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nord_828_4
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Related disorders of Mucopolysaccharidosis Type I
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Symptoms of the following disorders can be similar to those of mucopolysaccharidosis type I. Comparisons may be useful for a differential diagnosis.Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various materials in the body’s cells as a result of enzyme deficiencies. There are nearly 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. (For more information on this disorder, choose “lysosomal storage diseases” as your search term in the Rare Disease Database.)
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Related disorders of Mucopolysaccharidosis Type I. Symptoms of the following disorders can be similar to those of mucopolysaccharidosis type I. Comparisons may be useful for a differential diagnosis.Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various materials in the body’s cells as a result of enzyme deficiencies. There are nearly 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. (For more information on this disorder, choose “lysosomal storage diseases” as your search term in the Rare Disease Database.)
| 828 |
Mucopolysaccharidosis Type I
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nord_828_5
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Diagnosis of Mucopolysaccharidosis Type I
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A diagnosis of mucopolysaccharidosis type I is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected in infants with characteristic early signs. Currently newborn screening for MPS I is being implemented in many areas.Clinical Testing and Workup
A specialized examination of urine of people with MPS I can reveal elevated levels of glycosaminoglycans (mucopolysaccharides), specifically heparan and dermatan sulfate. This is not diagnostic of MPS I, but is indicative of a mucopolysaccharidosis disorder. The definitive diagnosis of MPS I requires testing specific cells such as white blood cells (leukocytes) or connective tissue cells (fibroblasts). These tests demonstrate low activity of the alpha-L-iduronidase enzyme. Molecular genetic testing is often used to confirm a diagnosis. Molecular genetic testing can detect disease-causing alterations (mutations) in the IDUA gene known to cause MPS I, but is available only as a diagnostic service at specialized laboratories.In the United States, newborn screening for MPS I has recently been approved for inclusion in the Recommended Universal Screening Panel, although each state decides independently when or if, it will be added to its newborn screening panel. One issue with newborn screening for MPS I is that in some cases doctors may not be able to distinguish whether a newborn with MPS I will develop a severe or attenuated form of the disorder. Because the treatments for these forms are different, this can lead to challenges with determining the proper course of treatment. Research is currently underway to look for methods to distinguish infants with severe MPS I from infants with attenuated MPS I.
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Diagnosis of Mucopolysaccharidosis Type I. A diagnosis of mucopolysaccharidosis type I is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected in infants with characteristic early signs. Currently newborn screening for MPS I is being implemented in many areas.Clinical Testing and Workup
A specialized examination of urine of people with MPS I can reveal elevated levels of glycosaminoglycans (mucopolysaccharides), specifically heparan and dermatan sulfate. This is not diagnostic of MPS I, but is indicative of a mucopolysaccharidosis disorder. The definitive diagnosis of MPS I requires testing specific cells such as white blood cells (leukocytes) or connective tissue cells (fibroblasts). These tests demonstrate low activity of the alpha-L-iduronidase enzyme. Molecular genetic testing is often used to confirm a diagnosis. Molecular genetic testing can detect disease-causing alterations (mutations) in the IDUA gene known to cause MPS I, but is available only as a diagnostic service at specialized laboratories.In the United States, newborn screening for MPS I has recently been approved for inclusion in the Recommended Universal Screening Panel, although each state decides independently when or if, it will be added to its newborn screening panel. One issue with newborn screening for MPS I is that in some cases doctors may not be able to distinguish whether a newborn with MPS I will develop a severe or attenuated form of the disorder. Because the treatments for these forms are different, this can lead to challenges with determining the proper course of treatment. Research is currently underway to look for methods to distinguish infants with severe MPS I from infants with attenuated MPS I.
| 828 |
Mucopolysaccharidosis Type I
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nord_828_6
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Therapies of Mucopolysaccharidosis Type I
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Treatment
There are three components in the treatment of MPS I:1) replacing the enzyme that is missing
2) alleviating specific symptoms of disease
3) providing the family with genetic counseling1) Replacing the deficient enzyme: Lysosomal enzymes are unique proteins by virtue of the fact that they can be taken up by cells and used. As such, one potential way to treat MPS I is to give patients the alpha-L-iduronidase enzyme they are missing. This can be done in 2 ways. One way is to infuse them with purified enzyme also known as enzyme replacement therapy (ERT). Enzyme replacement therapy involves replacing the missing enzyme, alpha-L-iduronidase, with a genetically engineered (recombinant) form. This is performed by infusing the enzyme into a patient weekly through an intravenous. In 2003, the U.S. Food and Drug Administration (FDA) approved laronidase (Aldurazyme) for the treatment of most individuals with MPS I. Aldurazyme does not help with symptoms related to damage to the brain and central nervous system because the medication cannot cross the blood-brain barrier, which is the protective network of blood vessels and cells that allow some materials to enter the brain, while keeping other materials out.Another method to replace the enzyme in patients is to perform hematopoietic stem cell (HSCT) or bone marrow transplantation. Hematopoietic stem cells are specialized cells found in the bone marrow (the soft spongy material found in long bones). These blood stem cells grow and eventually develop into one of the three main types of blood cells– red blood cells, white blood cells or platelets. A transplant is done to replace the bone marrow of an affected individual with marrow from a person who does not have MPS I. The healthy cells produced by the transplant contain sufficient levels of white blood cells that produce alpha-L-iduronidase and these cells then replace in the enzyme deficiency in the tissues. The procedure is expensive and carries the risk of serious complications including death, graft-versus-host disease and other long-term and late effects. HSCT is considered the standard of care for severe MPS I as it is the only treatment currently available that has shown to lead to improved intellectual outcomes in severe MPS I individuals.Although a HSCT and enzyme replacement therapy can dramatically improve the clinical course they do not cure this disorder and, therefore, many affected individuals still face significant challenges and issues as they age. Generally, the earlier treatment is started the better the outcome and the severity of the disorder and a child’s age often influence the outcome of the procedure. The impact of a HSCT on intellectual disability can vary. Usually, once significant intellectual disability is present, it cannot be reversed, although cognitive decline can be alleviated.2) Alleviating specific symptoms of disease: An important component of the treatment of mucopolysaccharidosis type I is directed toward the specific symptoms that are apparent in each individual. This requires the coordinated efforts of a team of specialists and include.Pediatricians3) Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Several of the organizations listed in the Resources section provide support and information on MPS disorders like MPS type I.
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Therapies of Mucopolysaccharidosis Type I. Treatment
There are three components in the treatment of MPS I:1) replacing the enzyme that is missing
2) alleviating specific symptoms of disease
3) providing the family with genetic counseling1) Replacing the deficient enzyme: Lysosomal enzymes are unique proteins by virtue of the fact that they can be taken up by cells and used. As such, one potential way to treat MPS I is to give patients the alpha-L-iduronidase enzyme they are missing. This can be done in 2 ways. One way is to infuse them with purified enzyme also known as enzyme replacement therapy (ERT). Enzyme replacement therapy involves replacing the missing enzyme, alpha-L-iduronidase, with a genetically engineered (recombinant) form. This is performed by infusing the enzyme into a patient weekly through an intravenous. In 2003, the U.S. Food and Drug Administration (FDA) approved laronidase (Aldurazyme) for the treatment of most individuals with MPS I. Aldurazyme does not help with symptoms related to damage to the brain and central nervous system because the medication cannot cross the blood-brain barrier, which is the protective network of blood vessels and cells that allow some materials to enter the brain, while keeping other materials out.Another method to replace the enzyme in patients is to perform hematopoietic stem cell (HSCT) or bone marrow transplantation. Hematopoietic stem cells are specialized cells found in the bone marrow (the soft spongy material found in long bones). These blood stem cells grow and eventually develop into one of the three main types of blood cells– red blood cells, white blood cells or platelets. A transplant is done to replace the bone marrow of an affected individual with marrow from a person who does not have MPS I. The healthy cells produced by the transplant contain sufficient levels of white blood cells that produce alpha-L-iduronidase and these cells then replace in the enzyme deficiency in the tissues. The procedure is expensive and carries the risk of serious complications including death, graft-versus-host disease and other long-term and late effects. HSCT is considered the standard of care for severe MPS I as it is the only treatment currently available that has shown to lead to improved intellectual outcomes in severe MPS I individuals.Although a HSCT and enzyme replacement therapy can dramatically improve the clinical course they do not cure this disorder and, therefore, many affected individuals still face significant challenges and issues as they age. Generally, the earlier treatment is started the better the outcome and the severity of the disorder and a child’s age often influence the outcome of the procedure. The impact of a HSCT on intellectual disability can vary. Usually, once significant intellectual disability is present, it cannot be reversed, although cognitive decline can be alleviated.2) Alleviating specific symptoms of disease: An important component of the treatment of mucopolysaccharidosis type I is directed toward the specific symptoms that are apparent in each individual. This requires the coordinated efforts of a team of specialists and include.Pediatricians3) Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Several of the organizations listed in the Resources section provide support and information on MPS disorders like MPS type I.
| 828 |
Mucopolysaccharidosis Type I
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nord_829_0
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Overview of Mucopolysaccharidosis Type II
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SummaryMucopolysaccharidosis type II (MPS II) is a rare lysosomal inborn error of metabolism that affects every organ of the body. Although the age of onset, disease severity and the rate of progression of the disease vary significantly, initial symptoms and findings associated with MPS II usually become apparent in children from two to four years of age. Manifestations of MPS II may include not inflammatory joint stiffness, with associated restriction of movements; and coarsening of facial features, including thickening of the lips, tongue (macroglossia), and nostrils. Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, enlargement of the liver and spleen (hepatosplenomegaly), cardiac valve disease and progressive growth delays resulting in short stature. Two relatively distinct clinical forms of MPS II have been recognized. In the non-neuronopathic form (formerly defined as slowly progressive milder form) of the disease, intelligence may be normal or only slightly impaired. In the neuronopathic form of the disease (formerly called early progressive more severe form), intellectual disabilities may be apparent in the early life of the patient.MPS II is an X-linked genetic condition that mostly affects males; although a few females have been described as well, and is caused by changes (mutations) of the IDS gene that regulates the production of the iduronate 2-sulfatase enzyme. This enzyme is needed to break-down complex sugars, known as glycosaminoglycans, produced in the body.IntroductionMPS II is one of a group of seven hereditary metabolic diseases known as the mucopolysaccharidoses, which in turn, are part of a group known as lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, including MPS II, deficiency or improper functioning of lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates in cells (mucopolysaccharides, also known as glycosaminoglycans) within various tissues, such as the skeleton, joints, brain, spinal cord, heart, spleen, or liver.
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Overview of Mucopolysaccharidosis Type II. SummaryMucopolysaccharidosis type II (MPS II) is a rare lysosomal inborn error of metabolism that affects every organ of the body. Although the age of onset, disease severity and the rate of progression of the disease vary significantly, initial symptoms and findings associated with MPS II usually become apparent in children from two to four years of age. Manifestations of MPS II may include not inflammatory joint stiffness, with associated restriction of movements; and coarsening of facial features, including thickening of the lips, tongue (macroglossia), and nostrils. Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, enlargement of the liver and spleen (hepatosplenomegaly), cardiac valve disease and progressive growth delays resulting in short stature. Two relatively distinct clinical forms of MPS II have been recognized. In the non-neuronopathic form (formerly defined as slowly progressive milder form) of the disease, intelligence may be normal or only slightly impaired. In the neuronopathic form of the disease (formerly called early progressive more severe form), intellectual disabilities may be apparent in the early life of the patient.MPS II is an X-linked genetic condition that mostly affects males; although a few females have been described as well, and is caused by changes (mutations) of the IDS gene that regulates the production of the iduronate 2-sulfatase enzyme. This enzyme is needed to break-down complex sugars, known as glycosaminoglycans, produced in the body.IntroductionMPS II is one of a group of seven hereditary metabolic diseases known as the mucopolysaccharidoses, which in turn, are part of a group known as lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, including MPS II, deficiency or improper functioning of lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates in cells (mucopolysaccharides, also known as glycosaminoglycans) within various tissues, such as the skeleton, joints, brain, spinal cord, heart, spleen, or liver.
| 829 |
Mucopolysaccharidosis Type II
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nord_829_1
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Symptoms of Mucopolysaccharidosis Type II
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In the neuronopathic form of this disorder, physical and mental development reaches a peak at 2-4 years of age with subsequent deterioration. Recurrent upper respiratory infections, a chronic runny nose, hearing impairment, liver and spleen enlargement, inguinal and abdominal hernias, joint stiffness and multiplex dysplasia, compression of tendons in the wrist (carpal tunnel syndrome), and joint stiffness which can result in reduction of hand function, growth failure and valvular disease commonly occur with this form of MPS II. Coarsening of the facial features with thickening of the nostrils, lips and tongue usually occur between 2 and 4 years of age. Hydrocephalus (fluid buildup in the cavities deep within the brain) is commonly found in this form of MPS II after 4 years of age. Thick skin, short neck, widely spaced teeth, and hearing loss of varying degree are also commonly present. Nodular skin lesions on the arm or the posterior chest wall, extra- high arched feet (pes cavus) and diarrhea may also occur.Corneal clouding and cervical spine compression (very common in other MPSs) are less frequent in MPSII thank in other MPSs.In the non-neuronopathic form of MPS II, mental function is usually normal, while the systemic complications are similar, although sometimes a reduced severity.
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Symptoms of Mucopolysaccharidosis Type II. In the neuronopathic form of this disorder, physical and mental development reaches a peak at 2-4 years of age with subsequent deterioration. Recurrent upper respiratory infections, a chronic runny nose, hearing impairment, liver and spleen enlargement, inguinal and abdominal hernias, joint stiffness and multiplex dysplasia, compression of tendons in the wrist (carpal tunnel syndrome), and joint stiffness which can result in reduction of hand function, growth failure and valvular disease commonly occur with this form of MPS II. Coarsening of the facial features with thickening of the nostrils, lips and tongue usually occur between 2 and 4 years of age. Hydrocephalus (fluid buildup in the cavities deep within the brain) is commonly found in this form of MPS II after 4 years of age. Thick skin, short neck, widely spaced teeth, and hearing loss of varying degree are also commonly present. Nodular skin lesions on the arm or the posterior chest wall, extra- high arched feet (pes cavus) and diarrhea may also occur.Corneal clouding and cervical spine compression (very common in other MPSs) are less frequent in MPSII thank in other MPSs.In the non-neuronopathic form of MPS II, mental function is usually normal, while the systemic complications are similar, although sometimes a reduced severity.
| 829 |
Mucopolysaccharidosis Type II
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nord_829_2
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Causes of Mucopolysaccharidosis Type II
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The gene responsible for MPS II is known as the iduronate 2-sulfatase (IDS) gene. In many individuals with MPS II, the condition is caused be relatively small changes (e.g., certain missense or nonsense mutations) in the IDS gene, or deletion or insertion of genetic material (e.g., single-base deletions or insertions) that affects gene function. Less commonly, MPS II may result from complete absence or major structural changes of the IDS gene, linking to a neuronopathic disease. Different mutations or structural changes of the gene account for the wide variability of symptoms and findings associated with the disorder (i.e., neuronopathic and non-neuronopathic types).The IDS gene is responsible for production of the lysosomal enzyme iduronate 2-sulfatase. The deficiency of the enzyme results in an abnormal accumulation of certain complex carbohydrates (glycosaminoglycans also known as mucopolysaccharides) within the cells of various tissues of the body.MPS II is an X-linked recessive genetic condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome inherited by the mother and manifest mostly in males. Females that have an altered 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 altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the altered 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.
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Causes of Mucopolysaccharidosis Type II. The gene responsible for MPS II is known as the iduronate 2-sulfatase (IDS) gene. In many individuals with MPS II, the condition is caused be relatively small changes (e.g., certain missense or nonsense mutations) in the IDS gene, or deletion or insertion of genetic material (e.g., single-base deletions or insertions) that affects gene function. Less commonly, MPS II may result from complete absence or major structural changes of the IDS gene, linking to a neuronopathic disease. Different mutations or structural changes of the gene account for the wide variability of symptoms and findings associated with the disorder (i.e., neuronopathic and non-neuronopathic types).The IDS gene is responsible for production of the lysosomal enzyme iduronate 2-sulfatase. The deficiency of the enzyme results in an abnormal accumulation of certain complex carbohydrates (glycosaminoglycans also known as mucopolysaccharides) within the cells of various tissues of the body.MPS II is an X-linked recessive genetic condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome inherited by the mother and manifest mostly in males. Females that have an altered 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 altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the altered 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.
| 829 |
Mucopolysaccharidosis Type II
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nord_829_3
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Affects of Mucopolysaccharidosis Type II
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MPS II typically affects only males, with symptoms becoming apparent at approximately 2-4 years of age. The disorder occurs in approximately 1 in 100,000 to 1 in 170,000 male births. A few affected females have been described, due to the selective inactivation of the X chromosome inherited by the father.
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Affects of Mucopolysaccharidosis Type II. MPS II typically affects only males, with symptoms becoming apparent at approximately 2-4 years of age. The disorder occurs in approximately 1 in 100,000 to 1 in 170,000 male births. A few affected females have been described, due to the selective inactivation of the X chromosome inherited by the father.
| 829 |
Mucopolysaccharidosis Type II
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nord_829_4
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Related disorders of Mucopolysaccharidosis Type II
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There are many types of mucopolysaccharidoses that have similar symptoms. (For more information, choose “mucopolysaccharidosis” as your search term in the Rare Disease Database.)The mucolipidoses, mannosidosis and multiple sulfatase deficiency are a family of similar disorders, producing symptoms very much like those of the mucopolysaccharidoses. (For more information on mucolipidosis, search the Rare Disease Database.)
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Related disorders of Mucopolysaccharidosis Type II. There are many types of mucopolysaccharidoses that have similar symptoms. (For more information, choose “mucopolysaccharidosis” as your search term in the Rare Disease Database.)The mucolipidoses, mannosidosis and multiple sulfatase deficiency are a family of similar disorders, producing symptoms very much like those of the mucopolysaccharidoses. (For more information on mucolipidosis, search the Rare Disease Database.)
| 829 |
Mucopolysaccharidosis Type II
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nord_829_5
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Diagnosis of Mucopolysaccharidosis Type II
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The signs and symptoms of MPS II vary greatly, so the diagnosis cannot be made by physical exam alone. Diagnosis requires documentation of reduced or absent iduronate 2-sulfatase enzyme activity in blood or skin cells. A very simple determination of glycosaminoglycans in the urine may help in screening potential positive patients. Patients with MPSII disease accumulate heparin and dermatan sulfates in the urines. Molecular genetic testing for mutations in the IDS gene is available to confirm the diagnosis. It is always important to rule out a multiple sulfatase deficiency by testing other sulfatase enzymes.
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Diagnosis of Mucopolysaccharidosis Type II. The signs and symptoms of MPS II vary greatly, so the diagnosis cannot be made by physical exam alone. Diagnosis requires documentation of reduced or absent iduronate 2-sulfatase enzyme activity in blood or skin cells. A very simple determination of glycosaminoglycans in the urine may help in screening potential positive patients. Patients with MPSII disease accumulate heparin and dermatan sulfates in the urines. Molecular genetic testing for mutations in the IDS gene is available to confirm the diagnosis. It is always important to rule out a multiple sulfatase deficiency by testing other sulfatase enzymes.
| 829 |
Mucopolysaccharidosis Type II
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nord_829_6
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Therapies of Mucopolysaccharidosis Type II
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An enzyme replacement therapy, idursulfase (Elaprase), was approved in 2006 by the U.S. Food and Drug Administration (FDA) as a treatment for MPS II. This drug is sponsored by Shire.Other treatments of MPS II are symptomatic and supportive. These management interventions commonly include developmental, occupational and physical therapy. Hernias and joint contractures may be corrected by surgery. Tonsillectomy and adenoidectomy (surgical removal of both the tonsils and the adenoids) can be used to alleviate breathing and swallowing problems. Positive pressure ventilation (CPAP or tracheostomy) can be used to apply mild air pressure to keep the airway open to alleviate breathing issues. Carpal tunnel release can treat carpal tunnel syndrome. Surgical implantation of a ventricular shunt may be used to treat possible hydrocephalus. Hearing devices may be prescribed to treat hearing loss. Developmental, physical, and occupational therapy can be helpful.Genetic counseling is recommended for families that have a child with MPS II.
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Therapies of Mucopolysaccharidosis Type II. An enzyme replacement therapy, idursulfase (Elaprase), was approved in 2006 by the U.S. Food and Drug Administration (FDA) as a treatment for MPS II. This drug is sponsored by Shire.Other treatments of MPS II are symptomatic and supportive. These management interventions commonly include developmental, occupational and physical therapy. Hernias and joint contractures may be corrected by surgery. Tonsillectomy and adenoidectomy (surgical removal of both the tonsils and the adenoids) can be used to alleviate breathing and swallowing problems. Positive pressure ventilation (CPAP or tracheostomy) can be used to apply mild air pressure to keep the airway open to alleviate breathing issues. Carpal tunnel release can treat carpal tunnel syndrome. Surgical implantation of a ventricular shunt may be used to treat possible hydrocephalus. Hearing devices may be prescribed to treat hearing loss. Developmental, physical, and occupational therapy can be helpful.Genetic counseling is recommended for families that have a child with MPS II.
| 829 |
Mucopolysaccharidosis Type II
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nord_830_0
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Overview of Mucopolysaccharidosis Type III
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SummaryMucopolysaccaridosis type III (MPS III) is a rare genetic condition that causes fatal brain damage. It is also known as Sanfilippo syndrome and is a type of childhood dementia.MPS III is caused by a lack of an enzyme that normally breaks down and recycles a large, complex sugar molecule called ‘heparan sulphate'. This heparan sulphate accumulates and causes damage to the cells of the central nervous system, including the brain. Sanfilippo belongs to a group of disorders known as the “mucopolysaccharidoses” (MPS), which are part of a larger group of disorders known as “lysosomal storage disorders”.There are four subtypes of MPS III: types A, B, C and D. Each type is caused by a change (mutation) in a different gene (see below). All types of MPS III are associated with mental deterioration, but the severity and rate of progression depends on the particular type of MPS lll. There is also variability in severity within the sub-types and even between affected siblings.
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Overview of Mucopolysaccharidosis Type III. SummaryMucopolysaccaridosis type III (MPS III) is a rare genetic condition that causes fatal brain damage. It is also known as Sanfilippo syndrome and is a type of childhood dementia.MPS III is caused by a lack of an enzyme that normally breaks down and recycles a large, complex sugar molecule called ‘heparan sulphate'. This heparan sulphate accumulates and causes damage to the cells of the central nervous system, including the brain. Sanfilippo belongs to a group of disorders known as the “mucopolysaccharidoses” (MPS), which are part of a larger group of disorders known as “lysosomal storage disorders”.There are four subtypes of MPS III: types A, B, C and D. Each type is caused by a change (mutation) in a different gene (see below). All types of MPS III are associated with mental deterioration, but the severity and rate of progression depends on the particular type of MPS lll. There is also variability in severity within the sub-types and even between affected siblings.
| 830 |
Mucopolysaccharidosis Type III
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nord_830_1
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Symptoms of Mucopolysaccharidosis Type III
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Children with MPS III usually appear healthy at birth, but developmental delay is usually evident by age 2-5 years. Mental and motor development peak by 3-6 years of age, after which intellectual decline usually occurs. Behavioral problems such as hyperactivity and irritability may become obvious earlier. Severe behavioral disturbance is a very common feature of Sanfilippo syndrome, and one of the more difficult aspects of the disorder to manage.Other symptoms can include coarse hair, excess hair growth (hirsutism), slightly coarse facial features, sleeping problems, mildly enlarged liver and/or spleen, speech delay, respiratory and ear infections, diarrhea, hernias, seizures and a wobbly and erratic walk. Children with MPS III also often experience hearing loss and vision impairment.Children with Sanfilippo syndrome usually start to lose their intellectual functions, especially speech, before their motor function declines. Death can occur from before the age of 10 or not until the third or fourth decades of life, with the average being around 15 to 20 years of age. Children with MPS IIIC have a longer life expectancy into the mid-twenties on average. There are attenuated forms of MPS III which result in slower progression and a longer life expectancy.
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Symptoms of Mucopolysaccharidosis Type III. Children with MPS III usually appear healthy at birth, but developmental delay is usually evident by age 2-5 years. Mental and motor development peak by 3-6 years of age, after which intellectual decline usually occurs. Behavioral problems such as hyperactivity and irritability may become obvious earlier. Severe behavioral disturbance is a very common feature of Sanfilippo syndrome, and one of the more difficult aspects of the disorder to manage.Other symptoms can include coarse hair, excess hair growth (hirsutism), slightly coarse facial features, sleeping problems, mildly enlarged liver and/or spleen, speech delay, respiratory and ear infections, diarrhea, hernias, seizures and a wobbly and erratic walk. Children with MPS III also often experience hearing loss and vision impairment.Children with Sanfilippo syndrome usually start to lose their intellectual functions, especially speech, before their motor function declines. Death can occur from before the age of 10 or not until the third or fourth decades of life, with the average being around 15 to 20 years of age. Children with MPS IIIC have a longer life expectancy into the mid-twenties on average. There are attenuated forms of MPS III which result in slower progression and a longer life expectancy.
| 830 |
Mucopolysaccharidosis Type III
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nord_830_2
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Causes of Mucopolysaccharidosis Type III
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All four types of MPS III are caused by changes (mutations) in different genes that contain the instructions for making enzymes that break down heparan sulfate.TYPE..……….GENE…………ENZYME
MPS IIIA……..SGSH…………heparan N-sulfatase
MPS IIIB……..NAGLU……….alpha-N-acetylglucosaminidase
MPS IIIC……..HGSNAT……..heparan-alpha-glucosaminide N-acetyltransferase
MPS IIID……..GNS………….N-acetylglucosamine 6-sulfataseMPS III is inherited in an autosomal recessive manner. This means that both parents have one copy of the altered gene and one normal copy – they are known as carriers and do not show signs of the condition. A child with MPS III inherits two copies of the altered gene, one from each parent.In autosomal recessive inheritance, in each pregnancy of a couple who are both carriers, there is a:
– 25% (1 in 4) chance of having an affected child
– 50% (1 in 2) chance of a child receiving only one copy of the altered gene and therefore being a carrier
– 25% (1 in 4) chance that a child will be neither affected nor a carrier.
The risk is the same for males and females.
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Causes of Mucopolysaccharidosis Type III. All four types of MPS III are caused by changes (mutations) in different genes that contain the instructions for making enzymes that break down heparan sulfate.TYPE..……….GENE…………ENZYME
MPS IIIA……..SGSH…………heparan N-sulfatase
MPS IIIB……..NAGLU……….alpha-N-acetylglucosaminidase
MPS IIIC……..HGSNAT……..heparan-alpha-glucosaminide N-acetyltransferase
MPS IIID……..GNS………….N-acetylglucosamine 6-sulfataseMPS III is inherited in an autosomal recessive manner. This means that both parents have one copy of the altered gene and one normal copy – they are known as carriers and do not show signs of the condition. A child with MPS III inherits two copies of the altered gene, one from each parent.In autosomal recessive inheritance, in each pregnancy of a couple who are both carriers, there is a:
– 25% (1 in 4) chance of having an affected child
– 50% (1 in 2) chance of a child receiving only one copy of the altered gene and therefore being a carrier
– 25% (1 in 4) chance that a child will be neither affected nor a carrier.
The risk is the same for males and females.
| 830 |
Mucopolysaccharidosis Type III
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nord_830_3
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Affects of Mucopolysaccharidosis Type III
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MPS III is classified as a rare disease with incidence reported to be between 0.28 and 4.1 cases per 100,000 births. MPS IIIA is the most common subtype affecting around 1 in 100,000 births, closely followed by type B at 1 in 200,000. In some countries in Southern Europe, type B has been reported to be more common than A. MPS IIIC and IIID are rarer with reported incidences of approximately 1 in 1.5 million and 1 in 1 million births respectively.
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Affects of Mucopolysaccharidosis Type III. MPS III is classified as a rare disease with incidence reported to be between 0.28 and 4.1 cases per 100,000 births. MPS IIIA is the most common subtype affecting around 1 in 100,000 births, closely followed by type B at 1 in 200,000. In some countries in Southern Europe, type B has been reported to be more common than A. MPS IIIC and IIID are rarer with reported incidences of approximately 1 in 1.5 million and 1 in 1 million births respectively.
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Mucopolysaccharidosis Type III
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Related disorders of Mucopolysaccharidosis Type III
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There are seven types of mucopolysaccharidoses some of which have similar symptoms. (For more information, choose “mucopolysaccharidosis” as your search term in the Rare Disease Database.)Other lysosomal diseases such as Batten disease, mucolipidoses, mannosidosis and multiple sulfatase deficiency have symptoms very much like those of the MPS III. (For more information on lysosomal storage disorders, search the Rare Disease Database.)There are more than 70 rare genetic neurodegenerative diseases that cause dementia in childhood including a range of inborn errors of metabolism, some mitochondrial diseases and several leukodystrophies.
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Related disorders of Mucopolysaccharidosis Type III. There are seven types of mucopolysaccharidoses some of which have similar symptoms. (For more information, choose “mucopolysaccharidosis” as your search term in the Rare Disease Database.)Other lysosomal diseases such as Batten disease, mucolipidoses, mannosidosis and multiple sulfatase deficiency have symptoms very much like those of the MPS III. (For more information on lysosomal storage disorders, search the Rare Disease Database.)There are more than 70 rare genetic neurodegenerative diseases that cause dementia in childhood including a range of inborn errors of metabolism, some mitochondrial diseases and several leukodystrophies.
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Mucopolysaccharidosis Type III
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nord_830_5
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Diagnosis of Mucopolysaccharidosis Type III
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To diagnose MPS III, mucopolysaccharides are usually first measured in urine, followed by measurement of enzyme activity in blood or a small skin sample. Increased heparan sulfate in urine, and a decrease in the activity of any one of the four enzymes (shown in the table above) is usually consistent with a diagnosis of MPS III and will identify the MPS III type (A, B, C or D). It is important to know the MPS III type as many of the treatments being developed are only for specific types.Genetic testing of a blood sample will allow the identification of the exact changes in the DNA. It is important to attend genetic counseling to learn the implications for other children in the family, future pregnancies and extended family members. The counselor will explain the inheritance pattern and help advise who should be tested.If the genetic diagnosis is known, this information can be used to test other at risk members of the family. It can also be used for prenatal testing of future pregnancies (testing a fetus while still in the womb) and/or preimplantation diagnosis (testing of embryos created through IVF to select those that do not carry the relevant gene mutation).
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Diagnosis of Mucopolysaccharidosis Type III. To diagnose MPS III, mucopolysaccharides are usually first measured in urine, followed by measurement of enzyme activity in blood or a small skin sample. Increased heparan sulfate in urine, and a decrease in the activity of any one of the four enzymes (shown in the table above) is usually consistent with a diagnosis of MPS III and will identify the MPS III type (A, B, C or D). It is important to know the MPS III type as many of the treatments being developed are only for specific types.Genetic testing of a blood sample will allow the identification of the exact changes in the DNA. It is important to attend genetic counseling to learn the implications for other children in the family, future pregnancies and extended family members. The counselor will explain the inheritance pattern and help advise who should be tested.If the genetic diagnosis is known, this information can be used to test other at risk members of the family. It can also be used for prenatal testing of future pregnancies (testing a fetus while still in the womb) and/or preimplantation diagnosis (testing of embryos created through IVF to select those that do not carry the relevant gene mutation).
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Mucopolysaccharidosis Type III
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nord_830_6
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Therapies of Mucopolysaccharidosis Type III
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Treatment
Treatment of Sanfilippo syndrome is symptomatic and supportive. It is important for children with MPS III to be managed by a multidisciplinary team of specialists to give these children the best quality of life. At different stages this could include a combination of the following: a neurologist, developmental pediatrician, metabolic/genetics specialist, orthopedics, gastroenterologist, ophthalmologist, cardiologist, endocrinologist, allied health (e.g. physiotherapy, OT, behavioral therapists, speech therapist) and an ENT (ear, nose and throat) specialist.
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Therapies of Mucopolysaccharidosis Type III. Treatment
Treatment of Sanfilippo syndrome is symptomatic and supportive. It is important for children with MPS III to be managed by a multidisciplinary team of specialists to give these children the best quality of life. At different stages this could include a combination of the following: a neurologist, developmental pediatrician, metabolic/genetics specialist, orthopedics, gastroenterologist, ophthalmologist, cardiologist, endocrinologist, allied health (e.g. physiotherapy, OT, behavioral therapists, speech therapist) and an ENT (ear, nose and throat) specialist.
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Mucopolysaccharidosis Type III
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nord_831_0
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Overview of Mucopolysaccharidosis Type VII
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SummaryMucopolysaccharidosis type VII (MPS VII) is a rare, progressive inborn error of metabolism that affects many parts of the body. The clinical features of MPS VII vary from patient to patient, but all have short stature due to growth retardation and skeletal abnormalities, changes in bones visible on X-rays (dysostosis multiplex), and some degree of intellectual disability. Survival into adulthood is common for patients with milder cases and osteoarthritis is a common complication. MPS VII is inherited as an autosomal recessive genetic condition.IntroductionMPS VII is in a group of hereditary metabolic diseases known as the mucopolysaccharidoses which in turn, are part of a group known as lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, including MPS VII, deficiency or improper functioning of lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates in cells (mucopolysaccharides, also known as glycosaminoglycans) within various tissues, such as the skeleton, joints, brain, spinal cord, heart, spleen, or liver.
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Overview of Mucopolysaccharidosis Type VII. SummaryMucopolysaccharidosis type VII (MPS VII) is a rare, progressive inborn error of metabolism that affects many parts of the body. The clinical features of MPS VII vary from patient to patient, but all have short stature due to growth retardation and skeletal abnormalities, changes in bones visible on X-rays (dysostosis multiplex), and some degree of intellectual disability. Survival into adulthood is common for patients with milder cases and osteoarthritis is a common complication. MPS VII is inherited as an autosomal recessive genetic condition.IntroductionMPS VII is in a group of hereditary metabolic diseases known as the mucopolysaccharidoses which in turn, are part of a group known as lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, including MPS VII, deficiency or improper functioning of lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates in cells (mucopolysaccharides, also known as glycosaminoglycans) within various tissues, such as the skeleton, joints, brain, spinal cord, heart, spleen, or liver.
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Mucopolysaccharidosis Type VII
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Symptoms of Mucopolysaccharidosis Type VII
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The most severe cases of MPS VII are characterized by hydrops fetalis, or when excess fluid accumulates in the body before birth. This can result in a stillborn or death shortly after birth. Neonatal jaundice or the yellowing of the skin may occur. Children with more mild cases of MPS VII begin to show symptoms in early childhood. Children with MPS VII may have an unusually short trunk and growth disability, resulting in short stature (short trunk dwarfism). The head may be excessively large (macrocephalic) and the neck may be short. A variety of multiple bone deformities (dysostosis multiplex), which are frequently observed in people with mucopolysaccharidoses, are also common in children with MPS VII. These bone deformities may include a prominent breast bone (pectus carinatum), flared ribs, frequent hip dislocations, “frozen” joints (contractures), club foot, and/or an inward curve of the knees and outward bowing of the ankles (genu valgum).Rarely, spinal malformations may be present including mild curvature of the spine from side to side (scoliosis) and/or front to back (kyphosis). Children with this disorder may develop an unusual “coarse” facial appearance. Between the ages of 7 months and 8 years, cloudiness (opacity) may occur in the corneas of the eyes.Affected individuals may have developmental delays in language and speech and progressive intellectual disability, although intelligence is normal in some people with this condition. Other symptoms of MPS VII may include a swollen abdomen due to abnormal enlargement of the liver and/or spleen (hepatosplenomegaly) and protrusion of the intestines through an abnormal opening in the muscular wall of the abdomen (inguinal hernia). In some children, the intestines may also protrude through the abdominal wall in the area of the navel (umbilical hernia). Some affected children may experience profound hearing loss, recurrent upper respiratory and middle ear infections, thickening of the soft tissues of the throat and/or vocal cords, an abnormally enlarged tongue (macroglossia), and/or heart problems (i.e., heart murmur or aortic regurgitation). Excessive hairiness (hirsutism) may be present.Children may develop carpal tunnel syndrome characterized by numbness, tingling and weakness in the hands and fingers. Survival to age 19-20 years has been reported in mild cases. Life expectancy is reduced as a result of frequent upper respiratory tract infections, neurodegenerative complications and abnormalities of the gastrointestinal tract.A mild form of MPS VII, beginning during the 2nd decade of life, has been described in the medical literature. In these patients, the symptoms of the disorder appear to be less severe than classical MPS VII and may include minor bony changes and very mild facial coarseness. Growth rate and mental abilities are usually normal. Abnormal enlargement of the liver and spleen has not been noticed in this form of MPS VII.
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Symptoms of Mucopolysaccharidosis Type VII. The most severe cases of MPS VII are characterized by hydrops fetalis, or when excess fluid accumulates in the body before birth. This can result in a stillborn or death shortly after birth. Neonatal jaundice or the yellowing of the skin may occur. Children with more mild cases of MPS VII begin to show symptoms in early childhood. Children with MPS VII may have an unusually short trunk and growth disability, resulting in short stature (short trunk dwarfism). The head may be excessively large (macrocephalic) and the neck may be short. A variety of multiple bone deformities (dysostosis multiplex), which are frequently observed in people with mucopolysaccharidoses, are also common in children with MPS VII. These bone deformities may include a prominent breast bone (pectus carinatum), flared ribs, frequent hip dislocations, “frozen” joints (contractures), club foot, and/or an inward curve of the knees and outward bowing of the ankles (genu valgum).Rarely, spinal malformations may be present including mild curvature of the spine from side to side (scoliosis) and/or front to back (kyphosis). Children with this disorder may develop an unusual “coarse” facial appearance. Between the ages of 7 months and 8 years, cloudiness (opacity) may occur in the corneas of the eyes.Affected individuals may have developmental delays in language and speech and progressive intellectual disability, although intelligence is normal in some people with this condition. Other symptoms of MPS VII may include a swollen abdomen due to abnormal enlargement of the liver and/or spleen (hepatosplenomegaly) and protrusion of the intestines through an abnormal opening in the muscular wall of the abdomen (inguinal hernia). In some children, the intestines may also protrude through the abdominal wall in the area of the navel (umbilical hernia). Some affected children may experience profound hearing loss, recurrent upper respiratory and middle ear infections, thickening of the soft tissues of the throat and/or vocal cords, an abnormally enlarged tongue (macroglossia), and/or heart problems (i.e., heart murmur or aortic regurgitation). Excessive hairiness (hirsutism) may be present.Children may develop carpal tunnel syndrome characterized by numbness, tingling and weakness in the hands and fingers. Survival to age 19-20 years has been reported in mild cases. Life expectancy is reduced as a result of frequent upper respiratory tract infections, neurodegenerative complications and abnormalities of the gastrointestinal tract.A mild form of MPS VII, beginning during the 2nd decade of life, has been described in the medical literature. In these patients, the symptoms of the disorder appear to be less severe than classical MPS VII and may include minor bony changes and very mild facial coarseness. Growth rate and mental abilities are usually normal. Abnormal enlargement of the liver and spleen has not been noticed in this form of MPS VII.
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Mucopolysaccharidosis Type VII
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Causes of Mucopolysaccharidosis Type VII
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MPS VII is caused by changes (mutations) in the GUSB gene that lead to deficiency of the beta-glucuronidase enzyme. A variety of different mutations in this gene may account for the wide range of symptoms and physical findings as well as the variability in the age of onset.The beta-glucuronidase enzyme is involved in the breakdown of large sugar molecules called glycosaminoglycans or GAGs. The shortage of beta-glucuronidase leads to a buildup of GAGs in the cells, specifically in the lysosomes. Lysosomes digest and recycle molecules; this disorder causes a lysosomal storage disorder. The accumulation of GAGs increases the size of the lysosomes causing the tissues and organs to become enlarged. GAGs are believed to interpret the function of proteins within the lysosomes and disrupt the normal function of cells. MPS VII is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to 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 Mucopolysaccharidosis Type VII. MPS VII is caused by changes (mutations) in the GUSB gene that lead to deficiency of the beta-glucuronidase enzyme. A variety of different mutations in this gene may account for the wide range of symptoms and physical findings as well as the variability in the age of onset.The beta-glucuronidase enzyme is involved in the breakdown of large sugar molecules called glycosaminoglycans or GAGs. The shortage of beta-glucuronidase leads to a buildup of GAGs in the cells, specifically in the lysosomes. Lysosomes digest and recycle molecules; this disorder causes a lysosomal storage disorder. The accumulation of GAGs increases the size of the lysosomes causing the tissues and organs to become enlarged. GAGs are believed to interpret the function of proteins within the lysosomes and disrupt the normal function of cells. MPS VII is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to 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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Mucopolysaccharidosis Type VII
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Affects of Mucopolysaccharidosis Type VII
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MPS VII is extremely rare, affecting only about one in 250,000 births. Fewer than 100 cases have been reported in the United States. Males and females are affected in equal numbers.
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Affects of Mucopolysaccharidosis Type VII. MPS VII is extremely rare, affecting only about one in 250,000 births. Fewer than 100 cases have been reported in the United States. Males and females are affected in equal numbers.
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Mucopolysaccharidosis Type VII
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nord_831_4
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Related disorders of Mucopolysaccharidosis Type VII
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There are many types of mucopolysaccharidoses that have similar symptoms. (For more information, choose “mucopolysaccharidosis” as your search term in the Rare Disease Database).The mucolipidoses are a family of similar disorders, producing symptoms very much like those of the mucopolysaccharidoses. (For more information, choose “mucolipidosis” as your search term in the Rare Disease Database.)
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Related disorders of Mucopolysaccharidosis Type VII. There are many types of mucopolysaccharidoses that have similar symptoms. (For more information, choose “mucopolysaccharidosis” as your search term in the Rare Disease Database).The mucolipidoses are a family of similar disorders, producing symptoms very much like those of the mucopolysaccharidoses. (For more information, choose “mucolipidosis” as your search term in the Rare Disease Database.)
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Mucopolysaccharidosis Type VII
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nord_831_5
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Diagnosis of Mucopolysaccharidosis Type VII
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Urinary levels of the mucopolysaccharides (dermatan sulfate, heparan sulfate, and chondroitin sulfate) are increased in affected individuals. The diagnosis of MPS VII may be confirmed by a thorough clinical evaluation that includes a detailed patient history and specialized tests that measure the level of beta-glucuronidase activity in blood or skin cells. Molecular genetic testing for mutations in the GUSB gene is available to confirm the diagnosis. Prenatal diagnosis is possible through amniocentesis or chorionic villus sampling to measure beta-glucuronidase activity or molecular genetic testing for GUSB gene mutations.
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Diagnosis of Mucopolysaccharidosis Type VII. Urinary levels of the mucopolysaccharides (dermatan sulfate, heparan sulfate, and chondroitin sulfate) are increased in affected individuals. The diagnosis of MPS VII may be confirmed by a thorough clinical evaluation that includes a detailed patient history and specialized tests that measure the level of beta-glucuronidase activity in blood or skin cells. Molecular genetic testing for mutations in the GUSB gene is available to confirm the diagnosis. Prenatal diagnosis is possible through amniocentesis or chorionic villus sampling to measure beta-glucuronidase activity or molecular genetic testing for GUSB gene mutations.
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Mucopolysaccharidosis Type VII
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nord_831_6
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Therapies of Mucopolysaccharidosis Type VII
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Treatment
In 2017, Mepsevii (vestronidase alfa-jvbk), an enzyme replacement therapy, was approved to treat pediatric and adult patients with MPS VII. Mepsevii is manufactured by Ultragenyx Pharmaceutical, Inc.Other treatment of MPS VII is symptomatic and supportive. Bone deformities and hernias may require surgical correction. Ocular and cardiovascular abnormalities may also be treated surgically. Patients with MSP disorders may be sensitive to anesthesia because of malformations in the airway or cervical spine; therefore, precautions should be taken prior to surgery. Genetic counseling is recommended for people with MPS VII and their families.Hematopoietic Stem Cell Therapy (HSCT)
A Japanese patient underwent successful HSCT at 12 years of age and after 2 years the levels of GUS were stable, with improvement of motor functions (walking, riding, and taking bath alone), recurrent infections and snoring; neurological damage has been kept stable (Yamada et al., 1998). A Mexican female patient with MPS VII with genotype p.P408S/p.P415L underwent HSCT at 11 years of age and was reported to be doing well 2 years after the transplantation (Islam et al., 1996). There were more than 7 patients that underwent HSCT (Islam et al., 1996; Yamada et al., 1998; Montaño et al., 2016). The limited results suggest that HSCT can slow or even prevent further neurological complications, but has little to no effect on the skeletal disease unless it is performed in an early stage.
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Therapies of Mucopolysaccharidosis Type VII. Treatment
In 2017, Mepsevii (vestronidase alfa-jvbk), an enzyme replacement therapy, was approved to treat pediatric and adult patients with MPS VII. Mepsevii is manufactured by Ultragenyx Pharmaceutical, Inc.Other treatment of MPS VII is symptomatic and supportive. Bone deformities and hernias may require surgical correction. Ocular and cardiovascular abnormalities may also be treated surgically. Patients with MSP disorders may be sensitive to anesthesia because of malformations in the airway or cervical spine; therefore, precautions should be taken prior to surgery. Genetic counseling is recommended for people with MPS VII and their families.Hematopoietic Stem Cell Therapy (HSCT)
A Japanese patient underwent successful HSCT at 12 years of age and after 2 years the levels of GUS were stable, with improvement of motor functions (walking, riding, and taking bath alone), recurrent infections and snoring; neurological damage has been kept stable (Yamada et al., 1998). A Mexican female patient with MPS VII with genotype p.P408S/p.P415L underwent HSCT at 11 years of age and was reported to be doing well 2 years after the transplantation (Islam et al., 1996). There were more than 7 patients that underwent HSCT (Islam et al., 1996; Yamada et al., 1998; Montaño et al., 2016). The limited results suggest that HSCT can slow or even prevent further neurological complications, but has little to no effect on the skeletal disease unless it is performed in an early stage.
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Mucopolysaccharidosis Type VII
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nord_832_0
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Overview of Mucormycosis
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SummaryMucormycosis is a general term for a group of uncommon infections cause by a fungus (fungal infection). Mucormycosis is caused by a group of related molds from the order Mucorales. An “order” is a scientific term for classifying similar organisms. These infections are usually acquired when spores from the molds are breathed in (inhaled) or, less commonly, enter the body through a cut in the skin. Mucormycosis is an aggressive, life-threatening infection that occurs in people whose immune system doesn’t function well (immune-compromised) including people with uncontrolled diabetes mellitus, people who have low levels of neutrophils, a type of white blood cell that helps the body fight off infection and heal itself (neutropenia), or people whose immune system is being suppressed by medications (immunosuppression) as part of their treatment for blood cancer (hematological malignancy), hematopoietic stem cell transplantation, or solid-organ transplant. The infection is not contagious; it cannot be spread from one person to another. Prompt diagnosis and early treatment are critical. Treatment usually consists of antifungal medications and surgery.IntroductionMucormycosis is an invasive fungal infection. These infections were once called zygomycosis, but the organisms that cause the infection, specific types of molds, have been scientifically reclassified and the term mucormycosis is now preferred. Generally, these infections are broken down into five presentations: rhinocerebellar, pulmonary, cutaneous, gastrointestinal and disseminated.
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Overview of Mucormycosis. SummaryMucormycosis is a general term for a group of uncommon infections cause by a fungus (fungal infection). Mucormycosis is caused by a group of related molds from the order Mucorales. An “order” is a scientific term for classifying similar organisms. These infections are usually acquired when spores from the molds are breathed in (inhaled) or, less commonly, enter the body through a cut in the skin. Mucormycosis is an aggressive, life-threatening infection that occurs in people whose immune system doesn’t function well (immune-compromised) including people with uncontrolled diabetes mellitus, people who have low levels of neutrophils, a type of white blood cell that helps the body fight off infection and heal itself (neutropenia), or people whose immune system is being suppressed by medications (immunosuppression) as part of their treatment for blood cancer (hematological malignancy), hematopoietic stem cell transplantation, or solid-organ transplant. The infection is not contagious; it cannot be spread from one person to another. Prompt diagnosis and early treatment are critical. Treatment usually consists of antifungal medications and surgery.IntroductionMucormycosis is an invasive fungal infection. These infections were once called zygomycosis, but the organisms that cause the infection, specific types of molds, have been scientifically reclassified and the term mucormycosis is now preferred. Generally, these infections are broken down into five presentations: rhinocerebellar, pulmonary, cutaneous, gastrointestinal and disseminated.
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Mucormycosis
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nord_832_1
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Symptoms of Mucormycosis
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The most common presentation is a sinus infection (sinusitis) that is accompanied by nasal congestion, nasal discharge and sinus pain. A fever and headache can also occur. If the infection spreads outside the sinuses, symptoms can include tissue loss (necrosis) of the roof of the mouth (palate), disintegration of thin wall of cartilage and bone (septum) that divides the nostrils (septum), swelling of the area around the nose (perinasal area) and redness (erythema) of the skin overlying the sinus and the eye socket (orbit). Sometimes, there is bluish discoloration of the skin near the sinuses or the eye socket due to a lack of oxygen (cyanosis). Sometimes, blurry vision or double vision can develop. If unrecognized and untreated, significant tissue death (necrosis) can occur and the infection can significantly damage facial structures.Sometimes, mucormycosis can spread to the brain. This can cause lethargy, seizures, slurred speech, partial paralysis, abnormalities of the nerves of the face and eyes (cranial neuropathies), a brain abscess, altered consciousness and coma. When the sinuses and brain is involved, this infection can be referred to as rhinocerebral mucormycosis.When the infection spreads to the eye, there can be swelling due to fluid buildup around the eyes (periorbital edema), bulging or displacement of the eye (proptosis), vision loss and potentially blindness. Some affected individuals experience paralysis or weakness of the muscles that move the eyes (ophthalmoplegia), making it difficult or painful to move the eyes.Mucormycosis can affect the lungs (pulmonary mucormycosis), most often when the spores are breathed in and reach the respiratory system. Pulmonary mucormycosis is often a rapidly progressive disease characterized by fever and a cough that does not produce any mucous (nonproductive cough). Less often, spitting or coughing up of blood (hemoptysis), chest pain and difficulty breathing (dyspnea) will occur.When mucormycosis affects the skin (cutaneous mucormycosis), affected individuals can develop a single, painful, hardened area of the skin and inflammation of the underlying tissue. Nearby skin may become reddened, warm, swollen and painful. Sometimes, open sores (ulcers) and blisters will form, and tissue loss (necrosis) can occur with the affected tissue turning black. Affected individuals may have a fever. Cutaneous mucormycosis can develop slowly or be severe and sudden in onset (fulminant).Sometimes, the gastrointestinal system can be affected. This most likely occurs when spores are breathed into the mouth and swallowed or contaminated food is eaten. Symptoms can include abdominal pain and vomiting of blood (hematemesis). Lesions can develop that cause a hole to form in the stomach or intestines (perforation). Inflammation of the peritoneum (peritonitis), the membrane that lines the wall of the abdomen and covers the organs inside the abdomen, can also develop. Sometimes, severe pain in the bowels can occur because of a lack of blood flow (bowel infarction) and affected individuals can go into shock because of significant blood loss (hemorrhagic shock).Disseminated mucormycosis is a rare form often seen in individuals who are severely immune compromised. In this form, the infection spreads to other areas of the body and becomes widespread (disseminated). Other areas that can be affected include the brain, heart, spleen, skin and other organs.In rare instances, mucormycosis can affect or spread to affect the kidneys, the inner lining of the chambers of the heart and the heart valves (endocarditis), and the bone (osteomyelitis). Signs and symptoms of disseminated mucormycosis vary greatly depending upon the organ system involved.
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Symptoms of Mucormycosis. The most common presentation is a sinus infection (sinusitis) that is accompanied by nasal congestion, nasal discharge and sinus pain. A fever and headache can also occur. If the infection spreads outside the sinuses, symptoms can include tissue loss (necrosis) of the roof of the mouth (palate), disintegration of thin wall of cartilage and bone (septum) that divides the nostrils (septum), swelling of the area around the nose (perinasal area) and redness (erythema) of the skin overlying the sinus and the eye socket (orbit). Sometimes, there is bluish discoloration of the skin near the sinuses or the eye socket due to a lack of oxygen (cyanosis). Sometimes, blurry vision or double vision can develop. If unrecognized and untreated, significant tissue death (necrosis) can occur and the infection can significantly damage facial structures.Sometimes, mucormycosis can spread to the brain. This can cause lethargy, seizures, slurred speech, partial paralysis, abnormalities of the nerves of the face and eyes (cranial neuropathies), a brain abscess, altered consciousness and coma. When the sinuses and brain is involved, this infection can be referred to as rhinocerebral mucormycosis.When the infection spreads to the eye, there can be swelling due to fluid buildup around the eyes (periorbital edema), bulging or displacement of the eye (proptosis), vision loss and potentially blindness. Some affected individuals experience paralysis or weakness of the muscles that move the eyes (ophthalmoplegia), making it difficult or painful to move the eyes.Mucormycosis can affect the lungs (pulmonary mucormycosis), most often when the spores are breathed in and reach the respiratory system. Pulmonary mucormycosis is often a rapidly progressive disease characterized by fever and a cough that does not produce any mucous (nonproductive cough). Less often, spitting or coughing up of blood (hemoptysis), chest pain and difficulty breathing (dyspnea) will occur.When mucormycosis affects the skin (cutaneous mucormycosis), affected individuals can develop a single, painful, hardened area of the skin and inflammation of the underlying tissue. Nearby skin may become reddened, warm, swollen and painful. Sometimes, open sores (ulcers) and blisters will form, and tissue loss (necrosis) can occur with the affected tissue turning black. Affected individuals may have a fever. Cutaneous mucormycosis can develop slowly or be severe and sudden in onset (fulminant).Sometimes, the gastrointestinal system can be affected. This most likely occurs when spores are breathed into the mouth and swallowed or contaminated food is eaten. Symptoms can include abdominal pain and vomiting of blood (hematemesis). Lesions can develop that cause a hole to form in the stomach or intestines (perforation). Inflammation of the peritoneum (peritonitis), the membrane that lines the wall of the abdomen and covers the organs inside the abdomen, can also develop. Sometimes, severe pain in the bowels can occur because of a lack of blood flow (bowel infarction) and affected individuals can go into shock because of significant blood loss (hemorrhagic shock).Disseminated mucormycosis is a rare form often seen in individuals who are severely immune compromised. In this form, the infection spreads to other areas of the body and becomes widespread (disseminated). Other areas that can be affected include the brain, heart, spleen, skin and other organs.In rare instances, mucormycosis can affect or spread to affect the kidneys, the inner lining of the chambers of the heart and the heart valves (endocarditis), and the bone (osteomyelitis). Signs and symptoms of disseminated mucormycosis vary greatly depending upon the organ system involved.
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Mucormycosis
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nord_832_2
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Causes of Mucormycosis
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Mucormycosis is a fungal infection caused by certain types of molds. These molds are known as mucormycetes. They are found throughout nature (ubiquitous) and can be found in the soil and decaying organic matter like decaying vegetation.Although they are found commonly throughout nature, these molds normally don’t cause problems. However, in individuals with a weakened or compromised immune system, they can cause severe, even life-threatening, infection. Most people develop this infection by breathing in mold spores. Less often, infection can develop when spores enter the body through a cut or open wound.There are people who are at a greater risk of developing mucormycosis. These risk groups include people who have low levels of neutrophils (neutropenia), which are white blood cells that help to fight off infection and are receiving broad-spectrum antibiotics; and individuals who are receiving drugs that suppress the activity of the immune system (immunosuppressive drugs). Neutropenia can be seen in, and immunosuppressive drugs can be taken for cancer, especially blood (hematologic) cancers.Mucormycosis affects people who have recently undergone hematopoietic stem cell transplantation (HSCT). Hematopoietic stem cells are found in the bone marrow and are cells that eventually grow into red blood cells, white blood cells, and platelets. A transplant involves wiping out the existing bone marrow and replacing it with bone marrow from a healthy donor. Affected individuals must take immunosuppressive drugs to help fight off rejection, but this can leave them more susceptible to infection including infection with mucormycosis. People receiving immunosuppressive drugs for other reasons such as receiving an organ transplant can also be at risk of developing this infection.Some individuals with diabetes may be at risk of developing mucormycosis, especially if their diabetes is poorly controlled and they develop diabetic ketoacidosis. Ketoacidosis is a complication of poorly controlled diabetes in which the body produces high levels of blood acids called ketones. Ketoacidosis can cause a variety of symptoms. The exact reasons why people with poorly controlled diabetes are more susceptible to mucormycosis is not completely understood, although it may be related to these patients have excess iron available in the tissues. A severe outbreak of Mucormycosis cases in India in May 2021 in the midst of the COVID19 wave in that country was linked to the excessive use of corticosteroids and the high prevalence of diabetes mellitus in the Indian population. Use of glucocorticosteroids often results in exacerbation of hyperglycemia, even the onset of diabetic ketoacidosis in diabetic patients.People who have too much iron in the body (iron overload), which occurs because of frequent blood transfusions or in certain blood disorders, are also at risk of developing mucormycosis. Researchers believe that these molds can use the excess iron to grow and spread. A medication called deferoxamine, which is used to rid the body of excess iron, can be used by mucormycosis infection to acquire iron from the affected individual. Deferoxamine leads to the growth and spread of infection and the use of this drug is another risk factor for mucormycosis infection.Other conditions can increase the risk of developing mucormycosis including kidney insufficiency; HIV/AIDS; the use of contaminated medical equipment near or in open wounds; long-term use of corticosteroids, which are very strong anti-inflammatory medications; skin trauma including burns or other injury to the skin; extreme malnutrition; and illegal drug use involving needles. Premature newborns can be at a greater risk to infection including mucormycosis as well.In rare instances, some people develop mucormycosis, but do not have any identifiable risk factor.Researchers have determined that mucormycosis infection has a high affinity for the blood vessels. This means that the infection often involves the blood vessels, but researchers do not know exactly why this is so. Infection of the blood vessels can block the flow of blood, depriving tissue of oxygen and causing tissue death (necrosis).
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Causes of Mucormycosis. Mucormycosis is a fungal infection caused by certain types of molds. These molds are known as mucormycetes. They are found throughout nature (ubiquitous) and can be found in the soil and decaying organic matter like decaying vegetation.Although they are found commonly throughout nature, these molds normally don’t cause problems. However, in individuals with a weakened or compromised immune system, they can cause severe, even life-threatening, infection. Most people develop this infection by breathing in mold spores. Less often, infection can develop when spores enter the body through a cut or open wound.There are people who are at a greater risk of developing mucormycosis. These risk groups include people who have low levels of neutrophils (neutropenia), which are white blood cells that help to fight off infection and are receiving broad-spectrum antibiotics; and individuals who are receiving drugs that suppress the activity of the immune system (immunosuppressive drugs). Neutropenia can be seen in, and immunosuppressive drugs can be taken for cancer, especially blood (hematologic) cancers.Mucormycosis affects people who have recently undergone hematopoietic stem cell transplantation (HSCT). Hematopoietic stem cells are found in the bone marrow and are cells that eventually grow into red blood cells, white blood cells, and platelets. A transplant involves wiping out the existing bone marrow and replacing it with bone marrow from a healthy donor. Affected individuals must take immunosuppressive drugs to help fight off rejection, but this can leave them more susceptible to infection including infection with mucormycosis. People receiving immunosuppressive drugs for other reasons such as receiving an organ transplant can also be at risk of developing this infection.Some individuals with diabetes may be at risk of developing mucormycosis, especially if their diabetes is poorly controlled and they develop diabetic ketoacidosis. Ketoacidosis is a complication of poorly controlled diabetes in which the body produces high levels of blood acids called ketones. Ketoacidosis can cause a variety of symptoms. The exact reasons why people with poorly controlled diabetes are more susceptible to mucormycosis is not completely understood, although it may be related to these patients have excess iron available in the tissues. A severe outbreak of Mucormycosis cases in India in May 2021 in the midst of the COVID19 wave in that country was linked to the excessive use of corticosteroids and the high prevalence of diabetes mellitus in the Indian population. Use of glucocorticosteroids often results in exacerbation of hyperglycemia, even the onset of diabetic ketoacidosis in diabetic patients.People who have too much iron in the body (iron overload), which occurs because of frequent blood transfusions or in certain blood disorders, are also at risk of developing mucormycosis. Researchers believe that these molds can use the excess iron to grow and spread. A medication called deferoxamine, which is used to rid the body of excess iron, can be used by mucormycosis infection to acquire iron from the affected individual. Deferoxamine leads to the growth and spread of infection and the use of this drug is another risk factor for mucormycosis infection.Other conditions can increase the risk of developing mucormycosis including kidney insufficiency; HIV/AIDS; the use of contaminated medical equipment near or in open wounds; long-term use of corticosteroids, which are very strong anti-inflammatory medications; skin trauma including burns or other injury to the skin; extreme malnutrition; and illegal drug use involving needles. Premature newborns can be at a greater risk to infection including mucormycosis as well.In rare instances, some people develop mucormycosis, but do not have any identifiable risk factor.Researchers have determined that mucormycosis infection has a high affinity for the blood vessels. This means that the infection often involves the blood vessels, but researchers do not know exactly why this is so. Infection of the blood vessels can block the flow of blood, depriving tissue of oxygen and causing tissue death (necrosis).
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Affects of Mucormycosis
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Mucormycosis is a rare fungal infection. The exact number of people who develop this infection in the United States is not known because there is no national surveillance of this infection. One estimate based on a study in the San Francisco area placed the incidence at 1.7 people per every 1,000,000 in the general population. Incidence refers to the number of new diagnoses of a disorder in one year. According to the medical literature, the incidence of mucormycosis is increasing. Mucormycosis has been reported all over the world. This infection can potentially affect individuals of any age, including premature newborns.
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Affects of Mucormycosis. Mucormycosis is a rare fungal infection. The exact number of people who develop this infection in the United States is not known because there is no national surveillance of this infection. One estimate based on a study in the San Francisco area placed the incidence at 1.7 people per every 1,000,000 in the general population. Incidence refers to the number of new diagnoses of a disorder in one year. According to the medical literature, the incidence of mucormycosis is increasing. Mucormycosis has been reported all over the world. This infection can potentially affect individuals of any age, including premature newborns.
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Related disorders of Mucormycosis
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Symptoms of the following disorders can be similar to those of mucormycosis. Comparisons may be useful for a differential diagnosis.Aspergillosis is a fungal infection caused by aspergillus, a species of mold that is found all over the world. More than 300 different types of aspergillus have been identified and more are continuing to be identified. Most of these molds are harmless, however, some types can cause a variety of diseases in humans ranging from simple allergic reactions to life-threatening invasive disease. Collectively, this group of diseases is referred to as aspergillosis and is broadly broken down into three categories – allergic, chronic and invasive. Four main clinical types of aspergilloses are usually identified – allergic bronchopulmonary aspergillosis, aspergilloma, invasive aspergillosis and chronic necrotizing aspergillosis. Aspergillosis rarely develops in healthy individuals; it is much more likely to develop in individuals with asthma, cystic fibrosis, diabetes mellitus and lung disease or in individuals who have a weakened immune system, who take corticosteroid drugs or who have had a bone marrow or organ transplant. In most cases, aspergillosis develops when susceptible individuals breathe in (inhale) Aspergillus spores. (For more information on this disorder, choose “aspergillosis” as your search term in the Rare Disease Database.)There are many different disorders, infections or conditions that may have symptoms similar to those found with aspergillosis. These include nocardiosis; fusariosis; anthrax; pseudallescheriasis; cavernous sinus thrombosis; sinusitis; bacterial orbital cellulitis; Churg-Strauss syndrome; granulomatosis with polyangiitis (Wegener granulomatosis); pulmonary eosinophilia; acute respiratory distress syndrome; tuberculosis; lung cancer; or fungal, bacterial or viral pneumonia. For more information, choose the specific disorder or condition name as your search term in the Rare Disease Database.
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Related disorders of Mucormycosis. Symptoms of the following disorders can be similar to those of mucormycosis. Comparisons may be useful for a differential diagnosis.Aspergillosis is a fungal infection caused by aspergillus, a species of mold that is found all over the world. More than 300 different types of aspergillus have been identified and more are continuing to be identified. Most of these molds are harmless, however, some types can cause a variety of diseases in humans ranging from simple allergic reactions to life-threatening invasive disease. Collectively, this group of diseases is referred to as aspergillosis and is broadly broken down into three categories – allergic, chronic and invasive. Four main clinical types of aspergilloses are usually identified – allergic bronchopulmonary aspergillosis, aspergilloma, invasive aspergillosis and chronic necrotizing aspergillosis. Aspergillosis rarely develops in healthy individuals; it is much more likely to develop in individuals with asthma, cystic fibrosis, diabetes mellitus and lung disease or in individuals who have a weakened immune system, who take corticosteroid drugs or who have had a bone marrow or organ transplant. In most cases, aspergillosis develops when susceptible individuals breathe in (inhale) Aspergillus spores. (For more information on this disorder, choose “aspergillosis” as your search term in the Rare Disease Database.)There are many different disorders, infections or conditions that may have symptoms similar to those found with aspergillosis. These include nocardiosis; fusariosis; anthrax; pseudallescheriasis; cavernous sinus thrombosis; sinusitis; bacterial orbital cellulitis; Churg-Strauss syndrome; granulomatosis with polyangiitis (Wegener granulomatosis); pulmonary eosinophilia; acute respiratory distress syndrome; tuberculosis; lung cancer; or fungal, bacterial or viral pneumonia. For more information, choose the specific disorder or condition name as your search term in the Rare Disease Database.
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Diagnosis of Mucormycosis
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A diagnosis of mucormycosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis of mucormycosis is challenging because the symptoms are common to many conditions including other types of infection. A diagnosis is made by identifying mold in affected tissue and sometimes can be confirmed by a test called a fungal culture. A prompt diagnosis is important so treatment can begin as early as possible.A diagnosis of mucormycosis can be suspected when affected individuals who have been identified as having a fungal infection do not respond to antifungal medications that target aspergillosis, especially when aspergillosis biomarkers are absent. Biomarkers for aspergillosis include the aspergillus galactomannan antigen. Antigens are substances that cause a response from the immune system; biomarkers are measurable substances that can indicate the presence of disease. The use of mucorales PCR in the blood is promisiing, yet non-culture-based diagnostics remain investigational.Clinical Testing and Workup
Doctors will take samples of affected tissue and a special doctor called a pathologist will study the tissue for changes caused by disease (histopathology). This can show the presence of mold. Samples can include fluid from the respiratory system or mucus coughed up from the lungs (sputum) if lung infection is suspected. Surgical removal of a small sample of skin tissue can be taken in cutaneous mucormycosis.A tissue sample can then be taken and used for a fungal culture. A fungal culture is a procedure in which a sample of affected tissue is taken and sent to a laboratory and any fungus or similar organism discovered in the tissue is given time to grow. This test can determine the presence and type of fungal infection. However, sometimes a fungal culture does not reveal a fungal infection despite the presence of infection. Thus, a negative result on a fungal culture does not rule out mucormycosis.If a histopathology study is positive for infection, but a fungal culture is negative, a test called polymerase chain reaction or PCR may be used. This test can identify the causative species of the infection. PCR is a test technique for identifying and making copies of specific segments of deoxyribonucleic acid (DNA). The test can identify tiny amounts of DNA including genetic material of infectious organisms like fungi. This test is not widely available and has not undergone clinical evaluation as to its effectiveness or appropriateness for diagnosing mucormycosis. Consequently, not all doctors recommend its use.Imaging techniques such as computerized tomography (CT) scanning may be used to determine the exact location and extent of an infection. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A CT scan may be taken of the lungs, sinuses, facial structures, or other areas of the body. In individuals with pulmonary mucormycosis, a CT scan of the lungs can reveal a reverse halo sign. This diagnostic clue is an area of tissue death (necrosis) that resembles ground glass on the film. It is suggestive of mucormycosis infection.
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Diagnosis of Mucormycosis. A diagnosis of mucormycosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis of mucormycosis is challenging because the symptoms are common to many conditions including other types of infection. A diagnosis is made by identifying mold in affected tissue and sometimes can be confirmed by a test called a fungal culture. A prompt diagnosis is important so treatment can begin as early as possible.A diagnosis of mucormycosis can be suspected when affected individuals who have been identified as having a fungal infection do not respond to antifungal medications that target aspergillosis, especially when aspergillosis biomarkers are absent. Biomarkers for aspergillosis include the aspergillus galactomannan antigen. Antigens are substances that cause a response from the immune system; biomarkers are measurable substances that can indicate the presence of disease. The use of mucorales PCR in the blood is promisiing, yet non-culture-based diagnostics remain investigational.Clinical Testing and Workup
Doctors will take samples of affected tissue and a special doctor called a pathologist will study the tissue for changes caused by disease (histopathology). This can show the presence of mold. Samples can include fluid from the respiratory system or mucus coughed up from the lungs (sputum) if lung infection is suspected. Surgical removal of a small sample of skin tissue can be taken in cutaneous mucormycosis.A tissue sample can then be taken and used for a fungal culture. A fungal culture is a procedure in which a sample of affected tissue is taken and sent to a laboratory and any fungus or similar organism discovered in the tissue is given time to grow. This test can determine the presence and type of fungal infection. However, sometimes a fungal culture does not reveal a fungal infection despite the presence of infection. Thus, a negative result on a fungal culture does not rule out mucormycosis.If a histopathology study is positive for infection, but a fungal culture is negative, a test called polymerase chain reaction or PCR may be used. This test can identify the causative species of the infection. PCR is a test technique for identifying and making copies of specific segments of deoxyribonucleic acid (DNA). The test can identify tiny amounts of DNA including genetic material of infectious organisms like fungi. This test is not widely available and has not undergone clinical evaluation as to its effectiveness or appropriateness for diagnosing mucormycosis. Consequently, not all doctors recommend its use.Imaging techniques such as computerized tomography (CT) scanning may be used to determine the exact location and extent of an infection. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A CT scan may be taken of the lungs, sinuses, facial structures, or other areas of the body. In individuals with pulmonary mucormycosis, a CT scan of the lungs can reveal a reverse halo sign. This diagnostic clue is an area of tissue death (necrosis) that resembles ground glass on the film. It is suggestive of mucormycosis infection.
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Therapies of Mucormycosis
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Treatment
Treatment for mucormycosis will include antifungal medications. Antifungal medications inhibit the growth of and destroy fungal infections and are essential in controlling the spread of infection. The most commonly used medication is called amphotericin B. Initially, high doses of this medication are given intravenously. If an affected individual shows improvement, which can take several weeks, doctors may have the patient switch to oral antifungal medications, such as posaconazole or isavuconazole (Cresemba). This is called step-down therapy. In 2015, the U.S. Food and Drug Administration (FDA) approved Cresemba for the treatment of adults with invasive mucormycosis.If affected individuals do not respond to amphotericin B, or cannot tolerate the medication due to side effects, then posaconazole or isavuconazole may be given intravenously. This is called salvage therapy.Surgery may be necessary to remove infected or dead tissue, damaged skin and involved subcutaneous tissue. This is called surgical debridement and if the infection is significant, this can potentially lead to changes in the structure or shape of the affected area. Individuals with rhinocerebral mucormycosis can experience significant changes to facial appearance. Surgical debridement should be done as soon as the infection is confirmed. There are reports of people being cured of infection by the surgical removal of the infected lobe of the lung (lobectomy) because the infection began in this area and had not yet spread. Specific surgical recommendations will vary depending upon the exact location and extent of the infection.Some affected individuals may receive adjunctive treatment with hyperbaric oxygen. Adjunctive treatment is a treatment given in addition to the initial, primary therapy. There have not been clinical trials on a large group of patients, but some small reviews on a small number of patients. Hyperbaric oxygen involves exposing the patient to pure oxygen in a pressure room or medical tube and has been effective in treating other types of serious infection. There is some research that shows that hyperbaric conditions can inhibit infection. However, there are risk with hyperbaric therapy including the need to move a patient out of intensive car where emergency intervention can be provided. More research is necessary to determine the long-term safety and effectiveness of hyperbaric oxygen and whether the therapy has a role in treating individuals with mucormycosis.Doctors will also treat the underlying risk factor that can be associated with mucormycosis infection. Controlling underlying conditions is important in the treatment of this infection. This can include medications to increase the levels of white blood cells in people with neutropenia; insulin for people with uncontrolled diabetes; or medications called iron chelators that lowers the level of iron in the blood like and deferiprone for people with iron overload. It is extremely important that an iron chelator called deferoxamine is avoided because this medication actually promotes the growth and spread of mucormycosis in the body.Mucormycosis is a serious, life-threatening infection that can prove fatal despite treatment. Many factors can influence treatment including the underlying condition associated with infection (e.g., hematologic cancer, diabetes, etc.), the exact location and extent of infection, how long until the proper diagnosis was made and when treatment was started, an individual’s age and overall health, and other factors.
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Therapies of Mucormycosis. Treatment
Treatment for mucormycosis will include antifungal medications. Antifungal medications inhibit the growth of and destroy fungal infections and are essential in controlling the spread of infection. The most commonly used medication is called amphotericin B. Initially, high doses of this medication are given intravenously. If an affected individual shows improvement, which can take several weeks, doctors may have the patient switch to oral antifungal medications, such as posaconazole or isavuconazole (Cresemba). This is called step-down therapy. In 2015, the U.S. Food and Drug Administration (FDA) approved Cresemba for the treatment of adults with invasive mucormycosis.If affected individuals do not respond to amphotericin B, or cannot tolerate the medication due to side effects, then posaconazole or isavuconazole may be given intravenously. This is called salvage therapy.Surgery may be necessary to remove infected or dead tissue, damaged skin and involved subcutaneous tissue. This is called surgical debridement and if the infection is significant, this can potentially lead to changes in the structure or shape of the affected area. Individuals with rhinocerebral mucormycosis can experience significant changes to facial appearance. Surgical debridement should be done as soon as the infection is confirmed. There are reports of people being cured of infection by the surgical removal of the infected lobe of the lung (lobectomy) because the infection began in this area and had not yet spread. Specific surgical recommendations will vary depending upon the exact location and extent of the infection.Some affected individuals may receive adjunctive treatment with hyperbaric oxygen. Adjunctive treatment is a treatment given in addition to the initial, primary therapy. There have not been clinical trials on a large group of patients, but some small reviews on a small number of patients. Hyperbaric oxygen involves exposing the patient to pure oxygen in a pressure room or medical tube and has been effective in treating other types of serious infection. There is some research that shows that hyperbaric conditions can inhibit infection. However, there are risk with hyperbaric therapy including the need to move a patient out of intensive car where emergency intervention can be provided. More research is necessary to determine the long-term safety and effectiveness of hyperbaric oxygen and whether the therapy has a role in treating individuals with mucormycosis.Doctors will also treat the underlying risk factor that can be associated with mucormycosis infection. Controlling underlying conditions is important in the treatment of this infection. This can include medications to increase the levels of white blood cells in people with neutropenia; insulin for people with uncontrolled diabetes; or medications called iron chelators that lowers the level of iron in the blood like and deferiprone for people with iron overload. It is extremely important that an iron chelator called deferoxamine is avoided because this medication actually promotes the growth and spread of mucormycosis in the body.Mucormycosis is a serious, life-threatening infection that can prove fatal despite treatment. Many factors can influence treatment including the underlying condition associated with infection (e.g., hematologic cancer, diabetes, etc.), the exact location and extent of infection, how long until the proper diagnosis was made and when treatment was started, an individual’s age and overall health, and other factors.
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Overview of Mucous Membrane Pemphigoid
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Mucous membrane pemphigoid (MMP) is a group of rare chronic autoimmune disorders characterized by blistering lesions that primarily affect the various mucous membranes of the body. The mucous membranes of the mouth and eyes are most often affected. The mucous membranes of the nose, throat, genitalia, and anus may also be affected. The symptoms of MMP vary among affected individuals depending upon the specific site(s) involved and the progression of the disease. Blistering lesions eventually heal, sometimes with scarring. Progressive scarring may potentially lead to serious complications affecting the eyes and throat. In some cases, blistering lesions also form on the skin, especially in the head and neck area. The exact cause of MMP is unknown.MMP has been known by many different names within the medical literature including benign mucous membrane pemphigoid, cicatricial (scarring) pemphigoid, and ocular cicatricial pemphigoid. In March of 2002, a consensus group of researchers determined that mucous membrane pemphigoid was the best designation for this group of disorders. The term “benign” mucous membrane pemphigoid was deemed inappropriate because of the potential for serious complications in some cases. The term “cicatricial” pemphigoid excluded affected individuals who do not develop scarring. Site-specific terms such as “ocular” cicatricial pemphigoid excluded individuals with multiple site involvement.
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Overview of Mucous Membrane Pemphigoid. Mucous membrane pemphigoid (MMP) is a group of rare chronic autoimmune disorders characterized by blistering lesions that primarily affect the various mucous membranes of the body. The mucous membranes of the mouth and eyes are most often affected. The mucous membranes of the nose, throat, genitalia, and anus may also be affected. The symptoms of MMP vary among affected individuals depending upon the specific site(s) involved and the progression of the disease. Blistering lesions eventually heal, sometimes with scarring. Progressive scarring may potentially lead to serious complications affecting the eyes and throat. In some cases, blistering lesions also form on the skin, especially in the head and neck area. The exact cause of MMP is unknown.MMP has been known by many different names within the medical literature including benign mucous membrane pemphigoid, cicatricial (scarring) pemphigoid, and ocular cicatricial pemphigoid. In March of 2002, a consensus group of researchers determined that mucous membrane pemphigoid was the best designation for this group of disorders. The term “benign” mucous membrane pemphigoid was deemed inappropriate because of the potential for serious complications in some cases. The term “cicatricial” pemphigoid excluded affected individuals who do not develop scarring. Site-specific terms such as “ocular” cicatricial pemphigoid excluded individuals with multiple site involvement.
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Symptoms of Mucous Membrane Pemphigoid
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MMP is characterized by the development of recurring blistering skin lesions affecting the mucous membranes of the body. These lesions may result in scarring of the affected area. Specific symptoms and severity vary from person to person depending upon the specific site(s) involved. It is important to note that affected individuals, in most cases, will not have all of the symptoms listed below.The mucous membranes lining the mouth and eyes are most commonly affected. In some cases, the first sign of MMP is a red and blistered mouth. The gums (gingivae), roof of the mouth (palate), and the mucous membrane lining the inner cheek (buccal mucosa) may be affected. Involvement of the gums usually results in very red, tender gums that bleed easily and tend to slough off in shreds or sheets. Blistering lesions may spread to affect the tube that carries food from the mouth to the stomach (esophagus) as well as the voice box (larynx) potentially resulting in difficulty swallowing (dysphagia) and hoarseness. After these lesions heal, progressive scarring may occur, resulting in serious complications including narrowing (stenosis) of the esophagus and/or the larynx. In addition, the opening between the vocal cords (supraglottic region) may also narrow (supraglottic stenosis). In rare severe cases, such symptoms can ultimately result in life-threatening complications such as asphyxiation (breathing is cut off).In many cases of MMP, the mucous membranes lining the eyes (conjunctiva) may be involved. Inflammation of conjunctiva (conjunctivitis) or erosions forming on the conjunctiva may be the initial signs of ocular involvement in MMP. Involvement of the eyes may not be obvious at first, however, and only a special examination by an eye doctor (ophthalmologist) can detect the earliest scarring that develops just beneath the conjunctiva. In most cases, one eye is involved first and the second eye becomes involved later, usually with two years. Ocular symptoms may include pain or grittiness of the eye, increased pressure within the eye (glaucoma), abnormal inward turning of the eyelid (entropion), and abnormal inward turning of the eyelashes (trichiasis) potentially causing irritation of the eyeball. Adhesions may form between the eyelids (symblepharon) or between the eyelid and the eye itself. In some cases, MMP may progress to cause clouding (opacity) of the corneas, loss of vision and, potentially, blindness.In some cases, affected individuals may develop blistering lesions affecting only the eyes or the mouth, with no involvement of other mucosal sites. Scarring occurs with less frequency in cases of MMP that only involve the mucous membranes of the mouth (oral mucosa). Additional sites where lesions may form include mucous membranes of the nose, genitalia, and anus. Pain, bleeding and scarring may occur at these sites. Urinary and sexual dysfunction may result secondary to genital involvement.In approximately 20-30 percent of cases, the skin may become involved. In these patients, the skin of the head and neck is usually affected. Skin lesions may be either fluid-filled blisters (bullous) or reddish (erythematous) plaques, which may bleed or itch. Eventually they scar upon healing. Scarring may result in areas of discoloration of the skin (known as hyperpigmentation when it is darkened patches and hypopigmentation when it is light patches). Involvement of the scalp may lead to patchy areas of hair loss (alopecia).MMP usually has a long duration with frequent remissions and recurrence.
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Symptoms of Mucous Membrane Pemphigoid. MMP is characterized by the development of recurring blistering skin lesions affecting the mucous membranes of the body. These lesions may result in scarring of the affected area. Specific symptoms and severity vary from person to person depending upon the specific site(s) involved. It is important to note that affected individuals, in most cases, will not have all of the symptoms listed below.The mucous membranes lining the mouth and eyes are most commonly affected. In some cases, the first sign of MMP is a red and blistered mouth. The gums (gingivae), roof of the mouth (palate), and the mucous membrane lining the inner cheek (buccal mucosa) may be affected. Involvement of the gums usually results in very red, tender gums that bleed easily and tend to slough off in shreds or sheets. Blistering lesions may spread to affect the tube that carries food from the mouth to the stomach (esophagus) as well as the voice box (larynx) potentially resulting in difficulty swallowing (dysphagia) and hoarseness. After these lesions heal, progressive scarring may occur, resulting in serious complications including narrowing (stenosis) of the esophagus and/or the larynx. In addition, the opening between the vocal cords (supraglottic region) may also narrow (supraglottic stenosis). In rare severe cases, such symptoms can ultimately result in life-threatening complications such as asphyxiation (breathing is cut off).In many cases of MMP, the mucous membranes lining the eyes (conjunctiva) may be involved. Inflammation of conjunctiva (conjunctivitis) or erosions forming on the conjunctiva may be the initial signs of ocular involvement in MMP. Involvement of the eyes may not be obvious at first, however, and only a special examination by an eye doctor (ophthalmologist) can detect the earliest scarring that develops just beneath the conjunctiva. In most cases, one eye is involved first and the second eye becomes involved later, usually with two years. Ocular symptoms may include pain or grittiness of the eye, increased pressure within the eye (glaucoma), abnormal inward turning of the eyelid (entropion), and abnormal inward turning of the eyelashes (trichiasis) potentially causing irritation of the eyeball. Adhesions may form between the eyelids (symblepharon) or between the eyelid and the eye itself. In some cases, MMP may progress to cause clouding (opacity) of the corneas, loss of vision and, potentially, blindness.In some cases, affected individuals may develop blistering lesions affecting only the eyes or the mouth, with no involvement of other mucosal sites. Scarring occurs with less frequency in cases of MMP that only involve the mucous membranes of the mouth (oral mucosa). Additional sites where lesions may form include mucous membranes of the nose, genitalia, and anus. Pain, bleeding and scarring may occur at these sites. Urinary and sexual dysfunction may result secondary to genital involvement.In approximately 20-30 percent of cases, the skin may become involved. In these patients, the skin of the head and neck is usually affected. Skin lesions may be either fluid-filled blisters (bullous) or reddish (erythematous) plaques, which may bleed or itch. Eventually they scar upon healing. Scarring may result in areas of discoloration of the skin (known as hyperpigmentation when it is darkened patches and hypopigmentation when it is light patches). Involvement of the scalp may lead to patchy areas of hair loss (alopecia).MMP usually has a long duration with frequent remissions and recurrence.
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Causes of Mucous Membrane Pemphigoid
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The exact cause of mucous membrane pemphigoid is unknown. MMP is an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses (antibodies or immunoglobulins) against “foreign” or invading organisms (antigens) begin to attack healthy tissue for unknown reasons. The term autoantibody is used to describe antibodies that are created to attack healthy tissue. The term autoantigen (“self” antigen) is used to describe the normal tissues and cells of the body that are targeted by the autoantibodies.In patients who have MMP, autoantibodies are being produced that attack the basement membrane zone (BMZ) of the epithelium. The BMZ can be thought of as a sort of “glue” that holds the outer layer of skin (epidermis or oral epithelium) onto the underlying tissues. Once this glue is attacked and destroyed by the autoantibodies, the skin is no longer tacked down, allowing it to lift off and produce blisters.Researchers believe that in some cases affected individuals may have a genetic susceptibility to developing some forms of MMP. In these cases several factors may contribute to the development of the disorder including immunological, genetic, environmental, and/or other factors.In a very small number of patients, MMP may be caused by the use of certain prescription drugs. Skin lesions associated with some cases of MMP may appear following trauma to the affected area. Some cases of MMP affecting the eyes may become apparent after eye (ocular) surgery such as cataract removal.
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Causes of Mucous Membrane Pemphigoid. The exact cause of mucous membrane pemphigoid is unknown. MMP is an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses (antibodies or immunoglobulins) against “foreign” or invading organisms (antigens) begin to attack healthy tissue for unknown reasons. The term autoantibody is used to describe antibodies that are created to attack healthy tissue. The term autoantigen (“self” antigen) is used to describe the normal tissues and cells of the body that are targeted by the autoantibodies.In patients who have MMP, autoantibodies are being produced that attack the basement membrane zone (BMZ) of the epithelium. The BMZ can be thought of as a sort of “glue” that holds the outer layer of skin (epidermis or oral epithelium) onto the underlying tissues. Once this glue is attacked and destroyed by the autoantibodies, the skin is no longer tacked down, allowing it to lift off and produce blisters.Researchers believe that in some cases affected individuals may have a genetic susceptibility to developing some forms of MMP. In these cases several factors may contribute to the development of the disorder including immunological, genetic, environmental, and/or other factors.In a very small number of patients, MMP may be caused by the use of certain prescription drugs. Skin lesions associated with some cases of MMP may appear following trauma to the affected area. Some cases of MMP affecting the eyes may become apparent after eye (ocular) surgery such as cataract removal.
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Affects of Mucous Membrane Pemphigoid
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Mucous membrane pemphigoid is a rare group of autoimmune blistering disorders that affects females twice as often as males. The average age of onset of MMP is during the seventh decade (60 to 70 years of age). However, the disorder can occur at any age. The exact incidence of MMP is unknown. Because the disorder is difficult to identify, many researchers believe it is under-diagnosed.
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Affects of Mucous Membrane Pemphigoid. Mucous membrane pemphigoid is a rare group of autoimmune blistering disorders that affects females twice as often as males. The average age of onset of MMP is during the seventh decade (60 to 70 years of age). However, the disorder can occur at any age. The exact incidence of MMP is unknown. Because the disorder is difficult to identify, many researchers believe it is under-diagnosed.
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Mucous Membrane Pemphigoid
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Related disorders of Mucous Membrane Pemphigoid
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Symptoms of the following disorders can be similar to those of mucous membrane pemphigoid. Comparisons may be useful for a differential diagnosis:Bullous pemphigoid (BP) is a chronic skin disease usually affecting the elderly that is characterized by firm, large blisters that develop on normal-appearing or reddened skin usually around cuts or scars. Within weeks, blisters spread to skin of the flexor (muscles that contract or flex) areas, groin, armpit, and the abdomen. Mucous membranes seldom are affected and tend to heal quickly. The blisters have little tendency to spread, but heal quickly when they do. There is, however, severe irritation. Bullous pemphigoid is an autoimmune disorder. (For more information on this disorder, choose “bullous pemphigoid” as your search term in the Rare Disease Database.)Epidermolysis bullosa acquista (EBA) is a rare autoimmune disorder of the skin that typically affects middle-aged and elderly people. Trauma to the skin can cause blisters on the elbows, knees, pelvis, buttocks, and/or scalp. Increased levels of IgG (an immunoglobulin) are usually found around the blisters. After the blisters heal, scars usually remain. In some cases, mucous membrane involvement may be present. (For more information on this disorder, choose “autoimmune blistering diseases” as your search term in the Rare Disease Database.)Pemphigus vulgaris (PV) is an autoimmune disorder that usually affects the middle-aged and elderly. Blisters usually start in the mouth (oral lesions) but they may not be recognized as blisters because they break easily, soon after they are formed. Lesions will heal, but new blisters occur as the older ones are healing. The blisters may persist for several months before affecting other mucous membranes such as the esophagus, nose, eyelids (conjunctiva), and rectum. In some cases, the skin blisters may not develop for one to three years after oral lesions are noticed. Pressure on the border of the blisters causes them to spread. Pressure on normal-looking skin also can cause a blister to form (Nikolsky’s sign) in patients with pemphigus vulgaris. (For more information on this disorder, choose “pemphigus” as your search term in the Rare Disease Database.)Lichen planus (LP) is a relatively common disorder of the skin that may present as a network of interlacing fine white lines affecting the lining of the cheek (buccal mucosa). The cause remains unknown. There is an erosive form of oral lichen planus that can produce red, sore, bleeding gums and sores on the lining of the cheeks similar to MMP. When the skin is involved, small, purplish, angular bumps develop most commonly on the skin of the wrists, the ankles and the lower back. The disorder affects women more frequently than men. (For more information on this disorder, choose “lichen planus” as your search term in the Rare Disease Database.)Brunsting-Perry syndrome is an old medical term used to describe a form of localized cicatricial pemphigoid in which blistering lesions affect the skin, usually of the head and neck, but do not affect any of the mucous membranes of the body. The skin lesions usually leave scars upon healing. The blisters associated with Brunsting-Perry syndrome may occur due to trauma.Additional disorders may involve lesions affecting the mucous membranes. These disorders include Stevens-Johnson syndrome, erythema multiforme minor, paraneoplastic pemphigus, and linear IgA bullous dermatosis. (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 Mucous Membrane Pemphigoid. Symptoms of the following disorders can be similar to those of mucous membrane pemphigoid. Comparisons may be useful for a differential diagnosis:Bullous pemphigoid (BP) is a chronic skin disease usually affecting the elderly that is characterized by firm, large blisters that develop on normal-appearing or reddened skin usually around cuts or scars. Within weeks, blisters spread to skin of the flexor (muscles that contract or flex) areas, groin, armpit, and the abdomen. Mucous membranes seldom are affected and tend to heal quickly. The blisters have little tendency to spread, but heal quickly when they do. There is, however, severe irritation. Bullous pemphigoid is an autoimmune disorder. (For more information on this disorder, choose “bullous pemphigoid” as your search term in the Rare Disease Database.)Epidermolysis bullosa acquista (EBA) is a rare autoimmune disorder of the skin that typically affects middle-aged and elderly people. Trauma to the skin can cause blisters on the elbows, knees, pelvis, buttocks, and/or scalp. Increased levels of IgG (an immunoglobulin) are usually found around the blisters. After the blisters heal, scars usually remain. In some cases, mucous membrane involvement may be present. (For more information on this disorder, choose “autoimmune blistering diseases” as your search term in the Rare Disease Database.)Pemphigus vulgaris (PV) is an autoimmune disorder that usually affects the middle-aged and elderly. Blisters usually start in the mouth (oral lesions) but they may not be recognized as blisters because they break easily, soon after they are formed. Lesions will heal, but new blisters occur as the older ones are healing. The blisters may persist for several months before affecting other mucous membranes such as the esophagus, nose, eyelids (conjunctiva), and rectum. In some cases, the skin blisters may not develop for one to three years after oral lesions are noticed. Pressure on the border of the blisters causes them to spread. Pressure on normal-looking skin also can cause a blister to form (Nikolsky’s sign) in patients with pemphigus vulgaris. (For more information on this disorder, choose “pemphigus” as your search term in the Rare Disease Database.)Lichen planus (LP) is a relatively common disorder of the skin that may present as a network of interlacing fine white lines affecting the lining of the cheek (buccal mucosa). The cause remains unknown. There is an erosive form of oral lichen planus that can produce red, sore, bleeding gums and sores on the lining of the cheeks similar to MMP. When the skin is involved, small, purplish, angular bumps develop most commonly on the skin of the wrists, the ankles and the lower back. The disorder affects women more frequently than men. (For more information on this disorder, choose “lichen planus” as your search term in the Rare Disease Database.)Brunsting-Perry syndrome is an old medical term used to describe a form of localized cicatricial pemphigoid in which blistering lesions affect the skin, usually of the head and neck, but do not affect any of the mucous membranes of the body. The skin lesions usually leave scars upon healing. The blisters associated with Brunsting-Perry syndrome may occur due to trauma.Additional disorders may involve lesions affecting the mucous membranes. These disorders include Stevens-Johnson syndrome, erythema multiforme minor, paraneoplastic pemphigus, and linear IgA bullous dermatosis. (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 Mucous Membrane Pemphigoid
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A diagnosis of MMP is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and certain tests known as a biopsy and direct immunofluorescence. For a biopsy, a small sample of skin tissue is removed (biopsy) and microscopically examined. For direct immunofluorescence, a second biopsied skin sample is tested to detect the presence of the specific autoantibodies (e.g., IgA, IgG, and C3) that cause pemphigoid.
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Diagnosis of Mucous Membrane Pemphigoid. A diagnosis of MMP is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and certain tests known as a biopsy and direct immunofluorescence. For a biopsy, a small sample of skin tissue is removed (biopsy) and microscopically examined. For direct immunofluorescence, a second biopsied skin sample is tested to detect the presence of the specific autoantibodies (e.g., IgA, IgG, and C3) that cause pemphigoid.
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Mucous Membrane Pemphigoid
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nord_833_6
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Therapies of Mucous Membrane Pemphigoid
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TreatmentThe treatment of MMP is directed toward the specific symptoms that are apparent in each individual. Treatment depends upon the specific area(s) of the body affected, the severity of the disease, and its rate of progression. Treatment may require the combined efforts of a team of specialists. Dental specialists (oral pathologists), specialists who assess and treat skin problems (dermatologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat ear and throat problems (otolaryngologists), and other healthcare professionals may need to systematically and comprehensively plan an affected individual's treatment. If the patient has not seen an ophthalmologist, then an appointment should be made right away to have the eyes evaluated because treatment often depends on whether or not there is eye involvement. The earliest changes of scarring just underneath the lining of the eye (subepithelial fibrosis) are often asymptomatic and can only be detected by slit-lamp microscopic evaluation by an ophthalmologist. Such scarring interferes with the glands that produce the tears, and this results in dryness of the eye. Affected patients may need to use artificial tears frequently to reduce damage to the eye.No large-scale, multi-center studies have been done regarding the treatment of MMP. The usual treatment for MMP is certain drugs, used either singly or in various combinations. Corticosteroid drugs are often prescribed for affected individuals. Topical corticosteroids such as fluocinonide can relieve inflammation and itching in mild cases such as those that affect oral cavity only or the oral cavity and the skin. Other, more potent, gel preparations such as betamethasone dipropionate or clobetasol may also be used. When pemphigoid affects the gums, keeping the teeth clean by tooth-brushing will help reduce the sores, especially when topical corticosteroids are used at the same time.Some antibiotic drugs can affect the inflammatory process. One such drug is dapsone, a sulfa-type medication that may be used to treat mild cases of MMP. Special blood tests are needed before this drug is used, however. A combination of the antibiotic drug tetracycline and nicotinamide (vitamin B3) can also be helpful in some cases of MMP.Individuals with widespread or severe MMP may be treated with systemic corticosteroids such as prednisone and/or immunosuppressive drugs such as mycophenolate mofetil, cyclophosphamide or azathioprine. Individuals with eye involvement, severe or rapidly progressing MMP may be treated with prednisone combined with cyclophosphamide, mycophenolate mofetil, or azathioprine. Patients who are taking the above mentioned drugs must be carefully monitored by a dermatologist or physician familiar with their use because of potentially significant side effects. If these drugs are not helping, or if the pemphigoid seems to be getting worse, then other treatments that can be tried include rituximab and IV-IG (intravenous immunoglobulin G). Rituximab is an antibody that destroys the cells that produce antibodies. IV-IG is produced by purifying and concentrating antibody molecules from hundreds of blood donors. Both rituximab and IV-IG can have very serious side effects, so they usually are not given unless the patient has pemphigoid that is not getting better with other treatments.In rare cases, surgical procedures such as a tracheostomy may become necessary if scarring narrows the airway and breathing becomes difficult. A tracheostomy is a procedure in which a tube is inserted through a surgical opening in the windpipe (trachea) to assist breathing. A procedure to widen (dilate) a narrowed or obstructed esophagus may also be necessary if the esophagus is involved. Surgical removal (ablation) of ingrown eyelashes may be performed if the eyes are affected.Other treatment is symptomatic and supportive.
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Therapies of Mucous Membrane Pemphigoid. TreatmentThe treatment of MMP is directed toward the specific symptoms that are apparent in each individual. Treatment depends upon the specific area(s) of the body affected, the severity of the disease, and its rate of progression. Treatment may require the combined efforts of a team of specialists. Dental specialists (oral pathologists), specialists who assess and treat skin problems (dermatologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat ear and throat problems (otolaryngologists), and other healthcare professionals may need to systematically and comprehensively plan an affected individual's treatment. If the patient has not seen an ophthalmologist, then an appointment should be made right away to have the eyes evaluated because treatment often depends on whether or not there is eye involvement. The earliest changes of scarring just underneath the lining of the eye (subepithelial fibrosis) are often asymptomatic and can only be detected by slit-lamp microscopic evaluation by an ophthalmologist. Such scarring interferes with the glands that produce the tears, and this results in dryness of the eye. Affected patients may need to use artificial tears frequently to reduce damage to the eye.No large-scale, multi-center studies have been done regarding the treatment of MMP. The usual treatment for MMP is certain drugs, used either singly or in various combinations. Corticosteroid drugs are often prescribed for affected individuals. Topical corticosteroids such as fluocinonide can relieve inflammation and itching in mild cases such as those that affect oral cavity only or the oral cavity and the skin. Other, more potent, gel preparations such as betamethasone dipropionate or clobetasol may also be used. When pemphigoid affects the gums, keeping the teeth clean by tooth-brushing will help reduce the sores, especially when topical corticosteroids are used at the same time.Some antibiotic drugs can affect the inflammatory process. One such drug is dapsone, a sulfa-type medication that may be used to treat mild cases of MMP. Special blood tests are needed before this drug is used, however. A combination of the antibiotic drug tetracycline and nicotinamide (vitamin B3) can also be helpful in some cases of MMP.Individuals with widespread or severe MMP may be treated with systemic corticosteroids such as prednisone and/or immunosuppressive drugs such as mycophenolate mofetil, cyclophosphamide or azathioprine. Individuals with eye involvement, severe or rapidly progressing MMP may be treated with prednisone combined with cyclophosphamide, mycophenolate mofetil, or azathioprine. Patients who are taking the above mentioned drugs must be carefully monitored by a dermatologist or physician familiar with their use because of potentially significant side effects. If these drugs are not helping, or if the pemphigoid seems to be getting worse, then other treatments that can be tried include rituximab and IV-IG (intravenous immunoglobulin G). Rituximab is an antibody that destroys the cells that produce antibodies. IV-IG is produced by purifying and concentrating antibody molecules from hundreds of blood donors. Both rituximab and IV-IG can have very serious side effects, so they usually are not given unless the patient has pemphigoid that is not getting better with other treatments.In rare cases, surgical procedures such as a tracheostomy may become necessary if scarring narrows the airway and breathing becomes difficult. A tracheostomy is a procedure in which a tube is inserted through a surgical opening in the windpipe (trachea) to assist breathing. A procedure to widen (dilate) a narrowed or obstructed esophagus may also be necessary if the esophagus is involved. Surgical removal (ablation) of ingrown eyelashes may be performed if the eyes are affected.Other treatment is symptomatic and supportive.
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Mucous Membrane Pemphigoid
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Overview of Mueller-Weisse Disease
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Summary Mueller-Weiss disease (MWD) is a rare foot condition characterized by a misshaped navicular bone and subsequent early-onset degenerative arthritis of the neighboring joints. It typically presents as longstanding subtle midfoot pain without a history of injury and progresses to severe, debilitating pain that worsens with weight-bearing activity. Most patients are females in their 40s to 60s but there are reported cases in males and patients as young as 18. MWD may be present in only one foot or both, and it is not unusual for one side to be more painful than the other. The exact cause of MWD is unknown, but it has traditionally been thought to be due to spontaneous bone cell death (osteonecrosis) of the navicular bone. The navicular bone is commonly described as “comma shaped” on X-ray and may be fragmented in later stages of disease. No gold standard treatment currently exists for MWD, but conservative and surgical options have been described in case reports and case series. Surgical treatment options should be considered if conservative therapy is unsuccessful after six months, and the decision about whether to operate should be based on patient discomfort rather than stage of deformity.IntroductionMueller-Weiss disease was originally described by Schmidt in 1925. W. Mueller, in 1927, was the first to suggest that this condition was caused by compression on the tarsus or an abnormality present at birth (congenital). In 1929, the radiologist, K. Weiss was the first to propose that the disease was due to decreased blood flow (ischemic process) based on radiographic findings. Thus, the condition was named for Mueller and Weiss for being the first to describe the cause of the disease. Mueller-Weiss disease is often misdiagnosed and therefore, not treated properly. Early recognition and treatment of this disease may lead to improved outcomes by prevention of extensive degenerative changes.
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Overview of Mueller-Weisse Disease. Summary Mueller-Weiss disease (MWD) is a rare foot condition characterized by a misshaped navicular bone and subsequent early-onset degenerative arthritis of the neighboring joints. It typically presents as longstanding subtle midfoot pain without a history of injury and progresses to severe, debilitating pain that worsens with weight-bearing activity. Most patients are females in their 40s to 60s but there are reported cases in males and patients as young as 18. MWD may be present in only one foot or both, and it is not unusual for one side to be more painful than the other. The exact cause of MWD is unknown, but it has traditionally been thought to be due to spontaneous bone cell death (osteonecrosis) of the navicular bone. The navicular bone is commonly described as “comma shaped” on X-ray and may be fragmented in later stages of disease. No gold standard treatment currently exists for MWD, but conservative and surgical options have been described in case reports and case series. Surgical treatment options should be considered if conservative therapy is unsuccessful after six months, and the decision about whether to operate should be based on patient discomfort rather than stage of deformity.IntroductionMueller-Weiss disease was originally described by Schmidt in 1925. W. Mueller, in 1927, was the first to suggest that this condition was caused by compression on the tarsus or an abnormality present at birth (congenital). In 1929, the radiologist, K. Weiss was the first to propose that the disease was due to decreased blood flow (ischemic process) based on radiographic findings. Thus, the condition was named for Mueller and Weiss for being the first to describe the cause of the disease. Mueller-Weiss disease is often misdiagnosed and therefore, not treated properly. Early recognition and treatment of this disease may lead to improved outcomes by prevention of extensive degenerative changes.
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Mueller-Weisse Disease
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Symptoms of Mueller-Weisse Disease
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Patients usually present with chronic, atraumatic mid and hindfoot pain without prior trauma that worsens with weight-bearing activity. The pain may be constant or intermittent, but typically worsens over time. Patients also complain of difficulty walking, foot swelling, joint stiffness and limitation of movement, and positional foot deformities including a paradoxical varus hindfoot deformity. In later stages of disease, it is common for MWD patients to have a positive heel raise test on physical exam, indicating posterior tibial tendon dysfunction. Patients may also present with arthritis and anterior knee pain.
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Symptoms of Mueller-Weisse Disease. Patients usually present with chronic, atraumatic mid and hindfoot pain without prior trauma that worsens with weight-bearing activity. The pain may be constant or intermittent, but typically worsens over time. Patients also complain of difficulty walking, foot swelling, joint stiffness and limitation of movement, and positional foot deformities including a paradoxical varus hindfoot deformity. In later stages of disease, it is common for MWD patients to have a positive heel raise test on physical exam, indicating posterior tibial tendon dysfunction. Patients may also present with arthritis and anterior knee pain.
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Mueller-Weisse Disease
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Causes of Mueller-Weisse Disease
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The exact cause of MWD is unknown. The most popular theory is that MWD is caused by decreased blood supply to the navicular bone of the foot. Decreased blood supply has many potential underlying causes including nutritional deficiency, smoking, alcohol, corticosteroid use, rheumatologic disorders, hematologic disorders and metabolic disorders. Other theories suggest a multifactorial cause that includes chronic pressure on the navicular bone, suboptimal ossification of the navicular bone during development, congenital causes, dysplasia and primary or secondary osteonecrosis of the navicular bone. Some medical experts think that osteonecrosis of the bone begins due to undiagnosed navicular stress fractures, eventually leading to MWD. MWD does not appear to run in families and there is no evidence of a genetic cause.
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Causes of Mueller-Weisse Disease. The exact cause of MWD is unknown. The most popular theory is that MWD is caused by decreased blood supply to the navicular bone of the foot. Decreased blood supply has many potential underlying causes including nutritional deficiency, smoking, alcohol, corticosteroid use, rheumatologic disorders, hematologic disorders and metabolic disorders. Other theories suggest a multifactorial cause that includes chronic pressure on the navicular bone, suboptimal ossification of the navicular bone during development, congenital causes, dysplasia and primary or secondary osteonecrosis of the navicular bone. Some medical experts think that osteonecrosis of the bone begins due to undiagnosed navicular stress fractures, eventually leading to MWD. MWD does not appear to run in families and there is no evidence of a genetic cause.
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Mueller-Weisse Disease
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Affects of Mueller-Weisse Disease
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The incidence and prevalence of MWD is currently unknown. It typically affects female adults more than male adults at a ratio of approximately 6:1. MWD most typically affects adults ages 40-60 but has been reported in a patient as young as 18 years old. Younger individuals tend to have unilateral deformities, while older individuals tend to have deformities of both feet.
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Affects of Mueller-Weisse Disease. The incidence and prevalence of MWD is currently unknown. It typically affects female adults more than male adults at a ratio of approximately 6:1. MWD most typically affects adults ages 40-60 but has been reported in a patient as young as 18 years old. Younger individuals tend to have unilateral deformities, while older individuals tend to have deformities of both feet.
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Related disorders of Mueller-Weisse Disease
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Kohler disease is similar to MWD in that it is also a disorder caused by decreased blood flow to the navicular bone of the foot and causes pain, limping and swelling of the foot. However, it is distinct because it occurs only in childhood, typically in children 3-7 years of age and resolves over time as the child grows. The navicular bone regains its density, size and structure, but symptoms rarely last up to two years. MWD has not been reported in children and will not resolve without intervention. (For more information on Kohler disease search for “Kohler” in the Rare Disease Database.)
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Related disorders of Mueller-Weisse Disease. Kohler disease is similar to MWD in that it is also a disorder caused by decreased blood flow to the navicular bone of the foot and causes pain, limping and swelling of the foot. However, it is distinct because it occurs only in childhood, typically in children 3-7 years of age and resolves over time as the child grows. The navicular bone regains its density, size and structure, but symptoms rarely last up to two years. MWD has not been reported in children and will not resolve without intervention. (For more information on Kohler disease search for “Kohler” in the Rare Disease Database.)
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Mueller-Weisse Disease
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Diagnosis of Mueller-Weisse Disease
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The diagnosis of MWD involves clinical findings, X-ray (radiologic) evidence and pathologic confirmation of the disease. Clinical findings are nonspecific and must be distinguished from those experienced due to trauma, metabolic bone disease, neoplastic bone tumor, secondary osteonecrosis and a previously undiagnosed stress fracture. The appearance of MWD on physical exam may be mistaken for acquired flat feet deformity. Suspicion of MWD can be confirmed with radiographic findings that show wedging and compression of the navicular bone, a comma shaped navicular bone and joint space narrowing.It is important to note that hindfoot varus is a sign that must be present to diagnose MWD, although its appearance may be subtle or masked due to the other foot deformities also present in MWD. A common misdiagnosis of MWD is acquired flat feet deformity (valgus pes planus); the varus position of the hindfoot in MWD, combined with the comma-shaped navicular bone, are the hallmark signs of this condition. MWD can be diagnosed with weight-bearing X-rays of both feet in multiple views. Radiologic evidence of MWD may include: a “comma shaped” or fragmented navicular bone, dorsolateral subluxation of the talus resulting in hindfoot varus, collapse of the medial arch and signs of degenerative arthritis in neighboring joints. MWD can be staged (Maceira’s classification) based on severity of morphological changes observed on the lateral weight-bearing view, from minimal changes (stage 1) to advanced disease characterized by extrusion of the navicular and direct articulation of the cuneiform and talus bones (stage 5). Clinical Testing and Work-UpBlood laboratory screening tests should be performed to rule out associated diagnoses that may be contributing to the clinical picture, such as evidence of rheumatological disease, neoplasm and disorders of metabolism. A positive bone scan, CT or MRI may demonstrate evidence of MWD prior to any changes that may be visible on physical examination or X-ray. MRI imaging is likely to show signs of osteonecrosis, effusion in adjacent joints and bone marrow edema (findings consistent with inflammation and bone death). There is no evidence of correlation between the patient’s reported pain and stage. Therefore, patient discomfort, rather than severity of deformity, is the basis for when to seek surgical treatment.Weight-bearing CT scans are considered the gold standard for planning surgical reconstruction because it allows a complex, dynamic deformity to be imaged in 3D while in a functional, load-bearing position. During surgery, excised bone fragments may be sent to pathology for analysis. Evidence of osteonecrosis is consistent with MWD, but the absence of such changes is also common.
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Diagnosis of Mueller-Weisse Disease. The diagnosis of MWD involves clinical findings, X-ray (radiologic) evidence and pathologic confirmation of the disease. Clinical findings are nonspecific and must be distinguished from those experienced due to trauma, metabolic bone disease, neoplastic bone tumor, secondary osteonecrosis and a previously undiagnosed stress fracture. The appearance of MWD on physical exam may be mistaken for acquired flat feet deformity. Suspicion of MWD can be confirmed with radiographic findings that show wedging and compression of the navicular bone, a comma shaped navicular bone and joint space narrowing.It is important to note that hindfoot varus is a sign that must be present to diagnose MWD, although its appearance may be subtle or masked due to the other foot deformities also present in MWD. A common misdiagnosis of MWD is acquired flat feet deformity (valgus pes planus); the varus position of the hindfoot in MWD, combined with the comma-shaped navicular bone, are the hallmark signs of this condition. MWD can be diagnosed with weight-bearing X-rays of both feet in multiple views. Radiologic evidence of MWD may include: a “comma shaped” or fragmented navicular bone, dorsolateral subluxation of the talus resulting in hindfoot varus, collapse of the medial arch and signs of degenerative arthritis in neighboring joints. MWD can be staged (Maceira’s classification) based on severity of morphological changes observed on the lateral weight-bearing view, from minimal changes (stage 1) to advanced disease characterized by extrusion of the navicular and direct articulation of the cuneiform and talus bones (stage 5). Clinical Testing and Work-UpBlood laboratory screening tests should be performed to rule out associated diagnoses that may be contributing to the clinical picture, such as evidence of rheumatological disease, neoplasm and disorders of metabolism. A positive bone scan, CT or MRI may demonstrate evidence of MWD prior to any changes that may be visible on physical examination or X-ray. MRI imaging is likely to show signs of osteonecrosis, effusion in adjacent joints and bone marrow edema (findings consistent with inflammation and bone death). There is no evidence of correlation between the patient’s reported pain and stage. Therefore, patient discomfort, rather than severity of deformity, is the basis for when to seek surgical treatment.Weight-bearing CT scans are considered the gold standard for planning surgical reconstruction because it allows a complex, dynamic deformity to be imaged in 3D while in a functional, load-bearing position. During surgery, excised bone fragments may be sent to pathology for analysis. Evidence of osteonecrosis is consistent with MWD, but the absence of such changes is also common.
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Mueller-Weisse Disease
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Therapies of Mueller-Weisse Disease
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TreatmentNo standard therapy or treatment exists for MWD. Current knowledge of managing this condition is based on results reported in individual case reports and small case series. Both conservative and surgical options have been described. Conservative measures include reducing activities that require weight bearing, non-steroidal anti-inflammatory medications, rest, elevation and ice. Custom orthotics that simultaneously support the medial arch and correct the hindfoot varus may provide some patients with significant pain relief while also correcting alignment of the knees and hips. Guided joint injections with lidocaine and steroids may provide moderate pain relief to patients for weeks to months. Identifying MWD in its early stages is helpful because progression of the disease may be slowed through both conservative and surgical measures that aim to reduce pain, retain joint integrity and preserve ideal lower extremity biomechanics. Correcting the alignment and biomechanics of the foot is essential for preventing undue wear and tear on more proximal joints, such as the knees and hips. The definitive treatment to halt the progression of MWD is surgery. Since there is no established correlation between pain and stage of disease, and no standard surgical intervention exists, the decision about whether to operate is based primarily on the pain and disruption to daily activities as reported by the patient. Numerous surgical procedures have been used. Almost all reported interventions include debridement of loose bone fragments, internal fixation of the navicular bone and various types of joint fusions (talonavicular, talonavicular-cuneiform, triple and association of triple with naviculo-cuneiform fusion). The exact surgical procedure performed will be specific to the radiographic findings in each patient. Joint fusions in the midfoot and hindfoot have many disadvantages including loss of motion impacting alignment and adjacent joint function. However, fusions may be necessary to achieve pain relief and stability if MWD is in the advanced stage. If MWD is diagnosed prior to significant joint destruction, joint-preserving surgery may be an option. There have been numerous case reports of restoration of the hindfoot varus through calcaneal osteotomies resulting in significant pain relief and preservation of the talonavicular joint function. Orthopedic foot and ankle specialist surgeons, radiologists, physical medicine and rehabilitation specialists (“physiotherapists”) and physical therapists all play an important role in the proper diagnosis and management of MWD.
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Therapies of Mueller-Weisse Disease. TreatmentNo standard therapy or treatment exists for MWD. Current knowledge of managing this condition is based on results reported in individual case reports and small case series. Both conservative and surgical options have been described. Conservative measures include reducing activities that require weight bearing, non-steroidal anti-inflammatory medications, rest, elevation and ice. Custom orthotics that simultaneously support the medial arch and correct the hindfoot varus may provide some patients with significant pain relief while also correcting alignment of the knees and hips. Guided joint injections with lidocaine and steroids may provide moderate pain relief to patients for weeks to months. Identifying MWD in its early stages is helpful because progression of the disease may be slowed through both conservative and surgical measures that aim to reduce pain, retain joint integrity and preserve ideal lower extremity biomechanics. Correcting the alignment and biomechanics of the foot is essential for preventing undue wear and tear on more proximal joints, such as the knees and hips. The definitive treatment to halt the progression of MWD is surgery. Since there is no established correlation between pain and stage of disease, and no standard surgical intervention exists, the decision about whether to operate is based primarily on the pain and disruption to daily activities as reported by the patient. Numerous surgical procedures have been used. Almost all reported interventions include debridement of loose bone fragments, internal fixation of the navicular bone and various types of joint fusions (talonavicular, talonavicular-cuneiform, triple and association of triple with naviculo-cuneiform fusion). The exact surgical procedure performed will be specific to the radiographic findings in each patient. Joint fusions in the midfoot and hindfoot have many disadvantages including loss of motion impacting alignment and adjacent joint function. However, fusions may be necessary to achieve pain relief and stability if MWD is in the advanced stage. If MWD is diagnosed prior to significant joint destruction, joint-preserving surgery may be an option. There have been numerous case reports of restoration of the hindfoot varus through calcaneal osteotomies resulting in significant pain relief and preservation of the talonavicular joint function. Orthopedic foot and ankle specialist surgeons, radiologists, physical medicine and rehabilitation specialists (“physiotherapists”) and physical therapists all play an important role in the proper diagnosis and management of MWD.
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Mueller-Weisse Disease
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Overview of Muenke Syndrome
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Summary
Muenke syndrome is a genetic condition characterized by an early closure of certain bones of the skull (craniosynostosis). The main signs and symptoms of Muenke syndrome include craniosynostosis and other bone defects on x-rays, different head shapes and distinct facial features. Other characteristics include hearing loss, developmental delay, intellectual disability, behavioral issues, epilepsy, eyes drifting inward or outward (strabismus), repetitive, uncontrolled eye movements (nystagmus), vision loss and interrupted breathing during sleep (obstructive sleep apnea). Craniosynostosis is typically diagnosed in newborns.Muenke syndrome is caused by changes (pathogenic variants) in the FGFR3 gene.The best outcomes are observed if the affected children receive early surgical procedures as well as early and continued medical management of the other signs and symptoms of the disorder. Introduction
Dr. Maximilian Muenke, a medical geneticist, first identified this disorder in 1997 making this diagnosis distinct from other previously defined craniosynostosis syndromes. Muenke syndrome may also be known as FGFR3-related craniosynostosis. Notably, Muenke syndrome is estimated to account for 25%-30% of all genetic causes of craniosynostosis.
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Overview of Muenke Syndrome. Summary
Muenke syndrome is a genetic condition characterized by an early closure of certain bones of the skull (craniosynostosis). The main signs and symptoms of Muenke syndrome include craniosynostosis and other bone defects on x-rays, different head shapes and distinct facial features. Other characteristics include hearing loss, developmental delay, intellectual disability, behavioral issues, epilepsy, eyes drifting inward or outward (strabismus), repetitive, uncontrolled eye movements (nystagmus), vision loss and interrupted breathing during sleep (obstructive sleep apnea). Craniosynostosis is typically diagnosed in newborns.Muenke syndrome is caused by changes (pathogenic variants) in the FGFR3 gene.The best outcomes are observed if the affected children receive early surgical procedures as well as early and continued medical management of the other signs and symptoms of the disorder. Introduction
Dr. Maximilian Muenke, a medical geneticist, first identified this disorder in 1997 making this diagnosis distinct from other previously defined craniosynostosis syndromes. Muenke syndrome may also be known as FGFR3-related craniosynostosis. Notably, Muenke syndrome is estimated to account for 25%-30% of all genetic causes of craniosynostosis.
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Muenke Syndrome
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Symptoms of Muenke Syndrome
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The signs and symptoms of Muenke syndrome vary among affected people, and a few people with Muenke syndrome do not have any of the characteristic features of the disorder. For example, some patients may not have craniosynostosis. The symptoms and signs may include:• Craniosynostosis, especially coronal craniosynostosis (present in about 85% of patients) which is the early horizontal fusion of the skull between the ears
• Hearing loss (70% of patients)
• Recurrent ear infections, which if not treated effectively can lead to hearing loss
• Large head (macrocephaly)
• Developmental delay (60% of patients), most commonly speech delay
• Intellectual disability (40% of patients)
• Behavioral issues which may include hyperactivity, attention deficit and hyperactivity disorder (ADHD) or autism
• Crossed eyes (strabismus)
• Differences in the structure or shape of the hands and toes (50% of patients), but these typically do not cause medical problems or difficulty in daily life
• Seizures, which are rare, but can occur at any time
• Distinctive face, such as down-slanting eyes, eyes that are spaced widely (hypertelorism), forehead that is more rounded (frontal bossing), an opening in the lip or roof of the mouth (cleft lip or palate), flattening of the middle part of face (midface hypoplasia) and a small jaw (retrognathia)
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Symptoms of Muenke Syndrome. The signs and symptoms of Muenke syndrome vary among affected people, and a few people with Muenke syndrome do not have any of the characteristic features of the disorder. For example, some patients may not have craniosynostosis. The symptoms and signs may include:• Craniosynostosis, especially coronal craniosynostosis (present in about 85% of patients) which is the early horizontal fusion of the skull between the ears
• Hearing loss (70% of patients)
• Recurrent ear infections, which if not treated effectively can lead to hearing loss
• Large head (macrocephaly)
• Developmental delay (60% of patients), most commonly speech delay
• Intellectual disability (40% of patients)
• Behavioral issues which may include hyperactivity, attention deficit and hyperactivity disorder (ADHD) or autism
• Crossed eyes (strabismus)
• Differences in the structure or shape of the hands and toes (50% of patients), but these typically do not cause medical problems or difficulty in daily life
• Seizures, which are rare, but can occur at any time
• Distinctive face, such as down-slanting eyes, eyes that are spaced widely (hypertelorism), forehead that is more rounded (frontal bossing), an opening in the lip or roof of the mouth (cleft lip or palate), flattening of the middle part of face (midface hypoplasia) and a small jaw (retrognathia)
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Muenke Syndrome
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Causes of Muenke Syndrome
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Muenke syndrome is caused by a specific disease causing (pathogenic) change (variant) in the fibroblast growth factor receptor-3 (FGFR3) gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. When a pathogenic variant in a gene occurs, it causes the protein to stop working or to not work properly. Depending on the function of the protein, it can affect different parts of the body. More than half (>50%) of the people affected with Muenke syndrome inherit a pathogenic variant from a parent. When not inherited from either parent, the genetic change in FGFR3 is new in the patient (de novo).The name of the specific genetic change that causes Muenke syndrome is known as p.Pro250Arg. It may also be written as p.P250R. This means that at position 250 in the FGFR3 gene, a building block (amino acid) of the protein was changed to a different amino acid and this causes the gene to stop working properly. The FGFR3 gene provides instructions for making a protein called fibroblast growth factor receptor 3. This protein is needed for the normal development of many parts of the body, including the brain and bone. The specific genetic change that causes Muenke syndrome makes the process of normal development occur too fast and leads to the signs and symptoms of the disease. Different changes in the FGFR3 gene are associated with different syndromes.Muenke syndrome is an autosomal dominant disorder. This means that a change (pathogenic variant) in only one of the two copies of the FGFR3 gene is necessary to cause the disease. The genetic change can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the pathogenic variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.Muenke syndrome is reported to have variable expressivity and reduced penetrance. Variable expressivity means that there is a range of symptoms that can occur in people affected with the same genetic condition. Reduced penetrance is when not all people with a disease-causing genetic change will have symptoms. It is possible for someone to have Muenke syndrome and not have medical problems but have children with Muenke syndrome who have many medical problems.
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Causes of Muenke Syndrome. Muenke syndrome is caused by a specific disease causing (pathogenic) change (variant) in the fibroblast growth factor receptor-3 (FGFR3) gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. When a pathogenic variant in a gene occurs, it causes the protein to stop working or to not work properly. Depending on the function of the protein, it can affect different parts of the body. More than half (>50%) of the people affected with Muenke syndrome inherit a pathogenic variant from a parent. When not inherited from either parent, the genetic change in FGFR3 is new in the patient (de novo).The name of the specific genetic change that causes Muenke syndrome is known as p.Pro250Arg. It may also be written as p.P250R. This means that at position 250 in the FGFR3 gene, a building block (amino acid) of the protein was changed to a different amino acid and this causes the gene to stop working properly. The FGFR3 gene provides instructions for making a protein called fibroblast growth factor receptor 3. This protein is needed for the normal development of many parts of the body, including the brain and bone. The specific genetic change that causes Muenke syndrome makes the process of normal development occur too fast and leads to the signs and symptoms of the disease. Different changes in the FGFR3 gene are associated with different syndromes.Muenke syndrome is an autosomal dominant disorder. This means that a change (pathogenic variant) in only one of the two copies of the FGFR3 gene is necessary to cause the disease. The genetic change can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the pathogenic variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.Muenke syndrome is reported to have variable expressivity and reduced penetrance. Variable expressivity means that there is a range of symptoms that can occur in people affected with the same genetic condition. Reduced penetrance is when not all people with a disease-causing genetic change will have symptoms. It is possible for someone to have Muenke syndrome and not have medical problems but have children with Muenke syndrome who have many medical problems.
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Muenke Syndrome
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Affects of Muenke Syndrome
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Muenke syndrome occurs in approximately one in 30,000 livebirths. Muenke syndrome occurs equally in males and females and does not occur more frequently in any specific ethnic group. About one third of individuals with Muenke syndrome are the first to be diagnosed in their families and two-thirds of individuals have a family history of the diagnosis.
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Affects of Muenke Syndrome. Muenke syndrome occurs in approximately one in 30,000 livebirths. Muenke syndrome occurs equally in males and females and does not occur more frequently in any specific ethnic group. About one third of individuals with Muenke syndrome are the first to be diagnosed in their families and two-thirds of individuals have a family history of the diagnosis.
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Muenke Syndrome
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Related disorders of Muenke Syndrome
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There are other genetic syndromes that can cause craniosynostosis, but people with these conditions have different medical problems than a person with Muenke syndrome. These syndromes include Pfeiffer syndrome, Apert syndrome, Crouzon syndrome and Saethre-Chotzen syndrome.Note that different pathogenic variants in the FGFR3 gene can cause other conditions, such as achondroplasia, Crouzon syndrome with acanthosis nigricans, SADDAN, thanatophoric dysplasia, hypochondroplasia, lacrimo-auriculo-dento-digital syndrome and others.
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Related disorders of Muenke Syndrome. There are other genetic syndromes that can cause craniosynostosis, but people with these conditions have different medical problems than a person with Muenke syndrome. These syndromes include Pfeiffer syndrome, Apert syndrome, Crouzon syndrome and Saethre-Chotzen syndrome.Note that different pathogenic variants in the FGFR3 gene can cause other conditions, such as achondroplasia, Crouzon syndrome with acanthosis nigricans, SADDAN, thanatophoric dysplasia, hypochondroplasia, lacrimo-auriculo-dento-digital syndrome and others.
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Muenke Syndrome
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Diagnosis of Muenke Syndrome
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Doctors may suspect of Muenke syndrome in people with:• An abnormal shape of the skull, especially a “tower-shaped” skull, known as turribrachycephaly or cloverleaf skull
• Craniosynostosis with sensorineural hearing loss
• A head computerized tomography (CT) scan demonstrating unilateral or bilateral coronal craniosynostosis or synostosis of other skull sutures
• Fusion of the bones in the wrist (carpal bones) or the bones of the ankles (tarsal bones)
• A short and broad middle finger of the hands and feet
• A cone-shaped end of the long bones of the body (epiphyseal coning)The diagnosis of Muenke syndrome is established by the identification of the FGFR3 pathogenic variant c.749C>G (p.Pro250Arg) by molecular genetic testing.Clinical Testing and Work-Up
Genetic testing for the p.Pro250Arg pathogenic variant in FGFR3 is usually done as part of single gene testing or as part of a multigene panel. This is because the signs and symptoms of Muenke syndrome overlap with those of other craniosynostosis syndromes. The recommended testing depends on what symptoms the person has.
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Diagnosis of Muenke Syndrome. Doctors may suspect of Muenke syndrome in people with:• An abnormal shape of the skull, especially a “tower-shaped” skull, known as turribrachycephaly or cloverleaf skull
• Craniosynostosis with sensorineural hearing loss
• A head computerized tomography (CT) scan demonstrating unilateral or bilateral coronal craniosynostosis or synostosis of other skull sutures
• Fusion of the bones in the wrist (carpal bones) or the bones of the ankles (tarsal bones)
• A short and broad middle finger of the hands and feet
• A cone-shaped end of the long bones of the body (epiphyseal coning)The diagnosis of Muenke syndrome is established by the identification of the FGFR3 pathogenic variant c.749C>G (p.Pro250Arg) by molecular genetic testing.Clinical Testing and Work-Up
Genetic testing for the p.Pro250Arg pathogenic variant in FGFR3 is usually done as part of single gene testing or as part of a multigene panel. This is because the signs and symptoms of Muenke syndrome overlap with those of other craniosynostosis syndromes. The recommended testing depends on what symptoms the person has.
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Muenke Syndrome
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Therapies of Muenke Syndrome
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Management focuses on the treatment of symptoms. This is best achieved in a pediatric craniofacial clinic, which typically includes a craniofacial surgeon and neurosurgeon, clinical geneticist, eye doctor (ophthalmologist), ear, nose and throat doctor (otolaryngologist), pediatrician, radiologist, psychologist, dentist, hearing specialist (audiologist), speech therapist and social worker.Cranyosisnostosis can be treated with surgery. Depending on severity, the first surgery for craniosynostosis repair (fronto-orbital advancement and cranial vault remodeling) is typically performed between ages three and six months. An alternative approach is endoscopic strip craniectomy, which is a less invasive procedure and is typically performed prior to age three months. Postoperative increased intracranial pressure and the need for additional surgeries (including secondary or tertiary extracranial contouring) may occur.
Standard interventions for hearing loss including hearing aids are usually needed. Affected people may have recurrent episodes of ear infections (otitis media) that can be treated with myringotomy tube placement. Early speech therapy and intervention programs (including physical, speech and occupational therapy) for those with developmental delay, intellectual impairment and behavioral issues has been shown to be helpful. Parents should work with their local early intervention centers and school systems on individualized educational plans (IEPs) to ensure appropriate accommodations. Social work and parent support systems are particularly important.Strabismus may require surgical correction. Since surgical correction of craniosynostosis is the priority, the strabismus repair can be delayed in the first two years of life. However, early repair can help the brain to fuse two independent images, one from each eye, into one (binocularity) and it should be considered as soon as feasible. In people with bulging eyes (proptosis), lubrication is needed to avoid damage to the corneas (exposure keratopathy).In addition to a neurologic exam and EEG to assess for the possibility of seizure, a detailed eye (ophthalmologic) assessment is important. Surveillance by multiple specialists is required to monitor for the multiple health issues that may arise in children with Muenke syndrome.Recommendations may include:• Hearing evaluations annually
• Eye evaluations at least annually or more frequently, if indicated
• Periodic developmental re-evaluations to monitor development in children, including a behavioral/developmental assessment
• Neurologic evaluations for seizures and any new movement disordersGenetic counseling is advised for families of a child with Muenke Syndrome. The absence of symptoms does not mean that a person is not affected with this condition. More than half of the people diagnosed with Muenke syndrome inherited their FGFR3 pathogenic variant from a parent. This could have implications for the risk to siblings, future pregnancies and other family members. A genetic counselor can help facilitate testing for family members and provide access to additional resources.
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Therapies of Muenke Syndrome. Management focuses on the treatment of symptoms. This is best achieved in a pediatric craniofacial clinic, which typically includes a craniofacial surgeon and neurosurgeon, clinical geneticist, eye doctor (ophthalmologist), ear, nose and throat doctor (otolaryngologist), pediatrician, radiologist, psychologist, dentist, hearing specialist (audiologist), speech therapist and social worker.Cranyosisnostosis can be treated with surgery. Depending on severity, the first surgery for craniosynostosis repair (fronto-orbital advancement and cranial vault remodeling) is typically performed between ages three and six months. An alternative approach is endoscopic strip craniectomy, which is a less invasive procedure and is typically performed prior to age three months. Postoperative increased intracranial pressure and the need for additional surgeries (including secondary or tertiary extracranial contouring) may occur.
Standard interventions for hearing loss including hearing aids are usually needed. Affected people may have recurrent episodes of ear infections (otitis media) that can be treated with myringotomy tube placement. Early speech therapy and intervention programs (including physical, speech and occupational therapy) for those with developmental delay, intellectual impairment and behavioral issues has been shown to be helpful. Parents should work with their local early intervention centers and school systems on individualized educational plans (IEPs) to ensure appropriate accommodations. Social work and parent support systems are particularly important.Strabismus may require surgical correction. Since surgical correction of craniosynostosis is the priority, the strabismus repair can be delayed in the first two years of life. However, early repair can help the brain to fuse two independent images, one from each eye, into one (binocularity) and it should be considered as soon as feasible. In people with bulging eyes (proptosis), lubrication is needed to avoid damage to the corneas (exposure keratopathy).In addition to a neurologic exam and EEG to assess for the possibility of seizure, a detailed eye (ophthalmologic) assessment is important. Surveillance by multiple specialists is required to monitor for the multiple health issues that may arise in children with Muenke syndrome.Recommendations may include:• Hearing evaluations annually
• Eye evaluations at least annually or more frequently, if indicated
• Periodic developmental re-evaluations to monitor development in children, including a behavioral/developmental assessment
• Neurologic evaluations for seizures and any new movement disordersGenetic counseling is advised for families of a child with Muenke Syndrome. The absence of symptoms does not mean that a person is not affected with this condition. More than half of the people diagnosed with Muenke syndrome inherited their FGFR3 pathogenic variant from a parent. This could have implications for the risk to siblings, future pregnancies and other family members. A genetic counselor can help facilitate testing for family members and provide access to additional resources.
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Muenke Syndrome
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Overview of Mulibrey Nanism
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Mulibrey nanism (MN) is an extremely rare genetic disorder characterized by severe progressive growth delays and abnormalities in multiple organs. Mulibrey is an acronym for MUscles, LIver, BRain, and EYes relating to the original clinical description of the disease. Nanism refers to the short stature (dwarfism) often observed in patients with this disorder. The growth delay usually begins before birth. Non-inflammatory constrictive pericarditis involving fibrotic overgrowth of the sac surrounding the heart is a common feature with a major impact on prognosis. Overgrowth of heart muscle walls (hypertrophy) may add to circulatory problems (congestive heart failure) in these patients as they get older. Short height and facial abnormalities are commonly present. Radiologic findings include slender long bones with thick cortex, narrow medullary channel and fibrous dysplasia, J-shaped sella turcica and a small thoracic cage. The liver is usually enlarged. Additionally, fibrous tissue may build up on the interior of the lungs (pulmonary fibrosis) causing difficulty breathing. Weak muscle tone (hypotonia) is another symptom. The clinical presentation is very variable. Early recognition and management of feeding, respiratory or cardiac problems are of major importance. Treatment involves addressing organ related problems including the heart through medications or surgery. In addition, hormone replacement therapy is offered, and abdominal ultrasound screening is warranted in all patients to detect Wilms’ tumor and to detect ovarian tumors in females. Mulibrey nanism is caused by mutations in the TRIM37 gene and is inherited in an autosomal recessive pattern (gene inherited from both parents for disease to occur).
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Overview of Mulibrey Nanism. Mulibrey nanism (MN) is an extremely rare genetic disorder characterized by severe progressive growth delays and abnormalities in multiple organs. Mulibrey is an acronym for MUscles, LIver, BRain, and EYes relating to the original clinical description of the disease. Nanism refers to the short stature (dwarfism) often observed in patients with this disorder. The growth delay usually begins before birth. Non-inflammatory constrictive pericarditis involving fibrotic overgrowth of the sac surrounding the heart is a common feature with a major impact on prognosis. Overgrowth of heart muscle walls (hypertrophy) may add to circulatory problems (congestive heart failure) in these patients as they get older. Short height and facial abnormalities are commonly present. Radiologic findings include slender long bones with thick cortex, narrow medullary channel and fibrous dysplasia, J-shaped sella turcica and a small thoracic cage. The liver is usually enlarged. Additionally, fibrous tissue may build up on the interior of the lungs (pulmonary fibrosis) causing difficulty breathing. Weak muscle tone (hypotonia) is another symptom. The clinical presentation is very variable. Early recognition and management of feeding, respiratory or cardiac problems are of major importance. Treatment involves addressing organ related problems including the heart through medications or surgery. In addition, hormone replacement therapy is offered, and abdominal ultrasound screening is warranted in all patients to detect Wilms’ tumor and to detect ovarian tumors in females. Mulibrey nanism is caused by mutations in the TRIM37 gene and is inherited in an autosomal recessive pattern (gene inherited from both parents for disease to occur).
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Mulibrey Nanism
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Symptoms of Mulibrey Nanism
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Mulibrey nanism is characterized by progressive growth failure that begins before birth. Infants often have characteristic abnormalities of the head and face including a triangularly shaped face. Yellow discoloration deep within the eyes and other ocular abnormalities may be present but vision is usually normal. Most patients have an enlarged skull (macrocephaly) and a J-shaped sella turcica, which is a depression in the sphenoid bone at the base of the skull. Because this is where the pituitary gland is located, individuals with MN often have underdevelopment of various endocrine glands that leads to hormone deficiencies. The voice of patients with MN is characteristically high pitched.Patients may also have symptoms related to overgrowth of the fibrous sac surrounding the heart (non-inflammatory constrictive pericarditis). When constrictive pericarditis presents early (affecting a minority of patients), infants may have a mildly bluish discoloration of the skin (cyanosis). Congestive heart failure of the right heart can also cause abnormal fluid accumulation in the abdomen (ascites) and swelling of the arms and/or legs (peripheral edema). Circulatory problems can progress and lead to failure-to-thrive. Prominent veins in the neck indicate an elevated pressure in the systemic veins that is commonly related to a lack of space in the sac surrounding the heart (pericardial constriction) limiting the filling phase of the heart cycle, and thus leading to fluid accumulation (congestion) in the body. Fibrous tissue in the walls of the lungs (pulmonary fibrosis) decreases the total volume capacity of the lungs.Enlargement of the liver (hepatomegaly) is another common symptom. In addition, patients often struggle to regulate the breakdown (metabolism) of sugars and fats, potentially resulting in type 2 diabetes, fatty liver and high blood pressure (hypertension). Structural abnormalities of the kidney and urinary tract such as non-cancerous pockets of membranous tissue (cysts) are also observed. However, most patients have normal kidney function. Another persistent kidney complication is a mildly decreased ability to filter the blood (glomerular filtration). Wilms’ tumor, the most common type of cancer originating in the kidney in children, is relatively common (about 8%) and screening is mandatory.Delayed puberty sometimes occurs accompanied by infrequent or very light menstrual periods. Females have an increased risk for premature ovarian failure and tumors. Both male and female patients show failure of sexual maturation and inability of the sex organs to function properly (hypogonadism) leading to infertility.Some individuals with MN may have additional physical abnormalities such as an unusually thin shinbone (fibrous tibia dysplasia). Some children suffer from airway obstruction related to infections or exercise but asthma in adulthood is rare. Large cerebral ventricles in the brain and delayed motor development are uncommon findings. Most affected individuals have normal intelligence.
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Symptoms of Mulibrey Nanism. Mulibrey nanism is characterized by progressive growth failure that begins before birth. Infants often have characteristic abnormalities of the head and face including a triangularly shaped face. Yellow discoloration deep within the eyes and other ocular abnormalities may be present but vision is usually normal. Most patients have an enlarged skull (macrocephaly) and a J-shaped sella turcica, which is a depression in the sphenoid bone at the base of the skull. Because this is where the pituitary gland is located, individuals with MN often have underdevelopment of various endocrine glands that leads to hormone deficiencies. The voice of patients with MN is characteristically high pitched.Patients may also have symptoms related to overgrowth of the fibrous sac surrounding the heart (non-inflammatory constrictive pericarditis). When constrictive pericarditis presents early (affecting a minority of patients), infants may have a mildly bluish discoloration of the skin (cyanosis). Congestive heart failure of the right heart can also cause abnormal fluid accumulation in the abdomen (ascites) and swelling of the arms and/or legs (peripheral edema). Circulatory problems can progress and lead to failure-to-thrive. Prominent veins in the neck indicate an elevated pressure in the systemic veins that is commonly related to a lack of space in the sac surrounding the heart (pericardial constriction) limiting the filling phase of the heart cycle, and thus leading to fluid accumulation (congestion) in the body. Fibrous tissue in the walls of the lungs (pulmonary fibrosis) decreases the total volume capacity of the lungs.Enlargement of the liver (hepatomegaly) is another common symptom. In addition, patients often struggle to regulate the breakdown (metabolism) of sugars and fats, potentially resulting in type 2 diabetes, fatty liver and high blood pressure (hypertension). Structural abnormalities of the kidney and urinary tract such as non-cancerous pockets of membranous tissue (cysts) are also observed. However, most patients have normal kidney function. Another persistent kidney complication is a mildly decreased ability to filter the blood (glomerular filtration). Wilms’ tumor, the most common type of cancer originating in the kidney in children, is relatively common (about 8%) and screening is mandatory.Delayed puberty sometimes occurs accompanied by infrequent or very light menstrual periods. Females have an increased risk for premature ovarian failure and tumors. Both male and female patients show failure of sexual maturation and inability of the sex organs to function properly (hypogonadism) leading to infertility.Some individuals with MN may have additional physical abnormalities such as an unusually thin shinbone (fibrous tibia dysplasia). Some children suffer from airway obstruction related to infections or exercise but asthma in adulthood is rare. Large cerebral ventricles in the brain and delayed motor development are uncommon findings. Most affected individuals have normal intelligence.
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Mulibrey Nanism
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Causes of Mulibrey Nanism
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Mulibrey nanism is caused by harmful changes (pathogenic variants) in the TRIM37 gene located on chromosome 17 (17q22-q23). This gene codes for a protein present in the peroxisome, the part of cell responsible for metabolism. Loss of function of the TRIM37 protein results in a defect in the proper separation of genetic material during cell division. Normal loss of TRIM37 protein activity leads to cell death to prevent mutations in the DNA from multiplying. However, if cell death does not occur, cells with these mutations have a higher likelihood of becoming cancerous. In addition, pathogenetic variants in the TRIM37 gene can impact the number and function of immune cells, leading to an increased risk of severe infections.Mulibrey nanism is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of Mulibrey Nanism. Mulibrey nanism is caused by harmful changes (pathogenic variants) in the TRIM37 gene located on chromosome 17 (17q22-q23). This gene codes for a protein present in the peroxisome, the part of cell responsible for metabolism. Loss of function of the TRIM37 protein results in a defect in the proper separation of genetic material during cell division. Normal loss of TRIM37 protein activity leads to cell death to prevent mutations in the DNA from multiplying. However, if cell death does not occur, cells with these mutations have a higher likelihood of becoming cancerous. In addition, pathogenetic variants in the TRIM37 gene can impact the number and function of immune cells, leading to an increased risk of severe infections.Mulibrey nanism is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Affects of Mulibrey Nanism
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Mulibrey nanism is an extremely rare disorder that affects males and females in equal numbers. Approximately 110 patients have been reported worldwide with this condition. Most of the reported cases are from Finland, but this condition has also been diagnosed in North America, South America, Central America, Spain, France and Egypt.
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Affects of Mulibrey Nanism. Mulibrey nanism is an extremely rare disorder that affects males and females in equal numbers. Approximately 110 patients have been reported worldwide with this condition. Most of the reported cases are from Finland, but this condition has also been diagnosed in North America, South America, Central America, Spain, France and Egypt.
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Related disorders of Mulibrey Nanism
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There are other conditions with symptoms similar to mulibrey nanism. Conditions that might be included in a differential diagnosis include Russell-Silver syndrome and Robinow syndrome. For more information about these disorders, search for them in the Rare Disease Database.
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Related disorders of Mulibrey Nanism. There are other conditions with symptoms similar to mulibrey nanism. Conditions that might be included in a differential diagnosis include Russell-Silver syndrome and Robinow syndrome. For more information about these disorders, search for them in the Rare Disease Database.
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Diagnosis of Mulibrey Nanism
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Mulibrey nanism may be diagnosed at birth by a thorough clinical evaluation, characteristic physical findings and specialized tests. The disease can be misdiagnosed as other similar syndromes such as Silver-Russell syndrome, especially in geographic areas where mulibrey nanism is less common. Molecular genetic testing for the TRIM37 gene is available to confirm the diagnosis. It is especially important to consider the possibility of genetic rearrangements when testing for TRIM37 gene variants due to frequent repeated sequences that are more prone to mutations. Early diagnosis of this disorder is important due to the risk of respiratory failure associated with congestive heart failure which can lead to premature death.
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Diagnosis of Mulibrey Nanism. Mulibrey nanism may be diagnosed at birth by a thorough clinical evaluation, characteristic physical findings and specialized tests. The disease can be misdiagnosed as other similar syndromes such as Silver-Russell syndrome, especially in geographic areas where mulibrey nanism is less common. Molecular genetic testing for the TRIM37 gene is available to confirm the diagnosis. It is especially important to consider the possibility of genetic rearrangements when testing for TRIM37 gene variants due to frequent repeated sequences that are more prone to mutations. Early diagnosis of this disorder is important due to the risk of respiratory failure associated with congestive heart failure which can lead to premature death.
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Therapies of Mulibrey Nanism
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Constrictive pericarditis may be treated with surgery (pericardiectomy) in symptomatic patients. Constriction-restriction assessments can be useful in determining the underlying cause of congestive heart failure and when to intervene. Diuretics may be prescribed for progressive heart failure. Difficulty breathing due to infection and/or exercise associated with abnormalities of the lungs can be treated with inhaled therapies and asthma medication. Hormone replacement therapy should be offered to children with growth hormone deficiency, delayed puberty, infrequent or very light menstrual periods, hypothyroidism, hypoadrenocorticism and abnormal ovaries or testes. Females with mulibrey nanism should be monitored closely for ovarian tumors, and all patients should be monitored for Wilms’ tumor. Patients who develop cancer can be treated with chemotherapy, surgery and multi-specialty care.
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Therapies of Mulibrey Nanism. Constrictive pericarditis may be treated with surgery (pericardiectomy) in symptomatic patients. Constriction-restriction assessments can be useful in determining the underlying cause of congestive heart failure and when to intervene. Diuretics may be prescribed for progressive heart failure. Difficulty breathing due to infection and/or exercise associated with abnormalities of the lungs can be treated with inhaled therapies and asthma medication. Hormone replacement therapy should be offered to children with growth hormone deficiency, delayed puberty, infrequent or very light menstrual periods, hypothyroidism, hypoadrenocorticism and abnormal ovaries or testes. Females with mulibrey nanism should be monitored closely for ovarian tumors, and all patients should be monitored for Wilms’ tumor. Patients who develop cancer can be treated with chemotherapy, surgery and multi-specialty care.
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Mulibrey Nanism
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Overview of Multifocal Motor Neuropathy
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Multifocal motor neuropathy is a rare disorder characterized by slowly progressive muscle weakness, primarily of the arms and legs. The disorder is considered to be immune-mediated, which means there is inflammation resulting from abnormal functioning of the immune system and the presence of specific autoantibodies that target a specific protein in the body. Other symptoms including muscles cramps and wasting (atrophy) of muscles can also occur. The term multifocal means arising from two or more spots. The term motor refers to the motor nerves, which are those that carry nerve impulses from the brain to the muscles. The exact, underlying cause of this disorder is not fully understood. The disorder is acquired at some point during a person’s life; a person is not born with the disorder. Multifocal motor neuropathy usually responds to treatment with intravenous immunoglobulin.
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Overview of Multifocal Motor Neuropathy. Multifocal motor neuropathy is a rare disorder characterized by slowly progressive muscle weakness, primarily of the arms and legs. The disorder is considered to be immune-mediated, which means there is inflammation resulting from abnormal functioning of the immune system and the presence of specific autoantibodies that target a specific protein in the body. Other symptoms including muscles cramps and wasting (atrophy) of muscles can also occur. The term multifocal means arising from two or more spots. The term motor refers to the motor nerves, which are those that carry nerve impulses from the brain to the muscles. The exact, underlying cause of this disorder is not fully understood. The disorder is acquired at some point during a person’s life; a person is not born with the disorder. Multifocal motor neuropathy usually responds to treatment with intravenous immunoglobulin.
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Multifocal Motor Neuropathy
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Symptoms of Multifocal Motor Neuropathy
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Multifocal motor neuropathy is a progressive disorder, this means that the signs and symptoms tend to worsen slowly over time. The main symptom is progressive muscle weakness of the arms and legs. Unlike other neurological disorders affecting the arms and legs, there usually is not any sensory deficits. This means that feelings of tingling or numbness or pain are not associated with the disorder. Muscle weakness often begins in the hands, causing hand weakness and affected individuals may drop objects frequently or have difficulty performing tasks that require fine motor skills such as turning a key in a lock. Fine motor skills are those that require small movements involving the hands and wrists. Some individuals have trouble extending or bending their wrist upward (wrist drop). Reduced grip strength of the hands and reduced dexterity of the hands is seen. Sometimes, muscle weakness starts in the legs. There may be reduced mobility of the toes and foot drop may be early signs. Foot drop occurs when weakness of the muscles involving in lifting the food cause the foot to drop or drag when attempting to walk. As muscle weakness progresses, severe fatigue in the affected muscles may be seen and the disorder will cause functional disability. Affected individuals may have limited endurance. The muscles on one side of the body that are affected may be different from the muscle affected on the other side of the body (asymmetrical muscle weakness). Additional symptoms associated with multifocal motor neuropathy include cramping, involuntary muscle contractions or “twitches” (fasciculations), decreased muscle tone, and, sometimes absent deep tendon reflexes. Later in the progression of the disease, wasting (atrophy) of the affected muscles may occur. Other muscles such as those affecting breathing are unaffected and the disorder usually does not affect life expectancy.
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Symptoms of Multifocal Motor Neuropathy. Multifocal motor neuropathy is a progressive disorder, this means that the signs and symptoms tend to worsen slowly over time. The main symptom is progressive muscle weakness of the arms and legs. Unlike other neurological disorders affecting the arms and legs, there usually is not any sensory deficits. This means that feelings of tingling or numbness or pain are not associated with the disorder. Muscle weakness often begins in the hands, causing hand weakness and affected individuals may drop objects frequently or have difficulty performing tasks that require fine motor skills such as turning a key in a lock. Fine motor skills are those that require small movements involving the hands and wrists. Some individuals have trouble extending or bending their wrist upward (wrist drop). Reduced grip strength of the hands and reduced dexterity of the hands is seen. Sometimes, muscle weakness starts in the legs. There may be reduced mobility of the toes and foot drop may be early signs. Foot drop occurs when weakness of the muscles involving in lifting the food cause the foot to drop or drag when attempting to walk. As muscle weakness progresses, severe fatigue in the affected muscles may be seen and the disorder will cause functional disability. Affected individuals may have limited endurance. The muscles on one side of the body that are affected may be different from the muscle affected on the other side of the body (asymmetrical muscle weakness). Additional symptoms associated with multifocal motor neuropathy include cramping, involuntary muscle contractions or “twitches” (fasciculations), decreased muscle tone, and, sometimes absent deep tendon reflexes. Later in the progression of the disease, wasting (atrophy) of the affected muscles may occur. Other muscles such as those affecting breathing are unaffected and the disorder usually does not affect life expectancy.
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Causes of Multifocal Motor Neuropathy
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The exact, underlying cause of multifocal motor neuropathy is not fully understood. The disorder is believed to be caused by or related to an abnormal response of the immune system. The immune system is the body’s natural defense system against foreign or invading organisms or substances. The immune system is a complex network of cells, tissues, organs, and proteins that work together to keep the body healthy. Conduction block affecting the motor nerves is a characteristic finding of the disorder. Motor nerves are those that carry nerve impulses from the brain to the muscles. Conduction block is when a nerve impulse does not travel all the way down the nerve and are not carried along properly to the muscles. Multiple motor nerves are damaged by this disorder, although the exact reason is not fully understood. Researchers believe that conduction block in multifocal motor neuropathy is reversible. Affected individuals have autoantibodies. Antibodies are part of the immune system; they are specialized proteins that target foreign or invading organisms. Autoantibodies are ones that mistakenly attack healthy tissue. Many individuals (30-60%) with multifocal motor neuropathy have autoantibodies that target GM 1 ganglioside, a fatty material (lipid) found within the peripheral nerves. The peripheral nerves are the nerves found outside the central nervous system and include the nerves of the arms and legs. Researchers do not know if these autoantibodies play a role in the development of this disorder or are a byproduct of the disorder. More research is necessary to determine what role, if any, antibodies to GM 1 ganglioside play in the development of multifocal motor neuropathy.
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Causes of Multifocal Motor Neuropathy. The exact, underlying cause of multifocal motor neuropathy is not fully understood. The disorder is believed to be caused by or related to an abnormal response of the immune system. The immune system is the body’s natural defense system against foreign or invading organisms or substances. The immune system is a complex network of cells, tissues, organs, and proteins that work together to keep the body healthy. Conduction block affecting the motor nerves is a characteristic finding of the disorder. Motor nerves are those that carry nerve impulses from the brain to the muscles. Conduction block is when a nerve impulse does not travel all the way down the nerve and are not carried along properly to the muscles. Multiple motor nerves are damaged by this disorder, although the exact reason is not fully understood. Researchers believe that conduction block in multifocal motor neuropathy is reversible. Affected individuals have autoantibodies. Antibodies are part of the immune system; they are specialized proteins that target foreign or invading organisms. Autoantibodies are ones that mistakenly attack healthy tissue. Many individuals (30-60%) with multifocal motor neuropathy have autoantibodies that target GM 1 ganglioside, a fatty material (lipid) found within the peripheral nerves. The peripheral nerves are the nerves found outside the central nervous system and include the nerves of the arms and legs. Researchers do not know if these autoantibodies play a role in the development of this disorder or are a byproduct of the disorder. More research is necessary to determine what role, if any, antibodies to GM 1 ganglioside play in the development of multifocal motor neuropathy.
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Affects of Multifocal Motor Neuropathy
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Multifocal motor neuropathy affects both men and women, although men are more frequently affected than women by a ratio of about 2.7:1. Men also tend to be diagnosed at a younger age. The median age of onset is 40 years old, although the disorder has been reported individuals ranging from 20-80 years of age. In a handful of instances, the disorder has occurred in children (pediatric cases). Multifocal motor neuropathy is estimated to affect about 0.6 per 100,000 in the general population. Because rare disorders often go undiagnosed or misdiagnosed, determining their true frequency in the general population is difficult.
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Affects of Multifocal Motor Neuropathy. Multifocal motor neuropathy affects both men and women, although men are more frequently affected than women by a ratio of about 2.7:1. Men also tend to be diagnosed at a younger age. The median age of onset is 40 years old, although the disorder has been reported individuals ranging from 20-80 years of age. In a handful of instances, the disorder has occurred in children (pediatric cases). Multifocal motor neuropathy is estimated to affect about 0.6 per 100,000 in the general population. Because rare disorders often go undiagnosed or misdiagnosed, determining their true frequency in the general population is difficult.
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Related disorders of Multifocal Motor Neuropathy
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Symptoms of the following disorders can be similar to those of multifocal motor neuropathy. Comparisons may be useful for a differential diagnosis.Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) sent messages to motor neurons in the spinal cord (lower motor neurons) and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig's disease. (For more information on this disorder, choose “amyotrophic lateral sclerosis” as your search term in the Rare Disease Database.)Primary lateral sclerosis (PLS) is a rare, neuromuscular disorder that affects the central motor neurons and is characterized by painless but progressive weakness and stiffness of the muscles of the legs. Such weakness may progress to affect the arms and the muscles at the base of the brain (bulbar muscles). Less frequently, the muscles of the face are affected. In most cases, the disorder affects adults during midlife. The exact cause of primary lateral sclerosis is unknown. (For more information on this disorder, choose “primary lateral sclerosis” as your search term in the Rare Disease Database.)There are other disorders that are associated with autoantibodies that target GM1 gangliosides. These disorders include Guillain-Barre syndrome, chronic demyelinating polyneuropathy, Lewis-Sumner syndrome, and acute motor axonal neuropathy. These are immune-mediated neurological disorders in which there is progressive muscle weakness and wasting. There are other disorders characterized by progressive muscle weakness Charcot-Marie-Tooth disease, multiple sclerosis, (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 Multifocal Motor Neuropathy. Symptoms of the following disorders can be similar to those of multifocal motor neuropathy. Comparisons may be useful for a differential diagnosis.Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) sent messages to motor neurons in the spinal cord (lower motor neurons) and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig's disease. (For more information on this disorder, choose “amyotrophic lateral sclerosis” as your search term in the Rare Disease Database.)Primary lateral sclerosis (PLS) is a rare, neuromuscular disorder that affects the central motor neurons and is characterized by painless but progressive weakness and stiffness of the muscles of the legs. Such weakness may progress to affect the arms and the muscles at the base of the brain (bulbar muscles). Less frequently, the muscles of the face are affected. In most cases, the disorder affects adults during midlife. The exact cause of primary lateral sclerosis is unknown. (For more information on this disorder, choose “primary lateral sclerosis” as your search term in the Rare Disease Database.)There are other disorders that are associated with autoantibodies that target GM1 gangliosides. These disorders include Guillain-Barre syndrome, chronic demyelinating polyneuropathy, Lewis-Sumner syndrome, and acute motor axonal neuropathy. These are immune-mediated neurological disorders in which there is progressive muscle weakness and wasting. There are other disorders characterized by progressive muscle weakness Charcot-Marie-Tooth disease, multiple sclerosis, (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Multifocal Motor Neuropathy
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Diagnosis of Multifocal Motor Neuropathy
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A diagnosis of multifocal motor neuropathy is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Asymmetrical muscle weakness without sensory problems (e.g. numbness, tingling, etc.) are the main signs of multifocal motor neuropathy. Diagnostic criteria for this disorder have been proposed by several groups. One set of guidelines (Van Schaik IN, 2010) is published by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS). Clinical Testing and Workup
A diagnosis of multifocal motor neuropathy can be supported by nerve conduction studies. Nerve conduction studies determine the ability of specific nerves in the peripheral nervous system to relay nerve impulses to the brain. During a nerve conduction study, electrodes are placed over specific nerves such as those of the shoulders and arms. The electrodes stimulate the nerves and record the conduction of the signal. This test can help to pinpoint the site of disease or injury to the nerve. These studies can show loss of myelin (demyelination) and conduction block. Electromyography is another test that may aid in the diagnosis. During an electromyography, a tiny needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to nerve activation and can help determine whether muscle weakness is caused by the muscles themselves or by the nerves that control those muscles. Laboratory blood tests may be done to detect antibodies to GM1 ganglioside. However, not every affected individual has these antibodies and a negative result does not exclude the disorder.
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Diagnosis of Multifocal Motor Neuropathy. A diagnosis of multifocal motor neuropathy is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Asymmetrical muscle weakness without sensory problems (e.g. numbness, tingling, etc.) are the main signs of multifocal motor neuropathy. Diagnostic criteria for this disorder have been proposed by several groups. One set of guidelines (Van Schaik IN, 2010) is published by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS). Clinical Testing and Workup
A diagnosis of multifocal motor neuropathy can be supported by nerve conduction studies. Nerve conduction studies determine the ability of specific nerves in the peripheral nervous system to relay nerve impulses to the brain. During a nerve conduction study, electrodes are placed over specific nerves such as those of the shoulders and arms. The electrodes stimulate the nerves and record the conduction of the signal. This test can help to pinpoint the site of disease or injury to the nerve. These studies can show loss of myelin (demyelination) and conduction block. Electromyography is another test that may aid in the diagnosis. During an electromyography, a tiny needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to nerve activation and can help determine whether muscle weakness is caused by the muscles themselves or by the nerves that control those muscles. Laboratory blood tests may be done to detect antibodies to GM1 ganglioside. However, not every affected individual has these antibodies and a negative result does not exclude the disorder.
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Therapies of Multifocal Motor Neuropathy
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The treatment of multifocal motor neuropathy may require the coordinated efforts of a team of specialists. General internists, specialists in diagnosing and treating disorders of the central nervous system and brain (neurologists), specialists in diagnosing and treating disorders of the immune system (immunologists), specialists in diagnosing and treating disorders of the skeleton and muscles (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan treatment. Physical therapy to strengthen muscles may be of benefit to some individuals. In 2012, the U.S. Food and Drug Administration (FDA) approved Gammagard Liquid 10% for the treatment of multifocal motor neuropathy. This medication is an intravenous immunoglobulin (IVIg) and most affected individuals respond to treatment with IVIg. There is usually a rapid improvement in muscle weakness when treated is started. The effects eventually wear off and affected individuals with need to take the medication again every 2-6 weeks (maintenance therapy). Sometimes, affected individuals become less response to the medication and will require higher doses or more frequent maintenance therapy. If affected individuals do not respond to treatment with IVIg or stop responding to this therapy, then other medications can be tried.
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Therapies of Multifocal Motor Neuropathy. The treatment of multifocal motor neuropathy may require the coordinated efforts of a team of specialists. General internists, specialists in diagnosing and treating disorders of the central nervous system and brain (neurologists), specialists in diagnosing and treating disorders of the immune system (immunologists), specialists in diagnosing and treating disorders of the skeleton and muscles (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan treatment. Physical therapy to strengthen muscles may be of benefit to some individuals. In 2012, the U.S. Food and Drug Administration (FDA) approved Gammagard Liquid 10% for the treatment of multifocal motor neuropathy. This medication is an intravenous immunoglobulin (IVIg) and most affected individuals respond to treatment with IVIg. There is usually a rapid improvement in muscle weakness when treated is started. The effects eventually wear off and affected individuals with need to take the medication again every 2-6 weeks (maintenance therapy). Sometimes, affected individuals become less response to the medication and will require higher doses or more frequent maintenance therapy. If affected individuals do not respond to treatment with IVIg or stop responding to this therapy, then other medications can be tried.
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Overview of Multiple Endocrine Neoplasia Type 1
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Multiple endocrine neoplasia (MEN) type 1 is a rare genetic disorder characterized by multiple tumors arising from cells of specific neuroendocrine tissues. The endocrine system is the network of glands that secrete hormones into the bloodstream to reach their target organs along the entire body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital and metabolic processes, including regulating heart rate, body temperature and blood pressure, as well as cell differentiation and growth.In individuals with MEN type 1, tumors develop in multiple endocrine glands, principally the parathyroids, gastro-entero-pancreatic tract and pituitary gland. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms and related syndromes. Some tumors associated with MEN type 1 are cancerous (malignant) (i.e gastrinomas and carcinoids) and can spread to other organs (metastasize). Other, less frequent, clinical manifestations of the MEN1 syndrome are: neuroendocrine tumors of thymus and bronchi, adrenocortical tumors, lipomas, visceral leiomyomas, truncal and facial collagenomas, facial angiofibromas, breast carcinoma, meningioma and ependymomas. MEN type 1 can run in families or can occur as the result of a new gene mutation in the affected person.
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Overview of Multiple Endocrine Neoplasia Type 1. Multiple endocrine neoplasia (MEN) type 1 is a rare genetic disorder characterized by multiple tumors arising from cells of specific neuroendocrine tissues. The endocrine system is the network of glands that secrete hormones into the bloodstream to reach their target organs along the entire body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital and metabolic processes, including regulating heart rate, body temperature and blood pressure, as well as cell differentiation and growth.In individuals with MEN type 1, tumors develop in multiple endocrine glands, principally the parathyroids, gastro-entero-pancreatic tract and pituitary gland. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms and related syndromes. Some tumors associated with MEN type 1 are cancerous (malignant) (i.e gastrinomas and carcinoids) and can spread to other organs (metastasize). Other, less frequent, clinical manifestations of the MEN1 syndrome are: neuroendocrine tumors of thymus and bronchi, adrenocortical tumors, lipomas, visceral leiomyomas, truncal and facial collagenomas, facial angiofibromas, breast carcinoma, meningioma and ependymomas. MEN type 1 can run in families or can occur as the result of a new gene mutation in the affected person.
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Symptoms of Multiple Endocrine Neoplasia Type 1
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MEN type 1-associated symptoms depend on which glands are affected by the overgrowth of tissue (hyperplasia) or tumor formation. Although most tumors are benign (noncancerous), tissue overgrowth or tumor formation causes the affected glands to become hyperactive and produce excess hormones. Elevated hormone levels are the main cause of MEN type 1-associated signs and symptoms. Certain tumors, such as gastrinomas and carcinoid tumors can potentially become malignant. The clinical expression of MEN type 1 is highly variable even within members of the same family and identical twins.More than 20 different endocrine and non-endocrine tumors have been identified in individuals with MEN type 1. Affected individuals will not necessarily develop tumors at the same age or in the same locations and, therefore, they can manifest variable spectra of clinical signs and symptoms during their lifetime. Some individuals may only develop mild symptoms; others may develop serious, life-threatening complications. Some individuals may develop symptoms as young adults or adolescents; other may not develop symptoms until middle-age or older. It is important to note that individual cases are highly variable and that affected individuals will not develop all of the symptoms discussed below.PARATHYROID GLANDS
The most common affected endocrine glands in MEN type 1 are parathyroids, both as tissue hyperplasia and/or adenomas. More than 90 percent of individuals with MEN type 1 develop, by age 50, primary hyperparathyroidism (PHPT). Mean age of onset is the third decade of life. In some cases, hyperparathyroidism may be detected during adolescence and infancy (by the age of 5). PHPT is the first sign of MEN type 1 in about 90% of cases. Parathyroid glands are generally represented by four very small glands (approximately the size of a pea) located in the neck that secrete parathyroid hormone (PTH), which controls the homeostasis of serum calcium level. Hyperparathyroidism is the medical term indicating a constantly high level of circulating PTH.PHPT can be very mild and may not cause any obvious symptoms (asymptomatic). Untreated hyperparathyroidism generally results in elevated serum level of calcium (hypercalcemia), which can cause kidney stones or damage the kidneys. Hyperparathyroidism can cause additional symptoms in some cases including fatigue, weakness, constipation, nausea, ulcers, indigestion, high blood pressure (hypertension), and muscle or bone pain. Central nervous system abnormalities can eventually develop including mental status changes, lethargy, depression, and confusion, as consequence of severe hypercalcemia. Some individuals may develop abnormal thinning of bones (osteoporosis), which can result in an increased risk of fragility fractures. Most individuals with hyperparathyroidism do not develop all of these symptoms, especially when the condition is diagnosed early.PANCREAS AND DUODENUM
Approximately 40 percent of adults with MEN type 1 develope multiple gastrinomas, usually located in the first portion of duodenum, and more rarely in the pancreas. Approximately, 50% of MEN1-gastrinomas have already metastasized at the time of clinical diagnosis. The pancreas is a small gland located behind the stomach. It contains specialized endocrine cells called islet cells, which secrete several hormones including insulin (which lowers blood sugar levels), glucagon (which raises blood sugar levels), and hormones that travel to the intestines and aid in digestion such as gastrin. The duodenum is the first portion of the small intestine, which connects the intestines to the stomach.Gastrinomas are benign tumors that secrete gastrin. Elevated levels of gastrin induce the stomach to release too much acid, which, in turn, can result in abdominal pain, diarrhea, backflow of the contents of the stomach into the esophagus (esophageal reflux) and peptic ulcers. This condition is clinically referred to as Zollinger-Ellison syndrome (ZES). Peptic ulcers are open sores lining the stomach, esophagus, and intestines. Peptic ulcers can cause a burning pain in the stomach, diarrhea, nausea, vomiting and fatty, smelly stools. In severe cases, peptic ulcers can cause serious complications including internal bleeding, vomiting up of blood, obstruction of the passage of food through the digestive tract (gastric outlet obstruction) or the development of a hole in the wall of the stomach or small intestines (perforation), allowing the contents of the stomach or intestines to leak into the abdomen.Less common symptoms associated with gastrinomas include unintended weight loss and heartburn. Gastrinomas and other tumors that arise from islet cells can potentially become malignant and spread (metastasize) to other areas of the body, especially nearby lymph nodes and the liver.Multiple gastrinomas are also found in a non-syndromic disorder called Zollinger-Ellison syndrome, which usually occurs randomly for unknown reasons.Additional tumors can affect the pancreas. Insulinoma, a benign tumor that secretes insulin, is the second most common tumor affecting the pancreas, occurring in approximately 10 percent of individuals with MEN type 1. Insulinoma can cause low blood sugar (hypoglycemia), especially when not eating over a period of time (fasting). Hypoglycemia can cause a variety of symptoms including confusion, abnormal behavior, blurred vision, double vision, anxiety, heart palpitations, sweating and hunger.Tumors that secrete too much glucagon or somatostatin (glucagonomas and somatostatinomas) can also occur in the pancreas. These tumors result in elevated levels of blood sugar (hyperglycemia). Hyperglycemia can cause diabetes.In rare cases, individuals with MEN type 1 can develop a VIPoma, a tumor that secretes a hormone called vasoactive intestinal peptide (VIP). VIPomas can cause chronic, watery diarrhea and eventually cause dehydration. In approximately 40 percent of cases, non-functioning pancreatic tumors, often multiple, small and scattered to the entire organ, may occur in MEN1 patients.PITUITARY GLAND
Approximately 25 percent of individuals with MEN type 1 develop benign overgrowth of the pituitary gland. In some cases, symptoms of pituitary gland involvement may be the first sign of the disorder. The pituitary is small pea-sized gland that sits in the base of brain and is sometimes called “the master gland” because it oversees the function of most of the endocrine glands in the body. The pituitary gland secretes a variety of different hormones including prolactin, which influences fertility and stimulates breast milk production; growth hormone, which regulates body growth especially during adolescence; and several hormones that stimulate the activity of other glands including the adrenal and thyroid glands and ovaries and testes.Benign tumors that secrete prolactin (prolactinomas) are the most common pituitary gland tumors associated with MEN type 1. They are the third most common tumors associated with MEN type 1 after parathyroid tumors and gastrinomas. In women, prolactinomas can cause irregular menstrual periods (oligomenorrhea to amenorrhea), infertility, diminished sexual drive, painful intercourse and the production of breast milk in women who are not pregnant (galactorrhea). The most common clinical manifestations in males are impotence and gynecomastia.Pituitary tumors, especially when more than 1 centimeter in diameter (macrodenoma), can result in additional symptoms because they can apply pressure upon other tissues of the brain. Resulting symptoms may include headaches and visual problems, such as blurred vision.In addition to a prolactinoma, other tumors affecting the pituitary gland may occur. One of these tumors can secrete excess growth hormone resulting in a condition characterized by excessive bone growth and enlargement of certain structures of the body such as the jaw, hands and feet (acromegaly) in post-puberal patients. Another of these tumors may secrete adrenocorticotrophin (ACTH), a hormone that stimulates the adrenal glands, which results in excessive corticosteroid production. Excessive corticosteroid levels can eventually cause a condition called Cushing’s syndrome which is characterized by a wide variety of signs and symptoms including a rounded face (moon face), increased fat around the neck, weight gain around the midsection and upper back, muscle weakness, fatigue and high blood pressure.Affected individuals may also have benign tumors that do not produce any hormones (non-functioning tumors). In approximately 20-40% of cases non-functioning tumors of the adrenal glands may occur. The adrenal glands are located on top of the kidneys. In rare cases, these tumors result in the overproduction of corticosteroid hormones and the development of Cushing’s syndrome.CARCINOID TUMORS
Approximately 10-15% of individuals with MEN type 1 develop slow-growing carcinoid tumors. These tumors usually develop in the stomach (gastric carcinoids), the large tubes that carry air to and from the lungs (bronchial tubes) (bronchial carcinoids) and the thymus (thymic carcinoids), a small gland located in the upper chest just behind the breastbone. Carcinoid tumors of the bronchial tubes primarily affect women; carcinoid tumors of the thymus primarily affect men.In most cases, these tumors do not produce hormones (non-functioning tumors) and usually do not cause any symptoms (asymptomatic), but they can present a rapid growth and malignant progression being responsible of some MEN1-asscociated deaths. In rare cases, carcinoid tumors may overproduce different hormones including ACTH, calcitonin, growth hormone releasing hormone (GHRH), serotonin, and histamine. When carcinoid tumors secrete serotonin, they can cause carcinoid syndrome, a condition characterized by migraines, diarrhea and episodes of feeling flushed.Carcinoid tumors associated with MEN type 1 are usually identified later during life, with a mean diagnosis of age 50. These tumors may be benign, but malignant (cancerous) carcinoids can develop. Thymic carcinoids associated with MEN type 1 may be particularly aggressive, especially in male smokers.ADDITIONAL ENDOCRINE TUMORS
In extremely rare cases, about 1%, a pheochromocytoma (PHEO) may occur in an individual with MEN type 1. Most PHEOs originate in the inner layer (medulla) of one of the two adrenal glands. Symptoms may include high blood pressure, headaches, excessive sweating, and heart palpitations. PHEOs occur much more often in individuals with multiple endocrine neoplasia type 2.NON-ENDOCRINE BENIGN TUMORS
Several tumors that do not arise from endocrine cells may also occur in individuals with MEN type 1. The most common is lipoma, a benign tumor consisting of fat cells. Lipomas usually develop just under the surface of the skin and are common in the general population. Multiple lipomas often form. Lipomas are not usually associated with any symptoms. Some individuals with MEN type 1 may also develop benign raised, reddish spots on the face (angiofibromas), and benign, raised, whitish spots on the skin (collagenomas).Less common, non-endocrine, benign tumors associated with MEN type 1 include tumors arising from the membranes (meninges) lining the brain and spinal cord (meningioma), tumors arising from smooth muscle cells (leiomyoma) and tumors arising from central nervous system tissue (ependymomas). These tumors generally do not cause any symptoms.
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Symptoms of Multiple Endocrine Neoplasia Type 1. MEN type 1-associated symptoms depend on which glands are affected by the overgrowth of tissue (hyperplasia) or tumor formation. Although most tumors are benign (noncancerous), tissue overgrowth or tumor formation causes the affected glands to become hyperactive and produce excess hormones. Elevated hormone levels are the main cause of MEN type 1-associated signs and symptoms. Certain tumors, such as gastrinomas and carcinoid tumors can potentially become malignant. The clinical expression of MEN type 1 is highly variable even within members of the same family and identical twins.More than 20 different endocrine and non-endocrine tumors have been identified in individuals with MEN type 1. Affected individuals will not necessarily develop tumors at the same age or in the same locations and, therefore, they can manifest variable spectra of clinical signs and symptoms during their lifetime. Some individuals may only develop mild symptoms; others may develop serious, life-threatening complications. Some individuals may develop symptoms as young adults or adolescents; other may not develop symptoms until middle-age or older. It is important to note that individual cases are highly variable and that affected individuals will not develop all of the symptoms discussed below.PARATHYROID GLANDS
The most common affected endocrine glands in MEN type 1 are parathyroids, both as tissue hyperplasia and/or adenomas. More than 90 percent of individuals with MEN type 1 develop, by age 50, primary hyperparathyroidism (PHPT). Mean age of onset is the third decade of life. In some cases, hyperparathyroidism may be detected during adolescence and infancy (by the age of 5). PHPT is the first sign of MEN type 1 in about 90% of cases. Parathyroid glands are generally represented by four very small glands (approximately the size of a pea) located in the neck that secrete parathyroid hormone (PTH), which controls the homeostasis of serum calcium level. Hyperparathyroidism is the medical term indicating a constantly high level of circulating PTH.PHPT can be very mild and may not cause any obvious symptoms (asymptomatic). Untreated hyperparathyroidism generally results in elevated serum level of calcium (hypercalcemia), which can cause kidney stones or damage the kidneys. Hyperparathyroidism can cause additional symptoms in some cases including fatigue, weakness, constipation, nausea, ulcers, indigestion, high blood pressure (hypertension), and muscle or bone pain. Central nervous system abnormalities can eventually develop including mental status changes, lethargy, depression, and confusion, as consequence of severe hypercalcemia. Some individuals may develop abnormal thinning of bones (osteoporosis), which can result in an increased risk of fragility fractures. Most individuals with hyperparathyroidism do not develop all of these symptoms, especially when the condition is diagnosed early.PANCREAS AND DUODENUM
Approximately 40 percent of adults with MEN type 1 develope multiple gastrinomas, usually located in the first portion of duodenum, and more rarely in the pancreas. Approximately, 50% of MEN1-gastrinomas have already metastasized at the time of clinical diagnosis. The pancreas is a small gland located behind the stomach. It contains specialized endocrine cells called islet cells, which secrete several hormones including insulin (which lowers blood sugar levels), glucagon (which raises blood sugar levels), and hormones that travel to the intestines and aid in digestion such as gastrin. The duodenum is the first portion of the small intestine, which connects the intestines to the stomach.Gastrinomas are benign tumors that secrete gastrin. Elevated levels of gastrin induce the stomach to release too much acid, which, in turn, can result in abdominal pain, diarrhea, backflow of the contents of the stomach into the esophagus (esophageal reflux) and peptic ulcers. This condition is clinically referred to as Zollinger-Ellison syndrome (ZES). Peptic ulcers are open sores lining the stomach, esophagus, and intestines. Peptic ulcers can cause a burning pain in the stomach, diarrhea, nausea, vomiting and fatty, smelly stools. In severe cases, peptic ulcers can cause serious complications including internal bleeding, vomiting up of blood, obstruction of the passage of food through the digestive tract (gastric outlet obstruction) or the development of a hole in the wall of the stomach or small intestines (perforation), allowing the contents of the stomach or intestines to leak into the abdomen.Less common symptoms associated with gastrinomas include unintended weight loss and heartburn. Gastrinomas and other tumors that arise from islet cells can potentially become malignant and spread (metastasize) to other areas of the body, especially nearby lymph nodes and the liver.Multiple gastrinomas are also found in a non-syndromic disorder called Zollinger-Ellison syndrome, which usually occurs randomly for unknown reasons.Additional tumors can affect the pancreas. Insulinoma, a benign tumor that secretes insulin, is the second most common tumor affecting the pancreas, occurring in approximately 10 percent of individuals with MEN type 1. Insulinoma can cause low blood sugar (hypoglycemia), especially when not eating over a period of time (fasting). Hypoglycemia can cause a variety of symptoms including confusion, abnormal behavior, blurred vision, double vision, anxiety, heart palpitations, sweating and hunger.Tumors that secrete too much glucagon or somatostatin (glucagonomas and somatostatinomas) can also occur in the pancreas. These tumors result in elevated levels of blood sugar (hyperglycemia). Hyperglycemia can cause diabetes.In rare cases, individuals with MEN type 1 can develop a VIPoma, a tumor that secretes a hormone called vasoactive intestinal peptide (VIP). VIPomas can cause chronic, watery diarrhea and eventually cause dehydration. In approximately 40 percent of cases, non-functioning pancreatic tumors, often multiple, small and scattered to the entire organ, may occur in MEN1 patients.PITUITARY GLAND
Approximately 25 percent of individuals with MEN type 1 develop benign overgrowth of the pituitary gland. In some cases, symptoms of pituitary gland involvement may be the first sign of the disorder. The pituitary is small pea-sized gland that sits in the base of brain and is sometimes called “the master gland” because it oversees the function of most of the endocrine glands in the body. The pituitary gland secretes a variety of different hormones including prolactin, which influences fertility and stimulates breast milk production; growth hormone, which regulates body growth especially during adolescence; and several hormones that stimulate the activity of other glands including the adrenal and thyroid glands and ovaries and testes.Benign tumors that secrete prolactin (prolactinomas) are the most common pituitary gland tumors associated with MEN type 1. They are the third most common tumors associated with MEN type 1 after parathyroid tumors and gastrinomas. In women, prolactinomas can cause irregular menstrual periods (oligomenorrhea to amenorrhea), infertility, diminished sexual drive, painful intercourse and the production of breast milk in women who are not pregnant (galactorrhea). The most common clinical manifestations in males are impotence and gynecomastia.Pituitary tumors, especially when more than 1 centimeter in diameter (macrodenoma), can result in additional symptoms because they can apply pressure upon other tissues of the brain. Resulting symptoms may include headaches and visual problems, such as blurred vision.In addition to a prolactinoma, other tumors affecting the pituitary gland may occur. One of these tumors can secrete excess growth hormone resulting in a condition characterized by excessive bone growth and enlargement of certain structures of the body such as the jaw, hands and feet (acromegaly) in post-puberal patients. Another of these tumors may secrete adrenocorticotrophin (ACTH), a hormone that stimulates the adrenal glands, which results in excessive corticosteroid production. Excessive corticosteroid levels can eventually cause a condition called Cushing’s syndrome which is characterized by a wide variety of signs and symptoms including a rounded face (moon face), increased fat around the neck, weight gain around the midsection and upper back, muscle weakness, fatigue and high blood pressure.Affected individuals may also have benign tumors that do not produce any hormones (non-functioning tumors). In approximately 20-40% of cases non-functioning tumors of the adrenal glands may occur. The adrenal glands are located on top of the kidneys. In rare cases, these tumors result in the overproduction of corticosteroid hormones and the development of Cushing’s syndrome.CARCINOID TUMORS
Approximately 10-15% of individuals with MEN type 1 develop slow-growing carcinoid tumors. These tumors usually develop in the stomach (gastric carcinoids), the large tubes that carry air to and from the lungs (bronchial tubes) (bronchial carcinoids) and the thymus (thymic carcinoids), a small gland located in the upper chest just behind the breastbone. Carcinoid tumors of the bronchial tubes primarily affect women; carcinoid tumors of the thymus primarily affect men.In most cases, these tumors do not produce hormones (non-functioning tumors) and usually do not cause any symptoms (asymptomatic), but they can present a rapid growth and malignant progression being responsible of some MEN1-asscociated deaths. In rare cases, carcinoid tumors may overproduce different hormones including ACTH, calcitonin, growth hormone releasing hormone (GHRH), serotonin, and histamine. When carcinoid tumors secrete serotonin, they can cause carcinoid syndrome, a condition characterized by migraines, diarrhea and episodes of feeling flushed.Carcinoid tumors associated with MEN type 1 are usually identified later during life, with a mean diagnosis of age 50. These tumors may be benign, but malignant (cancerous) carcinoids can develop. Thymic carcinoids associated with MEN type 1 may be particularly aggressive, especially in male smokers.ADDITIONAL ENDOCRINE TUMORS
In extremely rare cases, about 1%, a pheochromocytoma (PHEO) may occur in an individual with MEN type 1. Most PHEOs originate in the inner layer (medulla) of one of the two adrenal glands. Symptoms may include high blood pressure, headaches, excessive sweating, and heart palpitations. PHEOs occur much more often in individuals with multiple endocrine neoplasia type 2.NON-ENDOCRINE BENIGN TUMORS
Several tumors that do not arise from endocrine cells may also occur in individuals with MEN type 1. The most common is lipoma, a benign tumor consisting of fat cells. Lipomas usually develop just under the surface of the skin and are common in the general population. Multiple lipomas often form. Lipomas are not usually associated with any symptoms. Some individuals with MEN type 1 may also develop benign raised, reddish spots on the face (angiofibromas), and benign, raised, whitish spots on the skin (collagenomas).Less common, non-endocrine, benign tumors associated with MEN type 1 include tumors arising from the membranes (meninges) lining the brain and spinal cord (meningioma), tumors arising from smooth muscle cells (leiomyoma) and tumors arising from central nervous system tissue (ependymomas). These tumors generally do not cause any symptoms.
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Multiple Endocrine Neoplasia Type 1
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Causes of Multiple Endocrine Neoplasia Type 1
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MEN type 1 is a rare genetic disorder caused by mutations of the MEN1 gene. The MEN1 gene encodes a nuclear protein known as menin. The exact role of menin is not fully understood. The MEN1 gene is a tumor suppressor gene, a gene that when it operates normally may have several functions including inhibiting cell division, repairing and replicating DNA, and instructing cells when to die (a normal process called apoptosis). When tumor suppressor genes malfunction, certain cells may continue to grow and reproduce causing tumor formation.This genetic mutation may be inherited in an autosomal dominant pattern or occur as a new gene mutation in the affected person.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 at the embryo level. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
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Causes of Multiple Endocrine Neoplasia Type 1. MEN type 1 is a rare genetic disorder caused by mutations of the MEN1 gene. The MEN1 gene encodes a nuclear protein known as menin. The exact role of menin is not fully understood. The MEN1 gene is a tumor suppressor gene, a gene that when it operates normally may have several functions including inhibiting cell division, repairing and replicating DNA, and instructing cells when to die (a normal process called apoptosis). When tumor suppressor genes malfunction, certain cells may continue to grow and reproduce causing tumor formation.This genetic mutation may be inherited in an autosomal dominant pattern or occur as a new gene mutation in the affected person.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 at the embryo level. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
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Multiple Endocrine Neoplasia Type 1
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Affects of Multiple Endocrine Neoplasia Type 1
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MEN type 1 affects males and females in equal numbers. It affects approximately 1 in 30,000 individuals. Some researchers believe that many cases of MEN type 1 go undiagnosed, making it difficult to determine its true frequency in the general population. The onset of the disorder can vary widely and it has been identified in children as young as 8 and adults as old as 80. MEN type 1 was first recognized as a genetic disorder in 1954.
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Affects of Multiple Endocrine Neoplasia Type 1. MEN type 1 affects males and females in equal numbers. It affects approximately 1 in 30,000 individuals. Some researchers believe that many cases of MEN type 1 go undiagnosed, making it difficult to determine its true frequency in the general population. The onset of the disorder can vary widely and it has been identified in children as young as 8 and adults as old as 80. MEN type 1 was first recognized as a genetic disorder in 1954.
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Multiple Endocrine Neoplasia Type 1
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Related disorders of Multiple Endocrine Neoplasia Type 1
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Symptoms of the following disorders can be similar to those of MEN type 1. Comparisons may be useful for a differential diagnosis.Multiple endocrine neoplasia type 2 (MEN type 2) is a rare genetic disorder characterized by tissue overgrowth or tumor formation in various endocrine glands including the thyroid, the adrenal glands and the parathyroid. MEN type 2 is further classified into three distinct subtypes, MEN type 2A, MEN type 2B and familial medullary thyroid cancer (FMTC). All three subtypes of MEN type 2 carry an increased risk of developing a specific form of thyroid cancer called medullary carcinoma. Individuals with MEN type 2A also have an increased risk of developing benign tumors of the parathyroid (adenomas) and the adrenal glands (PHEOs). MEN type 2A is associated with PHEOs, multiple tumors of nerve tissue (neuromas), and multiple nerve cell tumors (ganglioneuromatosis) in the gastrointestinal tract. MEN type 2 can run in families or can occur as the result of a new gene mutation in the affected person. MEN type 2 is caused by mutation of the RET gene. (For more information on this disorder, choose “multiple endocrine neoplasia type 2” as your search term in the Rare Disease Database.)Tumors associated with MEN type 1 can occur also as isolated conditions or as part of other disorders including familial isolated hyperparathyroidism, hereditary hyperparathyroidism-jaw tumor syndrome, MEN4, von Hippel-Lindau syndrome, Carney complex, and Zollinger-Ellison syndrome. When these tumors secrete excessive hormones into the bloodstream a variety of different conditions can result including hyperparathyroidism, hyperprolactinemia, acromegaly, Cushing’s syndrome, hypoglycemia, hyperglycemia, and carcinoid syndrome. (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 Multiple Endocrine Neoplasia Type 1. Symptoms of the following disorders can be similar to those of MEN type 1. Comparisons may be useful for a differential diagnosis.Multiple endocrine neoplasia type 2 (MEN type 2) is a rare genetic disorder characterized by tissue overgrowth or tumor formation in various endocrine glands including the thyroid, the adrenal glands and the parathyroid. MEN type 2 is further classified into three distinct subtypes, MEN type 2A, MEN type 2B and familial medullary thyroid cancer (FMTC). All three subtypes of MEN type 2 carry an increased risk of developing a specific form of thyroid cancer called medullary carcinoma. Individuals with MEN type 2A also have an increased risk of developing benign tumors of the parathyroid (adenomas) and the adrenal glands (PHEOs). MEN type 2A is associated with PHEOs, multiple tumors of nerve tissue (neuromas), and multiple nerve cell tumors (ganglioneuromatosis) in the gastrointestinal tract. MEN type 2 can run in families or can occur as the result of a new gene mutation in the affected person. MEN type 2 is caused by mutation of the RET gene. (For more information on this disorder, choose “multiple endocrine neoplasia type 2” as your search term in the Rare Disease Database.)Tumors associated with MEN type 1 can occur also as isolated conditions or as part of other disorders including familial isolated hyperparathyroidism, hereditary hyperparathyroidism-jaw tumor syndrome, MEN4, von Hippel-Lindau syndrome, Carney complex, and Zollinger-Ellison syndrome. When these tumors secrete excessive hormones into the bloodstream a variety of different conditions can result including hyperparathyroidism, hyperprolactinemia, acromegaly, Cushing’s syndrome, hypoglycemia, hyperglycemia, and carcinoid syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Multiple Endocrine Neoplasia Type 1
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Diagnosis of Multiple Endocrine Neoplasia Type 1
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Affected individuals may receive a diagnosis of MEN type 1 following a thorough clinical evaluation, a detailed patient and family history and the identification of at least two of the three characteristic endocrine tumors associated with the disorder (i.e., parathyroid and pituitary tumors and islet cell tumors in the pancreas or duodenum). Individuals with only one of the associated tumors and a positive family history of the disorder may also receive a diagnosis of MEN type 1. The identification of an inactivating MEN1 gene mutation is a genetic diagnosis of the syndrome, with a complete penetrance by the age of 55. A variety of tests to detect elevated levels of certain hormones in the blood may be necessary to aid in the identification of tumors. For example, identification of elevated levels of PTH together with hypercalcemia can indicate the presence of a parathyroid tumor. A variety of imaging scans may be performed to aid in identifying the size and location of specific tumors.A diagnosis of MEN type 1 can be confirmed through genetic testing of the MEN1 gene, which can reveal the characteristic mutations of the MEN1 gene that causes the disorder. Individual clinical manifestations cannot be foreseen by the result of the genetic analysis (No direct genotype-phenotype correlation exists.).
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Diagnosis of Multiple Endocrine Neoplasia Type 1. Affected individuals may receive a diagnosis of MEN type 1 following a thorough clinical evaluation, a detailed patient and family history and the identification of at least two of the three characteristic endocrine tumors associated with the disorder (i.e., parathyroid and pituitary tumors and islet cell tumors in the pancreas or duodenum). Individuals with only one of the associated tumors and a positive family history of the disorder may also receive a diagnosis of MEN type 1. The identification of an inactivating MEN1 gene mutation is a genetic diagnosis of the syndrome, with a complete penetrance by the age of 55. A variety of tests to detect elevated levels of certain hormones in the blood may be necessary to aid in the identification of tumors. For example, identification of elevated levels of PTH together with hypercalcemia can indicate the presence of a parathyroid tumor. A variety of imaging scans may be performed to aid in identifying the size and location of specific tumors.A diagnosis of MEN type 1 can be confirmed through genetic testing of the MEN1 gene, which can reveal the characteristic mutations of the MEN1 gene that causes the disorder. Individual clinical manifestations cannot be foreseen by the result of the genetic analysis (No direct genotype-phenotype correlation exists.).
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Therapies of Multiple Endocrine Neoplasia Type 1
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TreatmentThe treatment of MEN type 1 may require the coordinated efforts of a team of specialists. Endocrinologists, surgeons, cancer specialists (oncologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Treatment is directed toward the specific symptoms that are apparent in each individual and may include drugs to counteract the effects of excess hormones, surgical removal of tumors or ,medical therapies, such as SSAs, peptide receptor radionuclide therapy (PRRT), cytotoxic chemotherapy (i.e. streptozocin and 5-fluorouracil, doxorubicin, temozolomide with capecitabine), inhibitors of thyrosin kinase receptors (i.e. sunitinib), inhibitors of mammalian target of rapamycin (mTOR; i.e. everolimus), and rarely radiation therapy or stereotaxic radiosurgery to help shrink or destroy tumors.Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as primary tumor location; the size and type of tumor; the severity of symptoms due to excess hormone production; whether malignant tumors are present and whether they have spread to lymph nodes or distant sites; individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.The main treatment for parathyroid tumors is surgery, although the best type of surgery and the best time for surgery is still controversial. Surgical removal of the parathyroid glands is called a parathyroidectomy. One approach is to remove three parathyroid glands entirely and a portion of the fourth (subtotal parathyroidectomy). There is a 50 percent risk that of recurrence of a parathyroid tumor with this method. Another approach is to remove all four glands (total parathyroidectomy). This procedure is usually followed by the transplantation of some of the apparently healthy parathyroid tissue into another area of the body (usually the nondominant forearm). Because of the high risk of disease recurrence, this would spare affected individuals from being operated on in the same area (i.e., the neck). In some cases, healthy parathyroid tissue is saved through cryopreservation (the process of cooling and storing tissue) and re-implanted at a later date Nonsurgical options in the treatment of MEN1-associated primary hyperparathyroidism, is cinacalcet in patients who do not meet the criteria for parathyroidectomy, for those who failed a previous intervention, or for those presenting recurrence who refuse to undergo any further surgical interventions.Surgical removal of part or all of the parathyroid glands may result in hypoparathyroidism (low levels of parathyroid hormones and calcium in the blood). Affected individuals may require daily supplementation of calcium and vitamin D to prevent the effects of hypoparathyroidism.Pituitary tumors that secrete prolactin (prolactinomas) may be treated with dopamine agonists, drugs that lower the levels of prolactin in the blood and shrink pituitary tumors. Some prolactinomas are small enough that no therapy is required. In cases where drug therapy is ineffective or cannot be tolerated, trans-sphenoidal surgery (procedure in which surgeons go through the cavity (sphenoid sinus) directly behind the nose) may be required.Pituitary tumors that produce ACTH are usually treated by transsphenoidal surgery. In cases of persistent hypercortisolism after surgery the medical therapies used provides adrenal steroidogenesis inhibitors such as ketoconazole, metyrapone. Pituitary tumors that produce GH are treated by transsphenoidal surgery. In patients with postoperative active disease pharmacological treatment includes SSAs (octreotide, lanreotide and pasireotide), dopamine agonist (cabergoline) and GH receptor antagonist (pegvisomant). In all pituitary tumors stereotaxic radiosurgery can be used when medical therapy is unavailable, unsuccessful or not tolerated.The objective of treatment for tumors that secrete gastrin (gastrinomas) is to reduce and control gastric acid hypersecretion with histamine-2 receptor antagonists (cimetidine, ranitidine, famotidine), proton pump inhibitors (PPIs; omeprazole, lansoprazole, pantoprazole) or somatostatin analogues (SSAs; octreotide and lanreotide). Timing and type of surgery (i.e. Thompson procedure (i.e., wide longitudinal duodenotomy with excision of duodenal gastrinomas and of peri-pancreatic lymph nodes, pancreatoduodenectomy (PD), or duodenectomy with reimplants of the papilla) are still controversial. Insulinomas are usually surgically removed through enucleation of the greatest pancreatic lesions or distal pancreatic resection preserving splenic vessels and spleen. If the tumor cannot be completely removed by surgery, the drug inhibits insulin release and it is able to control hypoglicemia in at least 50% of patients.Non-functioning neuroendocrine tumors of the gastro-entero-pancreatic tract are usually treated by surgery. Surgery is indicated when the dimension of tumors is approximately 2 cm in diameter or when imaging exams during the follow-up shows a significant growth of lesions. In case of unresectable tumors or advanced metastatic cancer some medical therapies can be considered: SSAs, peptide receptor radionuclide therapy (PRRT), cytotoxic chemotherapy, inhibitors of thyrosin kinase receptors, inhibitors of mammalian target of rapamycin.Carcinoid tumors are generally removed surgically. Medications including octreotide and lanreotide can be used to treat excess hormone production from these tumors, but the risk for malignant transformation remains. For this purpose, removal of thymus, through a transcervical approach, is recommended at the time of neck surgery for parathyroidectomy.Lipomas may be removed surgically. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Multiple Endocrine Neoplasia Type 1. TreatmentThe treatment of MEN type 1 may require the coordinated efforts of a team of specialists. Endocrinologists, surgeons, cancer specialists (oncologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Treatment is directed toward the specific symptoms that are apparent in each individual and may include drugs to counteract the effects of excess hormones, surgical removal of tumors or ,medical therapies, such as SSAs, peptide receptor radionuclide therapy (PRRT), cytotoxic chemotherapy (i.e. streptozocin and 5-fluorouracil, doxorubicin, temozolomide with capecitabine), inhibitors of thyrosin kinase receptors (i.e. sunitinib), inhibitors of mammalian target of rapamycin (mTOR; i.e. everolimus), and rarely radiation therapy or stereotaxic radiosurgery to help shrink or destroy tumors.Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as primary tumor location; the size and type of tumor; the severity of symptoms due to excess hormone production; whether malignant tumors are present and whether they have spread to lymph nodes or distant sites; individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.The main treatment for parathyroid tumors is surgery, although the best type of surgery and the best time for surgery is still controversial. Surgical removal of the parathyroid glands is called a parathyroidectomy. One approach is to remove three parathyroid glands entirely and a portion of the fourth (subtotal parathyroidectomy). There is a 50 percent risk that of recurrence of a parathyroid tumor with this method. Another approach is to remove all four glands (total parathyroidectomy). This procedure is usually followed by the transplantation of some of the apparently healthy parathyroid tissue into another area of the body (usually the nondominant forearm). Because of the high risk of disease recurrence, this would spare affected individuals from being operated on in the same area (i.e., the neck). In some cases, healthy parathyroid tissue is saved through cryopreservation (the process of cooling and storing tissue) and re-implanted at a later date Nonsurgical options in the treatment of MEN1-associated primary hyperparathyroidism, is cinacalcet in patients who do not meet the criteria for parathyroidectomy, for those who failed a previous intervention, or for those presenting recurrence who refuse to undergo any further surgical interventions.Surgical removal of part or all of the parathyroid glands may result in hypoparathyroidism (low levels of parathyroid hormones and calcium in the blood). Affected individuals may require daily supplementation of calcium and vitamin D to prevent the effects of hypoparathyroidism.Pituitary tumors that secrete prolactin (prolactinomas) may be treated with dopamine agonists, drugs that lower the levels of prolactin in the blood and shrink pituitary tumors. Some prolactinomas are small enough that no therapy is required. In cases where drug therapy is ineffective or cannot be tolerated, trans-sphenoidal surgery (procedure in which surgeons go through the cavity (sphenoid sinus) directly behind the nose) may be required.Pituitary tumors that produce ACTH are usually treated by transsphenoidal surgery. In cases of persistent hypercortisolism after surgery the medical therapies used provides adrenal steroidogenesis inhibitors such as ketoconazole, metyrapone. Pituitary tumors that produce GH are treated by transsphenoidal surgery. In patients with postoperative active disease pharmacological treatment includes SSAs (octreotide, lanreotide and pasireotide), dopamine agonist (cabergoline) and GH receptor antagonist (pegvisomant). In all pituitary tumors stereotaxic radiosurgery can be used when medical therapy is unavailable, unsuccessful or not tolerated.The objective of treatment for tumors that secrete gastrin (gastrinomas) is to reduce and control gastric acid hypersecretion with histamine-2 receptor antagonists (cimetidine, ranitidine, famotidine), proton pump inhibitors (PPIs; omeprazole, lansoprazole, pantoprazole) or somatostatin analogues (SSAs; octreotide and lanreotide). Timing and type of surgery (i.e. Thompson procedure (i.e., wide longitudinal duodenotomy with excision of duodenal gastrinomas and of peri-pancreatic lymph nodes, pancreatoduodenectomy (PD), or duodenectomy with reimplants of the papilla) are still controversial. Insulinomas are usually surgically removed through enucleation of the greatest pancreatic lesions or distal pancreatic resection preserving splenic vessels and spleen. If the tumor cannot be completely removed by surgery, the drug inhibits insulin release and it is able to control hypoglicemia in at least 50% of patients.Non-functioning neuroendocrine tumors of the gastro-entero-pancreatic tract are usually treated by surgery. Surgery is indicated when the dimension of tumors is approximately 2 cm in diameter or when imaging exams during the follow-up shows a significant growth of lesions. In case of unresectable tumors or advanced metastatic cancer some medical therapies can be considered: SSAs, peptide receptor radionuclide therapy (PRRT), cytotoxic chemotherapy, inhibitors of thyrosin kinase receptors, inhibitors of mammalian target of rapamycin.Carcinoid tumors are generally removed surgically. Medications including octreotide and lanreotide can be used to treat excess hormone production from these tumors, but the risk for malignant transformation remains. For this purpose, removal of thymus, through a transcervical approach, is recommended at the time of neck surgery for parathyroidectomy.Lipomas may be removed surgically. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Multiple Endocrine Neoplasia Type 1
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nord_839_0
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Overview of Multiple Endocrine Neoplasia Type 2
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Multiple endocrine neoplasia type 2 (MEN2) is a rare genetic polyglandular cancer syndrome, characterized by the 100% prevalence of medullary thyroid carcinoma (MTC) and an increased risk of develop other specific tumors affecting additional glands of the endocrine system. The endocrine system is the network of glands that secrete hormones into the bloodstream to reach distant target tissues and organs within the body. Hormones are active molecules, which through their binding to specific receptors in the target cells, regulate the chemical processes (metabolism) that influence vital processes and functions of various organs, including regulating heart rate, body temperature and blood pressure.MEN2 endocrine tumors may secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms.This syndrome includes two main clinical subtypes, characterized by different clinical characteristics (phenotype):MEN2A (accounting for 95% of all MEN2 cases); characterized by the uniform presence of MTC in association with tumors of the inner part of the adrenal gland called pheocromocytoma (PHEO) or tumors of the parathyroid gland called adenoma or both in some patients.MEN2B (accounting for less than 5% of all MEN2 cases); characterized by a 100% prevalence of an earlier onset and more severe MTC, PHEO but not PHPT.MEN2A includes four subvariants:The total prevalence of all MEN2A and MEN2B variants is approximately 1/35,000.MEN2 can run in families (familial cases) or can occur as the result of a spontaneous genetic change (i.e., new mutation) that occurs randomly for no apparent reason at embryo level.
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Overview of Multiple Endocrine Neoplasia Type 2. Multiple endocrine neoplasia type 2 (MEN2) is a rare genetic polyglandular cancer syndrome, characterized by the 100% prevalence of medullary thyroid carcinoma (MTC) and an increased risk of develop other specific tumors affecting additional glands of the endocrine system. The endocrine system is the network of glands that secrete hormones into the bloodstream to reach distant target tissues and organs within the body. Hormones are active molecules, which through their binding to specific receptors in the target cells, regulate the chemical processes (metabolism) that influence vital processes and functions of various organs, including regulating heart rate, body temperature and blood pressure.MEN2 endocrine tumors may secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms.This syndrome includes two main clinical subtypes, characterized by different clinical characteristics (phenotype):MEN2A (accounting for 95% of all MEN2 cases); characterized by the uniform presence of MTC in association with tumors of the inner part of the adrenal gland called pheocromocytoma (PHEO) or tumors of the parathyroid gland called adenoma or both in some patients.MEN2B (accounting for less than 5% of all MEN2 cases); characterized by a 100% prevalence of an earlier onset and more severe MTC, PHEO but not PHPT.MEN2A includes four subvariants:The total prevalence of all MEN2A and MEN2B variants is approximately 1/35,000.MEN2 can run in families (familial cases) or can occur as the result of a spontaneous genetic change (i.e., new mutation) that occurs randomly for no apparent reason at embryo level.
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Multiple Endocrine Neoplasia Type 2
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nord_839_1
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Symptoms of Multiple Endocrine Neoplasia Type 2
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The onset, progression, and specific symptoms of each case of MEN2 can vary, even among members of the same family. Some individuals may only develop mild symptoms; others may develop serious, life-threatening complications. Some individuals may develop symptoms during infancy or early childhood; others may not develop symptoms until adolescence or young adulthood. Some cases of MEN2 may not become apparent until later during adulthood. Nearly all individuals with MEN2 develop medullary thyroid carcinoma (MTC), usually very early in life. Additional symptoms vary depending upon the specific subtype of the syndrome. It is important to note that individual cases are highly variable and that not all the affected individuals will develop all of the symptoms discussed below. Three are the endocrine glands most often affected in MEN2 syndrome: the thyroid, the adrenal glands and, only in the MEN2A variants, the parathyroids. The thyroid is a small, butterfly-shaped gland located in the front of the neck. The thyroid absorbs iodine (a substance found in many foods) from the blood. The thyroid converts iodine into thyroid hormones, which are essential to regulate the chemical processes (metabolism) of virtually every cell in the body. The adrenal glands are located on top of the kidneys and produce two hormones called epinephrine and norepinephrine. Other hormones produced by the adrenal glands help to regulate the fluid and electrolyte balance in the body. The parathyroid glands are four very small glands (approximately the size of a pea) located in the neck that secrete parathyroid hormone (PTH), the principal regulator of calcium homeostasis and serum calcium level. Multiple Endocrine Neoplasia Type 2A
The first clinical manifestation in MEN2A is, in the majority of cases, is the MTC. Some individuals may have overgrowth (hyperplasia) of thyroid cells (C-cell hyperplasia), a condition that is a benign process, but is considered a precursor to the development of MTC. Nearly all individuals with MEN2A develop C-cell hyperplasia or MTC at some point during their lives. Signs of MTC can be seen early during childhood. If MTC is not detected and treated during childhood, most individuals will develop a mass in the neck or pain in the neck between 15 to 20 years of age. Approximately 50 percent of individuals with MEN2A will develop a PHEO, a usually benign tumor of the adrenal glands; in many cases of MEN2 both the adrenal glands are affected (bilateral PHEO). In rare MEN2A cases, PHEO can manifest as first clinical sign of the syndrome; the first symptom of a PHEO is usually high blood pressure not responding to pharmacological therapy (intractable hypertension). Other associated symptoms can be headache, palpitations, nervousness, and tachycardia. PHEO is almost always benign (noncancerous), but in approximately 4% of MEN2A patients malignant transformation can occur. Approximately 20-30% of MEN2A cases have PHPT due to overgrowth (hyperplasia) of parathyroid tissue or development of a benign tumor in the parathyroid glands (adenoma); one to four glands can be affected during lifetime. MEN2A PHPT is usually mild and asymptomatic. Symptoms, due to hypercalcemia, can be depression, muscle weakness and fatigue. In addition to the classical MEN2A, there are other two, extremely rare, variants which show additional specific symptoms. One variant of MEN2A is associated with cutaneous lichen amyloidosis (CLA), a condition in which a scaly, itchy skin rash develops due to the accumulation of certain proteins (amyloids) in the skin. These dermatological lesions are particularly evident in the scapular region of the back and have as classical symptom an intense pruritus that improves with sun exposure and worsens during periods of stress. In some cases, the CLA may be present at a young age and manifest prior to the onset of clinically evident MTC, thus serving as a sign for an early diagnosis of the syndrome. The second variant of MEN2A is associated with Hirschsprung disease, a gastrointestinal condition characterized by absence of certain nerve cell bodies (ganglia) in the smooth muscle wall within a region of the large intestine (i.e., colon). As a result, there is absence or impairment of the involuntary, rhythmic contractions that propel food through the GI tract (peristalsis). Symptoms of Hirschsprung disease include constipation, vomiting, loss of appetite, bloating or swelling (distention) of the abdomen, abnormal accumulation of feces within the colon, and widening of the colon above the affected segment (megacolon). Hirschsprung disease can eventually cause diarrhea, dehydration, and failure to grow and gain weight at the expected rate (failure to thrive). Multiple Endocrine Neoplasia Type 2B
The MEN2B subtype accounts for about 5% all cases of MEN2. MEN2B was formerly called MEN type 3 (MEN3); currently MEN2B is considered a clinically more aggressive variant of MEN2. Associated symptoms can vary greatly from one person to another. Some symptoms can be very subtle in certain cases. MTC usually occurs earlier in MEN2B than in MEN2A and is usually more aggressive. A neck mass may be detectable during childhood. Most affected children receive a thyroidectomy (surgical removal of the thyroid) at an early age because MTC can potentially spread (metastasize) at a very early age. In presence of certain specific RET variation, associated to a particularly aggressive form of MTC, a prophylactic thyroidectomy is suggested during the first year of age. PHEO occurs in approximately 50% of cases of MEN2B (50% of them being bilateral PHEO), with no differences in occurrence and clinical presentation from individuals with MEN2A. PHPT is absent in MEN2B. Individuals with MEN2B also have additional symptoms not present in all the MEN2A subtypes. MEN2B can be associated with development, during infancy or early childhood, of multiple, benign tumors, called neuromas, arising from certain nerve cells. MEN2B neuromas usually affect the mucous membranes (mucosa) lining the surface of the tongue, lips, the roof of the mouth (palate), eyelids, voice box (larynx), pharynx and nasal passages. The conjunctiva, the thin, clear membrane that covers the whites of the eyes, may also be affected. The presence of multiple neuromas can cause affected areas to appear swollen such as the lips, which often appear full and prominent. Infants and children with MEN2B may have additional distinctive facial features including eyelids that are flared forwarded (anteverted), broad-based nose, a wide-expression, and a coarse, elongated facial appearance. These distinctive facial features are not always present. In MEN2B, benign growths arising from nerve cells called ganglion cells may also occur (ganglioneuromatosis). These growths occur in the gastrointestinal tract and may cause swelling (distention) of the abdomen, diarrhea, constipation, and an abnormally enlarged colon (megacolon). Affected infants often fail to gain weight and grow at the expected rate for age and sex (failure to thrive). Some individuals with MEN2B may develop additional symptoms including a sunken breastbone (pectus excavatum), lax or loose joints, abnormal curvature of the spine, muscle weakness, and a “marfanoid habitus”, a condition in which affected individuals tend to be thin with unusually tall stature; long, slender fingers and toes (arachnodactyly); and elongated arms and legs. The term “marfanoid” refers to Marfan syndrome, a distinct genetic disorder in which these findings are characteristic. MEN2B is unrelated to Marfan syndrome other than sharing some similarities in build. Familial Medullary Thyroid Carcinoma
By definition, familial medullary thyroid carcinoma (FMTC) must occur in at least four members of a family in the absence of additional signs and symptoms MEN2A or MEN2B such as PHEO or parathyroid adenoma. MTC is less aggressive in this variant than other MEN2A variants and MEN2B familial form then when it is associated with MEN types 2A or 2B. Onset is usually during adulthood. FMTC is now considered a variant of MEN2A with a partial clinical penetrance. Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) is a form of cancer that arises from certain cells within the thyroid called C cells (parafollicular cells). This type of cell produces the hormone calcitonin, which helps to regulate calcium metabolism. MTC is an aggressive form of cancer and may spread via the lymph nodes or bloodstream to affect other organs. The first sign of MTC is often a firm mass in the thyroid or abnormal enlargement of nearby lymph nodes (lymphadenopathy). An MTC mass in the neck may be painful. MTC can spread (metastasize) to other areas of the body. Because MTC can be cured by surgical removal of the thyroid, prompt diagnosis of this condition is essential to prevent the cancer from spreading. Individuals with MTC that progresses to cause a large tumor or that spreads to other areas of the body may develop chronic diarrhea as a result of the overproduction of calcitonin. If MTC spreads, it may cause abdominal pain, jaundice and in rare cases bone pain or tenderness. Pheochromoctyoma
Pheochromocytoma (PHEO) is a rare type of tumor that arises from certain cells known as chromaffin cells, which produce hormones necessary for the body to function properly. PHEO produce norepinephrine and epinephrine, hormones that are involved with the sympathetic nervous system, which controls various involuntary activities in the body such as raising blood pressure or regulating the heartbeat. Most PHEOs originate in one of the two adrenal glands located above the kidneys. Most chromaffin cells are found in the adrenal gland’s inner layer, which is known as the adrenal medulla. Symptoms associated with PHEO include high blood pressure (hypertension), chronic headaches, excessive sweating, and/or heart palpitations. Nervousness, anxiety, and loss of color (blanching) of the skin may also occur. High blood pressure associated with PHEO often does not respond to therapy (intractable hypertension).In some cases, an undetected PHEO can potentially cause life-threatening complications such as hypertensive crisis when undergoing procedures requiring anesthesia. Hypertensive crisis is a severe increase in blood pressure that can damage blood vessels and lead to a stroke. However, because of better diagnosis, recognition, and therapies regarding PHEO, such life-threatening complications are rare in individuals with MEN2 who develop PHEO. Parathyroid
The parathyroid glands are four very small glands (approximately the size of a pea) located in the neck that secrete PTH, the main hormonal regulator of calcium homeostasis and serum calcium level. Hyperparathyroidism is a clinical condition indicating a prolonged high level of circulating PTH, which can be associated to hypercalcemia. Hyperparathyroidism can be very mild and may not cause any obvious symptoms (asymptomatic), or, conversely, it can result in persistent elevated serum level of calcium (hypercalcemia), which can eventually cause kidney stones or damage the kidneys or be responsible for bone demineralization (osteoporosis) and increased risk of fragility fractures. Hyperparathyroidism-derived hypercalcemia can cause additional symptoms including fatigue, weakness, constipation, nausea, ulcers, indigestion, high blood pressure (hypertension), and muscle or bone pain. Central nervous system abnormalities can eventually develop including mental status changes, lethargy, depression, and confusion. Most individuals with hyperparathyroidism do not develop all of these symptoms, especially when the condition is diagnosed early.
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Symptoms of Multiple Endocrine Neoplasia Type 2. The onset, progression, and specific symptoms of each case of MEN2 can vary, even among members of the same family. Some individuals may only develop mild symptoms; others may develop serious, life-threatening complications. Some individuals may develop symptoms during infancy or early childhood; others may not develop symptoms until adolescence or young adulthood. Some cases of MEN2 may not become apparent until later during adulthood. Nearly all individuals with MEN2 develop medullary thyroid carcinoma (MTC), usually very early in life. Additional symptoms vary depending upon the specific subtype of the syndrome. It is important to note that individual cases are highly variable and that not all the affected individuals will develop all of the symptoms discussed below. Three are the endocrine glands most often affected in MEN2 syndrome: the thyroid, the adrenal glands and, only in the MEN2A variants, the parathyroids. The thyroid is a small, butterfly-shaped gland located in the front of the neck. The thyroid absorbs iodine (a substance found in many foods) from the blood. The thyroid converts iodine into thyroid hormones, which are essential to regulate the chemical processes (metabolism) of virtually every cell in the body. The adrenal glands are located on top of the kidneys and produce two hormones called epinephrine and norepinephrine. Other hormones produced by the adrenal glands help to regulate the fluid and electrolyte balance in the body. The parathyroid glands are four very small glands (approximately the size of a pea) located in the neck that secrete parathyroid hormone (PTH), the principal regulator of calcium homeostasis and serum calcium level. Multiple Endocrine Neoplasia Type 2A
The first clinical manifestation in MEN2A is, in the majority of cases, is the MTC. Some individuals may have overgrowth (hyperplasia) of thyroid cells (C-cell hyperplasia), a condition that is a benign process, but is considered a precursor to the development of MTC. Nearly all individuals with MEN2A develop C-cell hyperplasia or MTC at some point during their lives. Signs of MTC can be seen early during childhood. If MTC is not detected and treated during childhood, most individuals will develop a mass in the neck or pain in the neck between 15 to 20 years of age. Approximately 50 percent of individuals with MEN2A will develop a PHEO, a usually benign tumor of the adrenal glands; in many cases of MEN2 both the adrenal glands are affected (bilateral PHEO). In rare MEN2A cases, PHEO can manifest as first clinical sign of the syndrome; the first symptom of a PHEO is usually high blood pressure not responding to pharmacological therapy (intractable hypertension). Other associated symptoms can be headache, palpitations, nervousness, and tachycardia. PHEO is almost always benign (noncancerous), but in approximately 4% of MEN2A patients malignant transformation can occur. Approximately 20-30% of MEN2A cases have PHPT due to overgrowth (hyperplasia) of parathyroid tissue or development of a benign tumor in the parathyroid glands (adenoma); one to four glands can be affected during lifetime. MEN2A PHPT is usually mild and asymptomatic. Symptoms, due to hypercalcemia, can be depression, muscle weakness and fatigue. In addition to the classical MEN2A, there are other two, extremely rare, variants which show additional specific symptoms. One variant of MEN2A is associated with cutaneous lichen amyloidosis (CLA), a condition in which a scaly, itchy skin rash develops due to the accumulation of certain proteins (amyloids) in the skin. These dermatological lesions are particularly evident in the scapular region of the back and have as classical symptom an intense pruritus that improves with sun exposure and worsens during periods of stress. In some cases, the CLA may be present at a young age and manifest prior to the onset of clinically evident MTC, thus serving as a sign for an early diagnosis of the syndrome. The second variant of MEN2A is associated with Hirschsprung disease, a gastrointestinal condition characterized by absence of certain nerve cell bodies (ganglia) in the smooth muscle wall within a region of the large intestine (i.e., colon). As a result, there is absence or impairment of the involuntary, rhythmic contractions that propel food through the GI tract (peristalsis). Symptoms of Hirschsprung disease include constipation, vomiting, loss of appetite, bloating or swelling (distention) of the abdomen, abnormal accumulation of feces within the colon, and widening of the colon above the affected segment (megacolon). Hirschsprung disease can eventually cause diarrhea, dehydration, and failure to grow and gain weight at the expected rate (failure to thrive). Multiple Endocrine Neoplasia Type 2B
The MEN2B subtype accounts for about 5% all cases of MEN2. MEN2B was formerly called MEN type 3 (MEN3); currently MEN2B is considered a clinically more aggressive variant of MEN2. Associated symptoms can vary greatly from one person to another. Some symptoms can be very subtle in certain cases. MTC usually occurs earlier in MEN2B than in MEN2A and is usually more aggressive. A neck mass may be detectable during childhood. Most affected children receive a thyroidectomy (surgical removal of the thyroid) at an early age because MTC can potentially spread (metastasize) at a very early age. In presence of certain specific RET variation, associated to a particularly aggressive form of MTC, a prophylactic thyroidectomy is suggested during the first year of age. PHEO occurs in approximately 50% of cases of MEN2B (50% of them being bilateral PHEO), with no differences in occurrence and clinical presentation from individuals with MEN2A. PHPT is absent in MEN2B. Individuals with MEN2B also have additional symptoms not present in all the MEN2A subtypes. MEN2B can be associated with development, during infancy or early childhood, of multiple, benign tumors, called neuromas, arising from certain nerve cells. MEN2B neuromas usually affect the mucous membranes (mucosa) lining the surface of the tongue, lips, the roof of the mouth (palate), eyelids, voice box (larynx), pharynx and nasal passages. The conjunctiva, the thin, clear membrane that covers the whites of the eyes, may also be affected. The presence of multiple neuromas can cause affected areas to appear swollen such as the lips, which often appear full and prominent. Infants and children with MEN2B may have additional distinctive facial features including eyelids that are flared forwarded (anteverted), broad-based nose, a wide-expression, and a coarse, elongated facial appearance. These distinctive facial features are not always present. In MEN2B, benign growths arising from nerve cells called ganglion cells may also occur (ganglioneuromatosis). These growths occur in the gastrointestinal tract and may cause swelling (distention) of the abdomen, diarrhea, constipation, and an abnormally enlarged colon (megacolon). Affected infants often fail to gain weight and grow at the expected rate for age and sex (failure to thrive). Some individuals with MEN2B may develop additional symptoms including a sunken breastbone (pectus excavatum), lax or loose joints, abnormal curvature of the spine, muscle weakness, and a “marfanoid habitus”, a condition in which affected individuals tend to be thin with unusually tall stature; long, slender fingers and toes (arachnodactyly); and elongated arms and legs. The term “marfanoid” refers to Marfan syndrome, a distinct genetic disorder in which these findings are characteristic. MEN2B is unrelated to Marfan syndrome other than sharing some similarities in build. Familial Medullary Thyroid Carcinoma
By definition, familial medullary thyroid carcinoma (FMTC) must occur in at least four members of a family in the absence of additional signs and symptoms MEN2A or MEN2B such as PHEO or parathyroid adenoma. MTC is less aggressive in this variant than other MEN2A variants and MEN2B familial form then when it is associated with MEN types 2A or 2B. Onset is usually during adulthood. FMTC is now considered a variant of MEN2A with a partial clinical penetrance. Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) is a form of cancer that arises from certain cells within the thyroid called C cells (parafollicular cells). This type of cell produces the hormone calcitonin, which helps to regulate calcium metabolism. MTC is an aggressive form of cancer and may spread via the lymph nodes or bloodstream to affect other organs. The first sign of MTC is often a firm mass in the thyroid or abnormal enlargement of nearby lymph nodes (lymphadenopathy). An MTC mass in the neck may be painful. MTC can spread (metastasize) to other areas of the body. Because MTC can be cured by surgical removal of the thyroid, prompt diagnosis of this condition is essential to prevent the cancer from spreading. Individuals with MTC that progresses to cause a large tumor or that spreads to other areas of the body may develop chronic diarrhea as a result of the overproduction of calcitonin. If MTC spreads, it may cause abdominal pain, jaundice and in rare cases bone pain or tenderness. Pheochromoctyoma
Pheochromocytoma (PHEO) is a rare type of tumor that arises from certain cells known as chromaffin cells, which produce hormones necessary for the body to function properly. PHEO produce norepinephrine and epinephrine, hormones that are involved with the sympathetic nervous system, which controls various involuntary activities in the body such as raising blood pressure or regulating the heartbeat. Most PHEOs originate in one of the two adrenal glands located above the kidneys. Most chromaffin cells are found in the adrenal gland’s inner layer, which is known as the adrenal medulla. Symptoms associated with PHEO include high blood pressure (hypertension), chronic headaches, excessive sweating, and/or heart palpitations. Nervousness, anxiety, and loss of color (blanching) of the skin may also occur. High blood pressure associated with PHEO often does not respond to therapy (intractable hypertension).In some cases, an undetected PHEO can potentially cause life-threatening complications such as hypertensive crisis when undergoing procedures requiring anesthesia. Hypertensive crisis is a severe increase in blood pressure that can damage blood vessels and lead to a stroke. However, because of better diagnosis, recognition, and therapies regarding PHEO, such life-threatening complications are rare in individuals with MEN2 who develop PHEO. Parathyroid
The parathyroid glands are four very small glands (approximately the size of a pea) located in the neck that secrete PTH, the main hormonal regulator of calcium homeostasis and serum calcium level. Hyperparathyroidism is a clinical condition indicating a prolonged high level of circulating PTH, which can be associated to hypercalcemia. Hyperparathyroidism can be very mild and may not cause any obvious symptoms (asymptomatic), or, conversely, it can result in persistent elevated serum level of calcium (hypercalcemia), which can eventually cause kidney stones or damage the kidneys or be responsible for bone demineralization (osteoporosis) and increased risk of fragility fractures. Hyperparathyroidism-derived hypercalcemia can cause additional symptoms including fatigue, weakness, constipation, nausea, ulcers, indigestion, high blood pressure (hypertension), and muscle or bone pain. Central nervous system abnormalities can eventually develop including mental status changes, lethargy, depression, and confusion. Most individuals with hyperparathyroidism do not develop all of these symptoms, especially when the condition is diagnosed early.
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Multiple Endocrine Neoplasia Type 2
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nord_839_2
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Causes of Multiple Endocrine Neoplasia Type 2
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MEN2 is caused by a change (mutation) of the RET gene. The RET gene is an oncogene, a gene that plays a role in the development of cancer. When operating normally, the RET protein produced by the RET gene exerts several key functions including control of cell division and regulation of cell death (apoptosis). Activating mutations of the RET gene lead to uncontrolled growth of cells, causing tumor formation in target organs. MEN2 is a dominant genetic disorder. A single copy of a mutated RET gene is sufficient for the appearance of the disease. The RET mutation may be inherited from one of the parents, or occur as a spontaneous genetic change (new mutation) that occurs randomly for no apparent reason at embryo level. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy, with equal risk for male and female children. No somatic mutations of the second copy of the RET gene have been reported or necessary for the development of tumors (as for MEN1 syndrome). Specific RET mutations drive the clinical presentation of the disease (genotype-phenotype correlation) and the identification of the mutation in patients can direct the therapeutic approaches for both MTC and PHEO, and the diagnostic plan for PHPT.
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Causes of Multiple Endocrine Neoplasia Type 2. MEN2 is caused by a change (mutation) of the RET gene. The RET gene is an oncogene, a gene that plays a role in the development of cancer. When operating normally, the RET protein produced by the RET gene exerts several key functions including control of cell division and regulation of cell death (apoptosis). Activating mutations of the RET gene lead to uncontrolled growth of cells, causing tumor formation in target organs. MEN2 is a dominant genetic disorder. A single copy of a mutated RET gene is sufficient for the appearance of the disease. The RET mutation may be inherited from one of the parents, or occur as a spontaneous genetic change (new mutation) that occurs randomly for no apparent reason at embryo level. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy, with equal risk for male and female children. No somatic mutations of the second copy of the RET gene have been reported or necessary for the development of tumors (as for MEN1 syndrome). Specific RET mutations drive the clinical presentation of the disease (genotype-phenotype correlation) and the identification of the mutation in patients can direct the therapeutic approaches for both MTC and PHEO, and the diagnostic plan for PHPT.
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Multiple Endocrine Neoplasia Type 2
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nord_839_3
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Affects of Multiple Endocrine Neoplasia Type 2
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MEN2 affects males and females in equal numbers. It has been estimated to affect 1 in 35,000 people in the general population. Some researchers believe that many cases of MEN2 go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. MEN2A is the most common subtype accounting for about 95% of all cases. MEN2B accounts only 5% of cases. All cases of MTC (i.e. including both those associated with MEN2 and those arising at sporadic tumors) account for approximately 5-10% of all thyroid cancers.
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Affects of Multiple Endocrine Neoplasia Type 2. MEN2 affects males and females in equal numbers. It has been estimated to affect 1 in 35,000 people in the general population. Some researchers believe that many cases of MEN2 go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. MEN2A is the most common subtype accounting for about 95% of all cases. MEN2B accounts only 5% of cases. All cases of MTC (i.e. including both those associated with MEN2 and those arising at sporadic tumors) account for approximately 5-10% of all thyroid cancers.
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Multiple Endocrine Neoplasia Type 2
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nord_839_4
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Related disorders of Multiple Endocrine Neoplasia Type 2
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Symptoms of the following disorders can be similar to those of MEN2. Comparisons may be useful for a differential diagnosis. Thyroid cancers (carcinoma) are tumors affecting the thyroid gland, a butterfly-shaped structure located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body’s activities as well as regulating the heart rate, body temperature, and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body. In many cases, there are no symptoms (asymptomatic) associated with thyroid cancer. Pain in the neck, hoarseness and swollen lymph nodes especially in the neck may be present in some cases. Different forms of cancer, including thyroid cancer, may be classified based upon the cell type involved, the specific nature of the malignancy, and the disease’s clinical course. The four main types of thyroid cancer are papillary, follicular, medullary and anaplastic. Rare forms of thyroid cancer include thyroid teratoma, lymphoma, and squamous cell carcinoma. Although thyroid cancer is rare, it is the most common form of cancer affecting the endocrine system. Most forms rarely cause pain or disability and are easily treated with surgery and follow-up therapy. (For more information on this disorder, choose “thyroid cancer” as your search term in the Rare Disease Database.) Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disorder in which benign (noncancerous) tumors arise from the cells of multiple glands of the endocrine system in a single patient, mainly parathyroids, neuroendocrine cells of the gastro-entero-pancreatic tract and anterior pituitary. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms. Some benign tumors associated with MEN type 1 can become malignant (cancerous). MEN1 can run in families or can occur as the result of a spontaneous genetic change (i.e., new mutation) that occurs randomly for no apparent reason. (For more information on this disorder, choose “multiple endocrine neoplasia” as your search term in the Rare Disease Database.) The various tumors associated with MEN1 can occur also as isolated conditions or as part of other complex inherited syndromic or non-syndromic disorders, including familial isolated hyperparathyroidism, hereditary hyperparathyroidism and jaw tumor, von Hippel-Lindau syndrome, Carney complex, and Zollinger-Ellison syndrome. When these tumors secrete excessive hormones into the bloodstream a variety of different conditions can result including hyperparathyroidism, acromegaly, Cushing’s syndrome, hypoglycemia, hyperglycemia, and carcinoid syndrome. (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 Multiple Endocrine Neoplasia Type 2. Symptoms of the following disorders can be similar to those of MEN2. Comparisons may be useful for a differential diagnosis. Thyroid cancers (carcinoma) are tumors affecting the thyroid gland, a butterfly-shaped structure located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body’s activities as well as regulating the heart rate, body temperature, and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body. In many cases, there are no symptoms (asymptomatic) associated with thyroid cancer. Pain in the neck, hoarseness and swollen lymph nodes especially in the neck may be present in some cases. Different forms of cancer, including thyroid cancer, may be classified based upon the cell type involved, the specific nature of the malignancy, and the disease’s clinical course. The four main types of thyroid cancer are papillary, follicular, medullary and anaplastic. Rare forms of thyroid cancer include thyroid teratoma, lymphoma, and squamous cell carcinoma. Although thyroid cancer is rare, it is the most common form of cancer affecting the endocrine system. Most forms rarely cause pain or disability and are easily treated with surgery and follow-up therapy. (For more information on this disorder, choose “thyroid cancer” as your search term in the Rare Disease Database.) Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disorder in which benign (noncancerous) tumors arise from the cells of multiple glands of the endocrine system in a single patient, mainly parathyroids, neuroendocrine cells of the gastro-entero-pancreatic tract and anterior pituitary. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms. Some benign tumors associated with MEN type 1 can become malignant (cancerous). MEN1 can run in families or can occur as the result of a spontaneous genetic change (i.e., new mutation) that occurs randomly for no apparent reason. (For more information on this disorder, choose “multiple endocrine neoplasia” as your search term in the Rare Disease Database.) The various tumors associated with MEN1 can occur also as isolated conditions or as part of other complex inherited syndromic or non-syndromic disorders, including familial isolated hyperparathyroidism, hereditary hyperparathyroidism and jaw tumor, von Hippel-Lindau syndrome, Carney complex, and Zollinger-Ellison syndrome. When these tumors secrete excessive hormones into the bloodstream a variety of different conditions can result including hyperparathyroidism, acromegaly, Cushing’s syndrome, hypoglycemia, hyperglycemia, and carcinoid syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Multiple Endocrine Neoplasia Type 2
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Diagnosis of Multiple Endocrine Neoplasia Type 2
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Affected individuals may receive a clinical diagnosis of MEN2 following a specific clinical evaluation for MEN2-associated tumors, a detailed patient and familial history and the identification of characteristic features. The characteristic features of MEN2A are the presence of two or more specific endocrine tumors (i.e., MTC, PHEO, and parathyroid hyperplasia or adenoma). Diagnostic features of MEN2B include the identification of MTC, PHEO, multiple neuromas, distinctive facial features, and a “marfanoid” habitus. FMTC is diagnosed in individuals with only MTC in at least four family members without the presence of other symptoms associated with MEN2A or MEN2B. A variety of tests can aid in the diagnosis of MEN2. Such tests include those designed to detect elevated levels of certain hormones in the blood. Identification of elevated hormones in the blood can be an indication of specific endocrine tumors. For example, identification of elevated levels of calcitonin can indicate the presence of MTC, elevated levels of PTH can indicate the presence of a parathyroid tumor, and elevated levels of catecholamines may indicate the presence of an active PHEO. A variety of imaging (x-ray) scans may also be performed to aid in identifying the size and specific location of tumors, and lead surgical interventions. The clinical diagnosis of MEN2 can be confirmed by genetic diagnosis through molecular genetic testing identifying a missense mutation of the RET gene.
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Diagnosis of Multiple Endocrine Neoplasia Type 2. Affected individuals may receive a clinical diagnosis of MEN2 following a specific clinical evaluation for MEN2-associated tumors, a detailed patient and familial history and the identification of characteristic features. The characteristic features of MEN2A are the presence of two or more specific endocrine tumors (i.e., MTC, PHEO, and parathyroid hyperplasia or adenoma). Diagnostic features of MEN2B include the identification of MTC, PHEO, multiple neuromas, distinctive facial features, and a “marfanoid” habitus. FMTC is diagnosed in individuals with only MTC in at least four family members without the presence of other symptoms associated with MEN2A or MEN2B. A variety of tests can aid in the diagnosis of MEN2. Such tests include those designed to detect elevated levels of certain hormones in the blood. Identification of elevated hormones in the blood can be an indication of specific endocrine tumors. For example, identification of elevated levels of calcitonin can indicate the presence of MTC, elevated levels of PTH can indicate the presence of a parathyroid tumor, and elevated levels of catecholamines may indicate the presence of an active PHEO. A variety of imaging (x-ray) scans may also be performed to aid in identifying the size and specific location of tumors, and lead surgical interventions. The clinical diagnosis of MEN2 can be confirmed by genetic diagnosis through molecular genetic testing identifying a missense mutation of the RET gene.
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Multiple Endocrine Neoplasia Type 2
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Therapies of Multiple Endocrine Neoplasia Type 2
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Treatment
The treatment of MEN2 may require the coordinated efforts of a team of specialists. Endocrinologists, surgeons, cancer specialists (oncologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Treatment is directed toward the specific symptoms that are apparent in each individual and may include surgical removal of tumors and drugs to counteract the effects of excess hormones or replacement of hormones no longer produced by the body (i.e., following surgical removal of a gland).Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as the specific subtype present, whether C-cell hyperplasia or cancer has developed; the size and type of tumors; the severity of symptoms due to excess hormone production; whether malignant cancer is already present and whether it has spread to lymph nodes or distant sites; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.Because of advancements made in the recognition, genetics (i.e., identifying the mutated gene), and treatment of MEN2, certain serious, life-threatening complications associated with the disorder such as the spread (metastasis) of MTC or rare complications of a PHEO have been greatly reduced. The result of the genetic test can drive the therapeutic approaches for both MTC and PHEO.The standard therapy for individuals with MEN2 is surgical removal of the thyroid, a procedure called a thyroidectomy. Surgical removal of the thyroid is often performed as a preventive measure, even if cancer or C-cell hyperplasia has not developed yet. Individuals will require life-long hormone replacement therapy of the hormones normally produced by the thyroid. The age of thyroidectomy performance may vary depending upon the specific MEN2 subtype and the specific RET mutation. The recommendations on the timing of prophylactic total thyroidectomy and extent of surgery are classified, accordingly to the American Thyroid Association (ATA), into three risk levels (highest risk, high risk, and moderate risk), based on the specific RET gene mutation:In all three cases, a life-long thyroid hormone supplementation is needed after thyroid removal.Thyroidectomy can potentially cause the partial or complete ablation of the parathyroid glands causing severe reduction/absence of PTH (hypoparathyroidism). The ability of surgeon is important in identifying parathyroid glands and preserving them to be re-implanted (autotransplant) into the non-dominant forearm, reducing/avoiding the risk of post-operatory hypoparathyroidism. Post-operatory hypoparathyroidism requires life-long treatment with calcium and vitamin D analogues.MEN2A PHPT is usually mild and it can be controlled by medical therapy with calcimimetics or, more frequently, by the surgical removal of the parathyroid gland followed by the re-implantation of some healthy parathyroid tissue into the arm. Because there is a risk of a benign tumor recurring in the healthy parathyroid tissue, transplanting that tissue into the arm would spare affected individuals from being operated on in the same area (i.e., the neck).Surgery is the main form of therapy for individuals with PHEO. Surgical removal of one or both of the adrenal glands is often performed. Both adrenal glands are often removed even in individuals with a PHEO affecting only one gland (unilateral) because of the high risk of the other adrenal gland becoming affected later on. The most common surgical procedure for treating PHEO is laparoscopic laparotomy. During this procedure, a small incision is made in the abdomen, a small tube is inserted (laparoscope) through the incision, and the tumor is removed. Before surgery, some affected individuals may need to be treated with alpha-adrenergic blockers and beta-adrenergic blockers to minimize the effects of adrenal hormones. Alpha-adrenergic blockers such as phenoxybenzamine are used to control hypertension. In some cases, beta-adrenergic blockers such as propranolol can also be used to treat hypertension.In cases where MTC has spread or where malignant transformation of a PHEO has occurred chemotherapy or radiation therapy may be used.Before any surgery for individuals with MEN2, screening for the presence of an active PHEO should be performed because of the risk of anesthesia-induced hypertensive crisis.The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved two orally administered thyrosin kinase inhibitors (TKIs), Caprelsa (vandetanib) in 2011 and Cabometyx (cabozantinib) in 2012, for the treatment of patients with advanced progressive MTC.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Multiple Endocrine Neoplasia Type 2. Treatment
The treatment of MEN2 may require the coordinated efforts of a team of specialists. Endocrinologists, surgeons, cancer specialists (oncologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Treatment is directed toward the specific symptoms that are apparent in each individual and may include surgical removal of tumors and drugs to counteract the effects of excess hormones or replacement of hormones no longer produced by the body (i.e., following surgical removal of a gland).Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as the specific subtype present, whether C-cell hyperplasia or cancer has developed; the size and type of tumors; the severity of symptoms due to excess hormone production; whether malignant cancer is already present and whether it has spread to lymph nodes or distant sites; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.Because of advancements made in the recognition, genetics (i.e., identifying the mutated gene), and treatment of MEN2, certain serious, life-threatening complications associated with the disorder such as the spread (metastasis) of MTC or rare complications of a PHEO have been greatly reduced. The result of the genetic test can drive the therapeutic approaches for both MTC and PHEO.The standard therapy for individuals with MEN2 is surgical removal of the thyroid, a procedure called a thyroidectomy. Surgical removal of the thyroid is often performed as a preventive measure, even if cancer or C-cell hyperplasia has not developed yet. Individuals will require life-long hormone replacement therapy of the hormones normally produced by the thyroid. The age of thyroidectomy performance may vary depending upon the specific MEN2 subtype and the specific RET mutation. The recommendations on the timing of prophylactic total thyroidectomy and extent of surgery are classified, accordingly to the American Thyroid Association (ATA), into three risk levels (highest risk, high risk, and moderate risk), based on the specific RET gene mutation:In all three cases, a life-long thyroid hormone supplementation is needed after thyroid removal.Thyroidectomy can potentially cause the partial or complete ablation of the parathyroid glands causing severe reduction/absence of PTH (hypoparathyroidism). The ability of surgeon is important in identifying parathyroid glands and preserving them to be re-implanted (autotransplant) into the non-dominant forearm, reducing/avoiding the risk of post-operatory hypoparathyroidism. Post-operatory hypoparathyroidism requires life-long treatment with calcium and vitamin D analogues.MEN2A PHPT is usually mild and it can be controlled by medical therapy with calcimimetics or, more frequently, by the surgical removal of the parathyroid gland followed by the re-implantation of some healthy parathyroid tissue into the arm. Because there is a risk of a benign tumor recurring in the healthy parathyroid tissue, transplanting that tissue into the arm would spare affected individuals from being operated on in the same area (i.e., the neck).Surgery is the main form of therapy for individuals with PHEO. Surgical removal of one or both of the adrenal glands is often performed. Both adrenal glands are often removed even in individuals with a PHEO affecting only one gland (unilateral) because of the high risk of the other adrenal gland becoming affected later on. The most common surgical procedure for treating PHEO is laparoscopic laparotomy. During this procedure, a small incision is made in the abdomen, a small tube is inserted (laparoscope) through the incision, and the tumor is removed. Before surgery, some affected individuals may need to be treated with alpha-adrenergic blockers and beta-adrenergic blockers to minimize the effects of adrenal hormones. Alpha-adrenergic blockers such as phenoxybenzamine are used to control hypertension. In some cases, beta-adrenergic blockers such as propranolol can also be used to treat hypertension.In cases where MTC has spread or where malignant transformation of a PHEO has occurred chemotherapy or radiation therapy may be used.Before any surgery for individuals with MEN2, screening for the presence of an active PHEO should be performed because of the risk of anesthesia-induced hypertensive crisis.The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved two orally administered thyrosin kinase inhibitors (TKIs), Caprelsa (vandetanib) in 2011 and Cabometyx (cabozantinib) in 2012, for the treatment of patients with advanced progressive MTC.Genetic counseling is recommended for affected individuals and their families.
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Multiple Endocrine Neoplasia Type 2
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Overview of Multiple Myeloma
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Multiple myeloma is a rare form of cancer characterized by excessive production (proliferation) and improper function of certain cells (plasma cells) found in the bone marrow. Plasma cells, which are a type of white blood cell, are produced in the bone marrow and normally reside there. Excessive plasma cells may eventually mass together to form a tumor or tumors in various sites of the body, especially the bone marrow. If only a single tumor is present, the term solitary plasmacytoma is used. When multiple tumors are present or the bone marrow has greater than 10% plasma cells, the term multiple myeloma is used.Plasma cells are a key component of the immune system and secrete a substance known as immunoglobulin proteins (M-proteins), a type of antibody. Antibodies are special proteins that the body produces to combat invading microorganisms, toxins, or other foreign substances. Overproduction of plasma cells in affected individuals results in abnormally high levels of these proteins within the body, referred to as M proteins. Major symptoms of multiple myeloma may include bone pain, especially in the back and the ribs; low levels of circulating red blood cells (anemia) resulting in weakness, fatigue, and lack of color (pallor); and kidney (renal) abnormalities. Some affected individuals are more susceptible to bacterial infections such as pneumonia. The cause of multiple myeloma is unknown.
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Overview of Multiple Myeloma. Multiple myeloma is a rare form of cancer characterized by excessive production (proliferation) and improper function of certain cells (plasma cells) found in the bone marrow. Plasma cells, which are a type of white blood cell, are produced in the bone marrow and normally reside there. Excessive plasma cells may eventually mass together to form a tumor or tumors in various sites of the body, especially the bone marrow. If only a single tumor is present, the term solitary plasmacytoma is used. When multiple tumors are present or the bone marrow has greater than 10% plasma cells, the term multiple myeloma is used.Plasma cells are a key component of the immune system and secrete a substance known as immunoglobulin proteins (M-proteins), a type of antibody. Antibodies are special proteins that the body produces to combat invading microorganisms, toxins, or other foreign substances. Overproduction of plasma cells in affected individuals results in abnormally high levels of these proteins within the body, referred to as M proteins. Major symptoms of multiple myeloma may include bone pain, especially in the back and the ribs; low levels of circulating red blood cells (anemia) resulting in weakness, fatigue, and lack of color (pallor); and kidney (renal) abnormalities. Some affected individuals are more susceptible to bacterial infections such as pneumonia. The cause of multiple myeloma is unknown.
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Multiple Myeloma
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Symptoms of Multiple Myeloma
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The specific symptoms, age of onset, and rate of progression of multiple myeloma varies from patient to patient. Some affected individuals will not exhibit any symptoms (asymptomatic or smoldering). Multiple myeloma may progress to cause life-threatening complications. It is important to note that affected individuals will not have all the symptoms listed below.The most common symptom associated with multiple myeloma is bone pain, usually of the lower back or ribs. In most patients, movement worsens the pain, which may be mild, moderate or severe. Affected individuals are usually more susceptible to fractures than the general population and may experience repeated fractures of affected bones. The bones of the spine may become involved, potentially collapsing and resulting in spinal cord compression (rare). Compression of the spinal cord results in pain, weakness and numbness in the arms and legs.Another possible sign of multiple myeloma is an elevated level of calcium in the blood, a condition called hypercalcemia. This occurs because damage to bones often results in the release of calcium into the bloodstream. Abnormally high levels of calcium may result in nausea, lack of appetite, fatigue, abdominal pain, muscle pain and weakness, excessive thirst and/or confusion.Overproduction of plasma cells may also hinder the production and decrease the effectiveness of other cells of the body resulting in a variety of symptoms. Affected individuals may experience low levels of circulating red blood cells (anemia) resulting in weakness, fatigue, dizziness, shortness of breath and lack of color (pallor). Affected individuals may also experience low levels of cells that assist in clotting (platelets), a condition known as thrombocytopenia. Symptoms associated with thrombocytopenia include abnormal bleeding episodes that often result in purplish discoloration of the skin resulting from bleeding (hemorrhaging) of small blood vessels near the surface of the skin (purpura). Rarely, affected individuals may experience repeated nosebleeds (epistaxis).Affected individuals may also have low levels of normal immunoglobulin (antibody) which weakens the immune system and results in a higher susceptibility than the general population to developing recurrent bacterial infections. The most common infection is pneumonia. In some patients, recurrent infections may be the first apparent symptom of multiple myeloma.Individuals with multiple myeloma may also develop kidney abnormalities. In some patients, hypercalcemia may cause kidney damage. Abnormal proteins found in the blood or urine (M-proteins), which are produced by myeloma cells, may cause kidney damage (myeloma kidney). Kidney abnormalities may develop slowly or rapidly and may eventually progress to cause kidney (renal) failure.Rarely, individuals with multiple myeloma may have an abnormally large liver (hepatomegaly) or spleen (splenomegaly). Rarely, multiple myeloma may occur in association with other disorders. The three most common disorders that may occur in association with multiple myeloma include hyperviscosity syndrome, cryoglobulinemia or amyloidosis.Hyperviscosity syndrome is characterized by the blood becoming abnormally thick and sticky due to the abnormal accumulation of M-proteins in the blood. As a result, blood flow is slowed. Hyperviscosity syndrome may cause headaches, nose bleeding, fatigue, frequent bruising, gastrointestinal bleeding, and vision abnormalities such as disease of the retina (retinopathy).Cryoglobulinemia is a rare disorder that occurs due to the accumulation of abnormal proteins (cryoglobulins) in the bloodstream. These proteins thicken or gel on exposure to cold. In some patients there are no symptoms and in others a variety of symptoms may develop. The most common symptoms are joint pain (arthralgia), pain and numbness in the fingers and toes in response to cold (Raynaud’s phenomenon), weakness, and purpura.Amyloidosis is a rare disorder characterized by the abnormal accumulation of a fibrous protein (amyloidosis) in tissues of the body. The excessive accumulation of amyloid causes an affected organ to malfunction. (For more information on this disorder, see the Related Disorders section below.)
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Symptoms of Multiple Myeloma. The specific symptoms, age of onset, and rate of progression of multiple myeloma varies from patient to patient. Some affected individuals will not exhibit any symptoms (asymptomatic or smoldering). Multiple myeloma may progress to cause life-threatening complications. It is important to note that affected individuals will not have all the symptoms listed below.The most common symptom associated with multiple myeloma is bone pain, usually of the lower back or ribs. In most patients, movement worsens the pain, which may be mild, moderate or severe. Affected individuals are usually more susceptible to fractures than the general population and may experience repeated fractures of affected bones. The bones of the spine may become involved, potentially collapsing and resulting in spinal cord compression (rare). Compression of the spinal cord results in pain, weakness and numbness in the arms and legs.Another possible sign of multiple myeloma is an elevated level of calcium in the blood, a condition called hypercalcemia. This occurs because damage to bones often results in the release of calcium into the bloodstream. Abnormally high levels of calcium may result in nausea, lack of appetite, fatigue, abdominal pain, muscle pain and weakness, excessive thirst and/or confusion.Overproduction of plasma cells may also hinder the production and decrease the effectiveness of other cells of the body resulting in a variety of symptoms. Affected individuals may experience low levels of circulating red blood cells (anemia) resulting in weakness, fatigue, dizziness, shortness of breath and lack of color (pallor). Affected individuals may also experience low levels of cells that assist in clotting (platelets), a condition known as thrombocytopenia. Symptoms associated with thrombocytopenia include abnormal bleeding episodes that often result in purplish discoloration of the skin resulting from bleeding (hemorrhaging) of small blood vessels near the surface of the skin (purpura). Rarely, affected individuals may experience repeated nosebleeds (epistaxis).Affected individuals may also have low levels of normal immunoglobulin (antibody) which weakens the immune system and results in a higher susceptibility than the general population to developing recurrent bacterial infections. The most common infection is pneumonia. In some patients, recurrent infections may be the first apparent symptom of multiple myeloma.Individuals with multiple myeloma may also develop kidney abnormalities. In some patients, hypercalcemia may cause kidney damage. Abnormal proteins found in the blood or urine (M-proteins), which are produced by myeloma cells, may cause kidney damage (myeloma kidney). Kidney abnormalities may develop slowly or rapidly and may eventually progress to cause kidney (renal) failure.Rarely, individuals with multiple myeloma may have an abnormally large liver (hepatomegaly) or spleen (splenomegaly). Rarely, multiple myeloma may occur in association with other disorders. The three most common disorders that may occur in association with multiple myeloma include hyperviscosity syndrome, cryoglobulinemia or amyloidosis.Hyperviscosity syndrome is characterized by the blood becoming abnormally thick and sticky due to the abnormal accumulation of M-proteins in the blood. As a result, blood flow is slowed. Hyperviscosity syndrome may cause headaches, nose bleeding, fatigue, frequent bruising, gastrointestinal bleeding, and vision abnormalities such as disease of the retina (retinopathy).Cryoglobulinemia is a rare disorder that occurs due to the accumulation of abnormal proteins (cryoglobulins) in the bloodstream. These proteins thicken or gel on exposure to cold. In some patients there are no symptoms and in others a variety of symptoms may develop. The most common symptoms are joint pain (arthralgia), pain and numbness in the fingers and toes in response to cold (Raynaud’s phenomenon), weakness, and purpura.Amyloidosis is a rare disorder characterized by the abnormal accumulation of a fibrous protein (amyloidosis) in tissues of the body. The excessive accumulation of amyloid causes an affected organ to malfunction. (For more information on this disorder, see the Related Disorders section below.)
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Causes of Multiple Myeloma
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The exact cause of multiple myeloma is not known. Symptoms occur as a result of a process that is initiated by the abnormal multiplication of plasma cells in bone marrow. Scientists suspect there may be a variety of causes that may include environmental factors (e.g., the effects of exposure to radiation), genetic abnormalities, and/or additional factors that may play varying contributing roles. Exposure to dioxin has been associated with an increased risk of myeloma.One factor of interest to researchers is that many myeloma cells have specific genetic abnormalities that impact prognosis. Also, the development of multiple myeloma is preceded in virtually all cases by a condition called monoclonal gammopathy of undetermined significance or MGUS (see Related Disorders section). The cause of MGUS is not known.The specific symptoms of multiple myeloma result from excessive and unnecessary growth (neoplastic proliferation) of plasma cells.
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Causes of Multiple Myeloma. The exact cause of multiple myeloma is not known. Symptoms occur as a result of a process that is initiated by the abnormal multiplication of plasma cells in bone marrow. Scientists suspect there may be a variety of causes that may include environmental factors (e.g., the effects of exposure to radiation), genetic abnormalities, and/or additional factors that may play varying contributing roles. Exposure to dioxin has been associated with an increased risk of myeloma.One factor of interest to researchers is that many myeloma cells have specific genetic abnormalities that impact prognosis. Also, the development of multiple myeloma is preceded in virtually all cases by a condition called monoclonal gammopathy of undetermined significance or MGUS (see Related Disorders section). The cause of MGUS is not known.The specific symptoms of multiple myeloma result from excessive and unnecessary growth (neoplastic proliferation) of plasma cells.
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Multiple Myeloma
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Affects of Multiple Myeloma
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Multiple myeloma is a rare cancer that is slightly more common in males than females. In 2019, over 32,000 individuals in the United States were diagnosed with this disease. It is believed that approximately 100,000 Americans currently have the disease.According to reports in the medical literature, multiple myeloma accounts for approximately 1% of all malignancies in Caucasians and about 2% of all malignancies in individuals of African descent. It accounts for 10% of all hematological malignancies in the United States. The yearly incidence rate is estimated to be approximately 6.5 persons out of 100,000.Multiple myeloma usually becomes apparent between the fourth and seventh decades of life, with a median age of 68 years at diagnosis. The occurrence of the disease before the age of 40 is rare.
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Affects of Multiple Myeloma. Multiple myeloma is a rare cancer that is slightly more common in males than females. In 2019, over 32,000 individuals in the United States were diagnosed with this disease. It is believed that approximately 100,000 Americans currently have the disease.According to reports in the medical literature, multiple myeloma accounts for approximately 1% of all malignancies in Caucasians and about 2% of all malignancies in individuals of African descent. It accounts for 10% of all hematological malignancies in the United States. The yearly incidence rate is estimated to be approximately 6.5 persons out of 100,000.Multiple myeloma usually becomes apparent between the fourth and seventh decades of life, with a median age of 68 years at diagnosis. The occurrence of the disease before the age of 40 is rare.
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Multiple Myeloma
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Related disorders of Multiple Myeloma
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Symptoms of the following disorders can be similar to those of multiple myeloma. Comparisons may be useful for a differential diagnosis:Waldenstrom macroglobulinemia is a lymph and blood cell disorder. Abnormally large quantities of homogeneous protein molecules are present in the blood. The disorder may run in families and occurs after the sixth decade. An enlarged spleen and liver with abnormalities of the lymph glands are the most frequent symptoms. Weakness, anemia, fatigue and excessive bleeding, especially from the nose and mouth, also occur. (For more information on this disorder, choose “Waldenstrom” as your search term in the Rare Disease Database.)Heavy chain diseases are characterized by the presence of too many plasma cells or certain white blood cells (lymphocytes) that resemble plasma cells in the bone marrow and lymph nodes. This condition includes gamma, alpha and Mu heavy chain disease, which are all disorders of the proliferative type. Gamma heavy chain disease is characterized by anemia. The liver, spleen and lymph nodes are enlarged. Alpha heavy chain disease occurs most often in men of Mediterranean ancestry. It involves the digestive tract with severe malabsorption of nutrients, loss of weight, diarrhea and loss of fat (steatorrhea). Symptoms are most often progressive. Mu heavy chain disease is characterized by a form of chronic lymphocytic leukemia or tumors of the lymph gland. Analysis of the blood serum usually reveals excessively low levels of antibodies in the blood (hypogammaglobulinemia).Monoclonal gammopathy of undetermined significance (MGUS) is a condition characterized by the presence of M-proteins in the blood. There may be low levels of M-proteins in the urine. Individuals with MGUS do not have the physical symptoms associated with multiple myeloma (e.g., anemia, bony lesions, kidney abnormalities). Some individuals with MGUS eventually develop a malignant disorder such as multiple myeloma, Waldenstrom macroglobulinemia, or amyloidosis. MGUS is common as we age with a prevalence of 3-4% after age 60.The term amyloidosis includes a group of disorders caused by abnormal folding, clumping, (aggregation) and/or accumulation of particular proteins (amyloids, fibrous proteins and their precursors) outside of the cell (extracellular), but within the tissues of various organs of the body. The accumulated amyloid causes the progressive malfunction of the affected organ. Normally, proteins are broken down at about the same rate as they are produced, however, these unusually stable proteins are deposited more rapidly than they can be broken down. The accumulation may be localized, or systemic. The most widely used classification of the amyloidoses is based on the biochemical nature of the fiber-like protein structures (fibrils) and on the nature of the precursor proteins that give rise to the amyloids. (See Disorder subdivisions above.) The different amyloidoses are named by combining the upper-case A (for amyloid) with an abbreviation of the name of the protein that makes up the fibril. There are at least twenty (20) different types of fibrils that make up the human amyloidoses, and each is responsible for a unique clinical presentation. Older discussions of amyloidosis refer often to “primary amyloidosis” or to “myeloma-associated amyloidosis” the fibril protein of each of which is an immunoglobulin light chain peptide or fragment. The newer classification labels both of these as “light chain amyloidosis” or AL. The Light chain amyloidosis (AL) form of the disorder occurs most often, but not always, in association with an increased number of plasma cells in the bone marrow. AL affects the kidney, heart, intestinal tract, liver and/or spleen. Kidney or cardiac involvement may result in renal or congestive heart failure, respectively.The following disorders may be considered variants of multiple myeloma:Smoldering multiple myeloma (SMM) is characterized by abnormally high levels of atypical plasma cells in the bone marrow without evidence of symptomatic disease. Many affected individuals exhibit M-proteins in the urine and blood but have no other evidence of the symptoms of multiple myeloma such as anemia, bone lesions or kidney failure. Individuals with smoldering multiple myeloma may eventually develop multiple myeloma.Plasma cell leukemia is characterized by the presence of excessive amounts of plasma cells in the blood.Non-secretory myeloma exists when an individual with multiple myeloma does not produce M-protein in either the urine or blood serum. Individuals with non-secretory myeloma make up only one percent of individuals with myeloma.Osteosclerotic myeloma is a variant of multiple myeloma. Major symptoms may include weakness, numbness in the legs, skin changes, hormonal abnormalities, and lung problems. In osteosclerotic myeloma, there is an association with osteosclerosis, a condition marked by hardening and abnormal density of bone. A common symptom of osteosclerotic myeloma is peripheral neuropathy. The exact cause of osteosclerotic myeloma is not known.Solitary plasmacytoma of bone is characterized by only one plasma cell tumor (plasmacytoma) of the bone. Diagnosis relies on cell examination, and no evidence of multiple myeloma in the bone marrow.Extramedullary plasmacytoma occurs when plasma cell tumors arise outside the bone marrow. The upper respiratory tract, which includes the nasal cavity and sinuses, nasopharynx, and larynx, is the most frequent site of involvement. However, extramedullary plasmacytomas have been found in virtually every organ of the body.
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Related disorders of Multiple Myeloma. Symptoms of the following disorders can be similar to those of multiple myeloma. Comparisons may be useful for a differential diagnosis:Waldenstrom macroglobulinemia is a lymph and blood cell disorder. Abnormally large quantities of homogeneous protein molecules are present in the blood. The disorder may run in families and occurs after the sixth decade. An enlarged spleen and liver with abnormalities of the lymph glands are the most frequent symptoms. Weakness, anemia, fatigue and excessive bleeding, especially from the nose and mouth, also occur. (For more information on this disorder, choose “Waldenstrom” as your search term in the Rare Disease Database.)Heavy chain diseases are characterized by the presence of too many plasma cells or certain white blood cells (lymphocytes) that resemble plasma cells in the bone marrow and lymph nodes. This condition includes gamma, alpha and Mu heavy chain disease, which are all disorders of the proliferative type. Gamma heavy chain disease is characterized by anemia. The liver, spleen and lymph nodes are enlarged. Alpha heavy chain disease occurs most often in men of Mediterranean ancestry. It involves the digestive tract with severe malabsorption of nutrients, loss of weight, diarrhea and loss of fat (steatorrhea). Symptoms are most often progressive. Mu heavy chain disease is characterized by a form of chronic lymphocytic leukemia or tumors of the lymph gland. Analysis of the blood serum usually reveals excessively low levels of antibodies in the blood (hypogammaglobulinemia).Monoclonal gammopathy of undetermined significance (MGUS) is a condition characterized by the presence of M-proteins in the blood. There may be low levels of M-proteins in the urine. Individuals with MGUS do not have the physical symptoms associated with multiple myeloma (e.g., anemia, bony lesions, kidney abnormalities). Some individuals with MGUS eventually develop a malignant disorder such as multiple myeloma, Waldenstrom macroglobulinemia, or amyloidosis. MGUS is common as we age with a prevalence of 3-4% after age 60.The term amyloidosis includes a group of disorders caused by abnormal folding, clumping, (aggregation) and/or accumulation of particular proteins (amyloids, fibrous proteins and their precursors) outside of the cell (extracellular), but within the tissues of various organs of the body. The accumulated amyloid causes the progressive malfunction of the affected organ. Normally, proteins are broken down at about the same rate as they are produced, however, these unusually stable proteins are deposited more rapidly than they can be broken down. The accumulation may be localized, or systemic. The most widely used classification of the amyloidoses is based on the biochemical nature of the fiber-like protein structures (fibrils) and on the nature of the precursor proteins that give rise to the amyloids. (See Disorder subdivisions above.) The different amyloidoses are named by combining the upper-case A (for amyloid) with an abbreviation of the name of the protein that makes up the fibril. There are at least twenty (20) different types of fibrils that make up the human amyloidoses, and each is responsible for a unique clinical presentation. Older discussions of amyloidosis refer often to “primary amyloidosis” or to “myeloma-associated amyloidosis” the fibril protein of each of which is an immunoglobulin light chain peptide or fragment. The newer classification labels both of these as “light chain amyloidosis” or AL. The Light chain amyloidosis (AL) form of the disorder occurs most often, but not always, in association with an increased number of plasma cells in the bone marrow. AL affects the kidney, heart, intestinal tract, liver and/or spleen. Kidney or cardiac involvement may result in renal or congestive heart failure, respectively.The following disorders may be considered variants of multiple myeloma:Smoldering multiple myeloma (SMM) is characterized by abnormally high levels of atypical plasma cells in the bone marrow without evidence of symptomatic disease. Many affected individuals exhibit M-proteins in the urine and blood but have no other evidence of the symptoms of multiple myeloma such as anemia, bone lesions or kidney failure. Individuals with smoldering multiple myeloma may eventually develop multiple myeloma.Plasma cell leukemia is characterized by the presence of excessive amounts of plasma cells in the blood.Non-secretory myeloma exists when an individual with multiple myeloma does not produce M-protein in either the urine or blood serum. Individuals with non-secretory myeloma make up only one percent of individuals with myeloma.Osteosclerotic myeloma is a variant of multiple myeloma. Major symptoms may include weakness, numbness in the legs, skin changes, hormonal abnormalities, and lung problems. In osteosclerotic myeloma, there is an association with osteosclerosis, a condition marked by hardening and abnormal density of bone. A common symptom of osteosclerotic myeloma is peripheral neuropathy. The exact cause of osteosclerotic myeloma is not known.Solitary plasmacytoma of bone is characterized by only one plasma cell tumor (plasmacytoma) of the bone. Diagnosis relies on cell examination, and no evidence of multiple myeloma in the bone marrow.Extramedullary plasmacytoma occurs when plasma cell tumors arise outside the bone marrow. The upper respiratory tract, which includes the nasal cavity and sinuses, nasopharynx, and larynx, is the most frequent site of involvement. However, extramedullary plasmacytomas have been found in virtually every organ of the body.
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Diagnosis of Multiple Myeloma
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A diagnosis of multiple myeloma is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Such tests may include removal and microscopic examination of small samples of bone marrow (biopsy or aspiration), blood tests to detect low levels of red and white blood cells, and various x-ray techniques including magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography (PET) scanning that may reveal characteristic changes to bones. A test that sorts proteins in the blood or urine (electrophoresis) may be used to detect elevated levels of M-proteins. An immunoglobulin free light chain assay of blood is considered a standard of evaluation.In 2018, the ClonoSEQ assay, a next generation sequencing-based test, was approved to measure the amount of cancer cells remaining in a person’s bone marrow in patients with multiple myeloma.
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Diagnosis of Multiple Myeloma. A diagnosis of multiple myeloma is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Such tests may include removal and microscopic examination of small samples of bone marrow (biopsy or aspiration), blood tests to detect low levels of red and white blood cells, and various x-ray techniques including magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography (PET) scanning that may reveal characteristic changes to bones. A test that sorts proteins in the blood or urine (electrophoresis) may be used to detect elevated levels of M-proteins. An immunoglobulin free light chain assay of blood is considered a standard of evaluation.In 2018, the ClonoSEQ assay, a next generation sequencing-based test, was approved to measure the amount of cancer cells remaining in a person’s bone marrow in patients with multiple myeloma.
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Therapies of Multiple Myeloma
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Treatment
The diagnosis and therapeutic management of multiple myeloma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; orthopedic surgeons; dietitians; and/or other professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; the presence or absence of certain symptoms; individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her medical history; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Some affected individuals may have a slow developing form of multiple myeloma that progresses over many years, often without symptoms (asymptomatic). Such individuals, and individuals with similar conditions like smoldering multiple myeloma and MGUS, may not require treatment. However, these individuals should be routinely monitored so that treatment can begin if symptoms appear.The treatment of multiple myeloma usually involves chemotherapy to reduce the numbers of abnormal plasma cells, drugs to help fight infection (e.g., antibiotics), and medications to reduce pain (analgesic drugs). Additional treatment may include the use of high energy x-rays (radiation therapy) to destroy cancer cells and reduce bone masses that may develop. The use of new biologic drugs may also be recommended. If affected individuals experience involvement of the kidneys, fluids may need to be administered to avoid dehydration.The following link provides information from the National Cancer Institute about medications that have been approved by the U.S. Food and Drug Administration (FDA) to treat multiple myeloma:http://www.cancer.gov/cancertopics/druginfo/multiplemyelomaStem-cell transplantation along with high-dose chemotherapy is regularly used for the treatment of multiple myeloma. Stem cells, which reside in the bone marrow, function as “parent” cells, undergoing a series of divisions that result in the formation of all the different types of blood cells (e.g., red blood cell, platelets, etc.).Other treatment is symptomatic and supportive.
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Therapies of Multiple Myeloma. Treatment
The diagnosis and therapeutic management of multiple myeloma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; orthopedic surgeons; dietitians; and/or other professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; the presence or absence of certain symptoms; individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her medical history; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Some affected individuals may have a slow developing form of multiple myeloma that progresses over many years, often without symptoms (asymptomatic). Such individuals, and individuals with similar conditions like smoldering multiple myeloma and MGUS, may not require treatment. However, these individuals should be routinely monitored so that treatment can begin if symptoms appear.The treatment of multiple myeloma usually involves chemotherapy to reduce the numbers of abnormal plasma cells, drugs to help fight infection (e.g., antibiotics), and medications to reduce pain (analgesic drugs). Additional treatment may include the use of high energy x-rays (radiation therapy) to destroy cancer cells and reduce bone masses that may develop. The use of new biologic drugs may also be recommended. If affected individuals experience involvement of the kidneys, fluids may need to be administered to avoid dehydration.The following link provides information from the National Cancer Institute about medications that have been approved by the U.S. Food and Drug Administration (FDA) to treat multiple myeloma:http://www.cancer.gov/cancertopics/druginfo/multiplemyelomaStem-cell transplantation along with high-dose chemotherapy is regularly used for the treatment of multiple myeloma. Stem cells, which reside in the bone marrow, function as “parent” cells, undergoing a series of divisions that result in the formation of all the different types of blood cells (e.g., red blood cell, platelets, etc.).Other treatment is symptomatic and supportive.
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Overview of Multiple Sclerosis
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Multiple sclerosis (MS) is a chronic neuroimmunologic (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal cord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occurs unpredictability, vary in intensity, and at many sites thus the name, multiple sclerosis. During the course of the disease, patients may have attacks (relapses or exacerbations), gradually worsen (progression), or stabilize. The randomness of the location of damage can result in a wide range of neurological symptoms, which may vary from person to person. Recently it has been learned that the nerve fibers themselves (axons), in addition to the myelin sheaths, are also affected early in the MS disease process. Damage to axons is irreversible thus clinicians recommend early treatment with one of the disease-modifying agents (see below).
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Overview of Multiple Sclerosis. Multiple sclerosis (MS) is a chronic neuroimmunologic (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal cord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occurs unpredictability, vary in intensity, and at many sites thus the name, multiple sclerosis. During the course of the disease, patients may have attacks (relapses or exacerbations), gradually worsen (progression), or stabilize. The randomness of the location of damage can result in a wide range of neurological symptoms, which may vary from person to person. Recently it has been learned that the nerve fibers themselves (axons), in addition to the myelin sheaths, are also affected early in the MS disease process. Damage to axons is irreversible thus clinicians recommend early treatment with one of the disease-modifying agents (see below).
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Symptoms of Multiple Sclerosis
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The symptoms of multiple sclerosis may vary greatly. Some people may have visual impairment (including central visual fields), double vision (diplopia), or involuntary rhythmic movements of the eyes (nystagmus). People with multiple sclerosis may also experience impairment of speech, numbness or tingling sensation in the limbs and difficulty walking. Dysfunction of the bladder and bowel may also be present along with sexual dysfunction. Multiple sclerosis is rarely fatal; the average life expectancy is 93 percent of that of the general population. In some cases however, changes in mobility make it necessary to use a cane, crutches, or other mobility devises. In a limited number of patients, the disease may result in life-threatening complications.In order to illustrate by how much symptoms of MS may vary, the National Multiple Sclerosis Society (NMSS) cites a study of 697 persons with MS who experienced the following symptoms in addition to pain, depression and other emotional changes:Fatigue—————————–88%
Ambulation problems———- 87%
Bowel/Bladder problems——65%
Visual Disturbances———–-58%
Cognitive problems————44%
Tremor—————————–41%
Difficulty moving arms———41%Over the past decade it has become common for clinical researchers to classify MS into several types. These types were originally proposed to improve experimental design but are used often at this time as a guide to treatment options. MS is classified as:Relapsing Remitting MS (RRMS)
This form of MS is characterized by clearly defined acute to subacute attacks with varying degrees of recovery often complete or nearly complete early in the disease course. Between attacks, the disease is stable. About 85% of initial diagnoses of MS are classified as RRMS. More recently the term “relapsing form of MS” has been used to identify patients with any clinical form of MS that demonstrate a clinical relapse. One could also logically posit that a new T2 lesion or a gadolinium enhancing lesion on MRI scan is the equivalent of a relapse. Secondary-Progressive MS (SPMS)
SPMS begins as RRMS. SPMS is characterized by progressive disability at a variable rate that may be accompanied by relapses, minor remissions, and plateaus. Of the people with an initial diagnosis of RRMS, 50% or more will develop SPMS within 10 years and 90% within 25 years. It is important to remember that most of these numbers are based on studies preceding the era of disease modifying therapy.Primary Progressive MS (PPMS)
From onset, PPMS shows steady rates of progression of disability or occasional plateaus and/or minor remissions. We now recognize that a small number of these patients may have superimposed clinical relapses and/or PPMS makes up about 15% of all MS diagnoses.
Clinical Isolated Syndrome (CIS)
Clinical isolated syndrome is the first episode of a neurologic event involving the central nervous system that is typical of multiple sclerosis. The suspicion and likelihood of an episode of CIS being the first attack increases with abnormalities on MRI of the brain and/or spinal cordRadiologically Isolated Syndrome (RIS)
Radiologically isolated syndrome is likely the preclinical stage of MS. It is defined as lesions typical of MS on an MRI scan done for a different reason such as headache, head injury or other reasons that are not as a result of symptoms not suggestive or typical of MS. Follow up of many of these individuals frequently demonstrates additional lesions typical of MS and/or a clinical event (CIS) and then RRMS. Some individuals go on to a clinical course of PPMS. Tumefactive MS is a rare form of MS characterized by a tumor-like lesion and signs and symptoms similar to those of a brain tumor. Symptoms often differ from other types of MS and may include headaches, changes in thinking, confusion, speech problems, seizures, and weakness. Tumefactive MS often but not always develops into RRMS. Pediatric MS is a rare form of MS. Approximately 3-5% of MS patients are diagnosed in childhood (under 18 years of age). It can be difficult to diagnose MS in young children because the symptoms overlap with many other conditions and the signs and symptoms can be different from adult-onset MS.
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Symptoms of Multiple Sclerosis. The symptoms of multiple sclerosis may vary greatly. Some people may have visual impairment (including central visual fields), double vision (diplopia), or involuntary rhythmic movements of the eyes (nystagmus). People with multiple sclerosis may also experience impairment of speech, numbness or tingling sensation in the limbs and difficulty walking. Dysfunction of the bladder and bowel may also be present along with sexual dysfunction. Multiple sclerosis is rarely fatal; the average life expectancy is 93 percent of that of the general population. In some cases however, changes in mobility make it necessary to use a cane, crutches, or other mobility devises. In a limited number of patients, the disease may result in life-threatening complications.In order to illustrate by how much symptoms of MS may vary, the National Multiple Sclerosis Society (NMSS) cites a study of 697 persons with MS who experienced the following symptoms in addition to pain, depression and other emotional changes:Fatigue—————————–88%
Ambulation problems———- 87%
Bowel/Bladder problems——65%
Visual Disturbances———–-58%
Cognitive problems————44%
Tremor—————————–41%
Difficulty moving arms———41%Over the past decade it has become common for clinical researchers to classify MS into several types. These types were originally proposed to improve experimental design but are used often at this time as a guide to treatment options. MS is classified as:Relapsing Remitting MS (RRMS)
This form of MS is characterized by clearly defined acute to subacute attacks with varying degrees of recovery often complete or nearly complete early in the disease course. Between attacks, the disease is stable. About 85% of initial diagnoses of MS are classified as RRMS. More recently the term “relapsing form of MS” has been used to identify patients with any clinical form of MS that demonstrate a clinical relapse. One could also logically posit that a new T2 lesion or a gadolinium enhancing lesion on MRI scan is the equivalent of a relapse. Secondary-Progressive MS (SPMS)
SPMS begins as RRMS. SPMS is characterized by progressive disability at a variable rate that may be accompanied by relapses, minor remissions, and plateaus. Of the people with an initial diagnosis of RRMS, 50% or more will develop SPMS within 10 years and 90% within 25 years. It is important to remember that most of these numbers are based on studies preceding the era of disease modifying therapy.Primary Progressive MS (PPMS)
From onset, PPMS shows steady rates of progression of disability or occasional plateaus and/or minor remissions. We now recognize that a small number of these patients may have superimposed clinical relapses and/or PPMS makes up about 15% of all MS diagnoses.
Clinical Isolated Syndrome (CIS)
Clinical isolated syndrome is the first episode of a neurologic event involving the central nervous system that is typical of multiple sclerosis. The suspicion and likelihood of an episode of CIS being the first attack increases with abnormalities on MRI of the brain and/or spinal cordRadiologically Isolated Syndrome (RIS)
Radiologically isolated syndrome is likely the preclinical stage of MS. It is defined as lesions typical of MS on an MRI scan done for a different reason such as headache, head injury or other reasons that are not as a result of symptoms not suggestive or typical of MS. Follow up of many of these individuals frequently demonstrates additional lesions typical of MS and/or a clinical event (CIS) and then RRMS. Some individuals go on to a clinical course of PPMS. Tumefactive MS is a rare form of MS characterized by a tumor-like lesion and signs and symptoms similar to those of a brain tumor. Symptoms often differ from other types of MS and may include headaches, changes in thinking, confusion, speech problems, seizures, and weakness. Tumefactive MS often but not always develops into RRMS. Pediatric MS is a rare form of MS. Approximately 3-5% of MS patients are diagnosed in childhood (under 18 years of age). It can be difficult to diagnose MS in young children because the symptoms overlap with many other conditions and the signs and symptoms can be different from adult-onset MS.
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Causes of Multiple Sclerosis
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The exact cause of multiple sclerosis is not known. Nevertheless, most clinical investigators agree that MS may be the result of an abnormal immunopathologically likely autoimmune in a genetically susceptible person in response to one or more environmental factors.Many researchers suggest that the disorder may represent an abnormal immune reaction directed against the body’s own tissues (autoimmune disorder). In autoimmune disorders, the body’s natural defenses (e.g., antibodies and inflammatory cells including lymphocytes and monocyte/macrophages) against substances that are perceived as foreign (antigens) inappropriately begin to attack healthy tissues, for unknown reasons. According to many researchers, the autoimmune process may be triggered by exposure to particular environmental agents (e.g., certain bacteria or viruses) in individuals with a genetic susceptibility for MS. Other important environmental factors seem to include vitamin D insufficiency, tobacco smoking, Research is concentrating on immune therapies designed to moderate the autoimmune attack without harming normal immune cells.Some researchers believe that one or more different viruses may play some role in triggering the disease process in individuals with MS. Different viruses have been implicated over many years but the best evidence seems to be an association with Epstein Barr virus (EBV). Other researchers suggest that a common bacterium may contribute to the development of MS. In one study, the cerebrospinal fluid from all 37 individuals with MS (relapsing-remitting or progressive MS) showed the presence of the bacterium that causes “walking pneumonia” (Chlamydia pneumoniae). In contrast, the study’s control group (i.e., individuals with neurologic diseases other than MS) the bacterium was present in only a small number of cases and few of the control subjects had developed antibodies against the microorganism. There has not been confirmation of these findings and it may represent an epiphenomenon. Evidence also suggests that individuals with MS may have a genetic susceptibility for the disorder that may be determined by the “cumulative” interaction of several genes (polygenic inheritance); in addition, there may be different genetic abnormalities or mechanisms that result in susceptibility to the disease (heterogeneity). Researchers have implicated several different genes that may be associated with MS. These include certain closely linked genes (major histocompatibility complex [MHC]) that regulate production of the major histocompatibility antigens, a group of proteins that play a role in the immune system. Researchers suggest that the presence of certain genetically determined histocompatibility antigens may play some role in predisposing individuals to MS.While conducted many years ago, two large studies reported in the New England Journal of Medicine (February 2001) failed to show any evidence of a link between vaccination and multiple sclerosis. There has been no recent evidence to link immunizations to multiple sclerosis.
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Causes of Multiple Sclerosis. The exact cause of multiple sclerosis is not known. Nevertheless, most clinical investigators agree that MS may be the result of an abnormal immunopathologically likely autoimmune in a genetically susceptible person in response to one or more environmental factors.Many researchers suggest that the disorder may represent an abnormal immune reaction directed against the body’s own tissues (autoimmune disorder). In autoimmune disorders, the body’s natural defenses (e.g., antibodies and inflammatory cells including lymphocytes and monocyte/macrophages) against substances that are perceived as foreign (antigens) inappropriately begin to attack healthy tissues, for unknown reasons. According to many researchers, the autoimmune process may be triggered by exposure to particular environmental agents (e.g., certain bacteria or viruses) in individuals with a genetic susceptibility for MS. Other important environmental factors seem to include vitamin D insufficiency, tobacco smoking, Research is concentrating on immune therapies designed to moderate the autoimmune attack without harming normal immune cells.Some researchers believe that one or more different viruses may play some role in triggering the disease process in individuals with MS. Different viruses have been implicated over many years but the best evidence seems to be an association with Epstein Barr virus (EBV). Other researchers suggest that a common bacterium may contribute to the development of MS. In one study, the cerebrospinal fluid from all 37 individuals with MS (relapsing-remitting or progressive MS) showed the presence of the bacterium that causes “walking pneumonia” (Chlamydia pneumoniae). In contrast, the study’s control group (i.e., individuals with neurologic diseases other than MS) the bacterium was present in only a small number of cases and few of the control subjects had developed antibodies against the microorganism. There has not been confirmation of these findings and it may represent an epiphenomenon. Evidence also suggests that individuals with MS may have a genetic susceptibility for the disorder that may be determined by the “cumulative” interaction of several genes (polygenic inheritance); in addition, there may be different genetic abnormalities or mechanisms that result in susceptibility to the disease (heterogeneity). Researchers have implicated several different genes that may be associated with MS. These include certain closely linked genes (major histocompatibility complex [MHC]) that regulate production of the major histocompatibility antigens, a group of proteins that play a role in the immune system. Researchers suggest that the presence of certain genetically determined histocompatibility antigens may play some role in predisposing individuals to MS.While conducted many years ago, two large studies reported in the New England Journal of Medicine (February 2001) failed to show any evidence of a link between vaccination and multiple sclerosis. There has been no recent evidence to link immunizations to multiple sclerosis.
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Affects of Multiple Sclerosis
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The number of people with MS has been estimated to be between 300,000 and 500,000 in the US and 2.5 million people worldwide. However, this may be an underestimate because these figures are based on data collected in the 1970’s, prior to the use of MRI for diagnosis. Twice as many females as males are affected. The disorder may appear at any age, although the diagnosis is most often made between 20 and 50 years of age.Multiple sclerosis is more common in Caucasian Americans than in Americans of African or Asian heritage, although the disease is not rate in African Americans. In a few ethnic societies (Inuits, Bantus and American Indians), multiple sclerosis is rare or absent. This may hint at a genetic link to this disorder. Multiple sclerosis seems to occur more often in the moderate regions (temperate climates).
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Affects of Multiple Sclerosis. The number of people with MS has been estimated to be between 300,000 and 500,000 in the US and 2.5 million people worldwide. However, this may be an underestimate because these figures are based on data collected in the 1970’s, prior to the use of MRI for diagnosis. Twice as many females as males are affected. The disorder may appear at any age, although the diagnosis is most often made between 20 and 50 years of age.Multiple sclerosis is more common in Caucasian Americans than in Americans of African or Asian heritage, although the disease is not rate in African Americans. In a few ethnic societies (Inuits, Bantus and American Indians), multiple sclerosis is rare or absent. This may hint at a genetic link to this disorder. Multiple sclerosis seems to occur more often in the moderate regions (temperate climates).
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Related disorders of Multiple Sclerosis
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Symptoms of the following disorders can be similar to those of multiple sclerosis. Comparisons may be useful for a differential diagnosis:Amyotrophic lateral sclerosis (ALS) is a disease of the motor neurons that send signals to the skeletal muscles. It generally affects both the upper and the lower muscle groups and results in the progressive weakness and wasting away of the muscles involved. There are several varieties of ALS. The early symptoms may include slight muscular weakness, clumsy hand movements and difficulty performing fine motor tasks. Weakness in the legs may result in clumsiness and tripping, and slurring of speech, difficulty swallowing and shortness of breath may also be present. Other symptoms may include muscle stiffness and coughing. Sensory and autonomic problems are not part of ALS among several distinguishing features differing from MS (For more information on this disorder, choose “amyotrophic lateral sclerosis” as your search term in the Rare Disease Database.)Charcot-Marie-Tooth disease (CMT disease) is a hereditary neurological disorder characterized by muscle weakness and atrophy, primarily in the muscles of the legs. Symptoms of Type I CMT disease usually begin in middle childhood or teenage years with a deformity of the foot characterized by a high arch and hyperextension of the toes. With time, CMT disease spreads to the upper extremities and produces a “stocking-glove” pattern of diminished sensitivity. There is a decrease in the sensitivity to vibration, pain and temperature. Ultimately it is the secondary changes in the axons that result in permanent disability (For more information on this disorder, choose “Charcot-Marie-Tooth disease” as your search term in the Rare Disease Database.)Dejerine-Sottas disease is a rare progressive hereditary disorder that causes the enlargement of the peripheral nerves and the loss of myelin. This results in a burning or tingling sensation in the limbs, generalized muscle weakness and the loss of coordination in the hands and forearms. Weakness in the back of the legs eventually spreads to the front of the legs resulting in difficulty and pain when walking. Mild vision problems may also be present. (For more information on this disorder, choose “Dejerine-Sottas disease” as your search term in the Rare Disease Database.)Friedreich’s ataxia is a progressive hereditary disorder that affects the neuromuscular system. It is generally diagnosed in childhood or adolescence. There are slow degenerative changes of the spinal cord and the brain that affect speech and motor coordination. These changes may produce an unsteady walk or numbness and weakness in the arms and legs. The legs generally become progressively weaker resulting in a staggering, lurching walk or trembling when standing still. (For more information on this disorder, choose “Friedreich’s ataxia” as your search term on the Rare Disorder Database.)Guillain-Barre syndrome (GBS) is a rare rapidly progressive polyneuropathy. Although the exact cause is not known, a gastrointestinal virus or respiratory infection precedes the onset of the syndrome in almost half the cases. In the form most common in the US and western Europe the myelin sheath that covers the nerves is damaged and results in muscle weakness (acute inflammatory demyelinating polyneuropathy; AIDP). The symptoms may include a burning or tingling sensation in the feet followed by weakness of the legs. Eventually upper limbs and face may be affected as can breathing, swallowing, and speaking. Autonomic involvement occurs commonly as well. There are other forms of GBS including a form that involves only motor weakness and primarily attacks the axons (acute motor axonal neuropathy; AMAN) and a form consisting of limitation of eye movements, ataxia (loss of balance) and reduction or loss of tendon reflexes called (Miller )Fisher syndrome. (For more information on this disorder, choose “Guillain-Barre syndrome” as your search term in the Rare Disease Database.)Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare disorder in which there is inflammation of the nerve roots and peripheral nerves and the destruction of the covering (myelin sheath) of the nerves. This causes weakness, paralysis and impairment of motor function especially in the limbs. Symptoms may include burning, numbness or tingling of the hands and feet or the arms and legs. Reflexes are reduced or absent, and the muscles of the face may become weak. Other symptoms may include difficulty in walking and respiratory problems. (For more information on this disorder, choose “CIDP” as your search term on the Rare Disease Database.)Leukodystrophy is the name given to a group of very rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each of the leukodystrophies will affect one of the chemicals that make up the myelin sheath that covers the nerve fibers or it may affect the white matter of the brain. Most of the leukodystrophies are present at birth but some may appear more slowly over time and even into adulthood. Leukodystrophies cause the patient to have problems with movement, vision, hearing, feeling and thinking. This can result in difficulty walking, stiffness, a “floppy” feeling in the muscles, paralysis or convulsions. (For more information on these disorders, choose “leukodystrophy” as your search term on the Rare Disease Database.)
|
Related disorders of Multiple Sclerosis. Symptoms of the following disorders can be similar to those of multiple sclerosis. Comparisons may be useful for a differential diagnosis:Amyotrophic lateral sclerosis (ALS) is a disease of the motor neurons that send signals to the skeletal muscles. It generally affects both the upper and the lower muscle groups and results in the progressive weakness and wasting away of the muscles involved. There are several varieties of ALS. The early symptoms may include slight muscular weakness, clumsy hand movements and difficulty performing fine motor tasks. Weakness in the legs may result in clumsiness and tripping, and slurring of speech, difficulty swallowing and shortness of breath may also be present. Other symptoms may include muscle stiffness and coughing. Sensory and autonomic problems are not part of ALS among several distinguishing features differing from MS (For more information on this disorder, choose “amyotrophic lateral sclerosis” as your search term in the Rare Disease Database.)Charcot-Marie-Tooth disease (CMT disease) is a hereditary neurological disorder characterized by muscle weakness and atrophy, primarily in the muscles of the legs. Symptoms of Type I CMT disease usually begin in middle childhood or teenage years with a deformity of the foot characterized by a high arch and hyperextension of the toes. With time, CMT disease spreads to the upper extremities and produces a “stocking-glove” pattern of diminished sensitivity. There is a decrease in the sensitivity to vibration, pain and temperature. Ultimately it is the secondary changes in the axons that result in permanent disability (For more information on this disorder, choose “Charcot-Marie-Tooth disease” as your search term in the Rare Disease Database.)Dejerine-Sottas disease is a rare progressive hereditary disorder that causes the enlargement of the peripheral nerves and the loss of myelin. This results in a burning or tingling sensation in the limbs, generalized muscle weakness and the loss of coordination in the hands and forearms. Weakness in the back of the legs eventually spreads to the front of the legs resulting in difficulty and pain when walking. Mild vision problems may also be present. (For more information on this disorder, choose “Dejerine-Sottas disease” as your search term in the Rare Disease Database.)Friedreich’s ataxia is a progressive hereditary disorder that affects the neuromuscular system. It is generally diagnosed in childhood or adolescence. There are slow degenerative changes of the spinal cord and the brain that affect speech and motor coordination. These changes may produce an unsteady walk or numbness and weakness in the arms and legs. The legs generally become progressively weaker resulting in a staggering, lurching walk or trembling when standing still. (For more information on this disorder, choose “Friedreich’s ataxia” as your search term on the Rare Disorder Database.)Guillain-Barre syndrome (GBS) is a rare rapidly progressive polyneuropathy. Although the exact cause is not known, a gastrointestinal virus or respiratory infection precedes the onset of the syndrome in almost half the cases. In the form most common in the US and western Europe the myelin sheath that covers the nerves is damaged and results in muscle weakness (acute inflammatory demyelinating polyneuropathy; AIDP). The symptoms may include a burning or tingling sensation in the feet followed by weakness of the legs. Eventually upper limbs and face may be affected as can breathing, swallowing, and speaking. Autonomic involvement occurs commonly as well. There are other forms of GBS including a form that involves only motor weakness and primarily attacks the axons (acute motor axonal neuropathy; AMAN) and a form consisting of limitation of eye movements, ataxia (loss of balance) and reduction or loss of tendon reflexes called (Miller )Fisher syndrome. (For more information on this disorder, choose “Guillain-Barre syndrome” as your search term in the Rare Disease Database.)Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare disorder in which there is inflammation of the nerve roots and peripheral nerves and the destruction of the covering (myelin sheath) of the nerves. This causes weakness, paralysis and impairment of motor function especially in the limbs. Symptoms may include burning, numbness or tingling of the hands and feet or the arms and legs. Reflexes are reduced or absent, and the muscles of the face may become weak. Other symptoms may include difficulty in walking and respiratory problems. (For more information on this disorder, choose “CIDP” as your search term on the Rare Disease Database.)Leukodystrophy is the name given to a group of very rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each of the leukodystrophies will affect one of the chemicals that make up the myelin sheath that covers the nerve fibers or it may affect the white matter of the brain. Most of the leukodystrophies are present at birth but some may appear more slowly over time and even into adulthood. Leukodystrophies cause the patient to have problems with movement, vision, hearing, feeling and thinking. This can result in difficulty walking, stiffness, a “floppy” feeling in the muscles, paralysis or convulsions. (For more information on these disorders, choose “leukodystrophy” as your search term on the Rare Disease Database.)
| 841 |
Multiple Sclerosis
|
nord_841_5
|
Diagnosis of Multiple Sclerosis
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The diagnosis MS is based on clinical expertise of a board certified neurologist. There are certain criteria observed that have evolved over time from Schumacher, to Poser, to currently McDonald. Clinicians must evaluate the characteristic age of onset, clinical pattern, history, and neurologic findings typical of MS. Criteria also require that changes in the central nervous system must be separated in space and time and not just occur one time only. Ultimately, MS is a clinical diagnosis because, while there are many laboratory tests, there is no one definitive test that firmly establishes the certainty of the disease; therefore, it is important that this diagnosis be made by an MS specialist.Clinical features that suggest MS include the age of onset which is typically between the ages of 15 and 50 years. The less common presentation is in an older man or woman with gradual development of neurologic problems (progressive form). The more common presentation is with symptoms that are episodic and spontaneously improve (relapsing-remitting). The least common is the diagnosis in children (pediatric MS). This type of MS is becoming more widely recognized in the medical community during recent years. The clinical profile for MS requires symptomatic disease activity over time (not occurring just once and never again) and confirmed by an objective neurologic examination. The more common symptoms are numbness, strange sensations in the body (paresthesias), pain, motor abnormalities, and visual problems. The course of the disease, once the diagnosis is established, can be categorized into relapsing-remitting (attacks and recovery), secondary progressive (relapsing MS that changes to a worsening form with little or no recovery), primary progressive (gradual worsening with no recovery), or progressive relapsing (worsening with occasional relapses). The establishment of the clinical course of MS takes time and careful monitoring before the classification can be certain.After symptoms occur that appear to be MS, findings of the neurologic examination must establish that these changes originate in the brain, spinal cord or both. Neurologic findings cause the first note of suspicion that the problem is MS. Magnetic resonance imaging (MRI) is the major diagnostic laboratory tool that can support the diagnosis. Particular characteristics of imaging findings include multiplicity of lesions (changes in the brain), large diameter, and ovoid shape in particular locations in the brain typical of MS. If the findings are inconclusive, the person might have to undergo a lumbar puncture (spinal tap) to examine the cerebrospinal fluid (spinal fluid contents) to evaluate for immunologic patterns. Spinal fluid provides important complementary information to rule out other conditions related to infections or other diseases as well as to support the diagnosis of MS. Blood tests may be required to exclude other diagnoses.
The Revised McDonald Criteria, published in 2011 by the International Panel on the Diagnosis of Multiple Sclerosis and recently updated (2016), provide specific guidelines for using MRI, VEP and cerebrospinal fluid analysis for diagnosis (see Polman, et al. 2011 in References).
|
Diagnosis of Multiple Sclerosis. The diagnosis MS is based on clinical expertise of a board certified neurologist. There are certain criteria observed that have evolved over time from Schumacher, to Poser, to currently McDonald. Clinicians must evaluate the characteristic age of onset, clinical pattern, history, and neurologic findings typical of MS. Criteria also require that changes in the central nervous system must be separated in space and time and not just occur one time only. Ultimately, MS is a clinical diagnosis because, while there are many laboratory tests, there is no one definitive test that firmly establishes the certainty of the disease; therefore, it is important that this diagnosis be made by an MS specialist.Clinical features that suggest MS include the age of onset which is typically between the ages of 15 and 50 years. The less common presentation is in an older man or woman with gradual development of neurologic problems (progressive form). The more common presentation is with symptoms that are episodic and spontaneously improve (relapsing-remitting). The least common is the diagnosis in children (pediatric MS). This type of MS is becoming more widely recognized in the medical community during recent years. The clinical profile for MS requires symptomatic disease activity over time (not occurring just once and never again) and confirmed by an objective neurologic examination. The more common symptoms are numbness, strange sensations in the body (paresthesias), pain, motor abnormalities, and visual problems. The course of the disease, once the diagnosis is established, can be categorized into relapsing-remitting (attacks and recovery), secondary progressive (relapsing MS that changes to a worsening form with little or no recovery), primary progressive (gradual worsening with no recovery), or progressive relapsing (worsening with occasional relapses). The establishment of the clinical course of MS takes time and careful monitoring before the classification can be certain.After symptoms occur that appear to be MS, findings of the neurologic examination must establish that these changes originate in the brain, spinal cord or both. Neurologic findings cause the first note of suspicion that the problem is MS. Magnetic resonance imaging (MRI) is the major diagnostic laboratory tool that can support the diagnosis. Particular characteristics of imaging findings include multiplicity of lesions (changes in the brain), large diameter, and ovoid shape in particular locations in the brain typical of MS. If the findings are inconclusive, the person might have to undergo a lumbar puncture (spinal tap) to examine the cerebrospinal fluid (spinal fluid contents) to evaluate for immunologic patterns. Spinal fluid provides important complementary information to rule out other conditions related to infections or other diseases as well as to support the diagnosis of MS. Blood tests may be required to exclude other diagnoses.
The Revised McDonald Criteria, published in 2011 by the International Panel on the Diagnosis of Multiple Sclerosis and recently updated (2016), provide specific guidelines for using MRI, VEP and cerebrospinal fluid analysis for diagnosis (see Polman, et al. 2011 in References).
| 841 |
Multiple Sclerosis
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nord_841_6
|
Therapies of Multiple Sclerosis
|
TreatmentAlthough multiple sclerosis (MS) has no known prevention or cure, there are treatments available to manage symptoms, alter the course of the disease, and help with exacerbations (relapses or flare-ups). Standard pain medications are not particularly effective for pain in MS, which are of several types including stiffness, spasmodic and neurogenic pain. Antispasmodics are used to treat spasmodic pain and neurogenic pain is usually treated by anticonvulsants and/or antidepressants. Trigeminal neuralgia is treated with anti-convulsants such as carbamezapine, gabapentin, pregabalin, topriamate and phenytoin. Recurrent attacks and relapses (exacerbations) are commonly treated with corticosteroids to reduce the inflammation in the central nervous system that damages the myelin and slows or blocks the transmission of nerve impulses. These drugs do not slow down, inhibit future relapses or stop the progression of this disorder. Physical therapy and exercise programs (especially aquatic or water therapy) are of value in most patients.The symptoms of MS can be classified as primary (directly due to the disease itself), secondary (due to inadequate management of primary symptoms), and tertiary (those that result from complications of the disease). For example, if a person has bladder problems that are uncontrolled, s/he can have infections and become socially isolated. S/he can stop driving or working due to this uncontrolled problem.Symptoms of MS can be subtle and mild (numbness, tingling) or severe (inability to walk or move) and can vary from time to time and from person to person. Therefore, treatment must be individualized to each person and dynamic, to address ever-changing problems related to the disease. Frequently people with MS require a team approach to manage their disease along with medications, rehabilitation, counseling, and educational services. Disease-modifying medications help to reduce the frequency and severity of attacks, reduce the accumulation of damaged or active disease areas (lesions) in the brain and spinal cord, and appear to slow down the progression of disability. It is believed that these drugs are most effective when started early, before the disease progresses further. The following consensus paper by the Multiple Sclerosis Coalition discusses disease-modifying drugs that have been approved by the FDA:
http://c.ymcdn.com/sites/www.mscare.org/resource/collection/A0711E7F-0EFA-43B2-AEB9-96ABB9D8F4E6/DMT_Consensus_MS_Coalition092016.pdfIn 2018, Gilenya (fingolimod) was approved by the FDA to treat relapsing MS in children and adolescents age 10 years and older. Gilenya is manufactured by Novartis Pharmaceuticals Corp.
|
Therapies of Multiple Sclerosis. TreatmentAlthough multiple sclerosis (MS) has no known prevention or cure, there are treatments available to manage symptoms, alter the course of the disease, and help with exacerbations (relapses or flare-ups). Standard pain medications are not particularly effective for pain in MS, which are of several types including stiffness, spasmodic and neurogenic pain. Antispasmodics are used to treat spasmodic pain and neurogenic pain is usually treated by anticonvulsants and/or antidepressants. Trigeminal neuralgia is treated with anti-convulsants such as carbamezapine, gabapentin, pregabalin, topriamate and phenytoin. Recurrent attacks and relapses (exacerbations) are commonly treated with corticosteroids to reduce the inflammation in the central nervous system that damages the myelin and slows or blocks the transmission of nerve impulses. These drugs do not slow down, inhibit future relapses or stop the progression of this disorder. Physical therapy and exercise programs (especially aquatic or water therapy) are of value in most patients.The symptoms of MS can be classified as primary (directly due to the disease itself), secondary (due to inadequate management of primary symptoms), and tertiary (those that result from complications of the disease). For example, if a person has bladder problems that are uncontrolled, s/he can have infections and become socially isolated. S/he can stop driving or working due to this uncontrolled problem.Symptoms of MS can be subtle and mild (numbness, tingling) or severe (inability to walk or move) and can vary from time to time and from person to person. Therefore, treatment must be individualized to each person and dynamic, to address ever-changing problems related to the disease. Frequently people with MS require a team approach to manage their disease along with medications, rehabilitation, counseling, and educational services. Disease-modifying medications help to reduce the frequency and severity of attacks, reduce the accumulation of damaged or active disease areas (lesions) in the brain and spinal cord, and appear to slow down the progression of disability. It is believed that these drugs are most effective when started early, before the disease progresses further. The following consensus paper by the Multiple Sclerosis Coalition discusses disease-modifying drugs that have been approved by the FDA:
http://c.ymcdn.com/sites/www.mscare.org/resource/collection/A0711E7F-0EFA-43B2-AEB9-96ABB9D8F4E6/DMT_Consensus_MS_Coalition092016.pdfIn 2018, Gilenya (fingolimod) was approved by the FDA to treat relapsing MS in children and adolescents age 10 years and older. Gilenya is manufactured by Novartis Pharmaceuticals Corp.
| 841 |
Multiple Sclerosis
|
nord_842_0
|
Overview of Multiple Sulfatase Deficiency
|
Multiple sulfatase deficiency (MSD) is an ultra-rare genetic disorder in which all of the known sulfatase enzymes are unable to be fully activated by formylglycine-generating enzyme (FGE), which is encoded by the SUMF1 gene. Because of the multisystemic importance of sulfatases, this disorder affects many parts of the body. While neurologic impairment is universal, major systemic symptoms can be variable and include bone abnormalities, coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Because of deficient activation of steroid sulfatase, the skin of children affected by MSD can be usually dry and scaly (ichthyosis).
|
Overview of Multiple Sulfatase Deficiency. Multiple sulfatase deficiency (MSD) is an ultra-rare genetic disorder in which all of the known sulfatase enzymes are unable to be fully activated by formylglycine-generating enzyme (FGE), which is encoded by the SUMF1 gene. Because of the multisystemic importance of sulfatases, this disorder affects many parts of the body. While neurologic impairment is universal, major systemic symptoms can be variable and include bone abnormalities, coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Because of deficient activation of steroid sulfatase, the skin of children affected by MSD can be usually dry and scaly (ichthyosis).
| 842 |
Multiple Sulfatase Deficiency
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nord_842_1
|
Symptoms of Multiple Sulfatase Deficiency
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Classically, the subtypes of MSD are defined by the age at symptom onset: neonatal, severe late infantile, mild infantile, and juvenile. The clinical relevance of these divisions is unknown, as subtle symptoms are present in infancy across all types. Because MSD is the result of a variable degree of deficiency across all human sulfatases, the systemic symptoms can be variable.METABOLICCRANIOFACIALEyesEarsMouth/oral/JawNEUROLOGICALCARDIOVASCULARRESPIRATORYDERMATOLOGIC (skin)GASTROINTESTINAL (GI)/ URINARYMUSCULOSKELETAL
|
Symptoms of Multiple Sulfatase Deficiency. Classically, the subtypes of MSD are defined by the age at symptom onset: neonatal, severe late infantile, mild infantile, and juvenile. The clinical relevance of these divisions is unknown, as subtle symptoms are present in infancy across all types. Because MSD is the result of a variable degree of deficiency across all human sulfatases, the systemic symptoms can be variable.METABOLICCRANIOFACIALEyesEarsMouth/oral/JawNEUROLOGICALCARDIOVASCULARRESPIRATORYDERMATOLOGIC (skin)GASTROINTESTINAL (GI)/ URINARYMUSCULOSKELETAL
| 842 |
Multiple Sulfatase Deficiency
|
nord_842_2
|
Causes of Multiple Sulfatase Deficiency
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Multiple sulfatase deficiency is an autosomal recessive disorder caused by a change (mutation) in the SUMF1 gene. This gene allows cells to make an enzyme called FGE (formylglycine-generating enzyme) that activates all sulfatases within the cell. Without activation, sulfatases are not able to do their jobs in the cell. The missing sulfatases are directly responsible for the changes in the body seen in MSD. More severe forms of the disease are associated with SUMF1 mutations that lead to the production of an unstable form of FGE, while the more mild forms are due to mutations that lead to reduced but correctly functioning FGE.Recessive genetic disorders like multiple sulfatase deficiency 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 have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
|
Causes of Multiple Sulfatase Deficiency. Multiple sulfatase deficiency is an autosomal recessive disorder caused by a change (mutation) in the SUMF1 gene. This gene allows cells to make an enzyme called FGE (formylglycine-generating enzyme) that activates all sulfatases within the cell. Without activation, sulfatases are not able to do their jobs in the cell. The missing sulfatases are directly responsible for the changes in the body seen in MSD. More severe forms of the disease are associated with SUMF1 mutations that lead to the production of an unstable form of FGE, while the more mild forms are due to mutations that lead to reduced but correctly functioning FGE.Recessive genetic disorders like multiple sulfatase deficiency 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 have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
| 842 |
Multiple Sulfatase Deficiency
|
nord_842_3
|
Affects of Multiple Sulfatase Deficiency
|
Multiple sulfatase deficiency is an ultra-rare disorder with a wide spectrum of disease. To date, over one hundred patients have been reported in the literature with 50 of those patients confirmed alive by patient organization registries. This number may be underestimated due under diagnosis or lack of reporting. Males and females are equally affected and no ethnic predisposition has been identified.
|
Affects of Multiple Sulfatase Deficiency. Multiple sulfatase deficiency is an ultra-rare disorder with a wide spectrum of disease. To date, over one hundred patients have been reported in the literature with 50 of those patients confirmed alive by patient organization registries. This number may be underestimated due under diagnosis or lack of reporting. Males and females are equally affected and no ethnic predisposition has been identified.
| 842 |
Multiple Sulfatase Deficiency
|
nord_842_4
|
Related disorders of Multiple Sulfatase Deficiency
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Symptoms of the following disorders can resemble those of multiple sulfatase deficiency. In particular, disorders caused by single sulfatase deficiencies, such as arylsulfatase A in metachromatic leukodystrophy, share many similarities. Comparisons are useful for differential diagnosis:Metachromatic leukodystrophy (MLD) is a rare hereditary disease characterized by accumulation of fats called sulfatides. This causes the destruction of the protective fatty layer (myelin sheath) surrounding the nerves in both the central nervous system and the peripheral nervous system. Three types of MLD ultimately affect both intellectual and motor function. Symptoms vary by type but can include difficulty talking, seizures, difficulty walking, personality changes, and behavior and personality changes. MLD is caused by mutations in the ASA gene. All forms of MLD are progressive. (For more information on this condition, choose “metachromatic leukodystrophy” as your search term in the Rare Disease Database.)Maroteaux-Lamy syndrome (arylsulfatase-B deficiency; mucopolysaccharidosis VI; polydystrophic dwarfism), is a form of mucopolysaccharidosis. These are a group of genetic disorders caused by the deficiency of one of ten specific lysosomal enzymes, resulting in an inability to metabolize certain complex carbohydrates (mucopolysaccharides) into simpler molecules. The accumulation of these large, ungraded mucopolysaccharides in the cells of the body causes a number of symptoms. This syndrome can occur as a severe type, an intermediate type, and a mild type. Growth delay generally occurs from 2-3 years of age, with coarsening of facial features and abnormalities in the bones of hands and spine. Joint stiffness also occurs. The intellect is usually normal. (For more information on this condition, choose “Maroteaux-Lamy” as your search term in the Rare Disease Database.)
Ichthyosis can be a symptom of multiple sulfatase deficiency. X-linked ichthyosis is caused by a mutation in steroid sulfatase. It is characterized by an abnormal accumulation of large amounts of dead skin (squamous) cells in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to cause a defect in the metabolism of skin cells known as “corneocytes” or of the fat-rich matrix around these cells. The cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (For more information, chose “Ichthyosis” as your search term in the Rare Disease Database.)
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Related disorders of Multiple Sulfatase Deficiency. Symptoms of the following disorders can resemble those of multiple sulfatase deficiency. In particular, disorders caused by single sulfatase deficiencies, such as arylsulfatase A in metachromatic leukodystrophy, share many similarities. Comparisons are useful for differential diagnosis:Metachromatic leukodystrophy (MLD) is a rare hereditary disease characterized by accumulation of fats called sulfatides. This causes the destruction of the protective fatty layer (myelin sheath) surrounding the nerves in both the central nervous system and the peripheral nervous system. Three types of MLD ultimately affect both intellectual and motor function. Symptoms vary by type but can include difficulty talking, seizures, difficulty walking, personality changes, and behavior and personality changes. MLD is caused by mutations in the ASA gene. All forms of MLD are progressive. (For more information on this condition, choose “metachromatic leukodystrophy” as your search term in the Rare Disease Database.)Maroteaux-Lamy syndrome (arylsulfatase-B deficiency; mucopolysaccharidosis VI; polydystrophic dwarfism), is a form of mucopolysaccharidosis. These are a group of genetic disorders caused by the deficiency of one of ten specific lysosomal enzymes, resulting in an inability to metabolize certain complex carbohydrates (mucopolysaccharides) into simpler molecules. The accumulation of these large, ungraded mucopolysaccharides in the cells of the body causes a number of symptoms. This syndrome can occur as a severe type, an intermediate type, and a mild type. Growth delay generally occurs from 2-3 years of age, with coarsening of facial features and abnormalities in the bones of hands and spine. Joint stiffness also occurs. The intellect is usually normal. (For more information on this condition, choose “Maroteaux-Lamy” as your search term in the Rare Disease Database.)
Ichthyosis can be a symptom of multiple sulfatase deficiency. X-linked ichthyosis is caused by a mutation in steroid sulfatase. It is characterized by an abnormal accumulation of large amounts of dead skin (squamous) cells in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to cause a defect in the metabolism of skin cells known as “corneocytes” or of the fat-rich matrix around these cells. The cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (For more information, chose “Ichthyosis” as your search term in the Rare Disease Database.)
| 842 |
Multiple Sulfatase Deficiency
|
nord_842_5
|
Diagnosis of Multiple Sulfatase Deficiency
|
MSD should be suspected in any individual with developmental delays, coarse facial features, bone abnormalities, and ichthyosis. MSD can be diagnosed when a child has low levels of at least two sulfatases and elevated sulfatide levels. Additional testing, such as glycosaminoglycan levels, can also be supportive, although can be normal in some individuals affected by MSD. Molecular genetic testing for mutations in the SUMF1 gene can be helpful as well, but with the rarity of the disease, only a limited number of disease-causing variants have been fully characterized.The MRI associated with MSD can be variable and nonspecific. The images can demonstrate demyelination, perivascular space prominence, and/or hydrocephalus.
|
Diagnosis of Multiple Sulfatase Deficiency. MSD should be suspected in any individual with developmental delays, coarse facial features, bone abnormalities, and ichthyosis. MSD can be diagnosed when a child has low levels of at least two sulfatases and elevated sulfatide levels. Additional testing, such as glycosaminoglycan levels, can also be supportive, although can be normal in some individuals affected by MSD. Molecular genetic testing for mutations in the SUMF1 gene can be helpful as well, but with the rarity of the disease, only a limited number of disease-causing variants have been fully characterized.The MRI associated with MSD can be variable and nonspecific. The images can demonstrate demyelination, perivascular space prominence, and/or hydrocephalus.
| 842 |
Multiple Sulfatase Deficiency
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