypokalemia) or high levels of calcium in the blood (hypercalcemia). Other drugs such as certain antibiotics, antivirals, antifungals or antineoplastic drugs have been reported to potentially cause acquired NDI. During pregnancy, some women may develop a temporary (transient) form of NDI.In most cases of hereditary NDI inheritance is X-linked recessive. In rare cases, inheritance is autosomal recessive or dominant. Some cases may occur randomly as the result of a spontaneous genetic change (i.e., new mutation).X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest almost exclusively 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 can 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.Although most females who carry the mutated gene usually do not develop the clinical symptoms (asymptomatic) of NDI, some females do develop certain symptoms such as varying degrees of excessive urination and excessive thirst. This occurs because of a process known as marked skewing of X chromosome inactivation. In this process, the X chromosome carrying the normal gene is inactivated instead of the X chromosome with the mutated gene.The X-linked recessive form of NDI, which account for approximately 90% of cases, is caused by disruptions or changes (mutations) of the AVPR2 gene on the X chromosome.Approximately 10% of cases of hereditary NDI are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.Less than 1% of cases hereditary NDI are inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Most (but not all) patients with autosomal recessive or dominant NDI are caused by mutations of the aquaporin-2 (AQP2) gene.The symptoms of NDI result from the inability of the kidneys to reabsorb water. Water within the body normally flows through the kidneys where it is reabsorbed through structures called nephrons – tubular filters that collect urine containing water and waste products. The water is filtered out and eventually returned the body. The amount of water retained is determined by the antidiuretic hormone, arginine vasopressin. This hormone works with a protein coating the cells of nephrons called a vasopressin-2 receptor (V2R). The V2R protein recognizes vasopressin in the body. Vasopressin and V2Rs bind together to begin a complex chemical process that manages water intake by the kidneys. As part of this process, another protein known as aquaporin-2 (AQP2) is activated to serve as a passageway or water channel through which water crosses the cell membrane.The V2R protein is encoded by the AVPR2 gene, which is abnormal in individuals with the X-linked form of this disorder. An abnormal AVPR2 gene results in abnormal V2Rs that are trapped within cells (intracellular) and do not reach the cell surface. A few abnormal V2Rs do reach the cell surface, but they fail to recognize or bind with vasopressin, thereby preventing the proper reabsorption of water.Individuals with autosomal recessive or dominant NDI generally have variants in the AQP2 gene, which encodes the water channel protein aquaporin-2. An abnormal AQP2 gene results in abnormal aquaporin-2. Abnormal aquaporin-2 proteins result in abnormal water channels that prevent enough water from passing through the cell membranes.If the kidneys do not properly reabsorb water, the water is lost through frequent urination. The urine of individuals with NDI is dilute or weak, meaning that the urine has too much water in it.
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Causes of Nephrogenic Diabetes Insipidus. A variety of factors can cause acquired NDI. A common cause is chronic use of the drug lithium. Less common causes include protein malnutrition, a variety of kidney diseases, obstruction of the urinary tract and prolonged metabolic imbalances, specifically low levels of potassium in the blood (hypokalemia) or high levels of calcium in the blood (hypercalcemia). Other drugs such as certain antibiotics, antivirals, antifungals or antineoplastic drugs have been reported to potentially cause acquired NDI. During pregnancy, some women may develop a temporary (transient) form of NDI.In most cases of hereditary NDI inheritance is X-linked recessive. In rare cases, inheritance is autosomal recessive or dominant. Some cases may occur randomly as the result of a spontaneous genetic change (i.e., new mutation).X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest almost exclusively 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 can 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.Although most females who carry the mutated gene usually do not develop the clinical symptoms (asymptomatic) of NDI, some females do develop certain symptoms such as varying degrees of excessive urination and excessive thirst. This occurs because of a process known as marked skewing of X chromosome inactivation. In this process, the X chromosome carrying the normal gene is inactivated instead of the X chromosome with the mutated gene.The X-linked recessive form of NDI, which account for approximately 90% of cases, is caused by disruptions or changes (mutations) of the AVPR2 gene on the X chromosome.Approximately 10% of cases of hereditary NDI are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.Less than 1% of cases hereditary NDI are inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Most (but not all) patients with autosomal recessive or dominant NDI are caused by mutations of the aquaporin-2 (AQP2) gene.The symptoms of NDI result from the inability of the kidneys to reabsorb water. Water within the body normally flows through the kidneys where it is reabsorbed through structures called nephrons – tubular filters that collect urine containing water and waste products. The water is filtered out and eventually returned the body. The amount of water retained is determined by the antidiuretic hormone, arginine vasopressin. This hormone works with a protein coating the cells of nephrons called a vasopressin-2 receptor (V2R). The V2R protein recognizes vasopressin in the body. Vasopressin and V2Rs bind together to begin a complex chemical process that manages water intake by the kidneys. As part of this process, another protein known as aquaporin-2 (AQP2) is activated to serve as a passageway or water channel through which water crosses the cell membrane.The V2R protein is encoded by the AVPR2 gene, which is abnormal in individuals with the X-linked form of this disorder. An abnormal AVPR2 gene results in abnormal V2Rs that are trapped within cells (intracellular) and do not reach the cell surface. A few abnormal V2Rs do reach the cell surface, but they fail to recognize or bind with vasopressin, thereby preventing the proper reabsorption of water.Individuals with autosomal recessive or dominant NDI generally have variants in the AQP2 gene, which encodes the water channel protein aquaporin-2. An abnormal AQP2 gene results in abnormal aquaporin-2. Abnormal aquaporin-2 proteins result in abnormal water channels that prevent enough water from passing through the cell membranes.If the kidneys do not properly reabsorb water, the water is lost through frequent urination. The urine of individuals with NDI is dilute or weak, meaning that the urine has too much water in it.
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Affects of Nephrogenic Diabetes Insipidus
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The X-linked inherited form of NDI usually affects males. Females can be carriers of the X-linked type, may develop mild symptoms and can pass it on to their male offspring. The autosomal dominant, autosomal recessive and acquired forms of NDI affect males and females in equal numbers. The symptoms of NDI may begin at any age, usually rapidly and without warning. The incidence of NDI is not known; the X-linked form is estimated to affect 4 males out of every 1,000,000.The acquired form of NDI is more common than the inherited forms. Approximately 55% of individuals on long-term lithium therapy develop NDI. The exact, overall incidence of acquired NDI is unknown.
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Affects of Nephrogenic Diabetes Insipidus. The X-linked inherited form of NDI usually affects males. Females can be carriers of the X-linked type, may develop mild symptoms and can pass it on to their male offspring. The autosomal dominant, autosomal recessive and acquired forms of NDI affect males and females in equal numbers. The symptoms of NDI may begin at any age, usually rapidly and without warning. The incidence of NDI is not known; the X-linked form is estimated to affect 4 males out of every 1,000,000.The acquired form of NDI is more common than the inherited forms. Approximately 55% of individuals on long-term lithium therapy develop NDI. The exact, overall incidence of acquired NDI is unknown.
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Related disorders of Nephrogenic Diabetes Insipidus
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Symptoms of the following disorders can be like those of NDI. Comparisons may be useful for a differential diagnosis.Central diabetes insipidus (CDI) is a rare disorder characterized by excessive urination (polyuria) and excessive thirst (polydipsia). CDI is caused by deficiency of arginine vasopressin (AVP), an antidiuretic hormone used by the kidney to manage water balance in the body. If affected individuals do not have access to water, dehydration and severe thirst may develop. Severe dehydration may result in confusion or changes in consciousness may develop. CDI is usually caused by trauma or damage to the pituitary gland. Rarely, it is inherited in an autosomal dominant pattern. In approximately one-third of affected individuals, no specific cause can be identified (idiopathic). (For more information on this disorder, choose “central diabetes insipidus” as your search term in the Rare Disease Database.)Diabetes mellitus (insulin dependent diabetes) is a common disorder in which the body does not produce enough insulin or is unable to properly use available insulin. Therefore, the body is not able to properly convert nutrients into the energy necessary for daily activities. The disorder is believed to be genetic, but environmental factors may play a role in determining which genetically predisposed people will develop the disorder. More females than males are affected by diabetes mellitus. Although the most obvious symptoms are unusually excessive thirst and urination, diabetes mellitus is not related to diabetes insipidus, and their causes are very different.Primary (or psychogenic) polydipsia is a rare disorder in which individuals drink excessive amounts of water in the absence of any normal stimulus for thirst. Affected individuals will produce excessive amounts of urine (polyuria). In response to the excessive intake of water, their pituitary will produce less vasopressin, a hormone used by the kidney to manage water balance in the body. Primary (psychogenic) polydispsia can potentially cause water intoxication, a condition that can cause serious complications. Some cases of primary (psychogenic) polydispsia occur as part of mental illness. In other cases, the cause is unknown.
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Related disorders of Nephrogenic Diabetes Insipidus. Symptoms of the following disorders can be like those of NDI. Comparisons may be useful for a differential diagnosis.Central diabetes insipidus (CDI) is a rare disorder characterized by excessive urination (polyuria) and excessive thirst (polydipsia). CDI is caused by deficiency of arginine vasopressin (AVP), an antidiuretic hormone used by the kidney to manage water balance in the body. If affected individuals do not have access to water, dehydration and severe thirst may develop. Severe dehydration may result in confusion or changes in consciousness may develop. CDI is usually caused by trauma or damage to the pituitary gland. Rarely, it is inherited in an autosomal dominant pattern. In approximately one-third of affected individuals, no specific cause can be identified (idiopathic). (For more information on this disorder, choose “central diabetes insipidus” as your search term in the Rare Disease Database.)Diabetes mellitus (insulin dependent diabetes) is a common disorder in which the body does not produce enough insulin or is unable to properly use available insulin. Therefore, the body is not able to properly convert nutrients into the energy necessary for daily activities. The disorder is believed to be genetic, but environmental factors may play a role in determining which genetically predisposed people will develop the disorder. More females than males are affected by diabetes mellitus. Although the most obvious symptoms are unusually excessive thirst and urination, diabetes mellitus is not related to diabetes insipidus, and their causes are very different.Primary (or psychogenic) polydipsia is a rare disorder in which individuals drink excessive amounts of water in the absence of any normal stimulus for thirst. Affected individuals will produce excessive amounts of urine (polyuria). In response to the excessive intake of water, their pituitary will produce less vasopressin, a hormone used by the kidney to manage water balance in the body. Primary (psychogenic) polydispsia can potentially cause water intoxication, a condition that can cause serious complications. Some cases of primary (psychogenic) polydispsia occur as part of mental illness. In other cases, the cause is unknown.
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Diagnosis of Nephrogenic Diabetes Insipidus
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A diagnosis of NDI may be suspected based upon the identification of characteristic findings, specifically excessive urination and excessive thirst. A thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests may be used to confirm a diagnosis. NDI may be suspected in children and adults who present with polyuria and polydipsia. Genetic testing can be done to look for variants in the V2R or AQP2 genes.Clinical Testing and Workup
Physicians may take blood and urine samples to determine the concentration of particles or solids (e.g., salts, minerals, sugar) within those samples. The ratio of particles to water within the blood or urine is known as osmolality. Individuals with NDI have a high proportion of solids in relation to water (high osmolality) in their blood and a low proportion of solids in relation to water (low osmolality) in their urine.Additional tests may be necessary to confirm a diagnosis or rule out other causes of diabetes insipidus. Affected individuals may also receive injections of the hormones vasopressin or desmopressin (DDAVP). Desmopressin is a synthetic derivative of vasopressin. Individuals with NDI do not respond to vasopressin supplementation because in NDI the kidneys are resistant to the effects of vasopressin.In some individuals an additional test, known as a water deprivation test, may be required to confirm a diagnosis. During this test, affected individuals cannot ingest any fluids and can only eat dry foods for a specific period of time. Blood and urine samples will be taken and studied. A water deprivation test studies body weight and both urine output and composition and can determine the levels of vasopressin in the body. This test may be used to distinguish between the various causes of diabetes insipidus. A water deprivation test can also differentiate between individuals with complete or partial NDI.Some individuals will have x-ray scans including computed tomography (CT scan) or magnetic resonance imaging (MRI) to rule out brain tumors that can affect the pituitary gland, a potential cause of central diabetes insipidus.An ultrasound may be used to detect whether any kidney (renal) abnormalities (e.g., hydronephrosis, dilation) are present. During an ultrasound, reflected sound waves are used to create an image of internal organs or structures.
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Diagnosis of Nephrogenic Diabetes Insipidus. A diagnosis of NDI may be suspected based upon the identification of characteristic findings, specifically excessive urination and excessive thirst. A thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests may be used to confirm a diagnosis. NDI may be suspected in children and adults who present with polyuria and polydipsia. Genetic testing can be done to look for variants in the V2R or AQP2 genes.Clinical Testing and Workup
Physicians may take blood and urine samples to determine the concentration of particles or solids (e.g., salts, minerals, sugar) within those samples. The ratio of particles to water within the blood or urine is known as osmolality. Individuals with NDI have a high proportion of solids in relation to water (high osmolality) in their blood and a low proportion of solids in relation to water (low osmolality) in their urine.Additional tests may be necessary to confirm a diagnosis or rule out other causes of diabetes insipidus. Affected individuals may also receive injections of the hormones vasopressin or desmopressin (DDAVP). Desmopressin is a synthetic derivative of vasopressin. Individuals with NDI do not respond to vasopressin supplementation because in NDI the kidneys are resistant to the effects of vasopressin.In some individuals an additional test, known as a water deprivation test, may be required to confirm a diagnosis. During this test, affected individuals cannot ingest any fluids and can only eat dry foods for a specific period of time. Blood and urine samples will be taken and studied. A water deprivation test studies body weight and both urine output and composition and can determine the levels of vasopressin in the body. This test may be used to distinguish between the various causes of diabetes insipidus. A water deprivation test can also differentiate between individuals with complete or partial NDI.Some individuals will have x-ray scans including computed tomography (CT scan) or magnetic resonance imaging (MRI) to rule out brain tumors that can affect the pituitary gland, a potential cause of central diabetes insipidus.An ultrasound may be used to detect whether any kidney (renal) abnormalities (e.g., hydronephrosis, dilation) are present. During an ultrasound, reflected sound waves are used to create an image of internal organs or structures.
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Therapies of Nephrogenic Diabetes Insipidus
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Treatment
The treatment of NDI is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), endocrinologists, nutritionists and other health care professionals may need to plan an individual’s treatment systematically and comprehensively.The mainstay of therapy is ensuring proper fluid intake and reducing urine output. Specific treatments include dietary modifications and the administration of certain drugs. Adequate water intake is essential for individuals with NDI to prevent dehydration. Infants may require periodic offerings of water. If the child cannot consume enough water to match their urine output, they may require a feeding tube to be placed into the stomach or intestine.Children, parents and adults should take precautions to ensure affected individuals have access to drinking water and toilet facilities. Heavy sleepers may need to be awakened during the night to drink water and to urinate. Parents should work with school officials and teachers to ensure that proper provisions are in place for their children. Affected individuals are encouraged to wear medic alert bracelets or some similar form of identification that indicates that they have NDI.Dietary modifications and drug therapy are used to decrease urine output. Individuals with NDI may be placed on a very low sodium diet (0.5 g/d) because sodium contributes to water loss. Drugs that affect how much water is excreted in the urine (diuretics) may also be used. Diuretics, which include hydrochlorthiazide or chlorothiazide, inhibit the amount of salt absorbed by the kidneys, thereby reducing water loss. These drugs may be used alone or in combination with other drugs such as indomethacin or amiloride. Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) that can increase urine concentration and reduce urine output. Indomethacin, which may also be used alone, may be associated with adverse side effects such as gastrointestinal bleeding. Amiloride is a diuretic that helps the body maintain potassium levels, which may drop with hydrochlorthiazide therapy.For individuals with acquired NDI treating the underlying cause (e.g., correcting metabolic imbalances or discontinuing drug use) can reverse the kidneys resistance to vasopressin. However, this reversal may take weeks. In some cases, caused by the use of drugs such as lithium, it may take years for the kidneys to respond to vasopressin again or it can become irreversible.Individuals with NDI undergoing surgery that requires no food or drink for a period of time preceding the surgery should consult with their physicians. Affected individuals will require proper hydration, usually via an IV, before and/or during surgery.Genetic counseling is recommended for affected individuals and their families with the inherited forms of the disorder. Other treatment is symptomatic and supportive.
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Therapies of Nephrogenic Diabetes Insipidus. Treatment
The treatment of NDI is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), endocrinologists, nutritionists and other health care professionals may need to plan an individual’s treatment systematically and comprehensively.The mainstay of therapy is ensuring proper fluid intake and reducing urine output. Specific treatments include dietary modifications and the administration of certain drugs. Adequate water intake is essential for individuals with NDI to prevent dehydration. Infants may require periodic offerings of water. If the child cannot consume enough water to match their urine output, they may require a feeding tube to be placed into the stomach or intestine.Children, parents and adults should take precautions to ensure affected individuals have access to drinking water and toilet facilities. Heavy sleepers may need to be awakened during the night to drink water and to urinate. Parents should work with school officials and teachers to ensure that proper provisions are in place for their children. Affected individuals are encouraged to wear medic alert bracelets or some similar form of identification that indicates that they have NDI.Dietary modifications and drug therapy are used to decrease urine output. Individuals with NDI may be placed on a very low sodium diet (0.5 g/d) because sodium contributes to water loss. Drugs that affect how much water is excreted in the urine (diuretics) may also be used. Diuretics, which include hydrochlorthiazide or chlorothiazide, inhibit the amount of salt absorbed by the kidneys, thereby reducing water loss. These drugs may be used alone or in combination with other drugs such as indomethacin or amiloride. Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) that can increase urine concentration and reduce urine output. Indomethacin, which may also be used alone, may be associated with adverse side effects such as gastrointestinal bleeding. Amiloride is a diuretic that helps the body maintain potassium levels, which may drop with hydrochlorthiazide therapy.For individuals with acquired NDI treating the underlying cause (e.g., correcting metabolic imbalances or discontinuing drug use) can reverse the kidneys resistance to vasopressin. However, this reversal may take weeks. In some cases, caused by the use of drugs such as lithium, it may take years for the kidneys to respond to vasopressin again or it can become irreversible.Individuals with NDI undergoing surgery that requires no food or drink for a period of time preceding the surgery should consult with their physicians. Affected individuals will require proper hydration, usually via an IV, before and/or during surgery.Genetic counseling is recommended for affected individuals and their families with the inherited forms of the disorder. Other treatment is symptomatic and supportive.
| 870 |
Nephrogenic Diabetes Insipidus
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nord_871_0
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Overview of Nephrogenic Systemic Fibrosis
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Nephrogenic systemic fibrosis (NSF) is a rare disorder that occurs in some individuals with reduced kidney function, who have been exposed to an intravenous contrast material that contains gadolinium. A contrast material is a dye that is sometimes used during magnetic resonance imaging (MRI). The term, fibrosis, refers to the thickening and scarring of connective tissue, most often the consequence of inflammation or injury. NSF is characterized by thickening and hardening (fibrosis) of the skin, subcutaneous tissues, and, sometimes, underlying skeletal muscle. The arms and legs are most often affected. In some cases, the skin on the trunk can also become involved. This proliferation of fibrotic tissue may become systemic, extending to other areas including the smooth, delicate membrane that surrounds the lungs (pleura), the sac surrounding the heart (pericardium), the thin sheet of muscle that aids respiration by moving up and down when breathing (diaphragm), and the outermost layer (dura mater) of the three membranes covering the brain and spinal cord.NSF was thought to predominantly involve the skin and was originally referred to as nephrogenic fibrosing dermopathy. However, it is now known that it may involve several internal organs (systemic disorder), potentially leading to a progressive and severe disease course. NSF has not been reported in individuals with normal kidney function.Since September of 2010, the U.S. Food and Drug Administration (FDA) has required that gadolinium-based contrast agents (GBCA) carry a warning on their labels about the risk of NSF when administered in certain individuals with kidney disease. In addition, the FDA also stated that three specific gadolinium-based contrast agents (Magnevist ®, OmniscanTM, and Optimark ®) were contraindicated in individuals with severe chronic kidney disease or acute kidney injury. These three agents were the ones most often associated with NSF.
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Overview of Nephrogenic Systemic Fibrosis. Nephrogenic systemic fibrosis (NSF) is a rare disorder that occurs in some individuals with reduced kidney function, who have been exposed to an intravenous contrast material that contains gadolinium. A contrast material is a dye that is sometimes used during magnetic resonance imaging (MRI). The term, fibrosis, refers to the thickening and scarring of connective tissue, most often the consequence of inflammation or injury. NSF is characterized by thickening and hardening (fibrosis) of the skin, subcutaneous tissues, and, sometimes, underlying skeletal muscle. The arms and legs are most often affected. In some cases, the skin on the trunk can also become involved. This proliferation of fibrotic tissue may become systemic, extending to other areas including the smooth, delicate membrane that surrounds the lungs (pleura), the sac surrounding the heart (pericardium), the thin sheet of muscle that aids respiration by moving up and down when breathing (diaphragm), and the outermost layer (dura mater) of the three membranes covering the brain and spinal cord.NSF was thought to predominantly involve the skin and was originally referred to as nephrogenic fibrosing dermopathy. However, it is now known that it may involve several internal organs (systemic disorder), potentially leading to a progressive and severe disease course. NSF has not been reported in individuals with normal kidney function.Since September of 2010, the U.S. Food and Drug Administration (FDA) has required that gadolinium-based contrast agents (GBCA) carry a warning on their labels about the risk of NSF when administered in certain individuals with kidney disease. In addition, the FDA also stated that three specific gadolinium-based contrast agents (Magnevist ®, OmniscanTM, and Optimark ®) were contraindicated in individuals with severe chronic kidney disease or acute kidney injury. These three agents were the ones most often associated with NSF.
| 871 |
Nephrogenic Systemic Fibrosis
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nord_871_1
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Symptoms of Nephrogenic Systemic Fibrosis
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The symptoms of NSF may develop slowly over a few weeks to a few months after exposure to gadolinium-based contrast agents. The severity and progression of the disorder can vary from one person to another. The disorder can have a rapid, progressive course and can cause debilitating symptoms. In rare, rapidly-progressive cases, NSF can contribute to the development of severe, life-threatening complications. The initial symptoms of NSF usually involve the skin, with a gradual tightening or thickening effect. Affected individuals may experience reddened (erythematous) or darkened patches or papules especially on the extremities. The areas between the ankles and the thighs and the wrists and the upper arms are most commonly affected. Swelling (edema) may also occur and the skin may be itchy (pruritic). In some cases, the skin may appear shiny. Skin abnormalities are usually symmetric, which means that the size, shape and location of the lesions are similar on both sides of the body. Over time, affected areas may eventually resemble the texture of an orange peel (peau d'orange). Skin hardening (induration) can become severe, causing chronic pain and loss of flexibility. The affected areas of skin can become hard to the touch. In general, the facial skin is not involved. In addition to the skin, underlying tissue may also be affected including the layer of connective tissue beneath the skin (subcutis), the tough band of fibrous tissue beneath the subcutis (fascia) and skeletal muscle. In some cases, skin tightening and hardening may affect the range of motion and flexibility of the joints, causing contractures. A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. Severely affected individuals can lose the ability to walk or to fully extend the upper and lower limbs, potentially becoming wheelchair bound. Complaints of muscle weakness are also common in individuals with NSF. Flesh-colored, reddish, or brownish papules (small, solid bumps arising from the skin) have been reported, and yellow scleral plaques (yellow areas in the whites [sclera] of the eyes) have also been observed. Additional symptoms associated with NSF are highly variable depending upon the specific organ systems involved. NSF can potentially affect multiple organ systems and structures of the body including the lungs, hearts, esophagus and diaphragm. Involvement of the lungs or diaphragm can lead to a variety of breathing (respiratory) complications. Involvement of the heart can impair the ability of the heart to pump blood throughout the body.
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Symptoms of Nephrogenic Systemic Fibrosis. The symptoms of NSF may develop slowly over a few weeks to a few months after exposure to gadolinium-based contrast agents. The severity and progression of the disorder can vary from one person to another. The disorder can have a rapid, progressive course and can cause debilitating symptoms. In rare, rapidly-progressive cases, NSF can contribute to the development of severe, life-threatening complications. The initial symptoms of NSF usually involve the skin, with a gradual tightening or thickening effect. Affected individuals may experience reddened (erythematous) or darkened patches or papules especially on the extremities. The areas between the ankles and the thighs and the wrists and the upper arms are most commonly affected. Swelling (edema) may also occur and the skin may be itchy (pruritic). In some cases, the skin may appear shiny. Skin abnormalities are usually symmetric, which means that the size, shape and location of the lesions are similar on both sides of the body. Over time, affected areas may eventually resemble the texture of an orange peel (peau d'orange). Skin hardening (induration) can become severe, causing chronic pain and loss of flexibility. The affected areas of skin can become hard to the touch. In general, the facial skin is not involved. In addition to the skin, underlying tissue may also be affected including the layer of connective tissue beneath the skin (subcutis), the tough band of fibrous tissue beneath the subcutis (fascia) and skeletal muscle. In some cases, skin tightening and hardening may affect the range of motion and flexibility of the joints, causing contractures. A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. Severely affected individuals can lose the ability to walk or to fully extend the upper and lower limbs, potentially becoming wheelchair bound. Complaints of muscle weakness are also common in individuals with NSF. Flesh-colored, reddish, or brownish papules (small, solid bumps arising from the skin) have been reported, and yellow scleral plaques (yellow areas in the whites [sclera] of the eyes) have also been observed. Additional symptoms associated with NSF are highly variable depending upon the specific organ systems involved. NSF can potentially affect multiple organ systems and structures of the body including the lungs, hearts, esophagus and diaphragm. Involvement of the lungs or diaphragm can lead to a variety of breathing (respiratory) complications. Involvement of the heart can impair the ability of the heart to pump blood throughout the body.
| 871 |
Nephrogenic Systemic Fibrosis
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nord_871_2
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Causes of Nephrogenic Systemic Fibrosis
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The exact underlying cause of NSF is not fully understood. The disorder occurs in individuals with advanced kidney disease who have been exposed to gadolinium-based contrasts agents that are used in magnetic resonance imaging. Gadolinium is a heavy metal with paramagnetic qualities that cause it to respond differently within a magnetic field. Because of this trait, gadolinium has been used for magnetic resonance imaging examinations. Gadolinium is considered toxic and, in order to be used in contrast dyes, is bound to other molecules to facilitate its passage through the body. Gadolinium contrast agents are ultimately excreted through the kidneys. Individuals with impaired kidney function cannot adequately and quickly eliminate GBCA from the body. Researchers believe this prolonged excretion may lead to a breakdown of the contrast chemical, with release of the Gadolinium atom (dechelation). This foreign material may then lead to a process resembling a chronic wound healing reaction, with abundant production of collagen. In addition to kidney disease and exposure to GBCAs, individuals with NSF may have a “proinflammatory” state, which refers to any condition that causes an inflammatory reaction in the body. In individuals who had developed NSF, this has included recent major surgery, infection, malignancy or the formation of blood clots (thrombosis). Many individuals with NSF have had recent vascular surgery or a thrombotic condition before the onset of the disorder. The exact relationship between these inflammatory conditions and risk for development of NSF is not known. Researchers have also detected the presence of “circulating fibrocytes” (CFs) in the skin of individuals with NSF. CFs are circulating cells that respond to tissue damage by exiting the circulation and maturing into cells that produce fibrous tissue (collagen). They are normally participants in the wound healing process. Researchers believe that these cells are inappropriately summoned to the skin in great numbers, despite the lack of an obvious injury. Currently investigators suspect the dechelation event allows the CFs to home to the skin, where they produce the abundant collagen typical of NSF. The precise details of this process are not fully understood and require further study.
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Causes of Nephrogenic Systemic Fibrosis. The exact underlying cause of NSF is not fully understood. The disorder occurs in individuals with advanced kidney disease who have been exposed to gadolinium-based contrasts agents that are used in magnetic resonance imaging. Gadolinium is a heavy metal with paramagnetic qualities that cause it to respond differently within a magnetic field. Because of this trait, gadolinium has been used for magnetic resonance imaging examinations. Gadolinium is considered toxic and, in order to be used in contrast dyes, is bound to other molecules to facilitate its passage through the body. Gadolinium contrast agents are ultimately excreted through the kidneys. Individuals with impaired kidney function cannot adequately and quickly eliminate GBCA from the body. Researchers believe this prolonged excretion may lead to a breakdown of the contrast chemical, with release of the Gadolinium atom (dechelation). This foreign material may then lead to a process resembling a chronic wound healing reaction, with abundant production of collagen. In addition to kidney disease and exposure to GBCAs, individuals with NSF may have a “proinflammatory” state, which refers to any condition that causes an inflammatory reaction in the body. In individuals who had developed NSF, this has included recent major surgery, infection, malignancy or the formation of blood clots (thrombosis). Many individuals with NSF have had recent vascular surgery or a thrombotic condition before the onset of the disorder. The exact relationship between these inflammatory conditions and risk for development of NSF is not known. Researchers have also detected the presence of “circulating fibrocytes” (CFs) in the skin of individuals with NSF. CFs are circulating cells that respond to tissue damage by exiting the circulation and maturing into cells that produce fibrous tissue (collagen). They are normally participants in the wound healing process. Researchers believe that these cells are inappropriately summoned to the skin in great numbers, despite the lack of an obvious injury. Currently investigators suspect the dechelation event allows the CFs to home to the skin, where they produce the abundant collagen typical of NSF. The precise details of this process are not fully understood and require further study.
| 871 |
Nephrogenic Systemic Fibrosis
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