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Symptoms of Marfan Syndrome
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The specific symptoms of Marfan syndrome vary greatly from person to person. Some individuals will develop only a few mild or isolated symptoms; others will develop more serious complications. In most cases, Marfan syndrome progresses as individuals grow older. In some infants, Marfan syndrome may cause severe, rapidly progressive complications during infancy, often quickly affecting multiple organ systems early in life. Marfan syndrome can potentially affect many systems of the body including the heart, blood vessels, skeleton, eyes, lungs, and skin.Individuals with Marfan syndrome often develop distinct physical findings often including an abnormally thin physique and disproportionately long, slender arms and legs (dolichostenomelia) due to overgrowth of the long bones. In addition, affected individuals usually have abnormally long, slender fingers (arachnodactyly). People with Marfan syndrome are usually very tall and thin in comparison to unaffected family members but not necessarily in comparison to the general population. They can lack muscle tone (hypotonia) and have little fat under the skin (subcutaneous fat).A variety of skeletal malformations affect individuals with Marfan syndrome including overgrowth of the ribs, which can push the breastbone (sternum) inward resulting in a sunken chest (pectus excavatum) or outward resulting in a protruding chest (pectus carinatum). Additional symptoms include abnormally loose or flexible joints (joint hypermobility), flat feet (pes planus), fingers that are permanently bent or “fixed” and cannot extend or straighten fully (camptodactyly or clinodactyly), and reduced extension of the elbow. In some cases, the joints may be unaffected or may become tight and stiff (contractures). Some individuals have an abnormally deep hip socket (acetabulum) with deep insertion of the head of the long bone (femur) of the leg (protrusio acetabulae) and signs of bone erosion. Many individuals with Marfan syndrome develop spinal abnormalities such as progressive curving of the spine (scoliosis) that may be mild or severe. Scoliosis may be associated with back pain in some affected individuals. In children, skeletal abnormalities may progress rapidly during phases of rapid growth, such as adolescence.Individuals with Marfan syndrome may have several distinct facial features including a long, narrow skull (dolichocephaly), deep-set eyes (enophthalmos), an abnormally small jaw (micrognathia) that may be recessed farther back than normal (retrognathia), abnormally flat cheek bones (malar hypoplasia), and an abnormal downward slant to the eyes (downward slanting palpebral fissures). Affected individuals may also exhibit a highly-arched roof of the mouth (palate), teeth that are crowded together and upper and lower teeth that do not meet (align) properly when biting (malocclusion).Individuals with Marfan syndrome may have significant cardiovascular problems such as a common heart defect known as mitral valve prolapse. The mitral valve is located between the left upper and left lower chambers (left atrium and left ventricle, respectively) of the heart. Mitral valve prolapse occurs when one or both of the flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left upper chamber (atrium) of the heart during ventricular contraction. In some cases, this may allow leakage or the backward flow of blood from the left lower chamber of the heart (ventricle) back into the left atrium (mitral regurgitation). Often no associated symptoms are apparent (asymptomatic). However, in other cases, mitral valve prolapse can result in chest pain, abnormal heart rhythms (arrhythmias), or evidence of inadequate heart function (congestive heart failure, most often in association with prolonged and severe mitral regurgitation).Additional cardiovascular findings include widening (aneurysm) and degeneration of the main artery that carries blood away from the heart (aorta), tearing (dissection) of the aorta so that blood seeps between the inner and outer layers of the aortic wall, and backward flow of blood from the aorta into the lower left chamber (ventricle) of the heart (aortic regurgitation). If severe and left untreated, these heart abnormalities associated with Marfan syndrome can cause life-threatening complications such as rupture of the aorta and congestive heart failure. Some individuals may develop widening of the main artery of the lungs (pulmonary artery dilatation). This typically does not cause any problems in people with Marfan syndrome.Individuals with Marfan syndrome commonly develop abnormalities of the eyes, especially nearsightedness (myopia), which may develop early in childhood and become progressively worse. Approximately 60 percent of individuals develop displacement of the lenses of the eyes away from the center of the eye (ectopia lentis). Ectopia lentis may occur at birth or later in life and may remain stable or become progressively worse.Additional issues affecting the eyes in Marfan syndrome include an abnormally flat cornea (the front portion of the eyes through which light passes), underdevelopment of the colored portion of the eye (hypoplastic iris), and detachment of the nerve-rich membrane (retina) lining the back of the eyes. Some individuals with Marfan syndrome are at risk for the early development of clouding of the lenses of the eyes (cataracts) or increased pressure and/or associated changes in the eyes (glaucoma). If left untreated, eye abnormalities can result in vision loss. Some individuals with Marfan syndrome may develop distended air pockets near the top of the lungs (apical pulmonary blebs), which can predispose individuals to a leak of air within the chest cavity and lung collapse that occurs for no readily apparent reason (spontaneous pneumothorax). In some cases, pneumothorax can recur in the same lung or even the opposite lung (recurrent pneumothorax).Some affected individuals may develop widening or bulging of the sac (dura) that surrounds the spinal cord (dural ectasia). This condition usually does not cause symptoms (asymptomatic), but has been associated with lower back pain and can cause pinching of a nerve leading to abnormal sensations or muscle performance in the legs. Affected individuals may also developed stretch marks (striae atrophicae) of the skin without an obvious cause. Some affected individuals may have an inguinal, umbilical or surgical hernia, in which a weakened portion of the pelvic or abdominal wall shows external bulging and even protrusion of a small segment of the intestines.Researchers have identified a subset of individuals with symptoms that are extremely similar to those associated with Marfan syndrome; however, these individuals have changes in different genes. Of equal importance, these individuals have now been recognized to be at risk for numerous features that are not seen in Marfan syndrome caused by mutations in FBN1. While a subset of these patients were historically designated as having Marfan syndrome type II, it is now more common practice to specify alternative diagnoses including Loeys-Dietz syndrome or Shprintzen-Goldberg syndrome (see the Related Disorders section below). People with a Marfan-like condition caused by mutations in a gene other than FBN1 may require specialized counseling, imaging protocols and management.
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Symptoms of Marfan Syndrome. The specific symptoms of Marfan syndrome vary greatly from person to person. Some individuals will develop only a few mild or isolated symptoms; others will develop more serious complications. In most cases, Marfan syndrome progresses as individuals grow older. In some infants, Marfan syndrome may cause severe, rapidly progressive complications during infancy, often quickly affecting multiple organ systems early in life. Marfan syndrome can potentially affect many systems of the body including the heart, blood vessels, skeleton, eyes, lungs, and skin.Individuals with Marfan syndrome often develop distinct physical findings often including an abnormally thin physique and disproportionately long, slender arms and legs (dolichostenomelia) due to overgrowth of the long bones. In addition, affected individuals usually have abnormally long, slender fingers (arachnodactyly). People with Marfan syndrome are usually very tall and thin in comparison to unaffected family members but not necessarily in comparison to the general population. They can lack muscle tone (hypotonia) and have little fat under the skin (subcutaneous fat).A variety of skeletal malformations affect individuals with Marfan syndrome including overgrowth of the ribs, which can push the breastbone (sternum) inward resulting in a sunken chest (pectus excavatum) or outward resulting in a protruding chest (pectus carinatum). Additional symptoms include abnormally loose or flexible joints (joint hypermobility), flat feet (pes planus), fingers that are permanently bent or “fixed” and cannot extend or straighten fully (camptodactyly or clinodactyly), and reduced extension of the elbow. In some cases, the joints may be unaffected or may become tight and stiff (contractures). Some individuals have an abnormally deep hip socket (acetabulum) with deep insertion of the head of the long bone (femur) of the leg (protrusio acetabulae) and signs of bone erosion. Many individuals with Marfan syndrome develop spinal abnormalities such as progressive curving of the spine (scoliosis) that may be mild or severe. Scoliosis may be associated with back pain in some affected individuals. In children, skeletal abnormalities may progress rapidly during phases of rapid growth, such as adolescence.Individuals with Marfan syndrome may have several distinct facial features including a long, narrow skull (dolichocephaly), deep-set eyes (enophthalmos), an abnormally small jaw (micrognathia) that may be recessed farther back than normal (retrognathia), abnormally flat cheek bones (malar hypoplasia), and an abnormal downward slant to the eyes (downward slanting palpebral fissures). Affected individuals may also exhibit a highly-arched roof of the mouth (palate), teeth that are crowded together and upper and lower teeth that do not meet (align) properly when biting (malocclusion).Individuals with Marfan syndrome may have significant cardiovascular problems such as a common heart defect known as mitral valve prolapse. The mitral valve is located between the left upper and left lower chambers (left atrium and left ventricle, respectively) of the heart. Mitral valve prolapse occurs when one or both of the flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left upper chamber (atrium) of the heart during ventricular contraction. In some cases, this may allow leakage or the backward flow of blood from the left lower chamber of the heart (ventricle) back into the left atrium (mitral regurgitation). Often no associated symptoms are apparent (asymptomatic). However, in other cases, mitral valve prolapse can result in chest pain, abnormal heart rhythms (arrhythmias), or evidence of inadequate heart function (congestive heart failure, most often in association with prolonged and severe mitral regurgitation).Additional cardiovascular findings include widening (aneurysm) and degeneration of the main artery that carries blood away from the heart (aorta), tearing (dissection) of the aorta so that blood seeps between the inner and outer layers of the aortic wall, and backward flow of blood from the aorta into the lower left chamber (ventricle) of the heart (aortic regurgitation). If severe and left untreated, these heart abnormalities associated with Marfan syndrome can cause life-threatening complications such as rupture of the aorta and congestive heart failure. Some individuals may develop widening of the main artery of the lungs (pulmonary artery dilatation). This typically does not cause any problems in people with Marfan syndrome.Individuals with Marfan syndrome commonly develop abnormalities of the eyes, especially nearsightedness (myopia), which may develop early in childhood and become progressively worse. Approximately 60 percent of individuals develop displacement of the lenses of the eyes away from the center of the eye (ectopia lentis). Ectopia lentis may occur at birth or later in life and may remain stable or become progressively worse.Additional issues affecting the eyes in Marfan syndrome include an abnormally flat cornea (the front portion of the eyes through which light passes), underdevelopment of the colored portion of the eye (hypoplastic iris), and detachment of the nerve-rich membrane (retina) lining the back of the eyes. Some individuals with Marfan syndrome are at risk for the early development of clouding of the lenses of the eyes (cataracts) or increased pressure and/or associated changes in the eyes (glaucoma). If left untreated, eye abnormalities can result in vision loss. Some individuals with Marfan syndrome may develop distended air pockets near the top of the lungs (apical pulmonary blebs), which can predispose individuals to a leak of air within the chest cavity and lung collapse that occurs for no readily apparent reason (spontaneous pneumothorax). In some cases, pneumothorax can recur in the same lung or even the opposite lung (recurrent pneumothorax).Some affected individuals may develop widening or bulging of the sac (dura) that surrounds the spinal cord (dural ectasia). This condition usually does not cause symptoms (asymptomatic), but has been associated with lower back pain and can cause pinching of a nerve leading to abnormal sensations or muscle performance in the legs. Affected individuals may also developed stretch marks (striae atrophicae) of the skin without an obvious cause. Some affected individuals may have an inguinal, umbilical or surgical hernia, in which a weakened portion of the pelvic or abdominal wall shows external bulging and even protrusion of a small segment of the intestines.Researchers have identified a subset of individuals with symptoms that are extremely similar to those associated with Marfan syndrome; however, these individuals have changes in different genes. Of equal importance, these individuals have now been recognized to be at risk for numerous features that are not seen in Marfan syndrome caused by mutations in FBN1. While a subset of these patients were historically designated as having Marfan syndrome type II, it is now more common practice to specify alternative diagnoses including Loeys-Dietz syndrome or Shprintzen-Goldberg syndrome (see the Related Disorders section below). People with a Marfan-like condition caused by mutations in a gene other than FBN1 may require specialized counseling, imaging protocols and management.
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Marfan Syndrome
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Causes of Marfan Syndrome
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Marfan syndrome is caused by defects or deletions (mutations) of the fibrillin-1 (FBN1) gene. Not everyone who has a mutation of this gene develops Marfan syndrome. Some changes do not alter the function of the gene or protein and therefore do not cause a medical problem. Other changes in the FBN1 gene can cause conditions that are distinct from Marfan syndrome.The FBN1 gene contains instructions for producing (encoding) a protein known as fibrillin-1. Fibrillin-1 is a component of structures called microfibrils, which are fiber-like structures that are part of the extracellular matrix, a complex material that surrounds and connects cells throughout the body. Researchers believe fibrillin-1 plays an essential role in maintaining the strength and structural integrity of the connective tissue. Without fibrillin-1, connective tissue may be weak. Current evidence also suggests that fibrillin-1 also influences the activity of molecules that instruct cells how to behave (growth factors), including a specific growth factor called transforming growth factor-β (TGF-β).Marfan syndrome is inherited as an autosomal dominant condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is sufficient to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. In approximately 25 percent of Marfan syndrome cases, the disease causing DNA change occurs as the result of a new mutation. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. The children of an individual with Marfan syndrome caused by a new mutation have a 50% chance of inheriting this gene change and hence Marfan syndrome from their affected parent.A disorder that includes many features of Marfan syndrome (MFS) called Loeys-Dietz syndrome (LDS) can be caused by mutations in at least 5 different genes that influence the activity of TGF-β (TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3). Another condition called Shprintzen-Goldberg syndrome or SGS includes many features of MFS and most features of LDS, but also problems with learning (intellectual disability). SGS is caused by mutations in another gene that regulates TGF-β activity called SKI.
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Causes of Marfan Syndrome. Marfan syndrome is caused by defects or deletions (mutations) of the fibrillin-1 (FBN1) gene. Not everyone who has a mutation of this gene develops Marfan syndrome. Some changes do not alter the function of the gene or protein and therefore do not cause a medical problem. Other changes in the FBN1 gene can cause conditions that are distinct from Marfan syndrome.The FBN1 gene contains instructions for producing (encoding) a protein known as fibrillin-1. Fibrillin-1 is a component of structures called microfibrils, which are fiber-like structures that are part of the extracellular matrix, a complex material that surrounds and connects cells throughout the body. Researchers believe fibrillin-1 plays an essential role in maintaining the strength and structural integrity of the connective tissue. Without fibrillin-1, connective tissue may be weak. Current evidence also suggests that fibrillin-1 also influences the activity of molecules that instruct cells how to behave (growth factors), including a specific growth factor called transforming growth factor-β (TGF-β).Marfan syndrome is inherited as an autosomal dominant condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is sufficient to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. In approximately 25 percent of Marfan syndrome cases, the disease causing DNA change occurs as the result of a new mutation. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. The children of an individual with Marfan syndrome caused by a new mutation have a 50% chance of inheriting this gene change and hence Marfan syndrome from their affected parent.A disorder that includes many features of Marfan syndrome (MFS) called Loeys-Dietz syndrome (LDS) can be caused by mutations in at least 5 different genes that influence the activity of TGF-β (TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3). Another condition called Shprintzen-Goldberg syndrome or SGS includes many features of MFS and most features of LDS, but also problems with learning (intellectual disability). SGS is caused by mutations in another gene that regulates TGF-β activity called SKI.
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nord_757_3
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Affects of Marfan Syndrome
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Marfan syndrome affects males and females in equal numbers and occurs worldwide with no ethnic predisposition. The prevalence has been estimated to be 1 in 5-10,000 individuals in the general population. Because of the difficulty in diagnosing mild cases of Marfan syndrome, the disorder is probably underdiagnosed, making it difficult to determine its true frequency in the general population.
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Affects of Marfan Syndrome. Marfan syndrome affects males and females in equal numbers and occurs worldwide with no ethnic predisposition. The prevalence has been estimated to be 1 in 5-10,000 individuals in the general population. Because of the difficulty in diagnosing mild cases of Marfan syndrome, the disorder is probably underdiagnosed, making it difficult to determine its true frequency in the general population.
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Related disorders of Marfan Syndrome
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Symptoms of the following disorders can be similar to those of Marfan syndrome. Comparisons are essential to arrive at a correct diagnosis.Beals syndrome, also known as congenital contractural arachnodactyly, is an extremely rare genetic disorder characterized by fixed flexion (contracture) of certain joints (e.g., fingers, elbows, knees, and hips); abnormally long, slender fingers and toes (arachnodactyly); and/or abnormally shaped ears resulting in a “crumpled” appearance. Contractures of joints tend to improve with age in Beals syndrome. In addition, affected individuals may exhibit front-to-back and side-to-side curvature of the spine (kyphoscoliosis); feet that are abnormally positioned (talipes equinovarus or clubfoot); outward displacement of the fingers (ulnar deviation of the fingers); and an abnormally short neck. There are extremely rare reports of displacement of the lens of the eye (ectopia lentis) or severe heart abnormalities in patients with Beals syndrome; the exceptional nature of these cases warrants further study to determine if these findings are truly related to the diagnosis of Beals syndrome. In some cases, affected individuals may have a deformity of the valve on the left side of the heart (mitral valve prolapse). Beals syndrome is inherited as an autosomal dominant trait and is caused by mutations in the FBN2 gene. (For more information on this disorder, choose “congenital contractural arachnodactyly” as your search term in the Rare Disease Database.)Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue disorders characterized by defects of the major structural protein in the body (collagen). Collagen, a strong and rigid protein, plays an essential role in holding together and strengthening the tissues of the body. Due to defects of collagen, primary EDS findings include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated and unusually loose, thin, stretchy (elastic) and/or fragile skin. Some forms of EDS can include weakness of tiny blood vessels (capillaries) and other tissues of the body, leading to easy bruising, hernias and other findings., The different types of EDS were originally categorized in a classification system that used Roman numerals (e.g., EDS I to EDS XI), based upon each form’s associated findings (clinical evidence) and underlying cause (gene involved). A revised, simplified classification system has since been described in the medical literature that categorizes EDS into six major subtypes, based upon clinical evidence, underlying biochemical defects, and mode of inheritance. Each subtype of EDS is a distinct hereditary disorder that typically holds true within a given family. In other words, parents with one subtype of EDS will potentially pass the predisposition for the same subtype (but not a different subtype) to their children. EDS is usually transmitted as an autosomal dominant trait. Rare forms of EDS pass as an autosomal recessive trait, meaning that an affected person has two abnormal copies of the same gene – typically one inherited from each parent who have one abnormal copy and are therefore unaffected. Only certain rare types of EDS include a predisposition for severe cardiovascular issues (such as vascular EDS); other types predominantly alter the skin and joints (e.g. hypermobile EDS). One type of EDS associated with life-threatening events (vascular EDS) is caused by mutations in the COL3A1 gene. These include enlargement and tear of any medium- to large-sized blood vessel carrying blood away from the heart (arteries, as opposed to veins that carry blood toward the heart) throughout the body and a risk of rupture of hollow internal organs such as the intestines or pregnant uterus. Individuals with this condition do not typically show the outward features of MFS and are not at risk for most of the eye features of MFS, with the exception of retinal detachment. (For more information on this disorder, choose “Ehlers-Danlos” as your search term in the Rare Disease Database.)Mitral valve prolapse (MVP) is a common condition in which one or both of the flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left atrium during ventricular contraction. In some cases, this may allow leakage or the backward flow of blood from the left ventricle back into the left atrium (mitral regurgitation). The exact underlying mechanism responsible for MVP remains unknown. In many affected individuals, the condition appears to occur in the absence of an associated disorder or syndrome (condition that involves multiple parts of the body). Sometimes MVP occurs in families in association with subtle connective tissue findings in other parts of the body (mitral valve prolapse syndrome). Evidence indicates that both the isolated and syndromic forms of MVP are sometimes familial, suggesting autosomal dominant inheritance. MVP can also occur in association with other defined connective tissue disorders including MFS, LDS, SGS and other conditions. In many individuals with MVP, no associated symptoms are apparent (isolated MVP). However, in other cases, the condition may result in chest pain, abnormal heart rhythms (arrhythmias), and signs of congestive heart failure, especially when valve leakage is longstanding (chronic) or severe. MVP is often associated with a characteristic click and/or a whooshing sound (murmur) that may be detected through use of a stethoscope during physical examination. If leakage through the mitral valve (mitral regurgitation) is severe, the extra work that the heart has to perform can lead to poor performance of the heart muscle (heart failure). Homocystinuria is a rare metabolic condition characterized by an excess of the compound homocystine in the blood and urine. The condition may result from deficiency of any of several enzymes involved in the conversion of the essential amino acid methionine to another amino acid called cysteine – or, less commonly, impaired conversion of the compound homocysteine to methionine. Enzymes are proteins that accelerate the rate of chemical reactions in the body. Certain amino acids, which are the chemical building blocks of proteins, are essential for proper growth and development. In most cases, homocystinuria is caused by reduced activity of an enzyme known as cystathionine beta-synthase (CBS). Due to deficiency of the CBS enzyme, infants with homocystinuria may fail to grow and gain weight at the expected rate (failure to thrive) and have developmental delay. By approximately age three, additional, more specific findings may become apparent. These may include dislocation (subluxation) of the lens of the eyes (ectopia lentis), associated “quivering” (iridodonesis) of the colored region of the eyes (iris), severe nearsightedness (myopia), and other eye (ocular) abnormalities. Although intelligence may be normal in some individuals, many children may be affected by progressive intellectual disability. In addition, some may develop psychiatric disturbances and/or episodes of uncontrolled electrical activity in the brain (seizures). Affected individuals also tend to be thin and somewhat tall and may have long, slender fingers and toes (arachnodactyly) and long arms and legs (dolichostenomelia) compared to the length of the trunk (collectively “marfanoid” features). Additional skeletal abnormalities may include progressive sideways curvature of the spine (scoliosis), abnormal protrusion or indentation of the breastbone (pectus carinatum or excavatum, respectively), and generalized loss of bone density (osteoporosis). In addition, in those with the disorder, blood clots tend to develop and can become lodged within certain large and small blood vessels (thromboembolism), potentially leading to life-threatening complications. Homocystinuria is an autosomal recessive trait, meaning that an affected person must have two abnormal copies of the underlying gene, most often one abnormal copy inherited from both parents, who each carry only a single abnormal gene and are therefore unaffected. Effective therapies are available for some forms of homocystinuria. (For more information on this disorder, choose “Homocystinuria” as your search term in the Rare Disease Database.)Loeys-Dietz syndrome (LDS) is a rare disorder characterized by a variety of symptoms that overlap with Marfan syndrome. Individuals with Loeys-Dietz syndrome have skeletal and cardiovascular abnormalities. Affected individuals may experience bulging of the wall of the aorta (aneurysm), tearing (dissection) of the aorta or rupture of the aorta. Unlike Marfan syndrome, the aorta in individuals with Loeys-Dietz syndrome is prone to tearing or rupturing early in childhood and at a relatively small size. In Loeys-Dietz syndrome the blood vessels typically follow a very winding course (tortuosity) and aneurysms and tears of blood vessels can occur throughout the entire arterial tree. Other heart features can include an aortic valves that forms with only two rather than the normal three cusps (bicuspid aortic valve), a hole between the left and right upper chambers of the heart (atrial septal defect) and maintenance of a blood vessel that connects the aorta and pulmonary artery during growth in the womb (fetal development) after birth (patent ductus arteriosus). Additional findings may include long, slender fingers (arachnodactyly), abnormal curvature of the spine (scoliosis), a sunken or protruding chest (pectus excavatum or pectus carninatum), widening of the spinal sac (dural ectasia), and loose joints. Features seen in Loeys-Dietz that are not seen in Marfan syndrome include accumulation of excessive cerebrospinal fluid (CSF) in the skull causing pressure on the tissues of the brain (hydrocephalus), incomplete closure of the roof of the mouth (cleft palate), premature closure of the fibrous joints (sutures) between certain bones of the skull (craniosynostosis), bluish discoloration of the whites of the eyes (blue sclerae), deviation of one of the eyes outward away from the other eye (exotropia) and abnormally formed or unstable joints in the spine of the neck (cervical spine malformation or instability). The fleshy mass (uvula) hanging in the back of the throat may be unusually broad or split (bifid uvula). Characteristic facial features often include widely spaced eyes (hypertelorism), a highly-arched roof of the mouth (palate), an abnormally small jaw (micrognathia) that is recessed farther back than normal (retrognathia), and underdeveloped cheek bones (malar hypoplasia). Unlike Marfan syndrome, the skin in Loeys-Dietz syndrome can be soft with easily visible underlying veins (translucency). The skin also tends to bruise easily and to develop abnormal (wide) scars. People with Loeys-Dietz syndrome can be prone to severe allergies and to inflammation of the gastrointestinal tract (eosinophilic esophagitis or inflammatory bowel disease). Loeys-Dietz syndrome is inherited as an autosomal dominant trait and is caused by mutations in at least five genes that are all known to influence the activity of TGF-β (TGFBR1, TGFBR2, SMAD3, TGFB2 or TGFB3). While all patients with mutations in these genes do not have outward discriminating features of Loeys-Dietz syndrome, they should have surveillance (imaging studies) to look for vascular issues throughout the arterial tree (from head through pelvis) and are at risk to have children with more typical Loeys-Dietz syndrome manifestations.Shprintzen-Goldberg syndrome (SGS) shares many features with Marfan syndrome and Loeys-Dietz syndrome including overgrowth of the long bones (dolichostenolelia), long and slender fingers (arachnodactyly), abnormal curvature of the spine (scoliosis), a sunken or protruding chest (pectus excavatum or pectus carninatum), widening of the spinal sac (dural ectasia), loose joints, wide spacing of the eyes (hypertelorism), premature fusion of the sutures of the skull (craniosynostosis) and a highly arched palate. While aortic root enlargement (aneurysm) can be seen in SGS, it is less frequent and typically less severe, when compared to MFS or LDS. Unlike either MFS or LDS, most people with SGS have at least some degree of developmental delay or intellectual disability. SGS is caused by mutations in the SKI gene that influences the activity of TGF-β. (For more information on this disorder, choose “Shprintzen” as your search term in the Rare Disease Database.)Familial aortic aneurysm and/or tear (dissection) in the chest (thoracic) can occur in the absence of other abnormalities throughout the body (nonsyndromic). In some circumstances, affected individuals can show subtle cysts of the colored portion of the eye (iris floculi) or a visible capillary network below the skin with a honeycomb appearance (livido reticularis). A subset of people with this condition can have an aortic valve that forms with only two cusps (bicuspid aortic valve) instead of the normal three cusps (tricuspid aortic valve). The base of the aorta (aortic root) is the most common site of enlargement (aneurysm), but other aortic segments and even blood vessels outside of the chest can more rarely show involvement. This condition most often passes in families as a dominant trait (only one abnormal gene copy is required to show disease). The age at which problems arise tends to be later and more variable than in Marfan syndrome or Loeys-Dietz syndrome, and some people who inherit the gene abnormality might never show a vascular problem (incomplete penetrance). Aortic root aneurysms tend to tear or rupture at a size similar to that in Marfan syndrome, and many of the same management principles apply. There are many genes that cause nonsyndromic familial thoracic aortic aneurysm, and only a few have been identified.
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Related disorders of Marfan Syndrome. Symptoms of the following disorders can be similar to those of Marfan syndrome. Comparisons are essential to arrive at a correct diagnosis.Beals syndrome, also known as congenital contractural arachnodactyly, is an extremely rare genetic disorder characterized by fixed flexion (contracture) of certain joints (e.g., fingers, elbows, knees, and hips); abnormally long, slender fingers and toes (arachnodactyly); and/or abnormally shaped ears resulting in a “crumpled” appearance. Contractures of joints tend to improve with age in Beals syndrome. In addition, affected individuals may exhibit front-to-back and side-to-side curvature of the spine (kyphoscoliosis); feet that are abnormally positioned (talipes equinovarus or clubfoot); outward displacement of the fingers (ulnar deviation of the fingers); and an abnormally short neck. There are extremely rare reports of displacement of the lens of the eye (ectopia lentis) or severe heart abnormalities in patients with Beals syndrome; the exceptional nature of these cases warrants further study to determine if these findings are truly related to the diagnosis of Beals syndrome. In some cases, affected individuals may have a deformity of the valve on the left side of the heart (mitral valve prolapse). Beals syndrome is inherited as an autosomal dominant trait and is caused by mutations in the FBN2 gene. (For more information on this disorder, choose “congenital contractural arachnodactyly” as your search term in the Rare Disease Database.)Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue disorders characterized by defects of the major structural protein in the body (collagen). Collagen, a strong and rigid protein, plays an essential role in holding together and strengthening the tissues of the body. Due to defects of collagen, primary EDS findings include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated and unusually loose, thin, stretchy (elastic) and/or fragile skin. Some forms of EDS can include weakness of tiny blood vessels (capillaries) and other tissues of the body, leading to easy bruising, hernias and other findings., The different types of EDS were originally categorized in a classification system that used Roman numerals (e.g., EDS I to EDS XI), based upon each form’s associated findings (clinical evidence) and underlying cause (gene involved). A revised, simplified classification system has since been described in the medical literature that categorizes EDS into six major subtypes, based upon clinical evidence, underlying biochemical defects, and mode of inheritance. Each subtype of EDS is a distinct hereditary disorder that typically holds true within a given family. In other words, parents with one subtype of EDS will potentially pass the predisposition for the same subtype (but not a different subtype) to their children. EDS is usually transmitted as an autosomal dominant trait. Rare forms of EDS pass as an autosomal recessive trait, meaning that an affected person has two abnormal copies of the same gene – typically one inherited from each parent who have one abnormal copy and are therefore unaffected. Only certain rare types of EDS include a predisposition for severe cardiovascular issues (such as vascular EDS); other types predominantly alter the skin and joints (e.g. hypermobile EDS). One type of EDS associated with life-threatening events (vascular EDS) is caused by mutations in the COL3A1 gene. These include enlargement and tear of any medium- to large-sized blood vessel carrying blood away from the heart (arteries, as opposed to veins that carry blood toward the heart) throughout the body and a risk of rupture of hollow internal organs such as the intestines or pregnant uterus. Individuals with this condition do not typically show the outward features of MFS and are not at risk for most of the eye features of MFS, with the exception of retinal detachment. (For more information on this disorder, choose “Ehlers-Danlos” as your search term in the Rare Disease Database.)Mitral valve prolapse (MVP) is a common condition in which one or both of the flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left atrium during ventricular contraction. In some cases, this may allow leakage or the backward flow of blood from the left ventricle back into the left atrium (mitral regurgitation). The exact underlying mechanism responsible for MVP remains unknown. In many affected individuals, the condition appears to occur in the absence of an associated disorder or syndrome (condition that involves multiple parts of the body). Sometimes MVP occurs in families in association with subtle connective tissue findings in other parts of the body (mitral valve prolapse syndrome). Evidence indicates that both the isolated and syndromic forms of MVP are sometimes familial, suggesting autosomal dominant inheritance. MVP can also occur in association with other defined connective tissue disorders including MFS, LDS, SGS and other conditions. In many individuals with MVP, no associated symptoms are apparent (isolated MVP). However, in other cases, the condition may result in chest pain, abnormal heart rhythms (arrhythmias), and signs of congestive heart failure, especially when valve leakage is longstanding (chronic) or severe. MVP is often associated with a characteristic click and/or a whooshing sound (murmur) that may be detected through use of a stethoscope during physical examination. If leakage through the mitral valve (mitral regurgitation) is severe, the extra work that the heart has to perform can lead to poor performance of the heart muscle (heart failure). Homocystinuria is a rare metabolic condition characterized by an excess of the compound homocystine in the blood and urine. The condition may result from deficiency of any of several enzymes involved in the conversion of the essential amino acid methionine to another amino acid called cysteine – or, less commonly, impaired conversion of the compound homocysteine to methionine. Enzymes are proteins that accelerate the rate of chemical reactions in the body. Certain amino acids, which are the chemical building blocks of proteins, are essential for proper growth and development. In most cases, homocystinuria is caused by reduced activity of an enzyme known as cystathionine beta-synthase (CBS). Due to deficiency of the CBS enzyme, infants with homocystinuria may fail to grow and gain weight at the expected rate (failure to thrive) and have developmental delay. By approximately age three, additional, more specific findings may become apparent. These may include dislocation (subluxation) of the lens of the eyes (ectopia lentis), associated “quivering” (iridodonesis) of the colored region of the eyes (iris), severe nearsightedness (myopia), and other eye (ocular) abnormalities. Although intelligence may be normal in some individuals, many children may be affected by progressive intellectual disability. In addition, some may develop psychiatric disturbances and/or episodes of uncontrolled electrical activity in the brain (seizures). Affected individuals also tend to be thin and somewhat tall and may have long, slender fingers and toes (arachnodactyly) and long arms and legs (dolichostenomelia) compared to the length of the trunk (collectively “marfanoid” features). Additional skeletal abnormalities may include progressive sideways curvature of the spine (scoliosis), abnormal protrusion or indentation of the breastbone (pectus carinatum or excavatum, respectively), and generalized loss of bone density (osteoporosis). In addition, in those with the disorder, blood clots tend to develop and can become lodged within certain large and small blood vessels (thromboembolism), potentially leading to life-threatening complications. Homocystinuria is an autosomal recessive trait, meaning that an affected person must have two abnormal copies of the underlying gene, most often one abnormal copy inherited from both parents, who each carry only a single abnormal gene and are therefore unaffected. Effective therapies are available for some forms of homocystinuria. (For more information on this disorder, choose “Homocystinuria” as your search term in the Rare Disease Database.)Loeys-Dietz syndrome (LDS) is a rare disorder characterized by a variety of symptoms that overlap with Marfan syndrome. Individuals with Loeys-Dietz syndrome have skeletal and cardiovascular abnormalities. Affected individuals may experience bulging of the wall of the aorta (aneurysm), tearing (dissection) of the aorta or rupture of the aorta. Unlike Marfan syndrome, the aorta in individuals with Loeys-Dietz syndrome is prone to tearing or rupturing early in childhood and at a relatively small size. In Loeys-Dietz syndrome the blood vessels typically follow a very winding course (tortuosity) and aneurysms and tears of blood vessels can occur throughout the entire arterial tree. Other heart features can include an aortic valves that forms with only two rather than the normal three cusps (bicuspid aortic valve), a hole between the left and right upper chambers of the heart (atrial septal defect) and maintenance of a blood vessel that connects the aorta and pulmonary artery during growth in the womb (fetal development) after birth (patent ductus arteriosus). Additional findings may include long, slender fingers (arachnodactyly), abnormal curvature of the spine (scoliosis), a sunken or protruding chest (pectus excavatum or pectus carninatum), widening of the spinal sac (dural ectasia), and loose joints. Features seen in Loeys-Dietz that are not seen in Marfan syndrome include accumulation of excessive cerebrospinal fluid (CSF) in the skull causing pressure on the tissues of the brain (hydrocephalus), incomplete closure of the roof of the mouth (cleft palate), premature closure of the fibrous joints (sutures) between certain bones of the skull (craniosynostosis), bluish discoloration of the whites of the eyes (blue sclerae), deviation of one of the eyes outward away from the other eye (exotropia) and abnormally formed or unstable joints in the spine of the neck (cervical spine malformation or instability). The fleshy mass (uvula) hanging in the back of the throat may be unusually broad or split (bifid uvula). Characteristic facial features often include widely spaced eyes (hypertelorism), a highly-arched roof of the mouth (palate), an abnormally small jaw (micrognathia) that is recessed farther back than normal (retrognathia), and underdeveloped cheek bones (malar hypoplasia). Unlike Marfan syndrome, the skin in Loeys-Dietz syndrome can be soft with easily visible underlying veins (translucency). The skin also tends to bruise easily and to develop abnormal (wide) scars. People with Loeys-Dietz syndrome can be prone to severe allergies and to inflammation of the gastrointestinal tract (eosinophilic esophagitis or inflammatory bowel disease). Loeys-Dietz syndrome is inherited as an autosomal dominant trait and is caused by mutations in at least five genes that are all known to influence the activity of TGF-β (TGFBR1, TGFBR2, SMAD3, TGFB2 or TGFB3). While all patients with mutations in these genes do not have outward discriminating features of Loeys-Dietz syndrome, they should have surveillance (imaging studies) to look for vascular issues throughout the arterial tree (from head through pelvis) and are at risk to have children with more typical Loeys-Dietz syndrome manifestations.Shprintzen-Goldberg syndrome (SGS) shares many features with Marfan syndrome and Loeys-Dietz syndrome including overgrowth of the long bones (dolichostenolelia), long and slender fingers (arachnodactyly), abnormal curvature of the spine (scoliosis), a sunken or protruding chest (pectus excavatum or pectus carninatum), widening of the spinal sac (dural ectasia), loose joints, wide spacing of the eyes (hypertelorism), premature fusion of the sutures of the skull (craniosynostosis) and a highly arched palate. While aortic root enlargement (aneurysm) can be seen in SGS, it is less frequent and typically less severe, when compared to MFS or LDS. Unlike either MFS or LDS, most people with SGS have at least some degree of developmental delay or intellectual disability. SGS is caused by mutations in the SKI gene that influences the activity of TGF-β. (For more information on this disorder, choose “Shprintzen” as your search term in the Rare Disease Database.)Familial aortic aneurysm and/or tear (dissection) in the chest (thoracic) can occur in the absence of other abnormalities throughout the body (nonsyndromic). In some circumstances, affected individuals can show subtle cysts of the colored portion of the eye (iris floculi) or a visible capillary network below the skin with a honeycomb appearance (livido reticularis). A subset of people with this condition can have an aortic valve that forms with only two cusps (bicuspid aortic valve) instead of the normal three cusps (tricuspid aortic valve). The base of the aorta (aortic root) is the most common site of enlargement (aneurysm), but other aortic segments and even blood vessels outside of the chest can more rarely show involvement. This condition most often passes in families as a dominant trait (only one abnormal gene copy is required to show disease). The age at which problems arise tends to be later and more variable than in Marfan syndrome or Loeys-Dietz syndrome, and some people who inherit the gene abnormality might never show a vascular problem (incomplete penetrance). Aortic root aneurysms tend to tear or rupture at a size similar to that in Marfan syndrome, and many of the same management principles apply. There are many genes that cause nonsyndromic familial thoracic aortic aneurysm, and only a few have been identified.
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Marfan Syndrome
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Diagnosis of Marfan Syndrome
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No universal, specific diagnostic test exists for Marfan syndrome despite the identification of the causative gene. A diagnosis is made based upon a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests performed to identify key findings associated with Marfan syndrome. Different criteria have been proposed for classifying someone as having Marfan syndrome. The most recent published criteria (the revised Ghent nosology) were published in 2010. According to these guidelines, the presence of aortic root aneurysm, eye lens dislocation, or a family history of definite Marfan syndrome weigh heavily in the diagnosis of Marfan syndrome, with an additional potential contribution of other findings throughout the body. Molecular testing (e.g. looking for a mutation in the FBN1 gene) can aid in the diagnosis of Marfan syndrome, but identifying a mutation is not sufficient to establish the diagnosis in the absence of sufficient physical findings or family history.Individuals suspected of having Marfan syndrome will usually undergo a complete skeletal examination, a heart examination including a test that uses sound waves to produce images of the heart (echocardiogram), and a specialized examination of the eyes (slit-lamp eye examination). A slit-lamp allows an eye doctor to examine the eyes under high magnification to detect lens dislocation and other eye issues. It is essential that this comprehensive diagnostic evaluation be coordinated by someone very familiar with Marfan syndrome and related diagnoses.
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Diagnosis of Marfan Syndrome. No universal, specific diagnostic test exists for Marfan syndrome despite the identification of the causative gene. A diagnosis is made based upon a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests performed to identify key findings associated with Marfan syndrome. Different criteria have been proposed for classifying someone as having Marfan syndrome. The most recent published criteria (the revised Ghent nosology) were published in 2010. According to these guidelines, the presence of aortic root aneurysm, eye lens dislocation, or a family history of definite Marfan syndrome weigh heavily in the diagnosis of Marfan syndrome, with an additional potential contribution of other findings throughout the body. Molecular testing (e.g. looking for a mutation in the FBN1 gene) can aid in the diagnosis of Marfan syndrome, but identifying a mutation is not sufficient to establish the diagnosis in the absence of sufficient physical findings or family history.Individuals suspected of having Marfan syndrome will usually undergo a complete skeletal examination, a heart examination including a test that uses sound waves to produce images of the heart (echocardiogram), and a specialized examination of the eyes (slit-lamp eye examination). A slit-lamp allows an eye doctor to examine the eyes under high magnification to detect lens dislocation and other eye issues. It is essential that this comprehensive diagnostic evaluation be coordinated by someone very familiar with Marfan syndrome and related diagnoses.
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Marfan Syndrome
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Therapies of Marfan Syndrome
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TreatmentThe treatment of Marfan syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists including geneticists, surgeons, cardiologists, dental specialists, eye specialists (ophthalmologists), orthopedists, and other healthcare professionals.Individuals with Marfan syndrome are encouraged to avoid competitive and contact sports, heavy lifting and any exercise that increases the strain on the aorta produced by rapid or vigorous beating of the heart or increased blood pressure. Restriction of such activities can slow the rate of the widening of the aorta (aortic dilatation) and decrease the tendency for aortic tear (dissection). In general, moving types of exercises performed in moderation are thought to be good for people with Marfan syndrome. Such exercises, performed regularly, will naturally lower heart rate and blood pressure.Beta-adrenergic receptor blocking drugs (β-blockers) such as propranalol or atenolol are often used in treating the cardiovascular problems associated with Marfan syndrome. Such drugs help to reduce the strength and frequency of the contractions of the heart. In doing so, they may reduce the strain on the walls of the aorta. Beta-blockers may delay the need for heart surgery. The dosage needs to be adjusted to the individual patient’s needs, and therapy should be closely monitored. Some individuals may not be able to tolerate these drugs and others such as those with asthma or depession may not be able to take them (contraindicated).A second class of blood pressure medication called angiotensin receptor blockers (ARBs) is commonly used in the treatment of cardiovascular problems associated with Marfan syndrome. This includes medications such as losartan or irbesatan. There is experimental evidence that ARBs can help by both lowering blood pressure and by blocking TGF-β activity. In animal models of Marfan syndrome the protective effects of ARBs was superior to that seen with β-blockers. In clinical trials, ARBs have variably been shown to be either better than or as good as β-blockers in suppressing aneurysm growth, but this may not be true for all patients or in all circumstances. In the largest trial performed to date, young patients receiving β-blockers (at high dosing) or ARBs (at standard dosing) had a comparable decline in the deviation of the aortic root size from that expected for age and body size (decreasing aortic root z-score). While both treatments were well tolerated in this study, in general, ARBs are thought to be better tolerated than β-blockers. It is the stated position of the Marfan Foundation that the choice of treatment should be guided by the particular circumstances. A combination of β-blocker and ARB therapy can be considered in circumstances where one or the other type of medication does not achieve an adequate response.Every person with Marfan syndrome should have at least a yearly echocardiogram to check the size and function of the heart and aorta. Surgical repair of the aorta may eventually become necessary if the aorta has severely widened or developed a tear (dissection). Preventive (prophylactic) surgery is recommended when the diameter of the aorta reaches 5 centimeters in older children or adults, when the rate of widening reaches 1 centimeter a year, or when there is severe or progressive backflow (regurgitation) of blood through the aortic valve. Surgery may also be necessary for leakage of the mitral valve. Replacement of the aortic valve may be performed; however, this surgery requires the lifelong use of medications to prevent blood clots (anticoagulation). In recent years, some physicians have preferred to use valve-sparing surgery (i.e., reimplantation of the natural aortic valve within a Dacron tube used to replace the enlarged segment of the aorta). Studies are underway to assess the durability of valve-sparing procedures, but early data are encouraging.Surgery to repair or replace the mitral valve in individuals who experience severe mitral valve regurgitation may become necessary. Cardiovascular problems related to Marfan syndrome increase affected individuals’ susceptibility to repeated bacterial infections such as infections of the heart valves (bacterial endocarditis). Leaking heart valves are more prone to infection with bacteria. While it had been common practice to treat patients with leaking valves with antibiotics before dental work or other procedures expected to contaminate the blood stream with bacteria, the American Heart Association recently withdrew this recommendation for most people. Given the predisposition of people with Marfan syndrome and other connective tissue disorders to progressive leakage through multiple heart valves, many physicians who routinely care for such individuals continue to recommend that antibiotics be used before dental work or other procedures expected to introduce bacteria into the bloodstream.Skeletal abnormalities such as scoliosis and deformity of the chest may represent serious problems for people with Marfan syndrome. Braces may be tried to correct skeletal curving (scoliosis) in some cases, but can be ineffective. Individuals with curvature of the spine of more than 10 degrees should be followed by an orthopedist. Surgical stabilization of the spine may be needed if the curvature is severe or progressive. A sunken chest (pectus excavatum) may be surgically corrected for cosmetic reason or, in very rare severe cases, to avoid medical complications.The eyes require careful attention (e.g., yearly ophthalmologic exams) from early childhood. Failure to detect any of the several abnormalities that can affect the eyes may result in poor vision and other visual impairment. Increased risk of retinal detachment does demand special attention. The eyes should receive special protection from injury during work or sports. Sports that may involve trauma to the head, such as football, boxing, and diving, should be avoided. Displacement of the lenses may be treated with eyeglasses or contact lenses. Some individuals such as those with a completely loose lens or with a displaced lens that disrupts vision may require surgical intervention. A detached retina can sometimes be corrected, especially if detected early.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Marfan Syndrome. TreatmentThe treatment of Marfan syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists including geneticists, surgeons, cardiologists, dental specialists, eye specialists (ophthalmologists), orthopedists, and other healthcare professionals.Individuals with Marfan syndrome are encouraged to avoid competitive and contact sports, heavy lifting and any exercise that increases the strain on the aorta produced by rapid or vigorous beating of the heart or increased blood pressure. Restriction of such activities can slow the rate of the widening of the aorta (aortic dilatation) and decrease the tendency for aortic tear (dissection). In general, moving types of exercises performed in moderation are thought to be good for people with Marfan syndrome. Such exercises, performed regularly, will naturally lower heart rate and blood pressure.Beta-adrenergic receptor blocking drugs (β-blockers) such as propranalol or atenolol are often used in treating the cardiovascular problems associated with Marfan syndrome. Such drugs help to reduce the strength and frequency of the contractions of the heart. In doing so, they may reduce the strain on the walls of the aorta. Beta-blockers may delay the need for heart surgery. The dosage needs to be adjusted to the individual patient’s needs, and therapy should be closely monitored. Some individuals may not be able to tolerate these drugs and others such as those with asthma or depession may not be able to take them (contraindicated).A second class of blood pressure medication called angiotensin receptor blockers (ARBs) is commonly used in the treatment of cardiovascular problems associated with Marfan syndrome. This includes medications such as losartan or irbesatan. There is experimental evidence that ARBs can help by both lowering blood pressure and by blocking TGF-β activity. In animal models of Marfan syndrome the protective effects of ARBs was superior to that seen with β-blockers. In clinical trials, ARBs have variably been shown to be either better than or as good as β-blockers in suppressing aneurysm growth, but this may not be true for all patients or in all circumstances. In the largest trial performed to date, young patients receiving β-blockers (at high dosing) or ARBs (at standard dosing) had a comparable decline in the deviation of the aortic root size from that expected for age and body size (decreasing aortic root z-score). While both treatments were well tolerated in this study, in general, ARBs are thought to be better tolerated than β-blockers. It is the stated position of the Marfan Foundation that the choice of treatment should be guided by the particular circumstances. A combination of β-blocker and ARB therapy can be considered in circumstances where one or the other type of medication does not achieve an adequate response.Every person with Marfan syndrome should have at least a yearly echocardiogram to check the size and function of the heart and aorta. Surgical repair of the aorta may eventually become necessary if the aorta has severely widened or developed a tear (dissection). Preventive (prophylactic) surgery is recommended when the diameter of the aorta reaches 5 centimeters in older children or adults, when the rate of widening reaches 1 centimeter a year, or when there is severe or progressive backflow (regurgitation) of blood through the aortic valve. Surgery may also be necessary for leakage of the mitral valve. Replacement of the aortic valve may be performed; however, this surgery requires the lifelong use of medications to prevent blood clots (anticoagulation). In recent years, some physicians have preferred to use valve-sparing surgery (i.e., reimplantation of the natural aortic valve within a Dacron tube used to replace the enlarged segment of the aorta). Studies are underway to assess the durability of valve-sparing procedures, but early data are encouraging.Surgery to repair or replace the mitral valve in individuals who experience severe mitral valve regurgitation may become necessary. Cardiovascular problems related to Marfan syndrome increase affected individuals’ susceptibility to repeated bacterial infections such as infections of the heart valves (bacterial endocarditis). Leaking heart valves are more prone to infection with bacteria. While it had been common practice to treat patients with leaking valves with antibiotics before dental work or other procedures expected to contaminate the blood stream with bacteria, the American Heart Association recently withdrew this recommendation for most people. Given the predisposition of people with Marfan syndrome and other connective tissue disorders to progressive leakage through multiple heart valves, many physicians who routinely care for such individuals continue to recommend that antibiotics be used before dental work or other procedures expected to introduce bacteria into the bloodstream.Skeletal abnormalities such as scoliosis and deformity of the chest may represent serious problems for people with Marfan syndrome. Braces may be tried to correct skeletal curving (scoliosis) in some cases, but can be ineffective. Individuals with curvature of the spine of more than 10 degrees should be followed by an orthopedist. Surgical stabilization of the spine may be needed if the curvature is severe or progressive. A sunken chest (pectus excavatum) may be surgically corrected for cosmetic reason or, in very rare severe cases, to avoid medical complications.The eyes require careful attention (e.g., yearly ophthalmologic exams) from early childhood. Failure to detect any of the several abnormalities that can affect the eyes may result in poor vision and other visual impairment. Increased risk of retinal detachment does demand special attention. The eyes should receive special protection from injury during work or sports. Sports that may involve trauma to the head, such as football, boxing, and diving, should be avoided. Displacement of the lenses may be treated with eyeglasses or contact lenses. Some individuals such as those with a completely loose lens or with a displaced lens that disrupts vision may require surgical intervention. A detached retina can sometimes be corrected, especially if detected early.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Marfan Syndrome
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nord_758_0
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Overview of Marinesco-Sjögren Syndrome
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Marinesco-Sjögren syndrome (MSS) is a rare genetic disorder that affects multiple organ systems of the body. Common symptoms include difficulty coordinating voluntary movements due to degeneration (atrophy) of the cerebellum (cerebellar ataxia), clouding of the lenses of the eyes (cataracts), delays in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor development), diminished muscle tone (hypotonia), and progressive muscle weakness. Many affected individuals exhibit additional physical abnormalities. Although Marinesco-Sjögren syndrome can be associated with significant disability, lifespan is often unaffected. Marinesco-Sjögren syndrome is caused by mutations of the SIL1 gene and at least one other, presently unknown, gene.
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Overview of Marinesco-Sjögren Syndrome. Marinesco-Sjögren syndrome (MSS) is a rare genetic disorder that affects multiple organ systems of the body. Common symptoms include difficulty coordinating voluntary movements due to degeneration (atrophy) of the cerebellum (cerebellar ataxia), clouding of the lenses of the eyes (cataracts), delays in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor development), diminished muscle tone (hypotonia), and progressive muscle weakness. Many affected individuals exhibit additional physical abnormalities. Although Marinesco-Sjögren syndrome can be associated with significant disability, lifespan is often unaffected. Marinesco-Sjögren syndrome is caused by mutations of the SIL1 gene and at least one other, presently unknown, gene.
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Marinesco-Sjögren Syndrome
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nord_758_1
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Symptoms of Marinesco-Sjögren Syndrome
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Some symptoms of Marinesco-Sjögren syndrome are often present at birth (congenital) including diminished muscle tone (hypotonia), a condition sometimes referred to as “floppy baby”. Cataracts can also be present at birth, but more often develop rapidly during early childhood. Cataracts occur when the lenses of the eyes become clouded preventing light from being focused onto the retina and thereby affecting vision. In most cases, cataracts affect both eyes (bilateral).Individuals Marinesco-Sjögren syndrome have difficulties coordinating voluntary movements due to a small cerebellum (cerebellar ataxia). The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movements. In most cases, ataxia is usually readily evident around the time a child can sit up.Affected infants may also exhibit significant delays in reaching developmental milestones that require the coordination of physical (motor) and mental activity (psychomotor development) as well as speech. Muscle weakness may grow progressively worse in adulthood.As affected individuals age, additional symptoms may become apparent including ataxia that primarily affects the torso (truncal ataxia) and impaired ability to perform rapidly alternating movements (dysdiadochokinesia). The degree of severity of motor dysfunction will vary from one person to another. Many affected individuals eventually can walk with an assistive device such as a walker. Other individuals, however, may require the use of a wheelchair.The intellectual abilities of individuals Marinesco-Sjögren syndrome can vary greatly. In some individuals intelligence is unaffected; others develop mild to moderate cognitive impairment. Neurological deterioration usually does not occur in Marinesco-Sjögren syndrome or may be extremely slow. In addition, some individuals may have difficulty speaking or slurred speech (dysarthria). Certain symptoms of Marinesco-Sjögren syndrome (e.g., vision problems, speech difficulties) make it easy to underestimate the intelligence of an affected child.Individuals with Marinesco-Sjögren syndrome usually exhibit growth deficiencies that can ultimately lead to short stature. Short stature refers to individuals who are significantly below average height for a person of the same age and sex. In some cases, affected individuals also have hypergonadotropic hypogonadism, a condition characterized by defective development or function of the ovaries or testes (gonads). Hypergonadotropic hypogonadism causes delays in the start of puberty and the development of secondary sexual characteristics and contributes to the development of short stature.Less frequently, additional symptoms have been associated with Marinesco-Sjögren syndrome. These symptoms include rapid, involuntary eye movements (nystagmus), misalignment of the eyes (strabismus), and degeneration of the main nerve of the eyes that transmits nerve impulses from the retina to the brain (optic atrophy). A variety of skeletal malformations have been reported including side-to-side curvature of the spine (scoliosis), abnormally short fingers and toes (brachydactyly), and an abnormal “cone-shape” to the end portions of the long bones (cone epiphyses).Although the severity of Marinesco-Sjögren syndrome can vary from one person to another and some affected individuals may be significantly disabled, lifespan is usually unaffected.
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Symptoms of Marinesco-Sjögren Syndrome. Some symptoms of Marinesco-Sjögren syndrome are often present at birth (congenital) including diminished muscle tone (hypotonia), a condition sometimes referred to as “floppy baby”. Cataracts can also be present at birth, but more often develop rapidly during early childhood. Cataracts occur when the lenses of the eyes become clouded preventing light from being focused onto the retina and thereby affecting vision. In most cases, cataracts affect both eyes (bilateral).Individuals Marinesco-Sjögren syndrome have difficulties coordinating voluntary movements due to a small cerebellum (cerebellar ataxia). The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movements. In most cases, ataxia is usually readily evident around the time a child can sit up.Affected infants may also exhibit significant delays in reaching developmental milestones that require the coordination of physical (motor) and mental activity (psychomotor development) as well as speech. Muscle weakness may grow progressively worse in adulthood.As affected individuals age, additional symptoms may become apparent including ataxia that primarily affects the torso (truncal ataxia) and impaired ability to perform rapidly alternating movements (dysdiadochokinesia). The degree of severity of motor dysfunction will vary from one person to another. Many affected individuals eventually can walk with an assistive device such as a walker. Other individuals, however, may require the use of a wheelchair.The intellectual abilities of individuals Marinesco-Sjögren syndrome can vary greatly. In some individuals intelligence is unaffected; others develop mild to moderate cognitive impairment. Neurological deterioration usually does not occur in Marinesco-Sjögren syndrome or may be extremely slow. In addition, some individuals may have difficulty speaking or slurred speech (dysarthria). Certain symptoms of Marinesco-Sjögren syndrome (e.g., vision problems, speech difficulties) make it easy to underestimate the intelligence of an affected child.Individuals with Marinesco-Sjögren syndrome usually exhibit growth deficiencies that can ultimately lead to short stature. Short stature refers to individuals who are significantly below average height for a person of the same age and sex. In some cases, affected individuals also have hypergonadotropic hypogonadism, a condition characterized by defective development or function of the ovaries or testes (gonads). Hypergonadotropic hypogonadism causes delays in the start of puberty and the development of secondary sexual characteristics and contributes to the development of short stature.Less frequently, additional symptoms have been associated with Marinesco-Sjögren syndrome. These symptoms include rapid, involuntary eye movements (nystagmus), misalignment of the eyes (strabismus), and degeneration of the main nerve of the eyes that transmits nerve impulses from the retina to the brain (optic atrophy). A variety of skeletal malformations have been reported including side-to-side curvature of the spine (scoliosis), abnormally short fingers and toes (brachydactyly), and an abnormal “cone-shape” to the end portions of the long bones (cone epiphyses).Although the severity of Marinesco-Sjögren syndrome can vary from one person to another and some affected individuals may be significantly disabled, lifespan is usually unaffected.
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Marinesco-Sjögren Syndrome
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nord_758_2
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Causes of Marinesco-Sjögren Syndrome
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Marinesco-Sjögren syndrome is often caused by mutation of the SIL1 gene. It is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.Investigators have determined that the SIL1 gene is located on the long arm (q) of chromosome 5 (5q31). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 5q31” refers to band 31 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The SIL1 gene contains instructions for creating (encoding) a protein that has a specific role in the body. A mutation of the SIL1 gene results in the production of a defective protein that cannot carry out its proper function, which, ultimately, results in the signs and symptoms of Marinesco-Sjögren syndrome. Researchers believe that the protein product of the SIL1 gene is involved in protein folding. Protein folding is a normal process in which a protein folds into a three-dimensional structure. This process is required for a protein to carry out its normal function. Defective protein folding is believed to cause abnormal proteins to accumulate in the endoplasmic reticulum, the extensive membrane network located in all cells including muscle cells.Some individuals with Marinesco-Sjögren syndrome do not have a mutation of the SIL1 gene, which suggests that another gene(s) may also cause the disorder (genetic heterogeneity). The other gene(s) that may play a role in the development of Marinesco-Sjögren syndrome have not been identified.
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Causes of Marinesco-Sjögren Syndrome. Marinesco-Sjögren syndrome is often caused by mutation of the SIL1 gene. It is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.Investigators have determined that the SIL1 gene is located on the long arm (q) of chromosome 5 (5q31). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 5q31” refers to band 31 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The SIL1 gene contains instructions for creating (encoding) a protein that has a specific role in the body. A mutation of the SIL1 gene results in the production of a defective protein that cannot carry out its proper function, which, ultimately, results in the signs and symptoms of Marinesco-Sjögren syndrome. Researchers believe that the protein product of the SIL1 gene is involved in protein folding. Protein folding is a normal process in which a protein folds into a three-dimensional structure. This process is required for a protein to carry out its normal function. Defective protein folding is believed to cause abnormal proteins to accumulate in the endoplasmic reticulum, the extensive membrane network located in all cells including muscle cells.Some individuals with Marinesco-Sjögren syndrome do not have a mutation of the SIL1 gene, which suggests that another gene(s) may also cause the disorder (genetic heterogeneity). The other gene(s) that may play a role in the development of Marinesco-Sjögren syndrome have not been identified.
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Marinesco-Sjögren Syndrome
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Affects of Marinesco-Sjögren Syndrome
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Marinesco-Sjögren syndrome affects males and females in equal numbers. More than 200 cases have been reported in the medical literature. The exact incidence of the disorder in the general population is unknown. Marinesco-Sjögren syndrome can affect all ethnic groups (panethnic), but most cases have occurred in isolated populations in rural areas.
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Affects of Marinesco-Sjögren Syndrome. Marinesco-Sjögren syndrome affects males and females in equal numbers. More than 200 cases have been reported in the medical literature. The exact incidence of the disorder in the general population is unknown. Marinesco-Sjögren syndrome can affect all ethnic groups (panethnic), but most cases have occurred in isolated populations in rural areas.
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Marinesco-Sjögren Syndrome
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Related disorders of Marinesco-Sjögren Syndrome
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Symptoms of the following disorders can be similar to those of Marinesco-Sjögren syndrome. Comparisons may be useful for a differential diagnosis.(C)ongenital (C)ataracts, (F)acial (D)ysmorphism, and (N)europathy (CCFDN) syndrome is an extremely rare genetic disorder with signs and symptoms that overlap with Marinesco-Sjögren syndrome including the presence of cerebellar ataxia, cataracts, muscle disease (myopathy), skeletal malformations, short stature, and developmental delays. Individuals with CCFDN may also exhibit symptoms not associated with Marinesco-Sjögren syndrome including nerve disease affecting the nerves outside the central nervous system (peripheral neuropathy), an abnormally thin and flat cornea (microcornea) and distinctive facial features (facial dysmorphism). Identification of the gene for CCFDN enabled researchers to clearly establish that Marinesco-Sjögren syndrome and CCFDN were distinct disorders despite the overlapping clinical findings. CCFDN is caused by mutations of CTDP1 gene located on the long arm of chromosome 18 (18q23). It is inherited as an autosomal recessive trait.Congenital disorders of glycosylation refers to a group of rare inherited metabolic disorders that share similar but not identical genetic changes (mutations) and biochemical characteristics. These disorders were once called “carbohydrate-deficient glycoprotein syndrome”. These disorders involve the metabolic activity of glycoproteins, complex chemical compounds created by attaching a simple or complex sugar molecule to a specific protein. Glycoproteins play key roles in the development and maintenance of the cell membrane, endocrine glandular function, and protein transport, and are active in specific parts of the brain (Golgi apparatus). Attaching the sugar to the protein is a process involving many enzymes, and a shortage or lack of any one of these enzymes causes the build-up of intermediate chemical compounds. The accumulation of these compounds is the triggering device of the disorder. Congenital disorders of glycosylation may affect many different parts of the body but are most serious when they involve the central and peripheral nervous systems. Congenital disorders of glycosylation can several different organ systems and can cause many of the symptoms seen in Marinesco-Sjögren syndrome including impaired coordination and balance (cerebellar ataxia) due to underdevelopment (hypoplasia) of certain portions of the brain (cerebellum), cognitive impairment, delays in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation), skeletal malformations, and/or visual impairment. Additional symptoms are often present. Congenital disorders of glycosylation are inherited as autosomal recessive genetic traits. (For more information on this disorder, choose “congenital disorders of glycosylation” as your search term in the Rare Disease Database.)Mitochondrial disorders are a group disorders characterized by mutations affecting the parts of the cell that release energy (mitochondria). Mitochondrial diseases often hamper the ability of affected cells to break down food and oxygen and produce energy. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body. Most mitochondrial disorders are associated with neurological and muscular abnormalities. (For more information on these disorders, choose the specific mitochondrial disorder name as your search term in the Rare Disease Database.)Several extremely rare disorders may also have symptoms similar to those found in individuals with Marinesco-Sjögren syndrome. These disorders include ataxia-microcephaly-cataract syndrome, cataract-ataxia-deafness-retardation syndrome, and familial Danish dysplasia.
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Related disorders of Marinesco-Sjögren Syndrome. Symptoms of the following disorders can be similar to those of Marinesco-Sjögren syndrome. Comparisons may be useful for a differential diagnosis.(C)ongenital (C)ataracts, (F)acial (D)ysmorphism, and (N)europathy (CCFDN) syndrome is an extremely rare genetic disorder with signs and symptoms that overlap with Marinesco-Sjögren syndrome including the presence of cerebellar ataxia, cataracts, muscle disease (myopathy), skeletal malformations, short stature, and developmental delays. Individuals with CCFDN may also exhibit symptoms not associated with Marinesco-Sjögren syndrome including nerve disease affecting the nerves outside the central nervous system (peripheral neuropathy), an abnormally thin and flat cornea (microcornea) and distinctive facial features (facial dysmorphism). Identification of the gene for CCFDN enabled researchers to clearly establish that Marinesco-Sjögren syndrome and CCFDN were distinct disorders despite the overlapping clinical findings. CCFDN is caused by mutations of CTDP1 gene located on the long arm of chromosome 18 (18q23). It is inherited as an autosomal recessive trait.Congenital disorders of glycosylation refers to a group of rare inherited metabolic disorders that share similar but not identical genetic changes (mutations) and biochemical characteristics. These disorders were once called “carbohydrate-deficient glycoprotein syndrome”. These disorders involve the metabolic activity of glycoproteins, complex chemical compounds created by attaching a simple or complex sugar molecule to a specific protein. Glycoproteins play key roles in the development and maintenance of the cell membrane, endocrine glandular function, and protein transport, and are active in specific parts of the brain (Golgi apparatus). Attaching the sugar to the protein is a process involving many enzymes, and a shortage or lack of any one of these enzymes causes the build-up of intermediate chemical compounds. The accumulation of these compounds is the triggering device of the disorder. Congenital disorders of glycosylation may affect many different parts of the body but are most serious when they involve the central and peripheral nervous systems. Congenital disorders of glycosylation can several different organ systems and can cause many of the symptoms seen in Marinesco-Sjögren syndrome including impaired coordination and balance (cerebellar ataxia) due to underdevelopment (hypoplasia) of certain portions of the brain (cerebellum), cognitive impairment, delays in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation), skeletal malformations, and/or visual impairment. Additional symptoms are often present. Congenital disorders of glycosylation are inherited as autosomal recessive genetic traits. (For more information on this disorder, choose “congenital disorders of glycosylation” as your search term in the Rare Disease Database.)Mitochondrial disorders are a group disorders characterized by mutations affecting the parts of the cell that release energy (mitochondria). Mitochondrial diseases often hamper the ability of affected cells to break down food and oxygen and produce energy. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body. Most mitochondrial disorders are associated with neurological and muscular abnormalities. (For more information on these disorders, choose the specific mitochondrial disorder name as your search term in the Rare Disease Database.)Several extremely rare disorders may also have symptoms similar to those found in individuals with Marinesco-Sjögren syndrome. These disorders include ataxia-microcephaly-cataract syndrome, cataract-ataxia-deafness-retardation syndrome, and familial Danish dysplasia.
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Marinesco-Sjögren Syndrome
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Diagnosis of Marinesco-Sjögren Syndrome
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A diagnosis of Marinesco-Sjögren syndrome may be suspected based upon the identification of characteristic findings. A diagnosis can be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of specialized tests including an eye (ophthalmologic) exam to detect cataracts and magnetic resonance imaging (MRI) to detect characteristic changes in the brain (e.g., cerebellar atrophy). Imaging studies of muscle may show significant damage to muscle tissue and the abnormal accumulation of fat and connective tissue.Molecular genetic testing (which can identify a mutation of the SIL1 gene) is available on a clinical basis. Prenatal diagnosis of Marinesco-Sjögren syndrome is possible if the SIL1 gene mutation is known to run in a family.
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Diagnosis of Marinesco-Sjögren Syndrome. A diagnosis of Marinesco-Sjögren syndrome may be suspected based upon the identification of characteristic findings. A diagnosis can be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of specialized tests including an eye (ophthalmologic) exam to detect cataracts and magnetic resonance imaging (MRI) to detect characteristic changes in the brain (e.g., cerebellar atrophy). Imaging studies of muscle may show significant damage to muscle tissue and the abnormal accumulation of fat and connective tissue.Molecular genetic testing (which can identify a mutation of the SIL1 gene) is available on a clinical basis. Prenatal diagnosis of Marinesco-Sjögren syndrome is possible if the SIL1 gene mutation is known to run in a family.
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Marinesco-Sjögren Syndrome
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Therapies of Marinesco-Sjögren Syndrome
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TreatmentThere is no specific treatment for individuals with Marinesco-Sjögren syndrome. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who asses and treat skeletal problems (orthopedists), eye specialists (ophthalmologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.Surgery may be necessary to remove cataracts and, in some cases, to implant artificial lenses. Orthotic devices such as walkers may be required. If hypergonadotropic hypogonadism is present, then hormone replacement therapy may be administered around the time puberty is expected.Early intervention is important in ensuring that children with Marinesco-Sjögren syndrome reach their highest potential. Services that may be beneficial may include special education programs tailored to an individual's specific needs, occupational therapy, physical therapy, and other medical, social, and/or vocational services.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Marinesco-Sjögren Syndrome. TreatmentThere is no specific treatment for individuals with Marinesco-Sjögren syndrome. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who asses and treat skeletal problems (orthopedists), eye specialists (ophthalmologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.Surgery may be necessary to remove cataracts and, in some cases, to implant artificial lenses. Orthotic devices such as walkers may be required. If hypergonadotropic hypogonadism is present, then hormone replacement therapy may be administered around the time puberty is expected.Early intervention is important in ensuring that children with Marinesco-Sjögren syndrome reach their highest potential. Services that may be beneficial may include special education programs tailored to an individual's specific needs, occupational therapy, physical therapy, and other medical, social, and/or vocational services.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Marinesco-Sjögren Syndrome
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Overview of Maroteaux Lamy Syndrome
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Summary Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is a rare genetic disorder characterized by complete or partial lack of activity of the enzyme arylsulfatase B (also called N-acetylgalactosamine-4-sulfatase), encoded by the ARSB gene. Deficiency or absence of this enzyme activity leads to the accumulation of complex carbohydrates called glycosaminoglycans (previously known as mucopolysaccharides) in the body. Abnormal accumulation of mucopolysaccharides leads to progressive involvement of multiple organ systems. The symptoms and severity of Maroteaux-Lamy syndrome can vary dramatically from one person to another; some individuals only develop mild symptoms, while others develop severe, even life-threatening complications. Common symptoms can include coarse facial features, corneal clouding, joint abnormalities, various skeletal malformations, an abnormally enlarged liver and/or spleen (hepatosplenomegaly), and hearing loss. Cardiac disease and restrictive pulmonary disease can also occur. Intelligence is usually not affected. In 2005, the Food and Drug Administration (FDA) approved the enzyme replacement therapy known as Naglazyme® for the treatment of Maroteaux-Lamy syndrome. Maroteaux-Lamy syndrome occurs due to mutations in the ARSB gene and is inherited as an autosomal recessive disorder.Introduction The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. More than 60 lysosomal storage disorders have been identified so far. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular metabolites, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates known as mucopolysaccharides or glycosaminoglycans in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow, causing progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of MPS. These disorders, with one exception (MPS type II), are inherited in an autosomal recessive manner. Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI, or MPS VI) was named from the two French physicians who first described this disorder in the medical literature in 1963.
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Overview of Maroteaux Lamy Syndrome. Summary Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is a rare genetic disorder characterized by complete or partial lack of activity of the enzyme arylsulfatase B (also called N-acetylgalactosamine-4-sulfatase), encoded by the ARSB gene. Deficiency or absence of this enzyme activity leads to the accumulation of complex carbohydrates called glycosaminoglycans (previously known as mucopolysaccharides) in the body. Abnormal accumulation of mucopolysaccharides leads to progressive involvement of multiple organ systems. The symptoms and severity of Maroteaux-Lamy syndrome can vary dramatically from one person to another; some individuals only develop mild symptoms, while others develop severe, even life-threatening complications. Common symptoms can include coarse facial features, corneal clouding, joint abnormalities, various skeletal malformations, an abnormally enlarged liver and/or spleen (hepatosplenomegaly), and hearing loss. Cardiac disease and restrictive pulmonary disease can also occur. Intelligence is usually not affected. In 2005, the Food and Drug Administration (FDA) approved the enzyme replacement therapy known as Naglazyme® for the treatment of Maroteaux-Lamy syndrome. Maroteaux-Lamy syndrome occurs due to mutations in the ARSB gene and is inherited as an autosomal recessive disorder.Introduction The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. More than 60 lysosomal storage disorders have been identified so far. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular metabolites, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates known as mucopolysaccharides or glycosaminoglycans in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow, causing progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of MPS. These disorders, with one exception (MPS type II), are inherited in an autosomal recessive manner. Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI, or MPS VI) was named from the two French physicians who first described this disorder in the medical literature in 1963.
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Maroteaux Lamy Syndrome
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Symptoms of Maroteaux Lamy Syndrome
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The symptoms, onset and rate of progression of Maroteaux-Lamy syndrome vary greatly from one person to another. The disorder can be thought of as a spectrum or continuum of disease. Some individuals may only have a few symptoms and others may have serious symptoms affecting several different organ systems simultaneously. Maroteaux-Lamy syndrome can potentially cause life-threatening complications. Some individuals will have severe symptoms during infancy, while others have slowly progressive symptoms that develop over the course of multiple decades. The variable nature of Maroteaux-Lamy syndrome means that most affected individuals will not have all of the symptoms potentially associated with the disorder. Individuals with this disorder can differ from one another dramatically. Parents should talk to their children’s physician and medical team about their child’s specific case, associated symptoms and overall prognosis. Most affected individuals come to medical attention during middle childhood. Rapidly progressive Maroteaux-Lamy syndrome is associated with an onset of symptoms before three years of age. Affected individuals may develop walking problems (impaired mobility) by the age of 10 and experience delayed or absence of puberty. These individuals may be at risk of heart failure by second or third decades of life. Slowly progressive disease is characterized by later onset. A diagnosis is usually obtained after five years of age, most often during the second or third decade. Despite a slower progression, individuals may still develop a decrease in overall function and ability by their late teen-aged years. Most individuals with Maroteaux-Lamy syndrome will develop serious complications at some point such as joint degeneration, cardiovascular disease, reduced pulmonary function or sleep apnea. Intelligence is usually not affected in Maroteaux-Lamy syndrome. However, learning difficulties may be present as a consequence of other problems associated with the disorder (e.g., hearing loss). Affected children may also exhibit failure to thrive and difficulty feeding. Short stature occurs in almost all patients and is described as disproportionate because the trunk may be shorter than the legs. In severe cases, final height may be less than 4 feet (120 centimeters). Degenerative joint disease is also common and can lead to the development of multiple joint contractures. A contracture occurs when thickening or shortening of tissue such as muscle fibers cause deformity and restrict the movement of an affected joint. Individuals with Maroteaux-Lamy syndrome may be described as having ‘dysostosis multiplex’ a group of skeletal abnormalities that can be seen on x-ray examination. These abnormalities include thickened, short bones of the palm of the hands (metacarpals), underdeveloped (hypoplastic) and irregular wrist bones (carpal bones), abnormal ankle bones (tarsal bones), malformation (dysplasia) of the head of the thighbone (dysplastic femoral head), severe malformation of the hip, abnormalities of the ribs and spine, thickened collarbones (clavicles), and underdevelopment of the bones of the forearm (ulna and radius). Additional skeletal malformations may include a prominent breastbone (pectus carinatum), abnormal curvature of the spine, and knock-knees (genu valgum). Skeletal malformations can be associated with a variety of complications. Affected individuals may develop pain, especially of the joints and hip, spinal cord compression, an abnormal manner of walking (gait), or difficulty walking. Affected joints may have a limited range of motion making daily tasks difficult. For example, the ability to fully move the shoulders may make simple tasks such as putting on a shirt or combing hair difficult. Distinctive facial features usually do not occur in individuals with mild forms of the disorder. Individuals with severe forms often share distinctive facial characteristics and these individuals may resemble one another in facial appearance. Such characteristics include chubby faces, thickened lips due to the overgrowth of the gums (gingival hypertrophy), an unusually prominent forehead (frontal bossing), and a broad, flattened bridge of the nose. In some affected individuals, the tongue may be enlarged (macroglossia). Abnormal growth of hair on the face or the body may also occur (hirsutism). Some individuals have a short, stiff neck. Clouding (opacity) of the thin transparent covering of the front of the eye (cornea) may also occur. If corneal clouding is severe the patient may present vision loss, particularly in dim light. Some individuals may sensitive to bright lights. If the nerve-rich lining the back of the eyes (retina) is involved, affected individuals may have reduced peripheral vision or develop night blindness. In some cases, increased pressure within the eye (glaucoma) may also develop. Increased intraocular pressure may cause “thinning, cupping, or notching of the disc rim. Less commonly, additional eye abnormalities may occur including degeneration of the nerve that transmits visual information from the retina to the brain (optic nerve atrophy). Affected individuals may experience chronic watery, mucous discharge from nose (rhinorrhea), frequent sinus infections, and middle ear infections (otitis media). Hearing loss is common. Hearing loss may be due to failure of sound to be conducted from the outer ear trough the eardrum and tiny bones of the middle ear (conductive hearing loss) or may be due to damage to the inner ear or the nerves that transmit sound from the inner ear to the brain (sensorineural). In some cases, hearing loss may be due to a combination of both problems (mixed hearing loss). Abnormalities of the heart are common in children with Maroteaux-Lamy syndrome. Symptoms associated with heart disease can include breathlessness, cough, wheezing, excessive sweating and recurrent chest infections. High blood pressure (hypertension) may also occur. Cardiac abnormalities can include narrowing (stenosis) and insufficiency of certain valves of the heart including the aortic, the mitral, and the tricuspid valves. Heart valves ensure that blood flows in only one direction within the heart. When a valve is damaged or malformed, blood can flow backward from one chamber back into another. Slowly progressive valvar heart disease can be present for years without causing symptoms. Eventually, valvar heart disease can cause a heart murmur. Narrowing of the heart valves can progressively make it more difficult for the heart to pump blood and can eventually result in heart failure. Additional heart abnormalities can include disease or weakening of the heart muscle (cardiomyopathy) and endocardial fibroelastosis. Cardiomyopathy can be associated with a progressive inability to pump blood, fatigue, heart block, and fast heartbeats (arrhythmia). Endocardial fibroelastosis is a condition characterized by thickening of the endocardium of the ventricles. The endocardium is the innermost layer of tissue that surrounds the heart. These conditions can make it more difficult for the heart to pump blood effectively and can eventually cause heart failure and sudden cardiac death. The lungs and other parts of the pulmonary system are usually affected. The storage of mucopolysaccharides may cause affected tissue to swell, which can obstruct various airways in the body, resulting in a high-pitched, loud respiratory sound (stridor) and airway compromise. Thick, mucous secretions can further clog the airways. The chest may become rigid, preventing the lungs from taking in sufficient amounts of air. Obstructive and restrictive lung disease can cause breathlessness, reduced endurance, recurrent episodes of pneumonia, and/or sleep apnea. Some affected infants have abnormal softening and weakening of the cartilage of the trachea (windpipe) so that the walls of the trachea are floppy instead of rigid (tracheomalacia). This is often mild, but can be severe, leading to collapse of the air passage. Tracheomalacia can contribute to breathing difficulties and may precipitate respiratory arrest. In some cases, the tonsils and adenoids may become enlarged narrowing the airway in the throat and contributing to breathing difficulties. Abnormal enlargement of the liver (hepatomegaly) is common in individuals with Maroteaux-Lamy syndrome. The spleen may also be enlarged (splenomegaly). Hernias, conditions in which the abdominal membrane or contents protrude through a weak point in the abdominal wall, are also common. Umbilical hernias occur when the contents protrude from behind the bellybutton; inguinal hernias occur in the groin area. Some affected individuals have a protruding or bulging abdomen because of weakened muscles and/or hepatosplenomegaly. Some affected individuals may develop hydrocephalus, a condition in which the accumulation of excess cerebrospinal fluid in the skull causes increased pressure on the brain, potentially causing a variety of signs and symptoms, including headache and/or papilledema. Another common symptom associated with Maroteaux-Lamy syndrome is carpal tunnel syndrome, a condition caused by compression of a nerve running through the wrist. Symptoms usually begin as chronic tingling, burning or numbness in the wrist. Eventually, it can progress to cause sharp, piercing pain. Less often, tarsal tunnel syndrome, a similar condition affecting the ankle, may also occur.
Certain gastrointestinal symptoms including loose stools, diarrhea, or severe constipation have also been reported in individuals with Maroteaux-Lamy syndrome.
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Symptoms of Maroteaux Lamy Syndrome. The symptoms, onset and rate of progression of Maroteaux-Lamy syndrome vary greatly from one person to another. The disorder can be thought of as a spectrum or continuum of disease. Some individuals may only have a few symptoms and others may have serious symptoms affecting several different organ systems simultaneously. Maroteaux-Lamy syndrome can potentially cause life-threatening complications. Some individuals will have severe symptoms during infancy, while others have slowly progressive symptoms that develop over the course of multiple decades. The variable nature of Maroteaux-Lamy syndrome means that most affected individuals will not have all of the symptoms potentially associated with the disorder. Individuals with this disorder can differ from one another dramatically. Parents should talk to their children’s physician and medical team about their child’s specific case, associated symptoms and overall prognosis. Most affected individuals come to medical attention during middle childhood. Rapidly progressive Maroteaux-Lamy syndrome is associated with an onset of symptoms before three years of age. Affected individuals may develop walking problems (impaired mobility) by the age of 10 and experience delayed or absence of puberty. These individuals may be at risk of heart failure by second or third decades of life. Slowly progressive disease is characterized by later onset. A diagnosis is usually obtained after five years of age, most often during the second or third decade. Despite a slower progression, individuals may still develop a decrease in overall function and ability by their late teen-aged years. Most individuals with Maroteaux-Lamy syndrome will develop serious complications at some point such as joint degeneration, cardiovascular disease, reduced pulmonary function or sleep apnea. Intelligence is usually not affected in Maroteaux-Lamy syndrome. However, learning difficulties may be present as a consequence of other problems associated with the disorder (e.g., hearing loss). Affected children may also exhibit failure to thrive and difficulty feeding. Short stature occurs in almost all patients and is described as disproportionate because the trunk may be shorter than the legs. In severe cases, final height may be less than 4 feet (120 centimeters). Degenerative joint disease is also common and can lead to the development of multiple joint contractures. A contracture occurs when thickening or shortening of tissue such as muscle fibers cause deformity and restrict the movement of an affected joint. Individuals with Maroteaux-Lamy syndrome may be described as having ‘dysostosis multiplex’ a group of skeletal abnormalities that can be seen on x-ray examination. These abnormalities include thickened, short bones of the palm of the hands (metacarpals), underdeveloped (hypoplastic) and irregular wrist bones (carpal bones), abnormal ankle bones (tarsal bones), malformation (dysplasia) of the head of the thighbone (dysplastic femoral head), severe malformation of the hip, abnormalities of the ribs and spine, thickened collarbones (clavicles), and underdevelopment of the bones of the forearm (ulna and radius). Additional skeletal malformations may include a prominent breastbone (pectus carinatum), abnormal curvature of the spine, and knock-knees (genu valgum). Skeletal malformations can be associated with a variety of complications. Affected individuals may develop pain, especially of the joints and hip, spinal cord compression, an abnormal manner of walking (gait), or difficulty walking. Affected joints may have a limited range of motion making daily tasks difficult. For example, the ability to fully move the shoulders may make simple tasks such as putting on a shirt or combing hair difficult. Distinctive facial features usually do not occur in individuals with mild forms of the disorder. Individuals with severe forms often share distinctive facial characteristics and these individuals may resemble one another in facial appearance. Such characteristics include chubby faces, thickened lips due to the overgrowth of the gums (gingival hypertrophy), an unusually prominent forehead (frontal bossing), and a broad, flattened bridge of the nose. In some affected individuals, the tongue may be enlarged (macroglossia). Abnormal growth of hair on the face or the body may also occur (hirsutism). Some individuals have a short, stiff neck. Clouding (opacity) of the thin transparent covering of the front of the eye (cornea) may also occur. If corneal clouding is severe the patient may present vision loss, particularly in dim light. Some individuals may sensitive to bright lights. If the nerve-rich lining the back of the eyes (retina) is involved, affected individuals may have reduced peripheral vision or develop night blindness. In some cases, increased pressure within the eye (glaucoma) may also develop. Increased intraocular pressure may cause “thinning, cupping, or notching of the disc rim. Less commonly, additional eye abnormalities may occur including degeneration of the nerve that transmits visual information from the retina to the brain (optic nerve atrophy). Affected individuals may experience chronic watery, mucous discharge from nose (rhinorrhea), frequent sinus infections, and middle ear infections (otitis media). Hearing loss is common. Hearing loss may be due to failure of sound to be conducted from the outer ear trough the eardrum and tiny bones of the middle ear (conductive hearing loss) or may be due to damage to the inner ear or the nerves that transmit sound from the inner ear to the brain (sensorineural). In some cases, hearing loss may be due to a combination of both problems (mixed hearing loss). Abnormalities of the heart are common in children with Maroteaux-Lamy syndrome. Symptoms associated with heart disease can include breathlessness, cough, wheezing, excessive sweating and recurrent chest infections. High blood pressure (hypertension) may also occur. Cardiac abnormalities can include narrowing (stenosis) and insufficiency of certain valves of the heart including the aortic, the mitral, and the tricuspid valves. Heart valves ensure that blood flows in only one direction within the heart. When a valve is damaged or malformed, blood can flow backward from one chamber back into another. Slowly progressive valvar heart disease can be present for years without causing symptoms. Eventually, valvar heart disease can cause a heart murmur. Narrowing of the heart valves can progressively make it more difficult for the heart to pump blood and can eventually result in heart failure. Additional heart abnormalities can include disease or weakening of the heart muscle (cardiomyopathy) and endocardial fibroelastosis. Cardiomyopathy can be associated with a progressive inability to pump blood, fatigue, heart block, and fast heartbeats (arrhythmia). Endocardial fibroelastosis is a condition characterized by thickening of the endocardium of the ventricles. The endocardium is the innermost layer of tissue that surrounds the heart. These conditions can make it more difficult for the heart to pump blood effectively and can eventually cause heart failure and sudden cardiac death. The lungs and other parts of the pulmonary system are usually affected. The storage of mucopolysaccharides may cause affected tissue to swell, which can obstruct various airways in the body, resulting in a high-pitched, loud respiratory sound (stridor) and airway compromise. Thick, mucous secretions can further clog the airways. The chest may become rigid, preventing the lungs from taking in sufficient amounts of air. Obstructive and restrictive lung disease can cause breathlessness, reduced endurance, recurrent episodes of pneumonia, and/or sleep apnea. Some affected infants have abnormal softening and weakening of the cartilage of the trachea (windpipe) so that the walls of the trachea are floppy instead of rigid (tracheomalacia). This is often mild, but can be severe, leading to collapse of the air passage. Tracheomalacia can contribute to breathing difficulties and may precipitate respiratory arrest. In some cases, the tonsils and adenoids may become enlarged narrowing the airway in the throat and contributing to breathing difficulties. Abnormal enlargement of the liver (hepatomegaly) is common in individuals with Maroteaux-Lamy syndrome. The spleen may also be enlarged (splenomegaly). Hernias, conditions in which the abdominal membrane or contents protrude through a weak point in the abdominal wall, are also common. Umbilical hernias occur when the contents protrude from behind the bellybutton; inguinal hernias occur in the groin area. Some affected individuals have a protruding or bulging abdomen because of weakened muscles and/or hepatosplenomegaly. Some affected individuals may develop hydrocephalus, a condition in which the accumulation of excess cerebrospinal fluid in the skull causes increased pressure on the brain, potentially causing a variety of signs and symptoms, including headache and/or papilledema. Another common symptom associated with Maroteaux-Lamy syndrome is carpal tunnel syndrome, a condition caused by compression of a nerve running through the wrist. Symptoms usually begin as chronic tingling, burning or numbness in the wrist. Eventually, it can progress to cause sharp, piercing pain. Less often, tarsal tunnel syndrome, a similar condition affecting the ankle, may also occur.
Certain gastrointestinal symptoms including loose stools, diarrhea, or severe constipation have also been reported in individuals with Maroteaux-Lamy syndrome.
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Maroteaux Lamy Syndrome
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Causes of Maroteaux Lamy Syndrome
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Maroteaux-Lamy syndrome is caused by changes (mutations) in the ARSB gene. Genes provide instructions for making proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The ARSB gene is related to (encodes) the lysosomal enzyme arylsulfatase B. Deficiency of this enzyme results in the accumulation of dermatan sulfate and chondroitin sulfate in the cells of various tissues because the body cannot breakdown glycosaminoglycans. More than 220 different mutations in the ARSB gene have been identified. Certain mutations are more likely to be associated with specific symptoms and/or severity (genotype-phenotype correlation). The ARSB mutation is inherited as an autosomal recessive disorder. Genetic diseases are determined by the combination of alleles for a particular gene that are on the chromosomes received from the father and the mother. Autosomal recessive genetic disorders occur when it is needed that the individual presents a pathogenic mutation in each copy (allele) of the gene, being one allele inherited from the father, and the other allele inherited from the mother. To have the disease the individual should inherit two mutated copies of the same gene, one from each parent. If an individual receives one normal copy of the gene and another copy with a mutation that causes the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% in each pregnancy. The risk to have a child who is a carrier like the parents is 50% in 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.
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Causes of Maroteaux Lamy Syndrome. Maroteaux-Lamy syndrome is caused by changes (mutations) in the ARSB gene. Genes provide instructions for making proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The ARSB gene is related to (encodes) the lysosomal enzyme arylsulfatase B. Deficiency of this enzyme results in the accumulation of dermatan sulfate and chondroitin sulfate in the cells of various tissues because the body cannot breakdown glycosaminoglycans. More than 220 different mutations in the ARSB gene have been identified. Certain mutations are more likely to be associated with specific symptoms and/or severity (genotype-phenotype correlation). The ARSB mutation is inherited as an autosomal recessive disorder. Genetic diseases are determined by the combination of alleles for a particular gene that are on the chromosomes received from the father and the mother. Autosomal recessive genetic disorders occur when it is needed that the individual presents a pathogenic mutation in each copy (allele) of the gene, being one allele inherited from the father, and the other allele inherited from the mother. To have the disease the individual should inherit two mutated copies of the same gene, one from each parent. If an individual receives one normal copy of the gene and another copy with a mutation that causes the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% in each pregnancy. The risk to have a child who is a carrier like the parents is 50% in 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.
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Maroteaux Lamy Syndrome
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Affects of Maroteaux Lamy Syndrome
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Maroteaux-Lamy syndrome affects males and females in equal proportion. The prevalence of all forms of MPS is estimated to be 1 in 65,000 births. Although the exact incidence and prevalence of the disorder is unknown, it is estimated to occur in one case in 250.000 to 600,000 individuals. In some areas, due to founder effect and endogamy, prevalence is higher. However, we should take into account that MPS disorders, especially milder forms, often go unrecognized, so they may be underdiagnosed or misdiagnosed, making it difficult to determine their true frequency in the general population.
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Affects of Maroteaux Lamy Syndrome. Maroteaux-Lamy syndrome affects males and females in equal proportion. The prevalence of all forms of MPS is estimated to be 1 in 65,000 births. Although the exact incidence and prevalence of the disorder is unknown, it is estimated to occur in one case in 250.000 to 600,000 individuals. In some areas, due to founder effect and endogamy, prevalence is higher. However, we should take into account that MPS disorders, especially milder forms, often go unrecognized, so they may be underdiagnosed or misdiagnosed, making it difficult to determine their true frequency in the general population.
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Maroteaux Lamy Syndrome
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Related disorders of Maroteaux Lamy Syndrome
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Symptoms of the following disorders can be similar to those of Maroteaux-Lamy syndrome. Comparisons may be useful for a differential diagnosis. Scheie syndrome (mucopolysaccharidosis type I-S; MPS 1-S) is the most attenuated form of mucopolysaccharidosis. As in Hurler syndrome, individuals with Scheie syndrome have a deficiency of the enzyme alpha-L-iduronidase. Individuals with Scheie syndrome have normal intelligence, height, and life expectancy. Symptoms include stiff joints, carpal tunnel syndrome, backward flow of blood into the heart (aortic regurgitation), and corneal clouding that may result in the loss of visual acuity. The onset of symptoms in individuals with Scheie syndrome usually occurs around the age of five. (For more information on this disorder, choose “Scheie” as your search term in the Rare Disease Database.) Multiple sulfatase deficiency is an extremely rare hereditary metabolic disorder in which all of the known sulfatase enzymes (thought to be seven in number) are not functional. Major symptoms include mildly coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Abnormalities of the skeleton may occur, such as curvature of the spine (lumbar kyphosis) and the breast bone. The skin is usually dry and scaly (ichthyosis). Before symptoms are noticeable, children with this disorder usually develop more slowly than normal. They may not learn to walk or speak at the same time of other children. The specific symptoms and severity of this disorder can vary greatly from one person to another. Multiple sulfatase deficiency is inherited in an autosomal recessive manner. (For more information on this disorder, choose “multiple sulfatase deficiency” as your search term in the Rare Disease Database.) Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. There are nearly 60 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 there are approved specific treatments for some LSDs, dozens of clinical trials are in progress on possible treatments for several conditions of this group. (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 Maroteaux Lamy Syndrome. Symptoms of the following disorders can be similar to those of Maroteaux-Lamy syndrome. Comparisons may be useful for a differential diagnosis. Scheie syndrome (mucopolysaccharidosis type I-S; MPS 1-S) is the most attenuated form of mucopolysaccharidosis. As in Hurler syndrome, individuals with Scheie syndrome have a deficiency of the enzyme alpha-L-iduronidase. Individuals with Scheie syndrome have normal intelligence, height, and life expectancy. Symptoms include stiff joints, carpal tunnel syndrome, backward flow of blood into the heart (aortic regurgitation), and corneal clouding that may result in the loss of visual acuity. The onset of symptoms in individuals with Scheie syndrome usually occurs around the age of five. (For more information on this disorder, choose “Scheie” as your search term in the Rare Disease Database.) Multiple sulfatase deficiency is an extremely rare hereditary metabolic disorder in which all of the known sulfatase enzymes (thought to be seven in number) are not functional. Major symptoms include mildly coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Abnormalities of the skeleton may occur, such as curvature of the spine (lumbar kyphosis) and the breast bone. The skin is usually dry and scaly (ichthyosis). Before symptoms are noticeable, children with this disorder usually develop more slowly than normal. They may not learn to walk or speak at the same time of other children. The specific symptoms and severity of this disorder can vary greatly from one person to another. Multiple sulfatase deficiency is inherited in an autosomal recessive manner. (For more information on this disorder, choose “multiple sulfatase deficiency” as your search term in the Rare Disease Database.) Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. There are nearly 60 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 there are approved specific treatments for some LSDs, dozens of clinical trials are in progress on possible treatments for several conditions of this group. (For more information on this disorder, choose “lysosomal storage diseases” as your search term in the Rare Disease Database.)
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Maroteaux Lamy Syndrome
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Diagnosis of Maroteaux Lamy Syndrome
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A diagnosis of Maroteaux-Lamy syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Clinical Testing and Workup
In individuals suspected of Maroteaux-Lamy syndrome the urine could be initially examined to assess the levels of the glycosaminoglycans (GAGs). Elevated levels of total urinary GAGs, with predominance of dermatan sulfate, suggests Maroteaux-Lamy syndrome. To confirm the diagnosis, a blood sample should be taken to measure the activity of the enzyme arylsulfatase B. Deficient or absent activity of this enzyme is confirms the diagnosis of Maroteaux-Lamy syndrome. Although less convenient, the enzyme activity can be also measured in certain types of skin cells (fibroblasts). When a deficiency of arylsulfatase B enzyme is detected, at least another sulfatase should be measured to rule out multiple sulfatase deficiency. In Maroteaux-Lamy syndrome the only enzyme deficient will be arylsulfatase B, while in multiple sulfatase deficiency several sulfatases have low activity. Whenever possible the sequencing of ARSB gene should be performed to identify the causative mutations. Although not mandatory to confirm the diagnosis, the identification of the mutations could help in the prediction of the clinical severity, in the identification of carriers in the family and prenatal diagnosis in future at-risk pregnancies. The quantification of dermatan sulfate levels, the measurement of the activities of arylsulfatase A and other sulfatases, and gene sequencing, can also be performed in dried blood spots, a very convenient sample that is becoming increasingly used. This makes technically feasible to include the detection of this disease in newborn screening panels.
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Diagnosis of Maroteaux Lamy Syndrome. A diagnosis of Maroteaux-Lamy syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Clinical Testing and Workup
In individuals suspected of Maroteaux-Lamy syndrome the urine could be initially examined to assess the levels of the glycosaminoglycans (GAGs). Elevated levels of total urinary GAGs, with predominance of dermatan sulfate, suggests Maroteaux-Lamy syndrome. To confirm the diagnosis, a blood sample should be taken to measure the activity of the enzyme arylsulfatase B. Deficient or absent activity of this enzyme is confirms the diagnosis of Maroteaux-Lamy syndrome. Although less convenient, the enzyme activity can be also measured in certain types of skin cells (fibroblasts). When a deficiency of arylsulfatase B enzyme is detected, at least another sulfatase should be measured to rule out multiple sulfatase deficiency. In Maroteaux-Lamy syndrome the only enzyme deficient will be arylsulfatase B, while in multiple sulfatase deficiency several sulfatases have low activity. Whenever possible the sequencing of ARSB gene should be performed to identify the causative mutations. Although not mandatory to confirm the diagnosis, the identification of the mutations could help in the prediction of the clinical severity, in the identification of carriers in the family and prenatal diagnosis in future at-risk pregnancies. The quantification of dermatan sulfate levels, the measurement of the activities of arylsulfatase A and other sulfatases, and gene sequencing, can also be performed in dried blood spots, a very convenient sample that is becoming increasingly used. This makes technically feasible to include the detection of this disease in newborn screening panels.
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Maroteaux Lamy Syndrome
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Therapies of Maroteaux Lamy Syndrome
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Treatment The treatment of Maroteaux-Lamy syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, orthopedists, cardiologists, dental specialists, ear-nose-throat specialists (otorhinolaryngologists), specialists who deal with diseases of the lungs and respiratory tract (pulmonologists), specialists who asses and treat hearing problems (audiologists), specialists who asses and treat vision problems (ophthalmologists), and other healthcare professionals may need to systematically and comprehensively plan the treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well. In 2005, the U.S. Food and Drug Administration (FDA) approved the orphan drug Naglazyme (galsulfase) for the treatment of individuals with Maroteaux-Lamy syndrome. Naglazyme is an enzyme replacement therapy (ERT), a therapy in which the missing or inactive enzyme is replaced with a genetically engineered (recombinant) version. Studies on long-term follow-up of ERT with galsulfase are now available, and indicate an acceptable safety profile with several improvements demonstrated, including extended survival. Additional treatment is symptomatic and supportive. For example, surgery may be necessary to treat various abnormalities associated with Maroteaux-Lamy syndrome including carpal tunnel syndrome, skeletal malformations, spinal cord compression, degeneration of the hip, and hernias. Heart valve replacement may be necessary in some cases. Surgical removal of the tonsils and/or adenoids may be recommended. Tracheomalacia is usually treated by noninvasive measures, but in rare cases can require surgical intervention. Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess of cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. A corneal transplantation can be performed for individuals with severe corneal clouding. Individuals with conductive hearing loss may experience the accumulation of a sticky fluid within the middle ear (glue ear). This is treated with a procedure called a myringotomy, in which a thin incision is made in the eardrum to release the fluid. There is no specific treatment for sensorineural hearing loss. Hearing aids may help to maximize remaining hearing. Certain medications can be used to treat heart abnormalities, asthma-like episodes, and chronic infections. Anti-inflammatory medications may be of benefit. Respiratory insufficiency may require treatment with supplemental oxygen. Aggressive management of airway secretions is necessary as well. Some affected individuals may undergo a sleep study, in which people are evaluated on how well they sleep and how well their body responds to sleep problems. Sleep apnea may be treated with continuous positive airway pressure (CPAP), which involves the use of a mask or similar device to deliver mild air pressure to keep airways open. In some cases, a similar treatment method known as bilevel positive airway pressure (BPAP) may be used. BPAP devices provide more pressure when you breathe in and less pressure when you breathe out. Physical therapy and exercise may improve joint stiffness. Speech therapy may help children with hearing loss communicate effectively. Nutritional counseling and occupational therapy may also beneficial.
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Therapies of Maroteaux Lamy Syndrome. Treatment The treatment of Maroteaux-Lamy syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, orthopedists, cardiologists, dental specialists, ear-nose-throat specialists (otorhinolaryngologists), specialists who deal with diseases of the lungs and respiratory tract (pulmonologists), specialists who asses and treat hearing problems (audiologists), specialists who asses and treat vision problems (ophthalmologists), and other healthcare professionals may need to systematically and comprehensively plan the treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well. In 2005, the U.S. Food and Drug Administration (FDA) approved the orphan drug Naglazyme (galsulfase) for the treatment of individuals with Maroteaux-Lamy syndrome. Naglazyme is an enzyme replacement therapy (ERT), a therapy in which the missing or inactive enzyme is replaced with a genetically engineered (recombinant) version. Studies on long-term follow-up of ERT with galsulfase are now available, and indicate an acceptable safety profile with several improvements demonstrated, including extended survival. Additional treatment is symptomatic and supportive. For example, surgery may be necessary to treat various abnormalities associated with Maroteaux-Lamy syndrome including carpal tunnel syndrome, skeletal malformations, spinal cord compression, degeneration of the hip, and hernias. Heart valve replacement may be necessary in some cases. Surgical removal of the tonsils and/or adenoids may be recommended. Tracheomalacia is usually treated by noninvasive measures, but in rare cases can require surgical intervention. Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess of cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. A corneal transplantation can be performed for individuals with severe corneal clouding. Individuals with conductive hearing loss may experience the accumulation of a sticky fluid within the middle ear (glue ear). This is treated with a procedure called a myringotomy, in which a thin incision is made in the eardrum to release the fluid. There is no specific treatment for sensorineural hearing loss. Hearing aids may help to maximize remaining hearing. Certain medications can be used to treat heart abnormalities, asthma-like episodes, and chronic infections. Anti-inflammatory medications may be of benefit. Respiratory insufficiency may require treatment with supplemental oxygen. Aggressive management of airway secretions is necessary as well. Some affected individuals may undergo a sleep study, in which people are evaluated on how well they sleep and how well their body responds to sleep problems. Sleep apnea may be treated with continuous positive airway pressure (CPAP), which involves the use of a mask or similar device to deliver mild air pressure to keep airways open. In some cases, a similar treatment method known as bilevel positive airway pressure (BPAP) may be used. BPAP devices provide more pressure when you breathe in and less pressure when you breathe out. Physical therapy and exercise may improve joint stiffness. Speech therapy may help children with hearing loss communicate effectively. Nutritional counseling and occupational therapy may also beneficial.
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Maroteaux Lamy Syndrome
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Overview of Marshall Smith Syndrome
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SummaryMarshall-Smith syndrome (MSS) typically begins before birth and is characterized by excessive and rapid physical growth, specifically in bone development (maturation). Other symptoms that may occur in an individual with Marshall-Smith syndrome are developmental delays, respiratory issues and infections, as well as distinguishing physical characteristics.IntroductionThe first cases of Marshall-Smith syndrome were identified in 1971 by physicians R.E. Marshall, C.B. Graham, C.R. Scott, and D.W. Smith. These two MSS cases were identified in male infant patients who died by the age of 20 months. (Note: Marshall-Smith syndrome is not to be confused with “Marshall” syndrome, which is very different from “Marshall-Smith” syndrome.)
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Overview of Marshall Smith Syndrome. SummaryMarshall-Smith syndrome (MSS) typically begins before birth and is characterized by excessive and rapid physical growth, specifically in bone development (maturation). Other symptoms that may occur in an individual with Marshall-Smith syndrome are developmental delays, respiratory issues and infections, as well as distinguishing physical characteristics.IntroductionThe first cases of Marshall-Smith syndrome were identified in 1971 by physicians R.E. Marshall, C.B. Graham, C.R. Scott, and D.W. Smith. These two MSS cases were identified in male infant patients who died by the age of 20 months. (Note: Marshall-Smith syndrome is not to be confused with “Marshall” syndrome, which is very different from “Marshall-Smith” syndrome.)
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Marshall Smith Syndrome
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Symptoms of Marshall Smith Syndrome
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Marshall-Smith syndrome (MSS) is largely characterized with faster than normal bone growth. Due to their taller stature, patients have low muscle tone, muscle weakness, and may experience difficulties in gaining weight. Patients with Marshall-Smith syndrome may also have abdominal hernias (umbilical hernias), intellectual developmental delays, psychomotor delays (slowing down of thought and voluntary movements), and/or breathing difficulties. The breathing difficulties can sound like a high-pitched noisy breath, due to abnormal neck extension, with the tongue blocking the airway. Some traits related to the windpipe of Marshall-Smith syndrome patients include the abnormal development of the leaf-shaped structure in the throat that stops foods and liquids from entering the windpipe. The nasal passages may be smaller, and these patients may have an abnormal larynx with soft cartilage. Patients with Marshall-Smith syndrome typically have a long head with a prominent forehead, prominent eyes, an upturned nose with a low nasal bridge, and excessive hair growth. The patient’s eye whites may appear bluish, and the lower jawbone may be smaller than average. Their fingertips may appear narrow while the rest of the finger may appear broad. Some patients with MSS may experience additional symptoms including a shorter breastbone, as well as a deep crease between the big toe and the second toe. Some brain abnormalities may occur, including atrophy (loss of brain cells), macrogyria (larger than normal grooves in the brain), or a missing corpus callosum. Patients with Marshall-Smith syndrome may have poor immune systems, and on rare occasions, babies with this syndrome could be born with part of their intestines outside of their bodies via the belly button.
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Symptoms of Marshall Smith Syndrome. Marshall-Smith syndrome (MSS) is largely characterized with faster than normal bone growth. Due to their taller stature, patients have low muscle tone, muscle weakness, and may experience difficulties in gaining weight. Patients with Marshall-Smith syndrome may also have abdominal hernias (umbilical hernias), intellectual developmental delays, psychomotor delays (slowing down of thought and voluntary movements), and/or breathing difficulties. The breathing difficulties can sound like a high-pitched noisy breath, due to abnormal neck extension, with the tongue blocking the airway. Some traits related to the windpipe of Marshall-Smith syndrome patients include the abnormal development of the leaf-shaped structure in the throat that stops foods and liquids from entering the windpipe. The nasal passages may be smaller, and these patients may have an abnormal larynx with soft cartilage. Patients with Marshall-Smith syndrome typically have a long head with a prominent forehead, prominent eyes, an upturned nose with a low nasal bridge, and excessive hair growth. The patient’s eye whites may appear bluish, and the lower jawbone may be smaller than average. Their fingertips may appear narrow while the rest of the finger may appear broad. Some patients with MSS may experience additional symptoms including a shorter breastbone, as well as a deep crease between the big toe and the second toe. Some brain abnormalities may occur, including atrophy (loss of brain cells), macrogyria (larger than normal grooves in the brain), or a missing corpus callosum. Patients with Marshall-Smith syndrome may have poor immune systems, and on rare occasions, babies with this syndrome could be born with part of their intestines outside of their bodies via the belly button.
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Marshall Smith Syndrome
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Causes of Marshall Smith Syndrome
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There are indications that Marshall-Smith syndrome is caused by a change (mutation) in the NFIX gene. This gene plays an important role in transcription initiation for various genes. In human embryonic development, expression of NFIX can be detected during brain and skeletal development. The most common variant types leading to Marshall Smith syndrome are frameshift and splice site variants. Most individuals with Marshall-Smith syndrome are the first individuals in their families to have this syndrome and as such they are “de-novo” cases.
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Causes of Marshall Smith Syndrome. There are indications that Marshall-Smith syndrome is caused by a change (mutation) in the NFIX gene. This gene plays an important role in transcription initiation for various genes. In human embryonic development, expression of NFIX can be detected during brain and skeletal development. The most common variant types leading to Marshall Smith syndrome are frameshift and splice site variants. Most individuals with Marshall-Smith syndrome are the first individuals in their families to have this syndrome and as such they are “de-novo” cases.
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Marshall Smith Syndrome
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Affects of Marshall Smith Syndrome
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Marshall-Smith Syndrome is a rare disorder that has only been documented in about 50 individuals worldwide. It appears to affect males and females equally. Symptoms are typically present at birth, such as the previously escribed characteristic facial features. There does not appear to be an ethnic population more at risk for the disorder and the fifty or so cases that have been described are part of an international cohort. The cases appear to be sporadic, in that there is no family history or parental relatedness that may lead to a disorder. Due to the infrequency of the disorder, demographic statistics are unavailable.
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Affects of Marshall Smith Syndrome. Marshall-Smith Syndrome is a rare disorder that has only been documented in about 50 individuals worldwide. It appears to affect males and females equally. Symptoms are typically present at birth, such as the previously escribed characteristic facial features. There does not appear to be an ethnic population more at risk for the disorder and the fifty or so cases that have been described are part of an international cohort. The cases appear to be sporadic, in that there is no family history or parental relatedness that may lead to a disorder. Due to the infrequency of the disorder, demographic statistics are unavailable.
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Marshall Smith Syndrome
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Related disorders of Marshall Smith Syndrome
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Weaver syndrome is similar to Marshall-Smith syndrome in that growth and bone ages faster than normal, or advanced bone age. Patients with both Weaver and Marshall-Smith syndromes tend to have their growth spurt early in age but will stop growing sooner compared to normal individuals. However, patients with Weaver syndrome are usually overweight, whereas patients with Marshall-Smith syndrome are underweight. There are several other distinguishing physical and behavioral characteristics between Marshall-Smith and Weaver syndrome. (For more information on this condition, search for “Weaver” in the Rare Disease Database.)Several features commonly found in Marshall-Smith syndrome – such as tallness, muscle myopathy, peripheral neuropathy – also appear in Klinefelter and Marfan syndrome. Patients with Marshall-Smith syndrome display an excess amount of growth hormones before puberty, leading to a significant growth in height and weight – gigantism – where they can grow up to 7 or 8 feet. In addition, patients with Marshall-Smith syndrome could experience muscle and nerve abnormalities. The muscle tissues soften gradually, and lead muscles to lose their strength – this condition is called muscle myopathy. Furthermore, patients can also have issues with their nerves – peripheral neuropathy – where the messages from the brain are not properly sent to the rest of the body. Sotos syndrome is a rare, hereditary disorder characterized by excessive growth (over the 90th percentile) during the first 4 to 5 years of life. Abnormalities of the nervous system, including aggressiveness, irritability, clumsiness, an awkward gait, and intellectual developmental delay sometimes also occur. Physical characteristics include eyes which appear to be abnormally far apart (hypertelorism) and slanted. Both Sotos syndrome and Marshall-Smith syndrome share overlapping symptoms including advanced bone age, overly large head, intellectual delay, scoliosis, and abnormal facial features. (For more information, input “Sotos” as your search term in the Rare Disease Database.)McCune-Albright syndrome (osteitis fibrosa disseminata) and Marshall-Smith syndrome have similar symptoms involving the endocrine, muscle and bone systems. However, McCune-Albright syndrome exhibits additional symptoms including a change in bone integrity which produces pain, increasing deformity and disability as well as changes in skin pigmentation. Marshall-Smith syndrome exhibits excessive secretion of growth hormone, resulting in early puberty as documented in a 4-year-old patient with high hormone levels, indicating she was undergoing puberty at an early age. Children with McCune-Albright syndrome are excessively tall during childhood, but their growth stops early and they usually don’t reach normal height during adulthood. (For more information, choose “McCune-Albright” as your search term in the Rare Disease Database.)
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Related disorders of Marshall Smith Syndrome. Weaver syndrome is similar to Marshall-Smith syndrome in that growth and bone ages faster than normal, or advanced bone age. Patients with both Weaver and Marshall-Smith syndromes tend to have their growth spurt early in age but will stop growing sooner compared to normal individuals. However, patients with Weaver syndrome are usually overweight, whereas patients with Marshall-Smith syndrome are underweight. There are several other distinguishing physical and behavioral characteristics between Marshall-Smith and Weaver syndrome. (For more information on this condition, search for “Weaver” in the Rare Disease Database.)Several features commonly found in Marshall-Smith syndrome – such as tallness, muscle myopathy, peripheral neuropathy – also appear in Klinefelter and Marfan syndrome. Patients with Marshall-Smith syndrome display an excess amount of growth hormones before puberty, leading to a significant growth in height and weight – gigantism – where they can grow up to 7 or 8 feet. In addition, patients with Marshall-Smith syndrome could experience muscle and nerve abnormalities. The muscle tissues soften gradually, and lead muscles to lose their strength – this condition is called muscle myopathy. Furthermore, patients can also have issues with their nerves – peripheral neuropathy – where the messages from the brain are not properly sent to the rest of the body. Sotos syndrome is a rare, hereditary disorder characterized by excessive growth (over the 90th percentile) during the first 4 to 5 years of life. Abnormalities of the nervous system, including aggressiveness, irritability, clumsiness, an awkward gait, and intellectual developmental delay sometimes also occur. Physical characteristics include eyes which appear to be abnormally far apart (hypertelorism) and slanted. Both Sotos syndrome and Marshall-Smith syndrome share overlapping symptoms including advanced bone age, overly large head, intellectual delay, scoliosis, and abnormal facial features. (For more information, input “Sotos” as your search term in the Rare Disease Database.)McCune-Albright syndrome (osteitis fibrosa disseminata) and Marshall-Smith syndrome have similar symptoms involving the endocrine, muscle and bone systems. However, McCune-Albright syndrome exhibits additional symptoms including a change in bone integrity which produces pain, increasing deformity and disability as well as changes in skin pigmentation. Marshall-Smith syndrome exhibits excessive secretion of growth hormone, resulting in early puberty as documented in a 4-year-old patient with high hormone levels, indicating she was undergoing puberty at an early age. Children with McCune-Albright syndrome are excessively tall during childhood, but their growth stops early and they usually don’t reach normal height during adulthood. (For more information, choose “McCune-Albright” as your search term in the Rare Disease Database.)
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Marshall Smith Syndrome
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Diagnosis of Marshall Smith Syndrome
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Patients with Marshall-Smith syndrome are diagnosed based on clinical findings and symptoms, as well as the use of x-ray exams to identify the skeletal indications. Genetic diagnosis can now be performed by looking for mutations in the NFIX gene.Animal Model
Animals that have been studied to better understand Marshall-Smith syndrome include the NFIX-deficient mouse. Observable characteristics in NFIX-deficient mice include the inability to gain weight, death by the third week of life, bone mineralization, as well as spine deformities. Similarity between clinical presentations between these NFIX-deficient mice and physical characteristics in humans lead to the investigation of NFIX as a candidate gene for Marshall-Smith syndrome.
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Diagnosis of Marshall Smith Syndrome. Patients with Marshall-Smith syndrome are diagnosed based on clinical findings and symptoms, as well as the use of x-ray exams to identify the skeletal indications. Genetic diagnosis can now be performed by looking for mutations in the NFIX gene.Animal Model
Animals that have been studied to better understand Marshall-Smith syndrome include the NFIX-deficient mouse. Observable characteristics in NFIX-deficient mice include the inability to gain weight, death by the third week of life, bone mineralization, as well as spine deformities. Similarity between clinical presentations between these NFIX-deficient mice and physical characteristics in humans lead to the investigation of NFIX as a candidate gene for Marshall-Smith syndrome.
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Marshall Smith Syndrome
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Therapies of Marshall Smith Syndrome
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Treatment
Treatment of Marshall-Smith Syndrome is based on treating the symptoms and giving supportive care to the patient. Malnutrition and respiratory infections should be treated aggressively and are dangerous complications of Marshall-Smith syndrome. Due to the developmental delays, special education programs and other supportive resources may be utilized in patients who are school-aged. Genetic counseling is recommended for affected individuals and their families.
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Therapies of Marshall Smith Syndrome. Treatment
Treatment of Marshall-Smith Syndrome is based on treating the symptoms and giving supportive care to the patient. Malnutrition and respiratory infections should be treated aggressively and are dangerous complications of Marshall-Smith syndrome. Due to the developmental delays, special education programs and other supportive resources may be utilized in patients who are school-aged. Genetic counseling is recommended for affected individuals and their families.
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Marshall Smith Syndrome
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Overview of Marshall Syndrome
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Marshall syndrome is a rare autosomal dominant genetic disorder caused by mutations in the COL11A1 gene. Major symptoms may include a distinctive face with a flattened nasal bridge and nostrils that are tilted upward, widely spaced eyes, nearsightedness, cataracts and hearing loss.
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Overview of Marshall Syndrome. Marshall syndrome is a rare autosomal dominant genetic disorder caused by mutations in the COL11A1 gene. Major symptoms may include a distinctive face with a flattened nasal bridge and nostrils that are tilted upward, widely spaced eyes, nearsightedness, cataracts and hearing loss.
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Marshall Syndrome
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Symptoms of Marshall Syndrome
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Patients with Marshall Syndrome have a distinctive flat sunken midface with a flattened nasal bridge (saddle nose), nostrils that turn upward, and a wide space between the eyes (hypertelorism). The dome-like upper portion of the skull (calvaria) is thicker than normal and calcium deposits can be found in the skull (cranium). Frontal sinuses may be absent. Eye defects found in patients with Marshall Syndrome are nearsightedness, a disease of the eye in which the lens loses its clarity (cataract), and a wide space between the eyes making the eyeballs appear to be larger than normal. Hearing loss may range from slight to severe; the distortion of the sound is a consequence of the nerve damage (sensorineural). Other symptoms exhibited by some patients with Marshall Syndrome are: crossed eyes (esotropia), a condition in which the line of vision is higher in one eye than the other (hypertropia), retinal detachment, glaucoma, protruding upper incisors (teeth) and a smaller than normal or missing nasal bone.
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Symptoms of Marshall Syndrome. Patients with Marshall Syndrome have a distinctive flat sunken midface with a flattened nasal bridge (saddle nose), nostrils that turn upward, and a wide space between the eyes (hypertelorism). The dome-like upper portion of the skull (calvaria) is thicker than normal and calcium deposits can be found in the skull (cranium). Frontal sinuses may be absent. Eye defects found in patients with Marshall Syndrome are nearsightedness, a disease of the eye in which the lens loses its clarity (cataract), and a wide space between the eyes making the eyeballs appear to be larger than normal. Hearing loss may range from slight to severe; the distortion of the sound is a consequence of the nerve damage (sensorineural). Other symptoms exhibited by some patients with Marshall Syndrome are: crossed eyes (esotropia), a condition in which the line of vision is higher in one eye than the other (hypertropia), retinal detachment, glaucoma, protruding upper incisors (teeth) and a smaller than normal or missing nasal bone.
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Marshall Syndrome
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Causes of Marshall Syndrome
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Marshall syndrome is a rare autosomal dominant genetic disorder caused by mutations in the collagen XI, alpha-1 polypeptide (COL11A1) gene located on chromosome 1p21.1. Typically mutations causing Marshall syndrome are splice site mutations involving base pair insertions or deletions of intron 50. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy.One Saudi family has been reported with two sons with Marshall syndrome with homozygous missense mutations of COL11A1. In this family there was concern for possible autosomal recessive inheritance, as each parent carried one missense mutation with glycine substitution, and these parents had short stature, thick calvaria, and mild hearing loss with normal ophthalmologic examination and did not have a diagnosis of Stickler or Marshall syndrome. Recessive genetic disorders occur when a child inherits two abnormal copies of a gene, one from each parent, who is unaffected. It may be in this family that both parents are mildly affected by Stickler syndrome and in this situation the inheritance would be termed double dominant. In either situation, the recurrence risk would be 25% with each pregnancy. The risk is the same for males and females.
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Causes of Marshall Syndrome. Marshall syndrome is a rare autosomal dominant genetic disorder caused by mutations in the collagen XI, alpha-1 polypeptide (COL11A1) gene located on chromosome 1p21.1. Typically mutations causing Marshall syndrome are splice site mutations involving base pair insertions or deletions of intron 50. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy.One Saudi family has been reported with two sons with Marshall syndrome with homozygous missense mutations of COL11A1. In this family there was concern for possible autosomal recessive inheritance, as each parent carried one missense mutation with glycine substitution, and these parents had short stature, thick calvaria, and mild hearing loss with normal ophthalmologic examination and did not have a diagnosis of Stickler or Marshall syndrome. Recessive genetic disorders occur when a child inherits two abnormal copies of a gene, one from each parent, who is unaffected. It may be in this family that both parents are mildly affected by Stickler syndrome and in this situation the inheritance would be termed double dominant. In either situation, the recurrence risk would be 25% with each pregnancy. The risk is the same for males and females.
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Marshall Syndrome
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Affects of Marshall Syndrome
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Marshall Syndrome affects males and females in equal numbers.
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Affects of Marshall Syndrome. Marshall Syndrome affects males and females in equal numbers.
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Marshall Syndrome
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Related disorders of Marshall Syndrome
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Symptoms of the following disorders can be similar to those of Marshall syndrome. Comparisons may be useful for a differential diagnosis:Congenital spondyloepiphyseal dysplasia is a rare genetic disorder characterized by growth deficiency before birth (prenatally), spinal malformations, and/or abnormalities affecting the eyes. As affected individuals age, growth deficiency eventually results in short stature (dwarfism) due, in part, to a disproportionately short neck and trunk, and a hip deformity in which the thigh bone is angled toward the center of the body (coxa vara). In most cases, affected individuals may have diminished muscle tone (hypotonia), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), abnormal inward curvature of the spine (lumbar lordosis), and/or unusual protrusion of the breastbone (sternum), a condition known as pectus carinatum. Affected individuals also have abnormalities affecting the eyes including nearsightedness (myopia) and, in approximately 50 percent of cases, detachment of the nerve-rich membrane lining the eye (retina). Congenital spondyloepiphyseal dysplasia is inherited as an autosomal dominant trait, also linked to mutations, deletions, and duplications the COL2A1 gene, with autosomal dominant inheritance. (For more information on this disorder, choose “spondyloepiphyseal dysplasia congenita” as your search term in the Rare Disease Database.)Congenital syphilis is a chronic infectious disease caused by a spirochete (treponema pallidum) acquired by the fetus in the uterus. Symptoms of this disease may not show up until several weeks or months after birth and in some cases they may take years to appear. Congenital syphilis is passed on to the child from the mother who acquired the disease prior to or during pregnancy. Symptoms of early congenital syphilis include fever, skin problems and low birth weight. In late congenital syphilis the symptoms of the disease do not usually become apparent until two to five years of age. Symptoms of late congenital syphilis may be bone pain, peg-shaped upper central incisors (teeth), blurred vision, eye pain and insensitivity to light, saddle nose, bony prominence of the forehead, short upper jawbone and deafness. In rare cases the disease may remain latent for years with symptoms not being diagnosed until well into adulthood. (For more information on this disorder, choose “congenital syphilis” as your search term in the Rare Disease Database.)Stickler syndrome refers to a group of disorders of the connective tissue that affect multiple organ systems of the body such as the eyes, skeleton, inner ear, and/or the head and face. Connective tissue, which is the material between cells of the body that gives the tissue form and strength, is found all over the body. Connective tissue is made up of a protein known as collagen of which there are several different varieties found in the body. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor), the specialized tissue that serves as a buffer or cushion for bones at joints (cartilage) and the ends of the bones that make up the joints of the body (epiphysis). Five distinct forms of Stickler syndrome have been identified in the medical literature based on location of the mutated gene, clinical symptoms and inheritance pattern. Type I with the membranous vitreous caused by mutations in the COL2A1 gene; type II with the beaded vitreous is caused by mutations in the COL11A1 gene; type III is the non-ocular type caused by mutations in COL11A2, type IV has a degenerated vitreous with progressive liquefaction and has autosomal recessive inheritance with mutations in COL9A1, type V has the same clinical symptoms as types I and II but the location of the mutation has not yet been found.Stickler syndrome type II is caused by mutations in the same gene COL11A1 as Marshall syndrome. Some researchers believe that the two disorders are the same or different expressions of the same disorder. Others believe that the two disorders are distinct. Recent studies show that the mutations in COL11A1 associated with Marshall syndrome are splicing mutations in the exons in the c-terminal regions of COL11A1, with a “hot spot” in exon 50. (For more information on this disorder, choose Stickler Syndrome as your search term in the Rare Diseases Database.)Wagner syndrome is a very rare genetic disorder inherited as an autosomal dominant trait and caused by a mutation in the CSPG2 gene on chromosome 5q13-14. The gene CSPG2 encodes for versican, a structural component of vitreous. It has been reported in one Swiss family. The ocular problems include vitreoretinal degeneration and cataracts. Retinal detachments occur only rarely. Extraocular problems have not been reported.
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Related disorders of Marshall Syndrome. Symptoms of the following disorders can be similar to those of Marshall syndrome. Comparisons may be useful for a differential diagnosis:Congenital spondyloepiphyseal dysplasia is a rare genetic disorder characterized by growth deficiency before birth (prenatally), spinal malformations, and/or abnormalities affecting the eyes. As affected individuals age, growth deficiency eventually results in short stature (dwarfism) due, in part, to a disproportionately short neck and trunk, and a hip deformity in which the thigh bone is angled toward the center of the body (coxa vara). In most cases, affected individuals may have diminished muscle tone (hypotonia), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), abnormal inward curvature of the spine (lumbar lordosis), and/or unusual protrusion of the breastbone (sternum), a condition known as pectus carinatum. Affected individuals also have abnormalities affecting the eyes including nearsightedness (myopia) and, in approximately 50 percent of cases, detachment of the nerve-rich membrane lining the eye (retina). Congenital spondyloepiphyseal dysplasia is inherited as an autosomal dominant trait, also linked to mutations, deletions, and duplications the COL2A1 gene, with autosomal dominant inheritance. (For more information on this disorder, choose “spondyloepiphyseal dysplasia congenita” as your search term in the Rare Disease Database.)Congenital syphilis is a chronic infectious disease caused by a spirochete (treponema pallidum) acquired by the fetus in the uterus. Symptoms of this disease may not show up until several weeks or months after birth and in some cases they may take years to appear. Congenital syphilis is passed on to the child from the mother who acquired the disease prior to or during pregnancy. Symptoms of early congenital syphilis include fever, skin problems and low birth weight. In late congenital syphilis the symptoms of the disease do not usually become apparent until two to five years of age. Symptoms of late congenital syphilis may be bone pain, peg-shaped upper central incisors (teeth), blurred vision, eye pain and insensitivity to light, saddle nose, bony prominence of the forehead, short upper jawbone and deafness. In rare cases the disease may remain latent for years with symptoms not being diagnosed until well into adulthood. (For more information on this disorder, choose “congenital syphilis” as your search term in the Rare Disease Database.)Stickler syndrome refers to a group of disorders of the connective tissue that affect multiple organ systems of the body such as the eyes, skeleton, inner ear, and/or the head and face. Connective tissue, which is the material between cells of the body that gives the tissue form and strength, is found all over the body. Connective tissue is made up of a protein known as collagen of which there are several different varieties found in the body. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor), the specialized tissue that serves as a buffer or cushion for bones at joints (cartilage) and the ends of the bones that make up the joints of the body (epiphysis). Five distinct forms of Stickler syndrome have been identified in the medical literature based on location of the mutated gene, clinical symptoms and inheritance pattern. Type I with the membranous vitreous caused by mutations in the COL2A1 gene; type II with the beaded vitreous is caused by mutations in the COL11A1 gene; type III is the non-ocular type caused by mutations in COL11A2, type IV has a degenerated vitreous with progressive liquefaction and has autosomal recessive inheritance with mutations in COL9A1, type V has the same clinical symptoms as types I and II but the location of the mutation has not yet been found.Stickler syndrome type II is caused by mutations in the same gene COL11A1 as Marshall syndrome. Some researchers believe that the two disorders are the same or different expressions of the same disorder. Others believe that the two disorders are distinct. Recent studies show that the mutations in COL11A1 associated with Marshall syndrome are splicing mutations in the exons in the c-terminal regions of COL11A1, with a “hot spot” in exon 50. (For more information on this disorder, choose Stickler Syndrome as your search term in the Rare Diseases Database.)Wagner syndrome is a very rare genetic disorder inherited as an autosomal dominant trait and caused by a mutation in the CSPG2 gene on chromosome 5q13-14. The gene CSPG2 encodes for versican, a structural component of vitreous. It has been reported in one Swiss family. The ocular problems include vitreoretinal degeneration and cataracts. Retinal detachments occur only rarely. Extraocular problems have not been reported.
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Marshall Syndrome
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Diagnosis of Marshall Syndrome
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Diagnosis of Marshall Syndrome.
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Marshall Syndrome
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Therapies of Marshall Syndrome
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Plastic surgery can improve saddle nose in Marshall syndrome. Other surgical procedures are used to remove the lenses of eyes affected by cataracts, after which lens implants are used as replacements. Subsequently, contact lenses may help improve sharpness of vision. Laser techniques are used to loosen any material, such as the cornea or the lens capsule that may adhere to the lens. The use of a hearing aid may be beneficial in some cases. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Marshall Syndrome. Plastic surgery can improve saddle nose in Marshall syndrome. Other surgical procedures are used to remove the lenses of eyes affected by cataracts, after which lens implants are used as replacements. Subsequently, contact lenses may help improve sharpness of vision. Laser techniques are used to loosen any material, such as the cornea or the lens capsule that may adhere to the lens. The use of a hearing aid may be beneficial in some cases. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Marshall Syndrome
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Overview of Mastocytosis
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Mastocytosis is a rare disorder characterized by abnormal accumulation and activation of mast cells in the skin, bone marrow and internal organs (liver, spleen, gastrointestinal tract and lymph nodes). Mastocytosis can affect both children and adults. Mastocytosis can be classified to a specific type depending on the patient’s symptoms and overall presentation. Cases beginning during adulthood tend to be chronic and involve the bone marrow in addition to the skin, whereas, during childhood, the condition is often marked by skin manifestations with no internal organ involvement and can often resolve during puberty. In adult patients, mastocytosis tends to be persistent, and may progress into a more advanced category in a minority of patients. ClassificationCutaneous mastocytosisThe skin is the only site of involvement in cutaneous mastocytosis. Urticaria pigmentosa (also known as maculopapular cutaneous mastocytosis) lesions are small, brownish, flat or elevated spots that may be surrounded by reddened, itchy skin when scratched (Darier’s sign). These lesions tend to be more apparent on areas of skin exposed to pressure or rubbing in adult patients. When skin lesions begin during childhood, the skin tends to be the only affected organ. Blistering of the skin lesions is seen exclusively in children younger than four years of age.Based on clinical appearance, prognosis, and disease course, cutaneous mastocytosis can be further categorized into the following: maculopapular cutaneous mastocytosis (MCPM), mastocytoma and diffuse cutaneous mastocytosis. Maculopapular cutaneous mastocytosis and mastocytoma are the most common forms, compared to diffuse cutaneous mastocytosis which is rarer. CM is most often diagnosed within the neonatal period. MCPM lesions may occur on scalp, neck, trunk and extremities. A mastocytoma is a single lesion, or up to 3 individual lesions, that is usually found early in life and resolves spontaneously with age. Diffuse cutaneous mastocytosis (DCM) is seen in children and is the most severe form of cutaneous mastocytosis. The skin is diffusely thickened and has a rough texture, generally without individual distinct lesions. Additional symptoms associated with DCM include itching, blistering, decreased blood pressure (hypotension), diarrhea, gastrointestinal bleeding, reddening of the skin (flushing) and anaphylactic shock.Indolent systemic mastocytosisSystemic mastocytosis is the main form of mastocytosis observed in adults whereas it is rarer in children. Systemic disease is defined by demonstration of pathologic accumulation of mast cells in a tissue other than skin (most commonly bone marrow). Indolent systemic mastocytosis is generally associated with low mast cell burden and presence of mediator-related symptoms. Most patients also have maculopapular skin lesions. Some patients may present with an enlarged liver or spleen and the gastrointestinal tract may also be affected. Life expectancy in ISM is comparable to general population with low risk of progression (approximately 3-5%) to a more advanced form.Systemic smoldering mastocytosisThis variant of systemic mastocytosis is characterized by high mast cell burden as evidenced by high level of tryptase (>200 ng/ml) and high degree of bone marrow involvement with mast cells (>30% in biopsy tissue), splenomegaly or hepatomegaly with or without mild abnormalities in production of other blood cells, without an overt hematologic disorder. Patients with SSM may have a higher likelihood of progressing to an advanced disease category below.The following categories are also known as advanced mastocytosis:Systemic mastocytosis with an associated hematologic neoplasmSystemic mastocytosis with an associated hematologic neoplasm affects approximately one-fifth of all patients with systemic mastocytosis. Myeloproliferative and myelodysplastic disorders are the most common diseases associated with this form and patients may lack urticaria pigmentosa-like skin lesions.Aggressive systemic mastocytosisIn aggressive systemic mastocytosis, there is an impairment or loss of organ function (usually liver, gut, bone or bone marrow) due to mast cell infiltrates. Examples of organ dysfunction include low numbers of white bloods cells, anemia, low platelets, liver dysfunction, malabsorption and pathologic bone fractures associated with large osteolytic bone lesions.Mast cell leukemiaMast cell leukemia is an aggressive hematological malignancy characterized by presence of circulating mast cells greater than 10%, or immature mast cells in bone marrow aspirates greater than 20%. This subtype is very rare; however, it is associated with the worst prognosis among all mastocytosis varieties.Mast cell sarcomaA mast cell sarcoma is a solid tumor composed of abnormal mast cells invading the tissue. This condition is very rare and often is not associated with additional skin involvement. More aggressive forms of mastocytosis, mast cell leukemias and mast cell sarcomas are very rarely encountered.
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Overview of Mastocytosis. Mastocytosis is a rare disorder characterized by abnormal accumulation and activation of mast cells in the skin, bone marrow and internal organs (liver, spleen, gastrointestinal tract and lymph nodes). Mastocytosis can affect both children and adults. Mastocytosis can be classified to a specific type depending on the patient’s symptoms and overall presentation. Cases beginning during adulthood tend to be chronic and involve the bone marrow in addition to the skin, whereas, during childhood, the condition is often marked by skin manifestations with no internal organ involvement and can often resolve during puberty. In adult patients, mastocytosis tends to be persistent, and may progress into a more advanced category in a minority of patients. ClassificationCutaneous mastocytosisThe skin is the only site of involvement in cutaneous mastocytosis. Urticaria pigmentosa (also known as maculopapular cutaneous mastocytosis) lesions are small, brownish, flat or elevated spots that may be surrounded by reddened, itchy skin when scratched (Darier’s sign). These lesions tend to be more apparent on areas of skin exposed to pressure or rubbing in adult patients. When skin lesions begin during childhood, the skin tends to be the only affected organ. Blistering of the skin lesions is seen exclusively in children younger than four years of age.Based on clinical appearance, prognosis, and disease course, cutaneous mastocytosis can be further categorized into the following: maculopapular cutaneous mastocytosis (MCPM), mastocytoma and diffuse cutaneous mastocytosis. Maculopapular cutaneous mastocytosis and mastocytoma are the most common forms, compared to diffuse cutaneous mastocytosis which is rarer. CM is most often diagnosed within the neonatal period. MCPM lesions may occur on scalp, neck, trunk and extremities. A mastocytoma is a single lesion, or up to 3 individual lesions, that is usually found early in life and resolves spontaneously with age. Diffuse cutaneous mastocytosis (DCM) is seen in children and is the most severe form of cutaneous mastocytosis. The skin is diffusely thickened and has a rough texture, generally without individual distinct lesions. Additional symptoms associated with DCM include itching, blistering, decreased blood pressure (hypotension), diarrhea, gastrointestinal bleeding, reddening of the skin (flushing) and anaphylactic shock.Indolent systemic mastocytosisSystemic mastocytosis is the main form of mastocytosis observed in adults whereas it is rarer in children. Systemic disease is defined by demonstration of pathologic accumulation of mast cells in a tissue other than skin (most commonly bone marrow). Indolent systemic mastocytosis is generally associated with low mast cell burden and presence of mediator-related symptoms. Most patients also have maculopapular skin lesions. Some patients may present with an enlarged liver or spleen and the gastrointestinal tract may also be affected. Life expectancy in ISM is comparable to general population with low risk of progression (approximately 3-5%) to a more advanced form.Systemic smoldering mastocytosisThis variant of systemic mastocytosis is characterized by high mast cell burden as evidenced by high level of tryptase (>200 ng/ml) and high degree of bone marrow involvement with mast cells (>30% in biopsy tissue), splenomegaly or hepatomegaly with or without mild abnormalities in production of other blood cells, without an overt hematologic disorder. Patients with SSM may have a higher likelihood of progressing to an advanced disease category below.The following categories are also known as advanced mastocytosis:Systemic mastocytosis with an associated hematologic neoplasmSystemic mastocytosis with an associated hematologic neoplasm affects approximately one-fifth of all patients with systemic mastocytosis. Myeloproliferative and myelodysplastic disorders are the most common diseases associated with this form and patients may lack urticaria pigmentosa-like skin lesions.Aggressive systemic mastocytosisIn aggressive systemic mastocytosis, there is an impairment or loss of organ function (usually liver, gut, bone or bone marrow) due to mast cell infiltrates. Examples of organ dysfunction include low numbers of white bloods cells, anemia, low platelets, liver dysfunction, malabsorption and pathologic bone fractures associated with large osteolytic bone lesions.Mast cell leukemiaMast cell leukemia is an aggressive hematological malignancy characterized by presence of circulating mast cells greater than 10%, or immature mast cells in bone marrow aspirates greater than 20%. This subtype is very rare; however, it is associated with the worst prognosis among all mastocytosis varieties.Mast cell sarcomaA mast cell sarcoma is a solid tumor composed of abnormal mast cells invading the tissue. This condition is very rare and often is not associated with additional skin involvement. More aggressive forms of mastocytosis, mast cell leukemias and mast cell sarcomas are very rarely encountered.
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Mastocytosis
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Symptoms of Mastocytosis
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The severity of the symptoms associated with mastocytosis may vary from mild to life-threatening. In general, symptoms occurring in mastocytosis are mainly due to the release of chemicals from the mast cells and thus produce symptoms associated with an allergic reaction, although a true allergic trigger may not be identified. Flushing and gastric acid hypersecretion due to mast cell-associated histamine release are common symptoms. Heartburn, stomach aches, abdominal discomfort, bloating and diarrhea may occur. The liver, spleen and lymph nodes may become enlarged in advanced disease varieties; therefore regular follow-up is necessary. Bones affected by mastocytosis may become softened (osteoporosis) and deteriorate, although some new bone growth may occur with thickening of the outer portions or spongy inner areas of the bones. In aggressive systemic mastocytosis, a decrease in blood cells (cytopenia), break-down of bones (osteolysis), swelling of the lymph nodes (lymphadenopathy), swelling of the liver (hepatomegaly), impaired liver function, ascites or portal hypertension and malabsorption, may also occur.Massive chemical release from the mast cells (degranulation) may lead to life-threatening episodes of anaphylaxis (anaphylactic shock). The most common triggers include, but are not limited to, insect stings, physical stress (heat, cold, mechanical irritation of the skin, exercise), emotional stress, alcohol, spicy foods and medications, including aspirin and non-steroidal anti-inflammatory drugs (NSAIDS), narcotics, muscle relaxants, radiocontrast material, among others. These are similar in nature to severe allergic reactions and may involve flushing, decreased blood pressure (hypotension), increased heart rate and loss of consciousness along with abdominal cramps. Recent studies have found that some patients with severe allergic reactions to bee stings, and some previously diagnosed with idiopathic anaphylaxis may have mastocytosis. Additional non-specific symptoms that can be seen with mastocytosis include pain, nausea, headache, memory and concentration difficulties, and/or malaise. Patients with an associated hematologic disorder may have symptoms of that disorder such as fatigue, left upper quadrant pain due to enlarged spleen, brusing/bleeding and weight loss.
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Symptoms of Mastocytosis. The severity of the symptoms associated with mastocytosis may vary from mild to life-threatening. In general, symptoms occurring in mastocytosis are mainly due to the release of chemicals from the mast cells and thus produce symptoms associated with an allergic reaction, although a true allergic trigger may not be identified. Flushing and gastric acid hypersecretion due to mast cell-associated histamine release are common symptoms. Heartburn, stomach aches, abdominal discomfort, bloating and diarrhea may occur. The liver, spleen and lymph nodes may become enlarged in advanced disease varieties; therefore regular follow-up is necessary. Bones affected by mastocytosis may become softened (osteoporosis) and deteriorate, although some new bone growth may occur with thickening of the outer portions or spongy inner areas of the bones. In aggressive systemic mastocytosis, a decrease in blood cells (cytopenia), break-down of bones (osteolysis), swelling of the lymph nodes (lymphadenopathy), swelling of the liver (hepatomegaly), impaired liver function, ascites or portal hypertension and malabsorption, may also occur.Massive chemical release from the mast cells (degranulation) may lead to life-threatening episodes of anaphylaxis (anaphylactic shock). The most common triggers include, but are not limited to, insect stings, physical stress (heat, cold, mechanical irritation of the skin, exercise), emotional stress, alcohol, spicy foods and medications, including aspirin and non-steroidal anti-inflammatory drugs (NSAIDS), narcotics, muscle relaxants, radiocontrast material, among others. These are similar in nature to severe allergic reactions and may involve flushing, decreased blood pressure (hypotension), increased heart rate and loss of consciousness along with abdominal cramps. Recent studies have found that some patients with severe allergic reactions to bee stings, and some previously diagnosed with idiopathic anaphylaxis may have mastocytosis. Additional non-specific symptoms that can be seen with mastocytosis include pain, nausea, headache, memory and concentration difficulties, and/or malaise. Patients with an associated hematologic disorder may have symptoms of that disorder such as fatigue, left upper quadrant pain due to enlarged spleen, brusing/bleeding and weight loss.
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Causes of Mastocytosis
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Genetic alterations (mutations) resulting in the over-activation of the receptor for mast cell growth factor (KIT) have been identified in the abnormal mast cells in almost all patients with adult-onset mastocytosis and in skin lesions of approximately 80% of affected children. The most common KIT mutation in mastocytosis is D816V and is believed to cause the abnormal proliferation and accumulation of mast cells in tissues. Over 90% of adults and 40% of children also express this mutation whereas another 40% of children have mutations involving other areas of the KIT gene. It is not yet clear if the type of KIT mutation in children has value in predicting disease severity. The mutations are present in the body cells (somatic) of affected individuals, but not in egg and sperm cells (germline) in the majority of patients and, therefore, are not passed on to the next generation.The release of mediators produced by mast cells, such as histamine, leukotriene C4, prostaglandin D2, chemokines, cytokines and heparin, among other cellular mediators, results in symptomatic episodes. Histamine is a natural chemical released during an allergic event that causes itching, wheezing, dilation of blood vessels and hypersecretion of stomach acid.
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Causes of Mastocytosis. Genetic alterations (mutations) resulting in the over-activation of the receptor for mast cell growth factor (KIT) have been identified in the abnormal mast cells in almost all patients with adult-onset mastocytosis and in skin lesions of approximately 80% of affected children. The most common KIT mutation in mastocytosis is D816V and is believed to cause the abnormal proliferation and accumulation of mast cells in tissues. Over 90% of adults and 40% of children also express this mutation whereas another 40% of children have mutations involving other areas of the KIT gene. It is not yet clear if the type of KIT mutation in children has value in predicting disease severity. The mutations are present in the body cells (somatic) of affected individuals, but not in egg and sperm cells (germline) in the majority of patients and, therefore, are not passed on to the next generation.The release of mediators produced by mast cells, such as histamine, leukotriene C4, prostaglandin D2, chemokines, cytokines and heparin, among other cellular mediators, results in symptomatic episodes. Histamine is a natural chemical released during an allergic event that causes itching, wheezing, dilation of blood vessels and hypersecretion of stomach acid.
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Affects of Mastocytosis
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Mastocytosis affects males and females in equal numbers. It can begin during childhood or adulthood. Childhood-onset disease most commonly presents within the first year of life.
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Affects of Mastocytosis. Mastocytosis affects males and females in equal numbers. It can begin during childhood or adulthood. Childhood-onset disease most commonly presents within the first year of life.
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Related disorders of Mastocytosis
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Symptoms of the following disorders can be similar to those of mastocytosis. Comparison may be useful for a differential diagnosis:Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is associated with an abnormal immune response to the natural bacteria in the gastrointestinal tract. Patients may experience weight loss, abdominal cramping and pain, nausea and vomiting, fatigue and irregular bowel movements. Diagnosis of IBD is often based on symptoms which can include increased heart rate (tachycardia), decreased red blood cell count (anemia) leading to fatigue, dehydration and fever. There are various tests and imaging studies that can be done to confirm a diagnosis and can include: complete blood count, serologic testing, stool studies, nutritional evaluation, colonoscopy, abdominal ultrasound and other gastrointestinal imaging studies.Irritable Bowel Syndrome
Irritable Bowel Syndrome (IBS) is a gastrointestinal disorder associated with abdominal discomfort, altered bowel patterns and, in some cases, inflammation of the gastrointestinal tract. Patients with IBS may experience heartburn, nausea and vomiting, presence of clear or white mucus, abdominal pain, as well as presence of constipation or diarrhea. Patients may also experience abdominal distention, which can be confirmed on an abdominal CT scan. Specific criteria on diagnosis IBS exists based on the frequency and duration of patient’s symptoms. Criteria for IBS diagnosis requires that patients have had recurrent abdominal pain or discomfort at least 1 day per week during the past three months associated with two or more of the following: related to defecation; associated with change in stool frequency; and/or associated with change in stool form or appearance. In order to establish a diagnosis of IBS, a physical exam and laboratory and radiographic studies may be performed to rule out any other causes.Malabsorption
Malabsorption is inclusive of any condition associated with abnormalities occurring during digestion and/or absorption of food nutrients. Patients may experience diarrhea and weight loss; however, more characteristic symptoms are often based on the specific cause. Various tests can be performed to identify the cause and can include blood tests, electrolytes and chemistry panel and serologic testing. However, no specific test exists for malabsorption. Treatment for malabsorption consists of correcting any nutritional deficiencies as well as treating the causative condition.Myeloproliferative Disease
Myeloproliferative diseases are a group of disorders associated with proliferation of one or more distinct cell lines. Patients can experience fatigue, weight loss, abdominal discomfort, easy bruising or bleeding, infections as well as other symptoms. A specific diagnosis can be based on laboratory studies (i.e. complete blood counts, leukocyte alkaline phosphatase score, polymerase chain reaction assay, serum uric acid level, red blood cell mass) and bone marrow biopsies, which would reflect a change in blood cell counts. Management of the myeloproliferative disease depends on the specific cause. Chronic eosinophilic leukemia is characterized by increased eosinophils carrying genetic alterations in blood and bone marrow and is often associated with increased mast cells.Urticaria
Urticaria is a condition of the skin associated with red, elevated patches of the skin that can be itchy and irritating to touch and more commonly referred to as hives. Urticaria is often an isolated event not associated with other systemic symptoms or findings. Often times urticaria is self-limiting and of short-duration. Skin lesions can last for 20 minutes up to three hours disappear and then reappear within a 24-48 hour period. New-onset urticaria is often associated with an identifiable cause such as direct contact and can be identified from the patient’s history. Urticaria may be confused with other dermatologic conditions. However, based on the characteristic appearance of urticaria (i.e. transient itchy red raised skin lesions) a diagnosis can be made. First step in treatment of urticaria often includes antihistamine agents.Endocrine disorders
Endocine tumors such as carcinoid, pheocromocytoma and medullary thyroid cancer can cause flushing. Postmenapausal flushing is usually brief in duration and is associated with sweating.Monoclonal mast cell activation syndrome
These patients have symptoms of mast cell activation including recurrent anaphylaxis but no evidence of cutaneous mastocytosis. Their bone marrow biopsy shows 1 or 2 minor criteria for systemic mastocytosis (such as D816V KIT mutation or CD25 expressing mast cells, but does not fulfill the complete World Health Organization (WHO) criteria (See diagnosis section below).Idiopathic mast cell activation syndrome and idiopathic anaphylaxis
Patients with this disorder have episodic symptoms of systemic mast cell activation or anaphylaxis associated with elevated mast cell mediators such as tryptase and urinary histamine or prostaglandin metabolites, respond favorably to treatment with mast cell mediator blocking drugs and have no diagnostic findings of cutaneous or systemic mastocytosis. Other disorders with similar symptoms such as allergic diseases should be ruled out before this diagnosis is considered.Hereditary alpha tryptasemia (H∝T)
H∝T is a germline genetic variant of uncertain significance observed in up to 7% of general population. Individuals with H∝T usually have baseline serum tryptase levels >8 ng/ml. It is transmitted in an autosomal dominant pattern. Most individuals with H∝T have no symptoms directly related to this trait. It is thought that presence of H∝T may make the symptoms of concurrent allergic disease make more severe (such as bee sting allergies or anaphylaxis).
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Related disorders of Mastocytosis. Symptoms of the following disorders can be similar to those of mastocytosis. Comparison may be useful for a differential diagnosis:Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is associated with an abnormal immune response to the natural bacteria in the gastrointestinal tract. Patients may experience weight loss, abdominal cramping and pain, nausea and vomiting, fatigue and irregular bowel movements. Diagnosis of IBD is often based on symptoms which can include increased heart rate (tachycardia), decreased red blood cell count (anemia) leading to fatigue, dehydration and fever. There are various tests and imaging studies that can be done to confirm a diagnosis and can include: complete blood count, serologic testing, stool studies, nutritional evaluation, colonoscopy, abdominal ultrasound and other gastrointestinal imaging studies.Irritable Bowel Syndrome
Irritable Bowel Syndrome (IBS) is a gastrointestinal disorder associated with abdominal discomfort, altered bowel patterns and, in some cases, inflammation of the gastrointestinal tract. Patients with IBS may experience heartburn, nausea and vomiting, presence of clear or white mucus, abdominal pain, as well as presence of constipation or diarrhea. Patients may also experience abdominal distention, which can be confirmed on an abdominal CT scan. Specific criteria on diagnosis IBS exists based on the frequency and duration of patient’s symptoms. Criteria for IBS diagnosis requires that patients have had recurrent abdominal pain or discomfort at least 1 day per week during the past three months associated with two or more of the following: related to defecation; associated with change in stool frequency; and/or associated with change in stool form or appearance. In order to establish a diagnosis of IBS, a physical exam and laboratory and radiographic studies may be performed to rule out any other causes.Malabsorption
Malabsorption is inclusive of any condition associated with abnormalities occurring during digestion and/or absorption of food nutrients. Patients may experience diarrhea and weight loss; however, more characteristic symptoms are often based on the specific cause. Various tests can be performed to identify the cause and can include blood tests, electrolytes and chemistry panel and serologic testing. However, no specific test exists for malabsorption. Treatment for malabsorption consists of correcting any nutritional deficiencies as well as treating the causative condition.Myeloproliferative Disease
Myeloproliferative diseases are a group of disorders associated with proliferation of one or more distinct cell lines. Patients can experience fatigue, weight loss, abdominal discomfort, easy bruising or bleeding, infections as well as other symptoms. A specific diagnosis can be based on laboratory studies (i.e. complete blood counts, leukocyte alkaline phosphatase score, polymerase chain reaction assay, serum uric acid level, red blood cell mass) and bone marrow biopsies, which would reflect a change in blood cell counts. Management of the myeloproliferative disease depends on the specific cause. Chronic eosinophilic leukemia is characterized by increased eosinophils carrying genetic alterations in blood and bone marrow and is often associated with increased mast cells.Urticaria
Urticaria is a condition of the skin associated with red, elevated patches of the skin that can be itchy and irritating to touch and more commonly referred to as hives. Urticaria is often an isolated event not associated with other systemic symptoms or findings. Often times urticaria is self-limiting and of short-duration. Skin lesions can last for 20 minutes up to three hours disappear and then reappear within a 24-48 hour period. New-onset urticaria is often associated with an identifiable cause such as direct contact and can be identified from the patient’s history. Urticaria may be confused with other dermatologic conditions. However, based on the characteristic appearance of urticaria (i.e. transient itchy red raised skin lesions) a diagnosis can be made. First step in treatment of urticaria often includes antihistamine agents.Endocrine disorders
Endocine tumors such as carcinoid, pheocromocytoma and medullary thyroid cancer can cause flushing. Postmenapausal flushing is usually brief in duration and is associated with sweating.Monoclonal mast cell activation syndrome
These patients have symptoms of mast cell activation including recurrent anaphylaxis but no evidence of cutaneous mastocytosis. Their bone marrow biopsy shows 1 or 2 minor criteria for systemic mastocytosis (such as D816V KIT mutation or CD25 expressing mast cells, but does not fulfill the complete World Health Organization (WHO) criteria (See diagnosis section below).Idiopathic mast cell activation syndrome and idiopathic anaphylaxis
Patients with this disorder have episodic symptoms of systemic mast cell activation or anaphylaxis associated with elevated mast cell mediators such as tryptase and urinary histamine or prostaglandin metabolites, respond favorably to treatment with mast cell mediator blocking drugs and have no diagnostic findings of cutaneous or systemic mastocytosis. Other disorders with similar symptoms such as allergic diseases should be ruled out before this diagnosis is considered.Hereditary alpha tryptasemia (H∝T)
H∝T is a germline genetic variant of uncertain significance observed in up to 7% of general population. Individuals with H∝T usually have baseline serum tryptase levels >8 ng/ml. It is transmitted in an autosomal dominant pattern. Most individuals with H∝T have no symptoms directly related to this trait. It is thought that presence of H∝T may make the symptoms of concurrent allergic disease make more severe (such as bee sting allergies or anaphylaxis).
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Diagnosis of Mastocytosis
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Other disorders associated with mast cell activation cannot be clinically distinguished from mastocytosis and diagnostic testing for mastocytosis should be performed. In cutaneous mastocytosis, a diagnosis can be made based on the appearance of the skin and can be confirmed by a skin biopsy revealing high numbers of mast cells. Diagnosis of systemic mastocytosis should be established by a bone marrow biopsy, which would reveal an abnormally high number of mast cells with abnormal appearance.Tryptase is a protease associated with mast cells. Measurable serum tryptase is made up of alpha and beta tryptases and the median serum tryptase level is approximately 5 ng/ml. Alpha tryptase is a protryptase that is secreted constitutively by mast cells and its serum levels correlate with mast cell numbers and is often found elevated in systemic mastocytosis. A baseline serum tryptase level of greater than 20 ng/ml is a minor diagnostic criterion for systemic mastocytosis. Beta tryptase is stored in mast cell granules and is detectable in circulation after anaphylaxis usually returns to baseline after 4 hours.The World Health Organization (WHO) has established criteria for diagnosing systemic mastocytosis which has been summarized by The Mast Cell Disease Society here:
http://tmsforacure.org/patients/mastocytosis_explained_2.php
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Diagnosis of Mastocytosis. Other disorders associated with mast cell activation cannot be clinically distinguished from mastocytosis and diagnostic testing for mastocytosis should be performed. In cutaneous mastocytosis, a diagnosis can be made based on the appearance of the skin and can be confirmed by a skin biopsy revealing high numbers of mast cells. Diagnosis of systemic mastocytosis should be established by a bone marrow biopsy, which would reveal an abnormally high number of mast cells with abnormal appearance.Tryptase is a protease associated with mast cells. Measurable serum tryptase is made up of alpha and beta tryptases and the median serum tryptase level is approximately 5 ng/ml. Alpha tryptase is a protryptase that is secreted constitutively by mast cells and its serum levels correlate with mast cell numbers and is often found elevated in systemic mastocytosis. A baseline serum tryptase level of greater than 20 ng/ml is a minor diagnostic criterion for systemic mastocytosis. Beta tryptase is stored in mast cell granules and is detectable in circulation after anaphylaxis usually returns to baseline after 4 hours.The World Health Organization (WHO) has established criteria for diagnosing systemic mastocytosis which has been summarized by The Mast Cell Disease Society here:
http://tmsforacure.org/patients/mastocytosis_explained_2.php
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Therapies of Mastocytosis
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TreatmentCurrently, there is no curative treatment for mastocytosis. Treatment of mastocytosis is primarily directed at controlling the symptoms caused by the release of mast cell mediators. H1 and H2 antihistamines are therefore cornerstones of the treatment to relieve symptoms. Cromolyn sodium can be especially effective for the treatment of some gastrointestinal symptoms. Mast-cell stabilizers such as ketotifen can be used to treat some mast cell activation symptoms. Leukotriene antagonists can also be used to improve symptoms in patients. Proton-pump inhibitors can be used to treat the increased acid production in the stomach. Bisphosphonates can be used if osteoporosis or significant osteopenia is present. PUVA (psoralen plus ultraviolet A radiation) treatment may cause temporary attenuation of the urticaria pigmentosa lesions. Glucocorticoids may be necessary in patients unresponsive to other therapy or with more advanced disease.Self-injectable epinephrine should be prescribed to all patients with systemic mastocytosis and can be administered in cases of severe anaphylactic episodes and all patients are advised to carry epinephrine self-injectors. Xolair (omalizumab), an IgE antibody, currently indicated for allergic asthma, chronic spontaneous urticaria and nasal polyposis, has been shown to be effective in preventing anaphylactic mast cell activation episodes in case reports.Associated hematologic disorders should be treated by a blood specialist (hematologist). In patients with advanced systemic mastocytosis, therapies to reduce mast cell numbers are considered. These include tyrosine kinase inhibitors (TKIs), cladribine and interferon alpha. Safety and tolerability of TKIs have made them the first line of therapy in most patients with advanced disease. TKIs include midostaurin, imatinib and some investigational drugs. Stem cell transplantation can be considered in selected patients with SM-AHNMD, ASM and MCL.In 2006, the U.S. Food and Drug Administration (FDA) granted expanded approval to treat aggressive systemic mastocytosis (SM) not associated with the genetic mutation D816V c-KIT or with an unknown mutation status with the cancer drug Gleevec (imatinib mesylate). Response to imatinib is rare in mastocytosis as most cases are associated with D816V KIT mutation.In 2017, the FDA approved Rydapt (midostaurin) for the treatment of adults with aggressive SM, SM with associated hematological neoplasm or mast cell leukemia. Most recently, in 2021, the FDA approved Ayvakit (avapritinib) for the treatment of adults with aggressive SM, SM with associated hematological neoplasm or mast cell leukemia.
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Therapies of Mastocytosis. TreatmentCurrently, there is no curative treatment for mastocytosis. Treatment of mastocytosis is primarily directed at controlling the symptoms caused by the release of mast cell mediators. H1 and H2 antihistamines are therefore cornerstones of the treatment to relieve symptoms. Cromolyn sodium can be especially effective for the treatment of some gastrointestinal symptoms. Mast-cell stabilizers such as ketotifen can be used to treat some mast cell activation symptoms. Leukotriene antagonists can also be used to improve symptoms in patients. Proton-pump inhibitors can be used to treat the increased acid production in the stomach. Bisphosphonates can be used if osteoporosis or significant osteopenia is present. PUVA (psoralen plus ultraviolet A radiation) treatment may cause temporary attenuation of the urticaria pigmentosa lesions. Glucocorticoids may be necessary in patients unresponsive to other therapy or with more advanced disease.Self-injectable epinephrine should be prescribed to all patients with systemic mastocytosis and can be administered in cases of severe anaphylactic episodes and all patients are advised to carry epinephrine self-injectors. Xolair (omalizumab), an IgE antibody, currently indicated for allergic asthma, chronic spontaneous urticaria and nasal polyposis, has been shown to be effective in preventing anaphylactic mast cell activation episodes in case reports.Associated hematologic disorders should be treated by a blood specialist (hematologist). In patients with advanced systemic mastocytosis, therapies to reduce mast cell numbers are considered. These include tyrosine kinase inhibitors (TKIs), cladribine and interferon alpha. Safety and tolerability of TKIs have made them the first line of therapy in most patients with advanced disease. TKIs include midostaurin, imatinib and some investigational drugs. Stem cell transplantation can be considered in selected patients with SM-AHNMD, ASM and MCL.In 2006, the U.S. Food and Drug Administration (FDA) granted expanded approval to treat aggressive systemic mastocytosis (SM) not associated with the genetic mutation D816V c-KIT or with an unknown mutation status with the cancer drug Gleevec (imatinib mesylate). Response to imatinib is rare in mastocytosis as most cases are associated with D816V KIT mutation.In 2017, the FDA approved Rydapt (midostaurin) for the treatment of adults with aggressive SM, SM with associated hematological neoplasm or mast cell leukemia. Most recently, in 2021, the FDA approved Ayvakit (avapritinib) for the treatment of adults with aggressive SM, SM with associated hematological neoplasm or mast cell leukemia.
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Overview of Maternally Inherited Leigh Syndrome and NARP Syndrome
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SummaryMaternally inherited Leigh syndrome (MILS) and neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome are rare genetic multisystem disorders that are part of a spectrum or continuum of disease caused by abnormalities affecting mitochondrial energy production. NARP is characterized by nerve disease affecting the nerves outside of the central nervous system (peripheral neuropathy), an impaired ability to coordinate voluntary movements (ataxia), an eye condition known as retinitis pigmentosa (RP), and a variety of additional abnormalities. MILS is generally a more severe mitochondrial disorder that often becomes apparent during infancy or childhood and is characterized by brain disease (encephalopathy), elevated levels of lactic acid in the body (lactic acidosis), seizures, heart disease (cardiomyopathy), breathing (respiratory) abnormalities, and developmental delays. The specific symptoms and severity of these disorders in each individual can vary greatly from one person to another and even among members of the same family.MILS and NARP syndrome are maternally inherited mitochondrial disorders. They are caused by specific mutations affecting the mitochondrial gene known as the ATPase 6 gene. When individuals have more than 90 percent of mutated mitochondrial DNA (mtDNA) in their cells, they are classified as having MILS and not NARP syndrome. Most individuals with NARP syndrome have 70-80 percent of mutated mtDNA. In some families, one individual may have NARP syndrome while another individual is diagnosed with MILS. (For more information on mtDNA see the Causes section below.)IntroductionMitochondrial disorders are characterized by mutations affecting the parts of the cell that release energy (mitochondria). Mitochondrial diseases often hamper the ability of affected cells to break down food and oxygen and produce energy. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body. NARP syndrome was first identified in the medical literature in 1990. Leigh syndrome was first reported in the medical literature in 1951.The term “Leigh Syndrome” represents a clinical constellation of symptoms and characteristic MRI pattern and can occur due to many metabolic and genetic causes of which mitochondrial disorders are the most common. MILS is one of many causes of Leigh syndrome.
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Overview of Maternally Inherited Leigh Syndrome and NARP Syndrome. SummaryMaternally inherited Leigh syndrome (MILS) and neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome are rare genetic multisystem disorders that are part of a spectrum or continuum of disease caused by abnormalities affecting mitochondrial energy production. NARP is characterized by nerve disease affecting the nerves outside of the central nervous system (peripheral neuropathy), an impaired ability to coordinate voluntary movements (ataxia), an eye condition known as retinitis pigmentosa (RP), and a variety of additional abnormalities. MILS is generally a more severe mitochondrial disorder that often becomes apparent during infancy or childhood and is characterized by brain disease (encephalopathy), elevated levels of lactic acid in the body (lactic acidosis), seizures, heart disease (cardiomyopathy), breathing (respiratory) abnormalities, and developmental delays. The specific symptoms and severity of these disorders in each individual can vary greatly from one person to another and even among members of the same family.MILS and NARP syndrome are maternally inherited mitochondrial disorders. They are caused by specific mutations affecting the mitochondrial gene known as the ATPase 6 gene. When individuals have more than 90 percent of mutated mitochondrial DNA (mtDNA) in their cells, they are classified as having MILS and not NARP syndrome. Most individuals with NARP syndrome have 70-80 percent of mutated mtDNA. In some families, one individual may have NARP syndrome while another individual is diagnosed with MILS. (For more information on mtDNA see the Causes section below.)IntroductionMitochondrial disorders are characterized by mutations affecting the parts of the cell that release energy (mitochondria). Mitochondrial diseases often hamper the ability of affected cells to break down food and oxygen and produce energy. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body. NARP syndrome was first identified in the medical literature in 1990. Leigh syndrome was first reported in the medical literature in 1951.The term “Leigh Syndrome” represents a clinical constellation of symptoms and characteristic MRI pattern and can occur due to many metabolic and genetic causes of which mitochondrial disorders are the most common. MILS is one of many causes of Leigh syndrome.
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Symptoms of Maternally Inherited Leigh Syndrome and NARP Syndrome
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The symptoms of this spectrum of disease can vary dramatically from one person to another. Some individuals may have no apparent symptoms (asymptomatic) or only mild symptoms; other individuals may have severe, life-threatening complications, even during infancy in some cases of MILS. The severity of symptoms often correlates to the amount of mutated mtDNA in cells. Generally, the more mutated mtDNA, the worse the symptoms.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individual and/or their families should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.NEUROPATHY, ATAXIA & RETINITIS PIGMENTOSA (NARP) SYNDROMEIndividuals with NARP syndrome will display some combination of the following symptoms. The onset of symptoms is often during early childhood. Individuals with NARP syndrome may remain stable for years. However, they often experience episodes of deterioration usually associated with a viral illness.Common symptoms associated with NARP syndrome include an impaired ability to coordinate voluntary movements (ataxia), migraines, seizures, learning disabilities, and delays in attaining development milestones such as sitting up, crawling, or walking (developmental delays).
Individuals with NARP syndrome also have disease affecting the nerves that results in loss of sensation (sensory neuropathy). Affected individuals may develop muscle weakness affecting the arms and legs, especially affecting the muscles of the upper arms and upper legs (proximal muscle weakness).Affected individuals also have eye (ocular) symptoms. The first ocular symptom is usually salt-and-pepper retinopathy, a condition where colored spots form on the membrane lining the eyes (retina) giving it a “salt and pepper” appearance. Affected individuals eventually develop retinitis pigmentosa (RP). RP is a general term for a group of vision disorders that cause progressive degeneration of the retina resulting in visual impairment. RP usually begins with difficulty seeing at night, eventually leading to night blindness. Additional ocular symptoms include rapid, involuntary eye movements (nystagmus) and sluggish pupils.Additional symptoms have been reported in individuals with NARP syndrome including hearing loss, progressive paralysis of certain eye muscles (progressive external ophthalmoplegia), cardiac conduction defects such as heart block, and a mild anxiety disorder. Affected individuals may eventually develop dementia. Short stature has also been reported.The abnormal accumulation of lactic acid in the blood (lactic acidosis), which is a common finding in mitochondrial disorders, rarely occurs in NARP syndrome.MATERNALLY INHERITED LEIGH SYNDROME (MILS)MILS is often apparent during the first three months to one year of life. However, onset can occur at any time from birth through adulthood. Later onset is often associated with a slower progression of symptoms. Many cases of MILS first become apparent following a viral infection.
The specific symptoms and severity of MILS can vary greatly from individual to the next. Generally, Leigh syndrome, which is also known as infantile necrotizing encephalopathy, is a progressive neurodegenerative disorder. If the onset is during infancy, the initial signs may be poor sucking ability and loss of head control. Additional early symptoms can include a profound loss of appetite, recurrent vomiting, irritability, continuous crying and possible seizure activity. Delays in reaching developmental milestones may also occur.Affected individuals may experience decompensation, which is the inability of an organ system to compensate for illness or deficiency. In MILS, decompensation occurs during an illness and is typically associated with the progressive loss of abilities requiring the coordination of mental and muscular activity (psychomotor regression).When the onset of the disorder is later during childhood, ataxia or difficulty articulating words (dysarthria) may be the initial signs. Ataxia can cause affected children to appear clumsy or unsteady. As mentioned above, affected children may also lose previously acquired intellectual skills and intellectual disability can occur. Progressive neurological deterioration associated with MILS may be characterized by additional symptoms including generalized muscle weakness, lack of muscle tone (hypotonia), tremors, movement disorders such as chorea (rapid, involuntary, jerky movements), seizures, infantile spasms, and spasticity, a condition characterized by involuntary muscle spasms that result in slow, stiff movements of the legs. Dystonia may also occur. Dystonia is a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions.Individuals with MILS may develop a variety of respiratory abnormalities including the temporary cessation of spontaneous breathing (apnea), difficulty breathing (dyspnea), abnormally rapid breathing (hyperventilation), and/or abnormal breathing patterns. Some infants may also experience difficulty swallowing (dysphagia). Visual problems may include abnormally rapid eye movements (nystagmus), sluggish pupils, crossed eyes (strabismus), paralysis of certain eye muscles (ophthalmoplegia), deterioration of the nerves of the eyes (optic atrophy), and/or visual impairment leading to blindness.MILS may also affect the heart. Some children with this disorder may have abnormal enlargement of the heart (hypertrophic cardiomyopathy) and overgrowth of the fibrous membrane that divides the various chambers of the heart (asymmetric septal hypertrophy). Disease affecting the nerves outside of the central nervous system (peripheral neuropathy) may eventually occur, causing progressive weakness of the arms and legs.
Episodes of lactic acidosis may occur and are characterized by abnormally high levels of lactic acid in the blood, brain and other tissues of the body.In some cases, life-threatening complications, often secondary to heart or breathing abnormalities, can develop. In some cases of MILS, such complications can develop by three years of age.
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Symptoms of Maternally Inherited Leigh Syndrome and NARP Syndrome. The symptoms of this spectrum of disease can vary dramatically from one person to another. Some individuals may have no apparent symptoms (asymptomatic) or only mild symptoms; other individuals may have severe, life-threatening complications, even during infancy in some cases of MILS. The severity of symptoms often correlates to the amount of mutated mtDNA in cells. Generally, the more mutated mtDNA, the worse the symptoms.It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individual and/or their families should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.NEUROPATHY, ATAXIA & RETINITIS PIGMENTOSA (NARP) SYNDROMEIndividuals with NARP syndrome will display some combination of the following symptoms. The onset of symptoms is often during early childhood. Individuals with NARP syndrome may remain stable for years. However, they often experience episodes of deterioration usually associated with a viral illness.Common symptoms associated with NARP syndrome include an impaired ability to coordinate voluntary movements (ataxia), migraines, seizures, learning disabilities, and delays in attaining development milestones such as sitting up, crawling, or walking (developmental delays).
Individuals with NARP syndrome also have disease affecting the nerves that results in loss of sensation (sensory neuropathy). Affected individuals may develop muscle weakness affecting the arms and legs, especially affecting the muscles of the upper arms and upper legs (proximal muscle weakness).Affected individuals also have eye (ocular) symptoms. The first ocular symptom is usually salt-and-pepper retinopathy, a condition where colored spots form on the membrane lining the eyes (retina) giving it a “salt and pepper” appearance. Affected individuals eventually develop retinitis pigmentosa (RP). RP is a general term for a group of vision disorders that cause progressive degeneration of the retina resulting in visual impairment. RP usually begins with difficulty seeing at night, eventually leading to night blindness. Additional ocular symptoms include rapid, involuntary eye movements (nystagmus) and sluggish pupils.Additional symptoms have been reported in individuals with NARP syndrome including hearing loss, progressive paralysis of certain eye muscles (progressive external ophthalmoplegia), cardiac conduction defects such as heart block, and a mild anxiety disorder. Affected individuals may eventually develop dementia. Short stature has also been reported.The abnormal accumulation of lactic acid in the blood (lactic acidosis), which is a common finding in mitochondrial disorders, rarely occurs in NARP syndrome.MATERNALLY INHERITED LEIGH SYNDROME (MILS)MILS is often apparent during the first three months to one year of life. However, onset can occur at any time from birth through adulthood. Later onset is often associated with a slower progression of symptoms. Many cases of MILS first become apparent following a viral infection.
The specific symptoms and severity of MILS can vary greatly from individual to the next. Generally, Leigh syndrome, which is also known as infantile necrotizing encephalopathy, is a progressive neurodegenerative disorder. If the onset is during infancy, the initial signs may be poor sucking ability and loss of head control. Additional early symptoms can include a profound loss of appetite, recurrent vomiting, irritability, continuous crying and possible seizure activity. Delays in reaching developmental milestones may also occur.Affected individuals may experience decompensation, which is the inability of an organ system to compensate for illness or deficiency. In MILS, decompensation occurs during an illness and is typically associated with the progressive loss of abilities requiring the coordination of mental and muscular activity (psychomotor regression).When the onset of the disorder is later during childhood, ataxia or difficulty articulating words (dysarthria) may be the initial signs. Ataxia can cause affected children to appear clumsy or unsteady. As mentioned above, affected children may also lose previously acquired intellectual skills and intellectual disability can occur. Progressive neurological deterioration associated with MILS may be characterized by additional symptoms including generalized muscle weakness, lack of muscle tone (hypotonia), tremors, movement disorders such as chorea (rapid, involuntary, jerky movements), seizures, infantile spasms, and spasticity, a condition characterized by involuntary muscle spasms that result in slow, stiff movements of the legs. Dystonia may also occur. Dystonia is a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions.Individuals with MILS may develop a variety of respiratory abnormalities including the temporary cessation of spontaneous breathing (apnea), difficulty breathing (dyspnea), abnormally rapid breathing (hyperventilation), and/or abnormal breathing patterns. Some infants may also experience difficulty swallowing (dysphagia). Visual problems may include abnormally rapid eye movements (nystagmus), sluggish pupils, crossed eyes (strabismus), paralysis of certain eye muscles (ophthalmoplegia), deterioration of the nerves of the eyes (optic atrophy), and/or visual impairment leading to blindness.MILS may also affect the heart. Some children with this disorder may have abnormal enlargement of the heart (hypertrophic cardiomyopathy) and overgrowth of the fibrous membrane that divides the various chambers of the heart (asymmetric septal hypertrophy). Disease affecting the nerves outside of the central nervous system (peripheral neuropathy) may eventually occur, causing progressive weakness of the arms and legs.
Episodes of lactic acidosis may occur and are characterized by abnormally high levels of lactic acid in the blood, brain and other tissues of the body.In some cases, life-threatening complications, often secondary to heart or breathing abnormalities, can develop. In some cases of MILS, such complications can develop by three years of age.
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Causes of Maternally Inherited Leigh Syndrome and NARP Syndrome
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MILS and NARP syndrome are associated with changes (mutations) in the genetic material found in the DNA of mitochondria (mtDNA). Mitochondria, which are found by the hundreds in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production. As opposed to the genetic instructions of cellular chromosomes (autosomal DNA), which are found within the nucleus of each cell, mitochondrial genetic instructions are found outside of the nucleus of the cell. The mutation associated with NARP syndrome affects the mitochondrial gene known as the ATPase 6 gene. Several mitochondrial genes including the ATPase 6 gene can cause MILS. Leigh syndrome is one of the most common pediatric presentations of mitochondrial disease and can also occur due to other changes (mutations) in the mitochondrial or nuclear DNA – changes that do not lead to NARP.Genetic information is contained in two types of DNA: nuclear DNA (nDNA) is contained in the nucleus of a cell and is inherited from both biological parents. Mitochondrial DNA (mtDNA) is contained in the mitochondria of cells and is inherited exclusively from a child’s mother. Genetic diseases due to nDNA mutations (change in genetic material), are determined by two genes, one received from the father and one from the mother. mtDNA that is found in sperm cells typically break off during fertilization. As a result, all human mtDNA comes from the mother. An affected mother will pass the mutation(s) on to all her children, but only her daughters will pass the mutation(s) on to their children.The genetic mutations that are present in the mtDNA may outnumber the normal copies of the genes. Generally, symptoms may not occur until mutations are present in a significant percentage of the mitochondria. The uneven distribution of normal and mutated mtDNA in different tissues can affect different organ systems in members of the same family. Thus, affected family members may exhibit a variety of different symptoms and varying degrees of severity. When individuals have more than 90 percent of mutated mitochondrial DNA (mtDNA) in their cells, they are classified as having MILS and not NARP syndrome. Most individuals with NARP syndrome have 70-80 percent of mutated mtDNA.As stated above, the percentage of mutated mtDNA generally corresponds to the overall severity of these disorders. However, affected individuals have been reported who have a high percentage of mutated mtDNA (<90%), but only develop mild symptoms. This suggests that other factors may play a role in the overall severity of MILS and NARP syndrome.
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Causes of Maternally Inherited Leigh Syndrome and NARP Syndrome. MILS and NARP syndrome are associated with changes (mutations) in the genetic material found in the DNA of mitochondria (mtDNA). Mitochondria, which are found by the hundreds in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production. As opposed to the genetic instructions of cellular chromosomes (autosomal DNA), which are found within the nucleus of each cell, mitochondrial genetic instructions are found outside of the nucleus of the cell. The mutation associated with NARP syndrome affects the mitochondrial gene known as the ATPase 6 gene. Several mitochondrial genes including the ATPase 6 gene can cause MILS. Leigh syndrome is one of the most common pediatric presentations of mitochondrial disease and can also occur due to other changes (mutations) in the mitochondrial or nuclear DNA – changes that do not lead to NARP.Genetic information is contained in two types of DNA: nuclear DNA (nDNA) is contained in the nucleus of a cell and is inherited from both biological parents. Mitochondrial DNA (mtDNA) is contained in the mitochondria of cells and is inherited exclusively from a child’s mother. Genetic diseases due to nDNA mutations (change in genetic material), are determined by two genes, one received from the father and one from the mother. mtDNA that is found in sperm cells typically break off during fertilization. As a result, all human mtDNA comes from the mother. An affected mother will pass the mutation(s) on to all her children, but only her daughters will pass the mutation(s) on to their children.The genetic mutations that are present in the mtDNA may outnumber the normal copies of the genes. Generally, symptoms may not occur until mutations are present in a significant percentage of the mitochondria. The uneven distribution of normal and mutated mtDNA in different tissues can affect different organ systems in members of the same family. Thus, affected family members may exhibit a variety of different symptoms and varying degrees of severity. When individuals have more than 90 percent of mutated mitochondrial DNA (mtDNA) in their cells, they are classified as having MILS and not NARP syndrome. Most individuals with NARP syndrome have 70-80 percent of mutated mtDNA.As stated above, the percentage of mutated mtDNA generally corresponds to the overall severity of these disorders. However, affected individuals have been reported who have a high percentage of mutated mtDNA (<90%), but only develop mild symptoms. This suggests that other factors may play a role in the overall severity of MILS and NARP syndrome.
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Affects of Maternally Inherited Leigh Syndrome and NARP Syndrome
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NARP syndrome and MILS affects males and females in equal numbers. Symptoms often become apparent in young adults. The exact incidence of NARP syndrome, MILS, and mitochondrial disorders in the general population is unknown. NARP syndrome is estimated to occur in 1 in 12,000 births. Leigh disease, in general, is estimated to affect 1 in 36,000-40,000 live births. Some researchers estimate that as many as 30% of Leigh disease patients are MILS.Mitochondrial disorders are estimated to occur in 1 in 4,000 births in the United States. Because these disorders often go unrecognized they are believed to be under-diagnosed, making it difficult to determine their true frequency in the general population.
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Affects of Maternally Inherited Leigh Syndrome and NARP Syndrome. NARP syndrome and MILS affects males and females in equal numbers. Symptoms often become apparent in young adults. The exact incidence of NARP syndrome, MILS, and mitochondrial disorders in the general population is unknown. NARP syndrome is estimated to occur in 1 in 12,000 births. Leigh disease, in general, is estimated to affect 1 in 36,000-40,000 live births. Some researchers estimate that as many as 30% of Leigh disease patients are MILS.Mitochondrial disorders are estimated to occur in 1 in 4,000 births in the United States. Because these disorders often go unrecognized they are believed to be under-diagnosed, making it difficult to determine their true frequency in the general population.
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Related disorders of Maternally Inherited Leigh Syndrome and NARP Syndrome
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Symptoms of the following disorders can be similar to those of MILS and NARP syndrome. Comparisons may be useful for a differential diagnosis.Leigh’s syndrome is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh’s syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh’s syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. Several different genetically determined enzyme defects can cause the syndrome, initially described over 60 years ago. Most individuals with Leigh’s syndrome have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most cases, Leigh’s syndrome is inherited as an autosomal recessive trait. However, X-linked recessive and mitochondrial inheritance are additional modes of transmission. Maternally inherited Leigh’s syndrome, as described above, is part of a disease spectrum with NARP syndrome. (For more information on this disorder, choose “Leigh’s syndrome” as your search term in the Rare Disease Database.)There are many different disorders that can resemble either MILS or NARP syndromes. These disorders include the various forms of ataxia, retinitis pigmentosa, Charcot-Marie-Tooth disease, pyruvate dehydrogenase deficiency, biotinidase deficiency, and several other neurodegenerative disorders. (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 Maternally Inherited Leigh Syndrome and NARP Syndrome. Symptoms of the following disorders can be similar to those of MILS and NARP syndrome. Comparisons may be useful for a differential diagnosis.Leigh’s syndrome is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh’s syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh’s syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. Several different genetically determined enzyme defects can cause the syndrome, initially described over 60 years ago. Most individuals with Leigh’s syndrome have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most cases, Leigh’s syndrome is inherited as an autosomal recessive trait. However, X-linked recessive and mitochondrial inheritance are additional modes of transmission. Maternally inherited Leigh’s syndrome, as described above, is part of a disease spectrum with NARP syndrome. (For more information on this disorder, choose “Leigh’s syndrome” as your search term in the Rare Disease Database.)There are many different disorders that can resemble either MILS or NARP syndromes. These disorders include the various forms of ataxia, retinitis pigmentosa, Charcot-Marie-Tooth disease, pyruvate dehydrogenase deficiency, biotinidase deficiency, and several other neurodegenerative disorders. (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 Maternally Inherited Leigh Syndrome and NARP Syndrome
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The diagnosis of a mitochondrial disorder such as MILS or NARP syndrome is difficult. However, physicians, especially those experienced with these types of disorders, can make a diagnosis based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.A diagnosis of some cases of MILS or NARP syndrome can be confirmed through molecular genetic testing. Molecular genetic testing can detect mutations in specific genes known to cause MILS and NARP syndrome, and is available on a clinical basis. The mtDNA mutations associated with these disorders can be detected in white blood cells (leukocytes), but other tissue samples may also be necessary such as skin, skeletal muscle, hair follicles or urinary sediment.Clinical Testing and WorkupA wide variety of tests may be necessary to rule out other conditions and to help obtain a diagnosis of a mitochondrial disorder. Such tests include metabolic screening tests including a complete blood count, urine analysis and cerebrospinal fluid (CSF) analysis. These tests measure for certain substances including lactate and pyruvate levels in the blood or CSF, creatinine kinase, ammonia, plasma amino acids, plasma carnitine, urinary organic acids, and plasma acetyl-carnitine profile.Imaging techniques including computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may reveal abnormal areas in certain parts of the brain. For example, in NARP syndrome, degeneration (atrophy) of the cerebellum and cerebrum may be noted on MRI. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.An electrocardiogram may be used to diagnose heart rhythm abnormalities and an echocardiogram may be used to diagnosis cardiomyopathy.
Surgical removal and microscopic study (biopsy) of certain tissue such as muscle or skin tissue may also be performed, although such test results are usually unremarkable. Additional biochemical and genetic studies can be performed in muscle as well. Due to advances in genetic testing, muscle biopsies are not needed as frequently in the evaluation of mitochondrial disorders. A test that assesses the health of muscles and the nerves that control muscles (electromyography) may be recommended. During this exam, a 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 the nerves and can determine whether muscle weakness is caused by the muscles themselves or nerves that control the muscles. A nerve conduction study, in which motor and sensory nerves are electrically stimulated to assess a nerve’s ability and speed in conducting nerve impulses, may also be performed. Electromyography and nerve conduction studies can demonstrate peripheral neuropathy.Individuals diagnosed with or suspected of having MILS or NARP syndrome should undergo a complete ophthalmological exam.
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Diagnosis of Maternally Inherited Leigh Syndrome and NARP Syndrome. The diagnosis of a mitochondrial disorder such as MILS or NARP syndrome is difficult. However, physicians, especially those experienced with these types of disorders, can make a diagnosis based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.A diagnosis of some cases of MILS or NARP syndrome can be confirmed through molecular genetic testing. Molecular genetic testing can detect mutations in specific genes known to cause MILS and NARP syndrome, and is available on a clinical basis. The mtDNA mutations associated with these disorders can be detected in white blood cells (leukocytes), but other tissue samples may also be necessary such as skin, skeletal muscle, hair follicles or urinary sediment.Clinical Testing and WorkupA wide variety of tests may be necessary to rule out other conditions and to help obtain a diagnosis of a mitochondrial disorder. Such tests include metabolic screening tests including a complete blood count, urine analysis and cerebrospinal fluid (CSF) analysis. These tests measure for certain substances including lactate and pyruvate levels in the blood or CSF, creatinine kinase, ammonia, plasma amino acids, plasma carnitine, urinary organic acids, and plasma acetyl-carnitine profile.Imaging techniques including computerized tomography (CT) scanning and magnetic resonance imaging (MRI) may reveal abnormal areas in certain parts of the brain. For example, in NARP syndrome, degeneration (atrophy) of the cerebellum and cerebrum may be noted on MRI. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.An electrocardiogram may be used to diagnose heart rhythm abnormalities and an echocardiogram may be used to diagnosis cardiomyopathy.
Surgical removal and microscopic study (biopsy) of certain tissue such as muscle or skin tissue may also be performed, although such test results are usually unremarkable. Additional biochemical and genetic studies can be performed in muscle as well. Due to advances in genetic testing, muscle biopsies are not needed as frequently in the evaluation of mitochondrial disorders. A test that assesses the health of muscles and the nerves that control muscles (electromyography) may be recommended. During this exam, a 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 the nerves and can determine whether muscle weakness is caused by the muscles themselves or nerves that control the muscles. A nerve conduction study, in which motor and sensory nerves are electrically stimulated to assess a nerve’s ability and speed in conducting nerve impulses, may also be performed. Electromyography and nerve conduction studies can demonstrate peripheral neuropathy.Individuals diagnosed with or suspected of having MILS or NARP syndrome should undergo a complete ophthalmological exam.
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Therapies of Maternally Inherited Leigh Syndrome and NARP Syndrome
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TreatmentThere are no proven therapies for MILS or NARP syndrome. Treatment recommendations are based primarily upon open label studies, case reports, and personal observations. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, cardiologists, neurologists, eye specialists (ophthalmologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for individuals and families of affected individuals with this disorder.Individuals with MILS may be treated with the administration of thiamine (vitamin B1) or thiamine derivatives. Some people with the disorder may experience a temporary symptomatic improvement and slight slowing of the progression of the disease.Additional treatment for these disorders is symptomatic and supportive. For example, sodium bicarbonate or sodium citrate may be used to treat acidosis, antiseizure medications (anticonvulsants) may be used to treat seizures, and anticongestive therapy may be necessary to treat heart abnormalities. Dystonia may be treated with baclofen, benzhexol, tetrabenezine and gabapentin alone or in combination. Injections of botulinum toxin may also be used to treat dystonia.Services that benefit people who are visually impaired may also be helpful for some affected individuals. Monitoring daily caloric intake and adequacy of diet is recommended. Psychosocial support for the entire family is essential as well.
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Therapies of Maternally Inherited Leigh Syndrome and NARP Syndrome. TreatmentThere are no proven therapies for MILS or NARP syndrome. Treatment recommendations are based primarily upon open label studies, case reports, and personal observations. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, cardiologists, neurologists, eye specialists (ophthalmologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for individuals and families of affected individuals with this disorder.Individuals with MILS may be treated with the administration of thiamine (vitamin B1) or thiamine derivatives. Some people with the disorder may experience a temporary symptomatic improvement and slight slowing of the progression of the disease.Additional treatment for these disorders is symptomatic and supportive. For example, sodium bicarbonate or sodium citrate may be used to treat acidosis, antiseizure medications (anticonvulsants) may be used to treat seizures, and anticongestive therapy may be necessary to treat heart abnormalities. Dystonia may be treated with baclofen, benzhexol, tetrabenezine and gabapentin alone or in combination. Injections of botulinum toxin may also be used to treat dystonia.Services that benefit people who are visually impaired may also be helpful for some affected individuals. Monitoring daily caloric intake and adequacy of diet is recommended. Psychosocial support for the entire family is essential as well.
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Overview of Maxillofacial Dysostosis
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Maxillofacial dysostosis is an extremely rare genetic disorder characterized by distinctive abnormalities of the head and face (craniofacial) area. Major symptoms include an underdeveloped (hypoplasia) upper jaw, downward-slanting palpebral fissures (which means that the opening between the eyelids slants downward), minor malformations of the external portion of the ears, and speech abnormalities. Maxillofacial dysostosis is inherited as an autosomal dominant trait. A second (distinct) form of maxillofacial dysostosis is believed to be inherited as an X-linked recessive trait.
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Overview of Maxillofacial Dysostosis. Maxillofacial dysostosis is an extremely rare genetic disorder characterized by distinctive abnormalities of the head and face (craniofacial) area. Major symptoms include an underdeveloped (hypoplasia) upper jaw, downward-slanting palpebral fissures (which means that the opening between the eyelids slants downward), minor malformations of the external portion of the ears, and speech abnormalities. Maxillofacial dysostosis is inherited as an autosomal dominant trait. A second (distinct) form of maxillofacial dysostosis is believed to be inherited as an X-linked recessive trait.
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Symptoms of Maxillofacial Dysostosis
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The symptoms and physical findings associated with maxillofacial dysostosis may vary from one person to another. Because so few cases have been identified and reported, it will be difficult to obtain an accurate clinical picture of the disorder. Affected individuals or parents of affected children should talk to their physicians and medical team about their specific case and associated symptoms. Characteristic findings associated with maxillofacial dysostosis include an underdeveloped (hypoplastic) upper jaw (maxilla), an abnormal downward slant of the opening between the eyelids (palpebral fissures), minor external ear malformations and speech abnormalities. Although most individuals with maxillofacial dysostosis have normal intelligence, they are often mistakenly thought to be mentally challenged due to their language problems. Their progress should be carefully monitored and educators should be informed of the potential for delayed onset of speech and difficulties with speech development including poor speech articulation (dysarthria). External ear abnormalities may include malformation of the upper, outer portion of the ear (pinna or auricle). Hearing loss was not seen in any of the individuals with maxillofacial dysostosis reported in the medical literature. Additional symptoms that have been reported in some cases of maxillofacial dysostosis include a sunken chest (pectus excavatum), incomplete or underdeveloped nipples, an abnormally flat skull, and a flattened bridge of the nose. Certain eye abnormalities including drooping of the upper eyelid (ptosis), crossed eyes (strabismus), and rapid, involuntary movements of the eyes (nystagmus) have also been reported.
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Symptoms of Maxillofacial Dysostosis. The symptoms and physical findings associated with maxillofacial dysostosis may vary from one person to another. Because so few cases have been identified and reported, it will be difficult to obtain an accurate clinical picture of the disorder. Affected individuals or parents of affected children should talk to their physicians and medical team about their specific case and associated symptoms. Characteristic findings associated with maxillofacial dysostosis include an underdeveloped (hypoplastic) upper jaw (maxilla), an abnormal downward slant of the opening between the eyelids (palpebral fissures), minor external ear malformations and speech abnormalities. Although most individuals with maxillofacial dysostosis have normal intelligence, they are often mistakenly thought to be mentally challenged due to their language problems. Their progress should be carefully monitored and educators should be informed of the potential for delayed onset of speech and difficulties with speech development including poor speech articulation (dysarthria). External ear abnormalities may include malformation of the upper, outer portion of the ear (pinna or auricle). Hearing loss was not seen in any of the individuals with maxillofacial dysostosis reported in the medical literature. Additional symptoms that have been reported in some cases of maxillofacial dysostosis include a sunken chest (pectus excavatum), incomplete or underdeveloped nipples, an abnormally flat skull, and a flattened bridge of the nose. Certain eye abnormalities including drooping of the upper eyelid (ptosis), crossed eyes (strabismus), and rapid, involuntary movements of the eyes (nystagmus) have also been reported.
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Causes of Maxillofacial Dysostosis
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Maxillofacial dysostosis is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
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Causes of Maxillofacial Dysostosis. Maxillofacial dysostosis is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
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Affects of Maxillofacial Dysostosis
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Maxillofacial dysostosis is extremely rare and the exact incidence of the disorder is unknown. Approximately 12 cases have been reported in the medical literature. Researchers believe that cases of maxillofacial dysostosis may go misdiagnosed or unrecognized making it difficult to determine the true frequency of the disorder in the general population. Maxillofacial dysostosis most likely affects males and females in equal numbers.
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Affects of Maxillofacial Dysostosis. Maxillofacial dysostosis is extremely rare and the exact incidence of the disorder is unknown. Approximately 12 cases have been reported in the medical literature. Researchers believe that cases of maxillofacial dysostosis may go misdiagnosed or unrecognized making it difficult to determine the true frequency of the disorder in the general population. Maxillofacial dysostosis most likely affects males and females in equal numbers.
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Related disorders of Maxillofacial Dysostosis
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Symptoms of the following disorders can be similar to those of maxillofacial dysostosis. Comparisons may be useful for a differential diagnosis.X-linked maxillofacial dysostosis, sometimes referred to as Toriello syndrome, is a rare genetic disorder characterized by an abnormally small jaw (micrognathia), underdevelopment of the middle portion of the face (midface hypoplasia), ear abnormalities, and an abnormal downward slant of the opening between the eyelids (palpebral fissures). Additional symptoms include short stature, cognitive impairment, a slightly webbed neck and hearing loss. The disorder is believed to be inherited as an X-linked recessive trait. Nager syndrome (also known as mandibulofacial dysostosis) is a rare inherited disorder characterized by craniofacial malformations similar to those in Treacher Collins syndrome occurring in association with abnormalities of the arms, hands, and/or feet. Craniofacial malformations include underdevelopment of the cheekbones (malar hypoplasia); incomplete development of the lower jaw (mandibular hypoplasia), causing the jaw to appear abnormally small (micrognathia); hypoplastic and/or malformed (dysplastic) external ears (pinnae) and blind ending or absent external ear canals (microtia), resulting in hearing impairment (conductive hearing loss); and/or downwardly slanted palpebral fissures, lack or absence of the lower eyelashes, and/or drooping upper eyelids (ptosis). Limb abnormalities include underdevelopment or absence of the thumbs, absence of one of the bones in the forearms (radius), abnormal fusion of bones in the forearms (radioulnar synostotis), permanent flexion of certain fingers (camptodactyly), and/or webbing of the toes (syndactyly). In most cases, Nager syndrome appears to occur randomly, for no apparent reason (sporadic). In other cases, researchers suggest that the disorder may be inherited as an autosomal dominant or recessive trait. (For more information on this disorder, choose “Nager” as your search term in the Rare Disease Database.)Treacher Collins syndrome is a rare genetic disorder characterized by distinctive abnormalities of the craniofacial area due to underdevelopment (hypoplasia) of certain bones of the head including the cheekbones and nearby structures (zygomatic complex and the jaw. The specific symptoms and physical characteristics associated with Treacher Collins syndrome may vary greatly from case to case. Craniofacial abnormalities tend to involve the cheekbones, jaws, mouth, ears, and/or eyes. In addition to the various facial abnormalities, affected individuals may have malformations of the external ears and middle ear structures and eye (ocular) abnormalities including an abnormal downward slant to the opening between the upper and lower eyelids (palpebral fissures). Affected individuals may develop hearing loss and breathing (respiratory) difficulties. In some cases, affected individuals may have mild symptoms and may go undiagnosed. In approximately 40 percent of cases, Treacher Collins syndrome has autosomal dominant inheritance. However, in about 60 percent of cases, a positive family history is not found. These cases likely represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose “Treacher Collins” as your search term in the Rare Disease Database.)Acrodysostosis is an extremely rare skeletal disorder characterized by abnormally short and malformed bones of the hands and feet (peripheral dysostosis) and underdevelopment of the nose (nasal hypoplasia). Other findings may include progressive growth delays, short stature, and/or unusual head and facial (craniofacial) features. Affected infants may exhibit premature maturation of bones of the hands and feet, malformation and shortening of the forearm bones (radius and ulna) near the wrist, and/or abnormally short fingers and toes (brachydactyly). Characteristic facial features may include a flattened, underdeveloped (hypoplastic) “pug” nose, an underdeveloped upper jaw bone (maxilliary hypoplasia), widely spaced eyes (ocular hypertelorism), and/or an extra fold of skin on either side of the nose that may cover the eyes' inner corners (epicanthal folds). It may be inherited as an autosomal dominant trait in some cases, although no gene has yet been identified with this disorder. (For more information on this disorder, choose “acrodysostosis” as your search term in the Rare Disease Database.)
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Related disorders of Maxillofacial Dysostosis. Symptoms of the following disorders can be similar to those of maxillofacial dysostosis. Comparisons may be useful for a differential diagnosis.X-linked maxillofacial dysostosis, sometimes referred to as Toriello syndrome, is a rare genetic disorder characterized by an abnormally small jaw (micrognathia), underdevelopment of the middle portion of the face (midface hypoplasia), ear abnormalities, and an abnormal downward slant of the opening between the eyelids (palpebral fissures). Additional symptoms include short stature, cognitive impairment, a slightly webbed neck and hearing loss. The disorder is believed to be inherited as an X-linked recessive trait. Nager syndrome (also known as mandibulofacial dysostosis) is a rare inherited disorder characterized by craniofacial malformations similar to those in Treacher Collins syndrome occurring in association with abnormalities of the arms, hands, and/or feet. Craniofacial malformations include underdevelopment of the cheekbones (malar hypoplasia); incomplete development of the lower jaw (mandibular hypoplasia), causing the jaw to appear abnormally small (micrognathia); hypoplastic and/or malformed (dysplastic) external ears (pinnae) and blind ending or absent external ear canals (microtia), resulting in hearing impairment (conductive hearing loss); and/or downwardly slanted palpebral fissures, lack or absence of the lower eyelashes, and/or drooping upper eyelids (ptosis). Limb abnormalities include underdevelopment or absence of the thumbs, absence of one of the bones in the forearms (radius), abnormal fusion of bones in the forearms (radioulnar synostotis), permanent flexion of certain fingers (camptodactyly), and/or webbing of the toes (syndactyly). In most cases, Nager syndrome appears to occur randomly, for no apparent reason (sporadic). In other cases, researchers suggest that the disorder may be inherited as an autosomal dominant or recessive trait. (For more information on this disorder, choose “Nager” as your search term in the Rare Disease Database.)Treacher Collins syndrome is a rare genetic disorder characterized by distinctive abnormalities of the craniofacial area due to underdevelopment (hypoplasia) of certain bones of the head including the cheekbones and nearby structures (zygomatic complex and the jaw. The specific symptoms and physical characteristics associated with Treacher Collins syndrome may vary greatly from case to case. Craniofacial abnormalities tend to involve the cheekbones, jaws, mouth, ears, and/or eyes. In addition to the various facial abnormalities, affected individuals may have malformations of the external ears and middle ear structures and eye (ocular) abnormalities including an abnormal downward slant to the opening between the upper and lower eyelids (palpebral fissures). Affected individuals may develop hearing loss and breathing (respiratory) difficulties. In some cases, affected individuals may have mild symptoms and may go undiagnosed. In approximately 40 percent of cases, Treacher Collins syndrome has autosomal dominant inheritance. However, in about 60 percent of cases, a positive family history is not found. These cases likely represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose “Treacher Collins” as your search term in the Rare Disease Database.)Acrodysostosis is an extremely rare skeletal disorder characterized by abnormally short and malformed bones of the hands and feet (peripheral dysostosis) and underdevelopment of the nose (nasal hypoplasia). Other findings may include progressive growth delays, short stature, and/or unusual head and facial (craniofacial) features. Affected infants may exhibit premature maturation of bones of the hands and feet, malformation and shortening of the forearm bones (radius and ulna) near the wrist, and/or abnormally short fingers and toes (brachydactyly). Characteristic facial features may include a flattened, underdeveloped (hypoplastic) “pug” nose, an underdeveloped upper jaw bone (maxilliary hypoplasia), widely spaced eyes (ocular hypertelorism), and/or an extra fold of skin on either side of the nose that may cover the eyes' inner corners (epicanthal folds). It may be inherited as an autosomal dominant trait in some cases, although no gene has yet been identified with this disorder. (For more information on this disorder, choose “acrodysostosis” as your search term in the Rare Disease Database.)
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Diagnosis of Maxillofacial Dysostosis
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A diagnosis of maxillofacial dysostosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests to rule out other disorders.
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Diagnosis of Maxillofacial Dysostosis. A diagnosis of maxillofacial dysostosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests to rule out other disorders.
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Therapies of Maxillofacial Dysostosis
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TreatmentThe treatment of maxillofacial dysostosis is directed toward the specific symptoms that are apparent in each individual. Facial features may improve with age, often resulting in a near normal appearance by adulthood. When facial abnormalities are severe a variety of medical techniques including plastic surgery or orthodontic repair may be necessary.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Maxillofacial Dysostosis. TreatmentThe treatment of maxillofacial dysostosis is directed toward the specific symptoms that are apparent in each individual. Facial features may improve with age, often resulting in a near normal appearance by adulthood. When facial abnormalities are severe a variety of medical techniques including plastic surgery or orthodontic repair may be necessary.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of May Hegglin Anomaly
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May-Hegglin Anomaly is a rare, inherited, blood platelet disorder characterized by abnormally large and misshapen platelets (giant platelets) and defects of the white blood cells known as leukocytes. The defect of the white blood cells consists of the presence of very small (2-5 micrometers) rods, known as Dohle bodies, in the fluid portion of the cell (cytoplasm). Some people with this disorder may have no symptoms while others may have various bleeding abnormalities. In mild cases, treatment for May-Hegglin Anomaly is not usually necessary. In more severe cases, transfusions of blood platelets may be necessary.In the past couple of years, it has become clear to physicians studying this disorder that May-Hegglin Anomaly is one of a family of five autosomal dominant, giant platelet disorders, each of which involves slight variants (alleles) of the same gene in the same location. The other giant platelet disorders related to May-Hegglin Anomaly are Sebastian Syndrome, Fechtner Syndrome, Epstein Syndrome, and the Alport-like Syndrome with macrothrombocytopenia. Advances in the understanding of one of these syndromes may help in understanding the others.
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Overview of May Hegglin Anomaly. May-Hegglin Anomaly is a rare, inherited, blood platelet disorder characterized by abnormally large and misshapen platelets (giant platelets) and defects of the white blood cells known as leukocytes. The defect of the white blood cells consists of the presence of very small (2-5 micrometers) rods, known as Dohle bodies, in the fluid portion of the cell (cytoplasm). Some people with this disorder may have no symptoms while others may have various bleeding abnormalities. In mild cases, treatment for May-Hegglin Anomaly is not usually necessary. In more severe cases, transfusions of blood platelets may be necessary.In the past couple of years, it has become clear to physicians studying this disorder that May-Hegglin Anomaly is one of a family of five autosomal dominant, giant platelet disorders, each of which involves slight variants (alleles) of the same gene in the same location. The other giant platelet disorders related to May-Hegglin Anomaly are Sebastian Syndrome, Fechtner Syndrome, Epstein Syndrome, and the Alport-like Syndrome with macrothrombocytopenia. Advances in the understanding of one of these syndromes may help in understanding the others.
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Symptoms of May Hegglin Anomaly
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Some people with May-Hegglin Anomaly may have symptoms at birth while others may have no symptoms throughout their lifetime. Symptoms may include red or purple colored spots on the skin (purpura), nose bleeds (epitaxis), excessive bleeding from the mouth during dental work, headaches, and/or muscle weakness on one side of the body due to bleeding within the brain (intracranial bleeding).Excessive bleeding may occur in some people with May-Hegglin Anomaly when steroid drugs used to treat another disorder are discontinued.
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Symptoms of May Hegglin Anomaly. Some people with May-Hegglin Anomaly may have symptoms at birth while others may have no symptoms throughout their lifetime. Symptoms may include red or purple colored spots on the skin (purpura), nose bleeds (epitaxis), excessive bleeding from the mouth during dental work, headaches, and/or muscle weakness on one side of the body due to bleeding within the brain (intracranial bleeding).Excessive bleeding may occur in some people with May-Hegglin Anomaly when steroid drugs used to treat another disorder are discontinued.
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Causes of May Hegglin Anomaly
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May-Hegglin Anomaly is inherited as an autosomal dominant genetic trait. The gene involved has been mapped to Gene Map Locus 22q11.2, and the protein generated by the gene is known as MYH9. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Causes of May Hegglin Anomaly. May-Hegglin Anomaly is inherited as an autosomal dominant genetic trait. The gene involved has been mapped to Gene Map Locus 22q11.2, and the protein generated by the gene is known as MYH9. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Affects of May Hegglin Anomaly
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May-Hegglin Anomaly is a rare blood platelet disorder that affects males and females in equal numbers. It occurs more often in people of Greek or Italian descent than among others. As of about 10 years ago, only about 170 cases were reported in the literature.
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Affects of May Hegglin Anomaly. May-Hegglin Anomaly is a rare blood platelet disorder that affects males and females in equal numbers. It occurs more often in people of Greek or Italian descent than among others. As of about 10 years ago, only about 170 cases were reported in the literature.
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Related disorders of May Hegglin Anomaly
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Symptoms of the following disorders can be similar to those of May-Hegglin Anomaly. Comparisons may be useful for a differential diagnosis:Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins (usually factor VIII). Factor VIII is one of several proteins that enables the blood to clot. Hemophilia is found in males almost exclusively and can be classified as mild, moderate, or severe. The most serious symptom of Hemophilia is uncontrolled internal bleeding that may begin spontaneously without any apparent cause. Internal bleeding may cause permanent damage to the joints and muscles. People with Hemophilia bleed for a longer period of time than people who have the normal percentage of active clotting factors in their blood. Bruises and trauma can trigger episodes of serious internal bleeding in males with this disorder. (For more information on this disorder, choose “Hemophilia” as your search term in the Rare Disease Database.)Bernard-Soulier Syndrome is a rare inherited blood clotting (coagulation) disorder characterized by abnormalities of platelets. Symptoms include a tendency to bleed excessively and bruise easily. People with Bernard-Soulier Syndrome tend to bleed profusely from cuts and other injuries. Nosebleeds and unusually heavy menstrual flow in women are also common. Bleeding under the skin may cause small or large purple colored spots (purpura) in different areas of the body. (For more information on this disorder, choose “Bernard- Soulier” as your search term in the Rare Disease Database.)Storage Pool Disease (SPD) is a rare inherited disorder of blood platelets characterized by clotting dysfunction due to the platelets' inability to store certain clotting factors. Symptoms occur mostly in women and may include mild bleeding, nosebleeds, and slightly heavier than normal menstrual periods. People with Storage Pool Disease may also have abnormally low levels of blood platelets (thrombocytopenia).Essential Thrombocytopenia is a rare blood platelet disorder characterized by an abnormally small number of circulating platelets that survive for a shorter than normal period of time. The major symptom is excessive hemorrhaging, especially under the skin, in the eyes, and in the mucous membranes of the mouth. In severe cases of Essential Thrombocytopenia abnormal bleeding may occur in the brain (intracranial hemorrhage). People with this disorder bruise easily and may also have sudden nosebleeds. Many small red or purple spots (petechiae) may appear on the skin, especially around the ankles and feet. (For more information on this disorder, choose “Essential Thrombocytopenia” as your search term in the Rare Disease Database.)Thrombasthenia of Glanzmann and Naegeli is a rare inherited blood clotting (coagulation) disorder characterized by the impaired function of the specialized red blood cells (platelets) that are essential for proper blood clotting. Symptoms may include abnormal bleeding and/or hemorrhage, easy bruising, bleeding from the gums, nosebleeds (epitaxis), and/or large red or purple colored spots on the skin (purpura). The symptoms of Thrombasthenia of Glanzmann and Naegeli are not progressive and may improve with age. (For more information on this disorder, choose “Thrombasthenia” as your search term in the Rare Disease Database.)Von Willebrand Disease is a rare inherited blood clotting (coagulation) disorder that occurs during infancy or early childhood and is characterized by prolonged bleeding and an abnormally slow blood clotting time. Symptoms may include bleeding from the gastrointestinal tract, nosebleeds, bleeding from the gums, and/or easy bruising. People with this disorder may also bleed easily after injury, childbirth, and/or surgery. These symptoms occur because of a deficiency of factor VIII and the von Willebrand factor. (For more information on this disorder, choose “von Willebrand” as your search term in the Rare Disease Database.)Platelet disorders are also associated with congenital conditions such as Wiskott-Aldrich Syndrome, Down Syndrome, Thrombocytopenia with Absent Radius Syndrome, and Chediak-Higashi Syndrome. (For more information on these disorders choose “Wiskott-Aldrich,” “Down Syndrome” “Thrombocytopenia with Absent Radius,” and “Chediak-Higashi” as your search terms in the Rare Disease Database.)
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Related disorders of May Hegglin Anomaly. Symptoms of the following disorders can be similar to those of May-Hegglin Anomaly. Comparisons may be useful for a differential diagnosis:Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins (usually factor VIII). Factor VIII is one of several proteins that enables the blood to clot. Hemophilia is found in males almost exclusively and can be classified as mild, moderate, or severe. The most serious symptom of Hemophilia is uncontrolled internal bleeding that may begin spontaneously without any apparent cause. Internal bleeding may cause permanent damage to the joints and muscles. People with Hemophilia bleed for a longer period of time than people who have the normal percentage of active clotting factors in their blood. Bruises and trauma can trigger episodes of serious internal bleeding in males with this disorder. (For more information on this disorder, choose “Hemophilia” as your search term in the Rare Disease Database.)Bernard-Soulier Syndrome is a rare inherited blood clotting (coagulation) disorder characterized by abnormalities of platelets. Symptoms include a tendency to bleed excessively and bruise easily. People with Bernard-Soulier Syndrome tend to bleed profusely from cuts and other injuries. Nosebleeds and unusually heavy menstrual flow in women are also common. Bleeding under the skin may cause small or large purple colored spots (purpura) in different areas of the body. (For more information on this disorder, choose “Bernard- Soulier” as your search term in the Rare Disease Database.)Storage Pool Disease (SPD) is a rare inherited disorder of blood platelets characterized by clotting dysfunction due to the platelets' inability to store certain clotting factors. Symptoms occur mostly in women and may include mild bleeding, nosebleeds, and slightly heavier than normal menstrual periods. People with Storage Pool Disease may also have abnormally low levels of blood platelets (thrombocytopenia).Essential Thrombocytopenia is a rare blood platelet disorder characterized by an abnormally small number of circulating platelets that survive for a shorter than normal period of time. The major symptom is excessive hemorrhaging, especially under the skin, in the eyes, and in the mucous membranes of the mouth. In severe cases of Essential Thrombocytopenia abnormal bleeding may occur in the brain (intracranial hemorrhage). People with this disorder bruise easily and may also have sudden nosebleeds. Many small red or purple spots (petechiae) may appear on the skin, especially around the ankles and feet. (For more information on this disorder, choose “Essential Thrombocytopenia” as your search term in the Rare Disease Database.)Thrombasthenia of Glanzmann and Naegeli is a rare inherited blood clotting (coagulation) disorder characterized by the impaired function of the specialized red blood cells (platelets) that are essential for proper blood clotting. Symptoms may include abnormal bleeding and/or hemorrhage, easy bruising, bleeding from the gums, nosebleeds (epitaxis), and/or large red or purple colored spots on the skin (purpura). The symptoms of Thrombasthenia of Glanzmann and Naegeli are not progressive and may improve with age. (For more information on this disorder, choose “Thrombasthenia” as your search term in the Rare Disease Database.)Von Willebrand Disease is a rare inherited blood clotting (coagulation) disorder that occurs during infancy or early childhood and is characterized by prolonged bleeding and an abnormally slow blood clotting time. Symptoms may include bleeding from the gastrointestinal tract, nosebleeds, bleeding from the gums, and/or easy bruising. People with this disorder may also bleed easily after injury, childbirth, and/or surgery. These symptoms occur because of a deficiency of factor VIII and the von Willebrand factor. (For more information on this disorder, choose “von Willebrand” as your search term in the Rare Disease Database.)Platelet disorders are also associated with congenital conditions such as Wiskott-Aldrich Syndrome, Down Syndrome, Thrombocytopenia with Absent Radius Syndrome, and Chediak-Higashi Syndrome. (For more information on these disorders choose “Wiskott-Aldrich,” “Down Syndrome” “Thrombocytopenia with Absent Radius,” and “Chediak-Higashi” as your search terms in the Rare Disease Database.)
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Diagnosis of May Hegglin Anomaly
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Diagnosis of May Hegglin Anomaly.
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Therapies of May Hegglin Anomaly
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The diagnosis of May-Hegglin Anomaly is made by specialized blood tests that reveal giant, oddly shaped platelets and characteristic cellular "inclusions" in certain white blood cells (leukocytes). There also might be fewer platelets than normal (mild thrombocytopenia). In severe rare cases, people with May-Hegglin Anomaly may require transfusions of platelets. People with Chediak-Higashi Syndrome, a form of Albinism, have cellular inclusions that are very similar to those of May-Hegglin Anomaly.Pregnant women with May-Hegglin Anomaly may experience episodes of bleeding. Therefore, expectant mothers and their unborn children should be monitored for abnormal bleeding and/or hemorrhages.May-Hegglin Anomaly generally does not require therapy in mild cases. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of May Hegglin Anomaly. The diagnosis of May-Hegglin Anomaly is made by specialized blood tests that reveal giant, oddly shaped platelets and characteristic cellular "inclusions" in certain white blood cells (leukocytes). There also might be fewer platelets than normal (mild thrombocytopenia). In severe rare cases, people with May-Hegglin Anomaly may require transfusions of platelets. People with Chediak-Higashi Syndrome, a form of Albinism, have cellular inclusions that are very similar to those of May-Hegglin Anomaly.Pregnant women with May-Hegglin Anomaly may experience episodes of bleeding. Therefore, expectant mothers and their unborn children should be monitored for abnormal bleeding and/or hemorrhages.May-Hegglin Anomaly generally does not require therapy in mild cases. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of Mayer-Rokitansky-Küster-Hauser Syndrome
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Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare disorder that affects women. It is characterized by the failure of the uterus and the vagina to develop properly in women who have normal ovarian function and normal external genitalia. Women with this disorder develop normal secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle (primary amenorrhea). Often, the failure to begin the menstrual cycle is the initial clinical sign of MRKH syndrome. The range and severity of MRKH syndrome can vary greatly and the disorder is generally broken down into type I, which occurs as an isolated finding, and type II, which occurs with abnormalities of additional organ systems including mainly the kidneys and the skeleton. Because of the nature of the disorder, MRKH syndrome can cause significant psychological challenges and counseling is recommended. The exact cause of MRKH syndrome remains largely unknown, but there is now no doubt of a genetic origin. In this respect, an update on the most recent research publications shows the involvement of several chromosomal segments, some of them including genes likely to account for the disorder.
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Overview of Mayer-Rokitansky-Küster-Hauser Syndrome. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare disorder that affects women. It is characterized by the failure of the uterus and the vagina to develop properly in women who have normal ovarian function and normal external genitalia. Women with this disorder develop normal secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle (primary amenorrhea). Often, the failure to begin the menstrual cycle is the initial clinical sign of MRKH syndrome. The range and severity of MRKH syndrome can vary greatly and the disorder is generally broken down into type I, which occurs as an isolated finding, and type II, which occurs with abnormalities of additional organ systems including mainly the kidneys and the skeleton. Because of the nature of the disorder, MRKH syndrome can cause significant psychological challenges and counseling is recommended. The exact cause of MRKH syndrome remains largely unknown, but there is now no doubt of a genetic origin. In this respect, an update on the most recent research publications shows the involvement of several chromosomal segments, some of them including genes likely to account for the disorder.
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Symptoms of Mayer-Rokitansky-Küster-Hauser Syndrome
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The symptoms of MRKH syndrome vary greatly from one woman to another. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. MAYER-ROKITANSKY KÜSTER-HAUSER SYNDROME TYPE I This form of MRKH syndrome is also known as isolated Mullerian aplasia, or Rokitansky sequence. The disorder is characterized by the failure of the uterus and the vagina to develop properly. The severity of MRKH syndrome type I may vary greatly from one person to another. In most cases, the uterus and/or the vagina have not developed (aplasia); in other rare cases, there may be narrowing (atresia) of the upper portion of the vagina and an underdeveloped or rudimentary uterus. In some cases, the Fallopian tubes may be affected as well. The ovaries of females with MRKH syndrome are unaffected and function normally. In most cases, the initial symptom of MRKH syndrome type I is the failure to begin menstrual cycles (primary amenorrhea). Despite amenorrhea, affected females do experience normal secondary sexual development including breast development, the growth of hair under the arms and in the pubic area, and an increase in body fat around the hips and other areas. Sex steroid levels, female sexual identification, and level of sexual desire (libido) are all also normal. However, because of the absence of the uterus and properly developed fallopian tubes, all affected women are unable to bear children (infertile). Many affected females also experience difficulty while attempting sexual intercourse due to the shortness of the vagina. Some women may also experience pain during intercourse. MRKH syndrome type I is sometimes referred to as Mullerian aplasia because the Mullerian ducts are a dual structure within a growing embryo that ultimately develops into the uterus, Fallopian tubes, cervix and the upper portion of the vagina. It is believed that improper development of tissues derived from the Mullerian ducts occurring during embryogenesis, ultimately causes the symptoms of MRKH syndrome. MAYER-ROKITANSKY-KÜSTER-HAUSER SYNDROME TYPE II When the abnormalities that characterize MRKH syndrome type I occur in association with additional physical findings, the disorder is classified as MRKH syndrome type II or (Mu)llerian duct aplasia, (R)enal dysplasia and (C)ervical (S)omite anomalies or MURCS association. The most common abnormalities associated with MRKH syndrome type II are failure of the kidneys to development properly (renal adysplasia) and various skeletal malformations, mainly vertebral. Much less frequent defects include heart malformations and hearing impairment. Women with MRKH syndrome type II may exhibit absence of a kidney (unilateral renal agenesis), malformation of one or the two kidneys (renal dysplasia), underdeveloped (hypoplastic) kidneys and/or improper positioning within the body of one or both kidneys (renal ectopia). Renal abnormalities can cause growth deficiency, kidney stones, an increased susceptibility to urinary tract infections and abnormal accumulation of urine in the kidney due to obstruction (hydronephrosis). Many females with MRKH syndrome type II also exhibit skeletal malformations. For example, bones (vertebrae) in the spinal column within the neck (cervical vertebrae) and the upper back (thoracic vertebrae) may develop improperly (dysplasia). As a result, some of the vertebrae within the neck may be missing and/or fused, causing shortness of the neck, limited neck motion, and an abnormally low hairline (Klippel-Feil syndrome). In addition, affected females may exhibit asymmetric, fused or wedge vertebrae; malformed or missing ribs; abnormal sideways curvature of the spine (scoliosis); elevation of the shoulder blade (scapula), due to the scapula's failure to move into the appropriate position during fetal development (Sprengel deformity). (For more information on Klippel-Feil syndrome and Sprengel deformity, please see the Related Disorders section of this report.). Abnormalities of the head and face may also occur including an abnormally small jaw (micrognathia), cleft lip, cleft palate and underdevelopment of one side of the face causing facial asymmetry. Some affected women develop hearing loss due to the failure of sound waves to be conducted through the middle ear (conductive hearing loss), usually due to structural abnormalities of the middle ear. Hearing loss may also be due to impaired ability of the auditory nerve to transmit sensory input to the brain (sensorineural hearing loss). The degree of hearing impairment may vary. The ears may be malformed (dysplastic) in some cases. When the ears are involved the disorder may be referred to as genital renal ear syndrome (GRES) In rare cases, some females with MRKH syndrome type II have had additional physical abnormalities including abnormalities of the hands and/or arms and heart malformations. Abnormalities of the extremities may include absence of a portion of one or more fingers or toes (ectrodactyly), webbing of the fingers or toes (syndactyly), duplicated thumb and absence of the long, thin bone of the forearm (absent radius). Heart malformations may include “a hole in the heart” between the two upper chambers of the heart (atrial septal defects), narrowing of the pulmonary valve (pulmonary valvular stenosis) or tetralogy of Fallot, a rare grouping of four different heart defects.
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Symptoms of Mayer-Rokitansky-Küster-Hauser Syndrome. The symptoms of MRKH syndrome vary greatly from one woman to another. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. MAYER-ROKITANSKY KÜSTER-HAUSER SYNDROME TYPE I This form of MRKH syndrome is also known as isolated Mullerian aplasia, or Rokitansky sequence. The disorder is characterized by the failure of the uterus and the vagina to develop properly. The severity of MRKH syndrome type I may vary greatly from one person to another. In most cases, the uterus and/or the vagina have not developed (aplasia); in other rare cases, there may be narrowing (atresia) of the upper portion of the vagina and an underdeveloped or rudimentary uterus. In some cases, the Fallopian tubes may be affected as well. The ovaries of females with MRKH syndrome are unaffected and function normally. In most cases, the initial symptom of MRKH syndrome type I is the failure to begin menstrual cycles (primary amenorrhea). Despite amenorrhea, affected females do experience normal secondary sexual development including breast development, the growth of hair under the arms and in the pubic area, and an increase in body fat around the hips and other areas. Sex steroid levels, female sexual identification, and level of sexual desire (libido) are all also normal. However, because of the absence of the uterus and properly developed fallopian tubes, all affected women are unable to bear children (infertile). Many affected females also experience difficulty while attempting sexual intercourse due to the shortness of the vagina. Some women may also experience pain during intercourse. MRKH syndrome type I is sometimes referred to as Mullerian aplasia because the Mullerian ducts are a dual structure within a growing embryo that ultimately develops into the uterus, Fallopian tubes, cervix and the upper portion of the vagina. It is believed that improper development of tissues derived from the Mullerian ducts occurring during embryogenesis, ultimately causes the symptoms of MRKH syndrome. MAYER-ROKITANSKY-KÜSTER-HAUSER SYNDROME TYPE II When the abnormalities that characterize MRKH syndrome type I occur in association with additional physical findings, the disorder is classified as MRKH syndrome type II or (Mu)llerian duct aplasia, (R)enal dysplasia and (C)ervical (S)omite anomalies or MURCS association. The most common abnormalities associated with MRKH syndrome type II are failure of the kidneys to development properly (renal adysplasia) and various skeletal malformations, mainly vertebral. Much less frequent defects include heart malformations and hearing impairment. Women with MRKH syndrome type II may exhibit absence of a kidney (unilateral renal agenesis), malformation of one or the two kidneys (renal dysplasia), underdeveloped (hypoplastic) kidneys and/or improper positioning within the body of one or both kidneys (renal ectopia). Renal abnormalities can cause growth deficiency, kidney stones, an increased susceptibility to urinary tract infections and abnormal accumulation of urine in the kidney due to obstruction (hydronephrosis). Many females with MRKH syndrome type II also exhibit skeletal malformations. For example, bones (vertebrae) in the spinal column within the neck (cervical vertebrae) and the upper back (thoracic vertebrae) may develop improperly (dysplasia). As a result, some of the vertebrae within the neck may be missing and/or fused, causing shortness of the neck, limited neck motion, and an abnormally low hairline (Klippel-Feil syndrome). In addition, affected females may exhibit asymmetric, fused or wedge vertebrae; malformed or missing ribs; abnormal sideways curvature of the spine (scoliosis); elevation of the shoulder blade (scapula), due to the scapula's failure to move into the appropriate position during fetal development (Sprengel deformity). (For more information on Klippel-Feil syndrome and Sprengel deformity, please see the Related Disorders section of this report.). Abnormalities of the head and face may also occur including an abnormally small jaw (micrognathia), cleft lip, cleft palate and underdevelopment of one side of the face causing facial asymmetry. Some affected women develop hearing loss due to the failure of sound waves to be conducted through the middle ear (conductive hearing loss), usually due to structural abnormalities of the middle ear. Hearing loss may also be due to impaired ability of the auditory nerve to transmit sensory input to the brain (sensorineural hearing loss). The degree of hearing impairment may vary. The ears may be malformed (dysplastic) in some cases. When the ears are involved the disorder may be referred to as genital renal ear syndrome (GRES) In rare cases, some females with MRKH syndrome type II have had additional physical abnormalities including abnormalities of the hands and/or arms and heart malformations. Abnormalities of the extremities may include absence of a portion of one or more fingers or toes (ectrodactyly), webbing of the fingers or toes (syndactyly), duplicated thumb and absence of the long, thin bone of the forearm (absent radius). Heart malformations may include “a hole in the heart” between the two upper chambers of the heart (atrial septal defects), narrowing of the pulmonary valve (pulmonary valvular stenosis) or tetralogy of Fallot, a rare grouping of four different heart defects.
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Causes of Mayer-Rokitansky-Küster-Hauser Syndrome
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The exact cause of MRKH syndrome remains largely unknown but ongoing research has begun to provide some clues to its mechanism. Initially, MRKH syndrome was thought to occur randomly (sporadically) due to the involvement of non-genetic or environmental factors such as gestational diabetes or exposure to a teratogen, which is an agent that can disrupt the development of an embryo. No link between an environmental cause and MRKH syndrome has ever been established. In recent years, increasing evidence suggests that MRKH syndrome is a genetic disorder. Some researchers have proposed that, in familial cases, the disorder is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. Increasing case studies have now reinforced this idea. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. Incomplete penetrance means that some individuals who inherit the gene for a dominant disorder will not be affected by the disorder. Variable expressivity a dominant disorder can have widely varying signs and symptoms among affected individuals. Polygenic multifactorial inheritance has also been proposed as a cause of MRKH syndrome. Polygenic multifactorial inheritance refers to the interaction of many genes (polygenic) in the development of a disorder with each gene having a small effect on the overall development of the disorder. Research is ongoing to determine the exact underlying causes of MRKH syndrome including identifying the gene or gene(s) involved in the development of the disorder and whether environmental factors play a role. It is now clear that different genes can each account for the disease, when they are mutated or involved in a chromosome segmental anomaly (deletion or duplication). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q21.1” refers to band 21.1 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome. To date, seven deletions and one duplication of chromosomal segments have been identified in several persons affected by MRKH syndrome. These anomalies have been found independently in different persons (i.e., one and only one of these chromosomal anomalies per person). These anomalies are of varying length and can contain one gene or many different genes. This has allowed researchers to hypothesize the involvement of certain genes, which are called candidate genes. These researchers are currently working on the characterization of these candidate genes to determine precisely their responsibility in the development of MRKH syndrome. At the present time, the seven segmental deletions likely to be involved in MRKH syndrome have been identified in chromosomes 1 (1q21.1), 4 (4q34-qter), 8 (8p23.1), 10 (10p14-15), 16 (16p11.2), 17 (17q12) and 22 (22q11.21), and the duplication was found on the chromosome X (Xpter-p22.32). This has led researchers to define several candidate genes: HNF1B (formerly TCF2), LHX1, TBX6, ITIH5 and SHOX, which are currently under investigation. These new data demonstrate the genetic origin of the MRKH syndrome. They also show that several different genes defects can cause the syndrome. In this case, the disease can be considered as of multigenic origin, meaning that different genes can independently be responsible for the syndrome.
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Causes of Mayer-Rokitansky-Küster-Hauser Syndrome. The exact cause of MRKH syndrome remains largely unknown but ongoing research has begun to provide some clues to its mechanism. Initially, MRKH syndrome was thought to occur randomly (sporadically) due to the involvement of non-genetic or environmental factors such as gestational diabetes or exposure to a teratogen, which is an agent that can disrupt the development of an embryo. No link between an environmental cause and MRKH syndrome has ever been established. In recent years, increasing evidence suggests that MRKH syndrome is a genetic disorder. Some researchers have proposed that, in familial cases, the disorder is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. Increasing case studies have now reinforced this idea. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. Incomplete penetrance means that some individuals who inherit the gene for a dominant disorder will not be affected by the disorder. Variable expressivity a dominant disorder can have widely varying signs and symptoms among affected individuals. Polygenic multifactorial inheritance has also been proposed as a cause of MRKH syndrome. Polygenic multifactorial inheritance refers to the interaction of many genes (polygenic) in the development of a disorder with each gene having a small effect on the overall development of the disorder. Research is ongoing to determine the exact underlying causes of MRKH syndrome including identifying the gene or gene(s) involved in the development of the disorder and whether environmental factors play a role. It is now clear that different genes can each account for the disease, when they are mutated or involved in a chromosome segmental anomaly (deletion or duplication). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q21.1” refers to band 21.1 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome. To date, seven deletions and one duplication of chromosomal segments have been identified in several persons affected by MRKH syndrome. These anomalies have been found independently in different persons (i.e., one and only one of these chromosomal anomalies per person). These anomalies are of varying length and can contain one gene or many different genes. This has allowed researchers to hypothesize the involvement of certain genes, which are called candidate genes. These researchers are currently working on the characterization of these candidate genes to determine precisely their responsibility in the development of MRKH syndrome. At the present time, the seven segmental deletions likely to be involved in MRKH syndrome have been identified in chromosomes 1 (1q21.1), 4 (4q34-qter), 8 (8p23.1), 10 (10p14-15), 16 (16p11.2), 17 (17q12) and 22 (22q11.21), and the duplication was found on the chromosome X (Xpter-p22.32). This has led researchers to define several candidate genes: HNF1B (formerly TCF2), LHX1, TBX6, ITIH5 and SHOX, which are currently under investigation. These new data demonstrate the genetic origin of the MRKH syndrome. They also show that several different genes defects can cause the syndrome. In this case, the disease can be considered as of multigenic origin, meaning that different genes can independently be responsible for the syndrome.
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Affects of Mayer-Rokitansky-Küster-Hauser Syndrome
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MRKH syndrome is estimated to affect 1 in 4,000-5,000 women in the general population. It is the second most common cause of primary amenorrhea. The disorder is thought to be underdiagnosed making it difficult to determine the true frequency of MRKH syndrome in the general population. The disorder is present at birth (congenital) but is often not identified until early adolescence. By definition, MRKH syndrome only affects females. However, some researchers have noted similar symptoms in males. Affected males have exhibited absence or underdevelopment of the Wolffian duct, an organ that is present in a developing embryo that eventually evolves into certain structures such as the tube connecting the testes to the urethra (vas deferens). Affected males may also have low levels of live sperm in their semen (azoospermia), kidney abnormalities, spinal malformations, hearing impairment and additional physical findings. This condition is sometimes referred to as ARCS (Azoospermia, Renal anomalies, Cervicothoracic Spine dysplasia). The relationship, if any, between ARCS and MRKH syndrome remains unsolved. However, rare cases of ARCS and MRKH in the same family have been reported, making both syndromes likely to be of identical genetic origin.
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Affects of Mayer-Rokitansky-Küster-Hauser Syndrome. MRKH syndrome is estimated to affect 1 in 4,000-5,000 women in the general population. It is the second most common cause of primary amenorrhea. The disorder is thought to be underdiagnosed making it difficult to determine the true frequency of MRKH syndrome in the general population. The disorder is present at birth (congenital) but is often not identified until early adolescence. By definition, MRKH syndrome only affects females. However, some researchers have noted similar symptoms in males. Affected males have exhibited absence or underdevelopment of the Wolffian duct, an organ that is present in a developing embryo that eventually evolves into certain structures such as the tube connecting the testes to the urethra (vas deferens). Affected males may also have low levels of live sperm in their semen (azoospermia), kidney abnormalities, spinal malformations, hearing impairment and additional physical findings. This condition is sometimes referred to as ARCS (Azoospermia, Renal anomalies, Cervicothoracic Spine dysplasia). The relationship, if any, between ARCS and MRKH syndrome remains unsolved. However, rare cases of ARCS and MRKH in the same family have been reported, making both syndromes likely to be of identical genetic origin.
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Related disorders of Mayer-Rokitansky-Küster-Hauser Syndrome
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Symptoms of the following disorders can be similar to those of MRKH syndrome. Comparisons may be useful for a differential diagnosis. WTN4 syndrome is a rare genetic disorder that affects females. It is characterized by the absence of the uterus and abnormally high levels of androgens. Androgens are male sex hormones that control the development of male sexual characteristics. Consequently, females with WTN4 syndrome may develop acne and a male pattern of hair growth in females (hirsutism), which can include hair growth on the face or chest. In some cases, the vagina may be abnormally short or small. In the particular case of WNT4 syndrome, it seems that the ovaries undergo partial musculinization during embryonic development and then produce both male and female sex hormones. This is why, despite the signs of hirsutism, females with WTN4 syndrome develop normal secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle (primary amenorrhea). In rare cases, one kidney may fail to develop properly (unilateral renal aplasia). WTN4 syndrome is extremely similar to MRKH syndrome and is sometimes referred to as MRKH-like syndrome. WTN4 syndrome is caused by mutations of the WTN4 gene. (For more research on this disorder, choose “WTN4” as your search term in the Rare Disease Database.) Complete androgen insensitivity syndrome is a rare disorder in which individuals who are genetically male (46, XY), but do not respond to male sex hormones known as androgens. The disorder is characterized by the failure of a developing fetus to respond to the presence of androgens in the fetal bloodstream. Consequently, infants appear female at birth, but are genetically male and lack a uterus, Fallopian tubes and ovaries. A vagina may be absent or may present, although is usually abnormally short or small. The initial clinical sign of complete androgen insensitivity syndrome may be the failure to start menstruation. Breast development, however, may occur normally. Pubic and underarm hair growth is sparse or absent. Complete androgen insensitivity syndrome is caused by mutations of the androgen receptor gene and is inherited as an X-linked recessive trait. In extremely rare cases, vaginal agenesis or atresia can occur as an isolated development defect that is not associated with additional physical findings. More commonly, vaginal agenesis or atresia occurs as part of a larger syndrome including MRKH syndrome, Winter syndrome, McKusick-Kaufman syndrome and Fraser syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) There are a variety of disorders that have signs and symptoms with multiple abnormalities, some of which are similar to those encountered in type II MRKH syndrome. These disorders include Goldenhar syndrome, VACTERL association, and Turner's syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) The following disorders may be associated with MRKH syndrome type II as secondary characteristics. They are not necessary for a differential diagnosis: Klippel-Feil syndrome (KFS) is a rare skeletal disorder primarily characterized by abnormal union or fusion of two or more bones of the spinal column (vertebrae) within the neck (cervical vertebrae). Some affected individuals may also have an abnormally short neck, restricted movement of the head and neck, and a low hairline at the back of the head (posterior hairline). The disorder is present at birth (congenital), but mild cases may go undiagnosed until later during life when symptoms worsen or first become apparent. In some individuals, KFS can be associated with a variety of additional symptoms and physical abnormalities. These may include abnormal curvature of the spine (scoliosis) and/or vertebral instability, spina bifida occulta, raised scapula (Sprengel deformity), absent rib(s) and other rib defects including cervical ribs, other skeletal abnormalities including skeletal malformations of the ear, nose, mouth and larynx including hearing impairment and cleft palate, malformations of the head and facial (craniofacial) area; anomalies of the urinary tract and/or kidney including absent or horse-shoe kidney; or structural abnormalities of the heart (congenital heart defects), mirror movements, webbing of the digits and digital hypoplasia. In addition, in some cases, neurological complications may result due to associated spinal cord injury. KFS may occur as an isolated abnormality or in association with certain syndromes. In many individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). In other cases, KFS may be inherited as an autosomal dominant or autosomal recessive trait. Researchers have determined that some cases of KFS are associated with mutations of the GDF6 gene on chromosome 8. (For more information on this disorder, choose “Klippel-Feil” as your search term in the Rare Disease Database.) Sprengel deformity is a rare birth defect characterized by elevation and/or underdevelopment of the shoulder blade (scapula), limited movement of the arm on the affected side, and the development of a lump at the base of the neck due to the scapular elevation. In most cases, affected individuals also exhibit additional abnormalities, such as underdevelopment (hypoplasia) of shoulder muscles, a sideways curvature of the spine (scoliosis), fused vertebrae, underdevelopment of one side of vertebrae (hemivertebrae), missing and/or fused ribs, and/or incomplete closure of bones in the spinal column surrounding the spinal cord (spina bifida occulta). In most cases, Sprengel deformity appears to occur randomly, with no apparent cause (sporadic). However, in rare cases, the disorder may be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Sprengel deformity” as your search term in the Rare Disease Database.) Among the chromosomal segments found affected in MRKH syndrome, some have already been described in association with another genetic syndrome called DiGeorge syndrome. This syndrome generally presents with very severe anomalies in affected persons. These anomalies include congenital heart defects that require surgery, such as tetralogy of Fallot, interrupted aortic arch, or ventricular septal defect. Other main features are facial dysmorphy, cleft palate, hearing loss, underdevelopment of the thymus (thymic hypoplasia) causing abnormalities of the immune system, underactivity of the parathyroid glands (hypoparathyroïdism), and developmental and behavioral problems. Other less common manifestations, which overlap with MRKH syndrome, include renal (horseshoe, hydronephrosis), vertebral (butterfly vertebrae, hemivertebrae, abnormalities of the cervical spine, scoliosis, Sprengel deformity) and extremity anomalies (polydactyly, syndactyly, club-foot). Ninety percent of cases of DiGeorge syndrome are caused by a segmental deletion in chromosome 22. However, the manifestations of DiGeorge syndrome are also but less frequently observed in persons presenting with deletions in chromosome 4, 8, 10, 17 or 18, with chromosomes 4 and 10 being the most frequently affected. It has recently been found that some persons affected by MRKH syndrome, presented with chromosomal segmental deletions, mainly in chromosome 22, but also in chromosome 4, 8, 10 and 17. (For more information on this disorder, choose “DiGeorge” as your search term in the Rare Disease Database.)
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Related disorders of Mayer-Rokitansky-Küster-Hauser Syndrome. Symptoms of the following disorders can be similar to those of MRKH syndrome. Comparisons may be useful for a differential diagnosis. WTN4 syndrome is a rare genetic disorder that affects females. It is characterized by the absence of the uterus and abnormally high levels of androgens. Androgens are male sex hormones that control the development of male sexual characteristics. Consequently, females with WTN4 syndrome may develop acne and a male pattern of hair growth in females (hirsutism), which can include hair growth on the face or chest. In some cases, the vagina may be abnormally short or small. In the particular case of WNT4 syndrome, it seems that the ovaries undergo partial musculinization during embryonic development and then produce both male and female sex hormones. This is why, despite the signs of hirsutism, females with WTN4 syndrome develop normal secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle (primary amenorrhea). In rare cases, one kidney may fail to develop properly (unilateral renal aplasia). WTN4 syndrome is extremely similar to MRKH syndrome and is sometimes referred to as MRKH-like syndrome. WTN4 syndrome is caused by mutations of the WTN4 gene. (For more research on this disorder, choose “WTN4” as your search term in the Rare Disease Database.) Complete androgen insensitivity syndrome is a rare disorder in which individuals who are genetically male (46, XY), but do not respond to male sex hormones known as androgens. The disorder is characterized by the failure of a developing fetus to respond to the presence of androgens in the fetal bloodstream. Consequently, infants appear female at birth, but are genetically male and lack a uterus, Fallopian tubes and ovaries. A vagina may be absent or may present, although is usually abnormally short or small. The initial clinical sign of complete androgen insensitivity syndrome may be the failure to start menstruation. Breast development, however, may occur normally. Pubic and underarm hair growth is sparse or absent. Complete androgen insensitivity syndrome is caused by mutations of the androgen receptor gene and is inherited as an X-linked recessive trait. In extremely rare cases, vaginal agenesis or atresia can occur as an isolated development defect that is not associated with additional physical findings. More commonly, vaginal agenesis or atresia occurs as part of a larger syndrome including MRKH syndrome, Winter syndrome, McKusick-Kaufman syndrome and Fraser syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) There are a variety of disorders that have signs and symptoms with multiple abnormalities, some of which are similar to those encountered in type II MRKH syndrome. These disorders include Goldenhar syndrome, VACTERL association, and Turner's syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) The following disorders may be associated with MRKH syndrome type II as secondary characteristics. They are not necessary for a differential diagnosis: Klippel-Feil syndrome (KFS) is a rare skeletal disorder primarily characterized by abnormal union or fusion of two or more bones of the spinal column (vertebrae) within the neck (cervical vertebrae). Some affected individuals may also have an abnormally short neck, restricted movement of the head and neck, and a low hairline at the back of the head (posterior hairline). The disorder is present at birth (congenital), but mild cases may go undiagnosed until later during life when symptoms worsen or first become apparent. In some individuals, KFS can be associated with a variety of additional symptoms and physical abnormalities. These may include abnormal curvature of the spine (scoliosis) and/or vertebral instability, spina bifida occulta, raised scapula (Sprengel deformity), absent rib(s) and other rib defects including cervical ribs, other skeletal abnormalities including skeletal malformations of the ear, nose, mouth and larynx including hearing impairment and cleft palate, malformations of the head and facial (craniofacial) area; anomalies of the urinary tract and/or kidney including absent or horse-shoe kidney; or structural abnormalities of the heart (congenital heart defects), mirror movements, webbing of the digits and digital hypoplasia. In addition, in some cases, neurological complications may result due to associated spinal cord injury. KFS may occur as an isolated abnormality or in association with certain syndromes. In many individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). In other cases, KFS may be inherited as an autosomal dominant or autosomal recessive trait. Researchers have determined that some cases of KFS are associated with mutations of the GDF6 gene on chromosome 8. (For more information on this disorder, choose “Klippel-Feil” as your search term in the Rare Disease Database.) Sprengel deformity is a rare birth defect characterized by elevation and/or underdevelopment of the shoulder blade (scapula), limited movement of the arm on the affected side, and the development of a lump at the base of the neck due to the scapular elevation. In most cases, affected individuals also exhibit additional abnormalities, such as underdevelopment (hypoplasia) of shoulder muscles, a sideways curvature of the spine (scoliosis), fused vertebrae, underdevelopment of one side of vertebrae (hemivertebrae), missing and/or fused ribs, and/or incomplete closure of bones in the spinal column surrounding the spinal cord (spina bifida occulta). In most cases, Sprengel deformity appears to occur randomly, with no apparent cause (sporadic). However, in rare cases, the disorder may be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Sprengel deformity” as your search term in the Rare Disease Database.) Among the chromosomal segments found affected in MRKH syndrome, some have already been described in association with another genetic syndrome called DiGeorge syndrome. This syndrome generally presents with very severe anomalies in affected persons. These anomalies include congenital heart defects that require surgery, such as tetralogy of Fallot, interrupted aortic arch, or ventricular septal defect. Other main features are facial dysmorphy, cleft palate, hearing loss, underdevelopment of the thymus (thymic hypoplasia) causing abnormalities of the immune system, underactivity of the parathyroid glands (hypoparathyroïdism), and developmental and behavioral problems. Other less common manifestations, which overlap with MRKH syndrome, include renal (horseshoe, hydronephrosis), vertebral (butterfly vertebrae, hemivertebrae, abnormalities of the cervical spine, scoliosis, Sprengel deformity) and extremity anomalies (polydactyly, syndactyly, club-foot). Ninety percent of cases of DiGeorge syndrome are caused by a segmental deletion in chromosome 22. However, the manifestations of DiGeorge syndrome are also but less frequently observed in persons presenting with deletions in chromosome 4, 8, 10, 17 or 18, with chromosomes 4 and 10 being the most frequently affected. It has recently been found that some persons affected by MRKH syndrome, presented with chromosomal segmental deletions, mainly in chromosome 22, but also in chromosome 4, 8, 10 and 17. (For more information on this disorder, choose “DiGeorge” as your search term in the Rare Disease Database.)
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Diagnosis of Mayer-Rokitansky-Küster-Hauser Syndrome
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In most cases, females with MRKH syndrome come to the attention of physicians due to the failure of menstrual cycles to begin during puberty (primary amenorrhea). Some may seek medical attention due to fertility problems. In rare cases, multiple congenital malformations and/or symptoms caused by renal abnormalities may lead to a possible diagnosis of MRKH syndrome type II.A diagnosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as specialized imaging techniques. Transabdominal ultrasonography must be the first investigation. It may be complemented by magnetic resonance imaging (MRI). An ultrasound records echoes of high-frequency sound waves to produce a detailed image of deep structures within the body. An ultrasound can depict the uterus and vagina. It can also be used to evaluate the kidneys. An ultrasound is a simple, noninvasive procedure that lacks radiation. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. It is also noninvasive and is generally more sensitive than an ultrasound. In addition to evaluating the uterus and vagina, an MRI can simultaneously be used to evaluate the kidney and skeleton.Karyotyping may be performed to rule out other conditions. Karyotyping is used to examine the chromosomes in a sample of cells. Females with MRKH syndrome have a normal 46, XX karyotype.Establishing an accurate diagnosis of MRKH syndrome also requires the search for other eventually associated malformations, and will also include some biological tests necessary for the differential diagnosis. Once MRKH syndrome is diagnosed, a full check-up must be undertaken to search for associated malformations. Since renal and skeletal abnormalities may not be symptomatic, it is necessary to perform at least a transabdominal ultrasonography and spinal radiography. In case of suspicion of hearing impairment and/or a cardiac anomaly, complementary audiogram and/or heart echography must also be carried out.In women diagnosed for MRKH syndrome, levels of FSH (plasmatic follicle stimulating hormone), LH (luteinizing hormone) and 17ß-oestradiol are normal, proving the integrity of ovarian function. There is no biological hyperandrogenism, as shown by a normal plasmatic level of testosterone. Hyperandrogenism is the term for the excessive secretion of male sex hormones (androgens) and is caused by a variety of ovarian and adrenal diseases.
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Diagnosis of Mayer-Rokitansky-Küster-Hauser Syndrome. In most cases, females with MRKH syndrome come to the attention of physicians due to the failure of menstrual cycles to begin during puberty (primary amenorrhea). Some may seek medical attention due to fertility problems. In rare cases, multiple congenital malformations and/or symptoms caused by renal abnormalities may lead to a possible diagnosis of MRKH syndrome type II.A diagnosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as specialized imaging techniques. Transabdominal ultrasonography must be the first investigation. It may be complemented by magnetic resonance imaging (MRI). An ultrasound records echoes of high-frequency sound waves to produce a detailed image of deep structures within the body. An ultrasound can depict the uterus and vagina. It can also be used to evaluate the kidneys. An ultrasound is a simple, noninvasive procedure that lacks radiation. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. It is also noninvasive and is generally more sensitive than an ultrasound. In addition to evaluating the uterus and vagina, an MRI can simultaneously be used to evaluate the kidney and skeleton.Karyotyping may be performed to rule out other conditions. Karyotyping is used to examine the chromosomes in a sample of cells. Females with MRKH syndrome have a normal 46, XX karyotype.Establishing an accurate diagnosis of MRKH syndrome also requires the search for other eventually associated malformations, and will also include some biological tests necessary for the differential diagnosis. Once MRKH syndrome is diagnosed, a full check-up must be undertaken to search for associated malformations. Since renal and skeletal abnormalities may not be symptomatic, it is necessary to perform at least a transabdominal ultrasonography and spinal radiography. In case of suspicion of hearing impairment and/or a cardiac anomaly, complementary audiogram and/or heart echography must also be carried out.In women diagnosed for MRKH syndrome, levels of FSH (plasmatic follicle stimulating hormone), LH (luteinizing hormone) and 17ß-oestradiol are normal, proving the integrity of ovarian function. There is no biological hyperandrogenism, as shown by a normal plasmatic level of testosterone. Hyperandrogenism is the term for the excessive secretion of male sex hormones (androgens) and is caused by a variety of ovarian and adrenal diseases.
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Therapies of Mayer-Rokitansky-Küster-Hauser Syndrome
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TreatmentThe treatment of MRKH syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Depending upon the affected individual's age at diagnosis, pediatricians or internists, gynecologists, kidney specialists (nephrologists), endocrinologist, orthopedic surgeons, plastic surgeons, physical therapists, psychiatrists and other health care professionals may need to work together to ensure a comprehensive approach to treatment.Women with MRKH syndrome are encouraged to seek counseling after a diagnosis and before treatment because the diagnosis can cause anxiety and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected females and their families.Treatment will usually include appropriate management of the physical findings associated with MRKH syndrome and psychological support for the emotional issues that often accompany the diagnosis.The treatment of vaginal aplasia consists of creating a neovagina for sexual intercourse. This should be proposed to the women when they are emotionally mature and ready to start sexual activity. Treatment may be either nonsurgical or surgical. Nonsurgical techniques are considered the first-line approach. Vaginal dilators are specially designed plastic tubes that are used to help enlarge or create a vagina. The most common method is known as Franck's dilator method. With this method, a physician (and then woman herself) applies a vaginal dilator, which progressively stretches and widens the vagina. This daily procedure may be continued for up to six weeks to several months.Plastic surgery may be necessary to create an artificial vagina (vaginoplasty). There are a variety of different surgical techniques that may be used and there is no consensus as to which technique is best. Females who undergo surgery to create an artificial vagina will most likely need to use vaginal dilators after the surgery to enhance the chance of success.Because females with MRKH syndrome do not have a functional uterus, they cannot bear children (infertile). However, some affected women have been able to have a child by using in vitro fertilization of their own eggs and surrogate pregnancy. However, because MRKH syndrome appears to be of genetic origin, the risk of passing on the disease to children exists and any decision to conceive should therefore be undertaken after careful consultation with their physicians and appropriate medical personnel.Females with MRKH syndrome who exhibit absence of one kidney (unilateral renal agenesis) may have an increased susceptibility to urinary tract infections and/or kidney stones (renal calculi). Physicians should carefully monitor affected females for infection and prescribe antibiotics as necessary. Skeletal abnormalities may also require reconstructive surgery, physical therapy, and/or other medical management depending upon the specifics and severity of the bone deformities.
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Therapies of Mayer-Rokitansky-Küster-Hauser Syndrome. TreatmentThe treatment of MRKH syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Depending upon the affected individual's age at diagnosis, pediatricians or internists, gynecologists, kidney specialists (nephrologists), endocrinologist, orthopedic surgeons, plastic surgeons, physical therapists, psychiatrists and other health care professionals may need to work together to ensure a comprehensive approach to treatment.Women with MRKH syndrome are encouraged to seek counseling after a diagnosis and before treatment because the diagnosis can cause anxiety and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected females and their families.Treatment will usually include appropriate management of the physical findings associated with MRKH syndrome and psychological support for the emotional issues that often accompany the diagnosis.The treatment of vaginal aplasia consists of creating a neovagina for sexual intercourse. This should be proposed to the women when they are emotionally mature and ready to start sexual activity. Treatment may be either nonsurgical or surgical. Nonsurgical techniques are considered the first-line approach. Vaginal dilators are specially designed plastic tubes that are used to help enlarge or create a vagina. The most common method is known as Franck's dilator method. With this method, a physician (and then woman herself) applies a vaginal dilator, which progressively stretches and widens the vagina. This daily procedure may be continued for up to six weeks to several months.Plastic surgery may be necessary to create an artificial vagina (vaginoplasty). There are a variety of different surgical techniques that may be used and there is no consensus as to which technique is best. Females who undergo surgery to create an artificial vagina will most likely need to use vaginal dilators after the surgery to enhance the chance of success.Because females with MRKH syndrome do not have a functional uterus, they cannot bear children (infertile). However, some affected women have been able to have a child by using in vitro fertilization of their own eggs and surrogate pregnancy. However, because MRKH syndrome appears to be of genetic origin, the risk of passing on the disease to children exists and any decision to conceive should therefore be undertaken after careful consultation with their physicians and appropriate medical personnel.Females with MRKH syndrome who exhibit absence of one kidney (unilateral renal agenesis) may have an increased susceptibility to urinary tract infections and/or kidney stones (renal calculi). Physicians should carefully monitor affected females for infection and prescribe antibiotics as necessary. Skeletal abnormalities may also require reconstructive surgery, physical therapy, and/or other medical management depending upon the specifics and severity of the bone deformities.
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Mayer-Rokitansky-Küster-Hauser Syndrome
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Overview of McCune Albright Syndrome
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SummaryMcCune-Albright syndrome (MAS) is an extremely rare disorder that classically affects the bones, skin, and endocrine system. MAS is characterized by fibrous dysplasia of bone that occurs with at least two additional findings – patches of abnormal skin pigmentation (i.e., areas of light-brown skin [cafe-au-lait spots] with jagged borders) and dysfunction of certain glands that regulate the body’s rate of growth, its sexual development, and certain other metabolic functions (multiple endocrine dysfunction). Fibrous dysplasia refers to bone that is replaced by abnormal scar-like (fibrous) connective tissue. This abnormal fibrous tissue weakens the bone, making it abnormally fragile and prone to fracture. Pain may occur in the affected areas. Malfunctioning endocrine glands can result in the development of secondary sexual characteristics at an age younger than normal (gonadotropin independent precocious puberty). MAS is the result of a genetic change (mutation) in the GNAS1 gene that occurs randomly, for no apparent reason (sporadic). In individuals with the disorder, this sporadic genetic mutation is present in only some of the body’s cells (mosaic pattern). The symptoms and physical characteristics associated with the disorder vary greatly from person to person, depending upon the specific body cells and tissues that are affected by the genetic mutation. This mutation occurs after fertilization (postzygotic somatic mutation). It is not inherited from the parents.
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Overview of McCune Albright Syndrome. SummaryMcCune-Albright syndrome (MAS) is an extremely rare disorder that classically affects the bones, skin, and endocrine system. MAS is characterized by fibrous dysplasia of bone that occurs with at least two additional findings – patches of abnormal skin pigmentation (i.e., areas of light-brown skin [cafe-au-lait spots] with jagged borders) and dysfunction of certain glands that regulate the body’s rate of growth, its sexual development, and certain other metabolic functions (multiple endocrine dysfunction). Fibrous dysplasia refers to bone that is replaced by abnormal scar-like (fibrous) connective tissue. This abnormal fibrous tissue weakens the bone, making it abnormally fragile and prone to fracture. Pain may occur in the affected areas. Malfunctioning endocrine glands can result in the development of secondary sexual characteristics at an age younger than normal (gonadotropin independent precocious puberty). MAS is the result of a genetic change (mutation) in the GNAS1 gene that occurs randomly, for no apparent reason (sporadic). In individuals with the disorder, this sporadic genetic mutation is present in only some of the body’s cells (mosaic pattern). The symptoms and physical characteristics associated with the disorder vary greatly from person to person, depending upon the specific body cells and tissues that are affected by the genetic mutation. This mutation occurs after fertilization (postzygotic somatic mutation). It is not inherited from the parents.
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McCune Albright Syndrome
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Symptoms of McCune Albright Syndrome
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The range of severity of McCune-Albright syndrome is broad: some children are diagnosed in early infancy with obvious anomalies of bone and increased hormone production by one or more of the endocrine glands; others show no evidence of bone, skin or endocrine malfunction in childhood and may enter puberty at an appropriate age. The degree of severity of individual symptoms may also vary greatly. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every individual case is unique. Parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.The parts of the body most commonly affected by MAS are the bone, skin and endocrine system.BONE
Polyostotic fibrous dysplasia is a distinctive finding in affected individuals. Fibrous dysplasia refers to bone that is replaced by abnormal scar-like (fibrous) connective tissue. This abnormal fibrous tissue weakens the bone, making it abnormally fragile and prone to fracture. Fracture may be the presenting symptom in some cases. Pain may occur in the affected areas. Polyostotic refers to cases in which multiple skeletal sites are affected, but in some cases only one skeletal site is affected (monostotic fibrous dysplasia). Fibrous dysplasia often predominates on one side of the body (unilateral).Specific symptoms associated with polyostotic fibrous dysplasia depend upon the specific bones involved. Any part of the skeleton can potentially be affected, but the long bones of the arms and legs, the bones of the face and skull (craniofacial area), and the ribs are most often affected. Polyostotic fibrous dysplasia often presents as a painless swellings on the ribs. Fibrous dysplasia affecting the spine can cause abnormal curvature of the spine (scoliosis), which is often progressive. When the long bones of the legs are affected, this can lead to frequent fractures due to weight bearing when walking or standing. Additionally, the long bones can eventually become bowed. In children, their legs may not be of equal length (limb length discrepancy). Eventually, this can affect a person’s ability to walk, causing an abnormal gait (e.g. walking with a limp).Some affected individual develop polyostotic fibrous dysplasia of the craniofacial region, which can cause a variety of symptoms depending on the type and specific location of the lesions(s). Such symptoms can include pain, nasal congestion, misaligned or displaced teeth, uneven jaws, and facial asymmetry, in which one side of the face does not match the other side. Polyostotic fibrous dysplasia in the craniofacial region can alter the facial features resulting in an abnormally prominent forehead (frontal bossing), bulging eyes (proptosis), and difference in the vertical positions of the eyes so that the eyes are uneven (vertical dystopia). The degree of facial abnormality can vary greatly from one person to another. The shape of the skull may be altered in certain cases.Fibrous dysplasia lesions can potentially cause a variety of neurological symptoms as areas of abnormal tissue development can compress nearby nerves. Specific symptoms are related to the specific nerves involved. For example, vision loss or hearing impairment can occur because of compression of optic and auditory nerves in the skull. However, vision loss and hearing impairment only occur in rare instances.SKIN
Some individuals with MAS have abnormal skin coloring (pigmentation) known as café-au-lait spots. Café-au-lait spots are abnormal patches of light-brown skin that have irregularly-shaped, jagged borders. They may be present at birth or shortly thereafter (neonatal period) and may become more pronounced with age. Individual lesions often abruptly stop at the midline of the body, which is the imaginary line that divides the body into right and left halves. The lesions can be of varying size and often affect only one side of the body. Some individuals do not develop café-au-lait spots.ENDOCRINE DYSFUNCTION
The endocrine system is the system of glands that regulate the body’s rate of growth, its sexual development, and certain other metabolic functions. Individuals with MAS often experience an abnormally early onset of puberty (gonadotropin independent precocious puberty). A sequence of events occurs during which a child develops adult secondary sexual characteristics beginning at an unexpectedly early age. In MAS, this occurs because glands that secrete sex hormones are inappropriately active abnormally early in life.In females, there may be vaginal bleeding or early development of breast tissue. Onset can be within the first few months of life or later during childhood around 6 or 7 years of age. Some females may have frequent episodes of vaginal bleeding, while others may only have a few sporadic episodes. Precocious puberty is often associated with the development of benign ovarian cysts. Precocious puberty may result in an advanced bone age, which could potentially limit growth potential and final adult height.Precocious puberty is more common in females than males with more than 50% of females experiencing precocious puberty. In males, there may be enlargement of the penis and one or both testicles. The scrotum may thicken and gain wrinkles (rugae). Males may also grow pubic hair, hair under the armpits, and body odor.Children with precocious puberty are often tall and have an increased growth velocity while they are still growing. Individuals end up short because they finish growing earlier than other people.Other endocrine disorders may occur in individuals with MAS including those affecting the thyroid, the pituitary, and adrenal glands.The thyroid is a butterfly-shaped gland at the base of the neck. Involvement of the thyroid may range from no obvious clinical symptoms to enlargement of the thyroid (goiter) and overproduction of thyroid hormone (hyperthyroidism). Hyperthyroidism can cause anxiety, fatigue, prominence of the eyes, sweating, heart palpitations, unintended weight loss, and heat intolerance. Osteoporosis may be caused by or worsened by hyperthyroidism. In some cases, hyperthyroidism cannot be controlled by medication.The pituitary gland is a small gland located near the base of the skull that stores several hormones including growth hormone and releases them into the bloodstream as needed by the body. Some individuals with MAS experience excessive levels of growth hormone. Growth hormone has several functions in the body such as affecting growth and muscle mass. Increased growth velocity is the most common sign of growth hormone excess, however, in individuals with precocious puberty this may be masked (because precocious puberty has already increased the growth spurt). Growth hormone excess can lead to an abnormally large head (macrocephaly) and can potentially cause vision problems. Some individuals with MAS develop a disorder known as acromegaly, which is due to growth hormone excess after the growth plates have fused. The development of acromegaly can be associated with fibrous dysplasia affecting the skull base. (For more information on this disorder, choose “acromegaly” as your search term in the Rare Disease Database.)The adrenal glands are located above the kidneys near the lower back and produce several hormones including cortisol. Cortisol is a glucocorticoid, a class of steroid hormone that is important in regulating metabolism of glucose and modulating stress. Individuals with MAS may have elevated levels of cortisol and can development a disorder known as Cushing syndrome. Symptoms can include upper body obesity, a round face, thin purple streaks (striae) that occur on the skin, increased fat around the neck, and thin, slender arms and legs. Children with Cushing syndrome are typically obese with slowed growth rates. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)Some individuals with MAS develop elevated levels of phosphate in the blood (hypophosphatemia) because the kidneys cannot properly reabsorb phosphate. This occurs because fibrous dysplasia tissue produces a protein known as fibroblast growth factor 23 (FGF23). The amount of FGF23 correlates to the inability of the kidneys to metabolize phosphate (renal phosphate wasting). Therefore, individuals with significant fibrous dysplasia are more likely to develop hypophosphatemia. Hypophosphatemia can cause severe rickets or osteomalacia. Rickets is a childhood bone disease with characteristic bowing deformity of the legs and can contribute to short stature. Individuals with hypophosphatemia generally experience their first fracture at a younger age than individuals with MAS who do not have hypophosphatemia. Individuals with hypophosphatemia also develop more fractures and bone pain. In adults, hypophosphatemia can cause osteomalacia, a softening of the bones.ADDITIONAL FINDINGS
Less common symptoms sometimes associated with MAS include gastroesophageal reflux, gastrointestinal polyps, inflammation of the pancreas (pancreatitis), and several abnormalities of the heart (cardiac abnormalities). Such abnormalities include a faster than normal heart rate (tachycardia), high output heart failure, and aortic root dilatation.Although the term tumor may be used to describe fibrous dysplasia lesions, these growths are benign (non-cancerous). Only in extremely rare cases, likely less than 1% of patients, have these lesions become cancerous (malignant transformation). These malignant tumors (osteosarcomas) developed in individuals who had been radiated for bone pain; a treatment option that has been abandoned.Individuals may also be at an increased risk of developing breast cancer or tumors of the liver, bile duct or pancreas. Some reports suggest that this increased risk is more likely in individuals with growth hormone excess. Thyroid cancer and testicular cancer have also been reported in individuals with MAS in extremely rare instances.
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Symptoms of McCune Albright Syndrome. The range of severity of McCune-Albright syndrome is broad: some children are diagnosed in early infancy with obvious anomalies of bone and increased hormone production by one or more of the endocrine glands; others show no evidence of bone, skin or endocrine malfunction in childhood and may enter puberty at an appropriate age. The degree of severity of individual symptoms may also vary greatly. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every individual case is unique. Parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.The parts of the body most commonly affected by MAS are the bone, skin and endocrine system.BONE
Polyostotic fibrous dysplasia is a distinctive finding in affected individuals. Fibrous dysplasia refers to bone that is replaced by abnormal scar-like (fibrous) connective tissue. This abnormal fibrous tissue weakens the bone, making it abnormally fragile and prone to fracture. Fracture may be the presenting symptom in some cases. Pain may occur in the affected areas. Polyostotic refers to cases in which multiple skeletal sites are affected, but in some cases only one skeletal site is affected (monostotic fibrous dysplasia). Fibrous dysplasia often predominates on one side of the body (unilateral).Specific symptoms associated with polyostotic fibrous dysplasia depend upon the specific bones involved. Any part of the skeleton can potentially be affected, but the long bones of the arms and legs, the bones of the face and skull (craniofacial area), and the ribs are most often affected. Polyostotic fibrous dysplasia often presents as a painless swellings on the ribs. Fibrous dysplasia affecting the spine can cause abnormal curvature of the spine (scoliosis), which is often progressive. When the long bones of the legs are affected, this can lead to frequent fractures due to weight bearing when walking or standing. Additionally, the long bones can eventually become bowed. In children, their legs may not be of equal length (limb length discrepancy). Eventually, this can affect a person’s ability to walk, causing an abnormal gait (e.g. walking with a limp).Some affected individual develop polyostotic fibrous dysplasia of the craniofacial region, which can cause a variety of symptoms depending on the type and specific location of the lesions(s). Such symptoms can include pain, nasal congestion, misaligned or displaced teeth, uneven jaws, and facial asymmetry, in which one side of the face does not match the other side. Polyostotic fibrous dysplasia in the craniofacial region can alter the facial features resulting in an abnormally prominent forehead (frontal bossing), bulging eyes (proptosis), and difference in the vertical positions of the eyes so that the eyes are uneven (vertical dystopia). The degree of facial abnormality can vary greatly from one person to another. The shape of the skull may be altered in certain cases.Fibrous dysplasia lesions can potentially cause a variety of neurological symptoms as areas of abnormal tissue development can compress nearby nerves. Specific symptoms are related to the specific nerves involved. For example, vision loss or hearing impairment can occur because of compression of optic and auditory nerves in the skull. However, vision loss and hearing impairment only occur in rare instances.SKIN
Some individuals with MAS have abnormal skin coloring (pigmentation) known as café-au-lait spots. Café-au-lait spots are abnormal patches of light-brown skin that have irregularly-shaped, jagged borders. They may be present at birth or shortly thereafter (neonatal period) and may become more pronounced with age. Individual lesions often abruptly stop at the midline of the body, which is the imaginary line that divides the body into right and left halves. The lesions can be of varying size and often affect only one side of the body. Some individuals do not develop café-au-lait spots.ENDOCRINE DYSFUNCTION
The endocrine system is the system of glands that regulate the body’s rate of growth, its sexual development, and certain other metabolic functions. Individuals with MAS often experience an abnormally early onset of puberty (gonadotropin independent precocious puberty). A sequence of events occurs during which a child develops adult secondary sexual characteristics beginning at an unexpectedly early age. In MAS, this occurs because glands that secrete sex hormones are inappropriately active abnormally early in life.In females, there may be vaginal bleeding or early development of breast tissue. Onset can be within the first few months of life or later during childhood around 6 or 7 years of age. Some females may have frequent episodes of vaginal bleeding, while others may only have a few sporadic episodes. Precocious puberty is often associated with the development of benign ovarian cysts. Precocious puberty may result in an advanced bone age, which could potentially limit growth potential and final adult height.Precocious puberty is more common in females than males with more than 50% of females experiencing precocious puberty. In males, there may be enlargement of the penis and one or both testicles. The scrotum may thicken and gain wrinkles (rugae). Males may also grow pubic hair, hair under the armpits, and body odor.Children with precocious puberty are often tall and have an increased growth velocity while they are still growing. Individuals end up short because they finish growing earlier than other people.Other endocrine disorders may occur in individuals with MAS including those affecting the thyroid, the pituitary, and adrenal glands.The thyroid is a butterfly-shaped gland at the base of the neck. Involvement of the thyroid may range from no obvious clinical symptoms to enlargement of the thyroid (goiter) and overproduction of thyroid hormone (hyperthyroidism). Hyperthyroidism can cause anxiety, fatigue, prominence of the eyes, sweating, heart palpitations, unintended weight loss, and heat intolerance. Osteoporosis may be caused by or worsened by hyperthyroidism. In some cases, hyperthyroidism cannot be controlled by medication.The pituitary gland is a small gland located near the base of the skull that stores several hormones including growth hormone and releases them into the bloodstream as needed by the body. Some individuals with MAS experience excessive levels of growth hormone. Growth hormone has several functions in the body such as affecting growth and muscle mass. Increased growth velocity is the most common sign of growth hormone excess, however, in individuals with precocious puberty this may be masked (because precocious puberty has already increased the growth spurt). Growth hormone excess can lead to an abnormally large head (macrocephaly) and can potentially cause vision problems. Some individuals with MAS develop a disorder known as acromegaly, which is due to growth hormone excess after the growth plates have fused. The development of acromegaly can be associated with fibrous dysplasia affecting the skull base. (For more information on this disorder, choose “acromegaly” as your search term in the Rare Disease Database.)The adrenal glands are located above the kidneys near the lower back and produce several hormones including cortisol. Cortisol is a glucocorticoid, a class of steroid hormone that is important in regulating metabolism of glucose and modulating stress. Individuals with MAS may have elevated levels of cortisol and can development a disorder known as Cushing syndrome. Symptoms can include upper body obesity, a round face, thin purple streaks (striae) that occur on the skin, increased fat around the neck, and thin, slender arms and legs. Children with Cushing syndrome are typically obese with slowed growth rates. (For more information on this disorder, choose “Cushing” as your search term in the Rare Disease Database.)Some individuals with MAS develop elevated levels of phosphate in the blood (hypophosphatemia) because the kidneys cannot properly reabsorb phosphate. This occurs because fibrous dysplasia tissue produces a protein known as fibroblast growth factor 23 (FGF23). The amount of FGF23 correlates to the inability of the kidneys to metabolize phosphate (renal phosphate wasting). Therefore, individuals with significant fibrous dysplasia are more likely to develop hypophosphatemia. Hypophosphatemia can cause severe rickets or osteomalacia. Rickets is a childhood bone disease with characteristic bowing deformity of the legs and can contribute to short stature. Individuals with hypophosphatemia generally experience their first fracture at a younger age than individuals with MAS who do not have hypophosphatemia. Individuals with hypophosphatemia also develop more fractures and bone pain. In adults, hypophosphatemia can cause osteomalacia, a softening of the bones.ADDITIONAL FINDINGS
Less common symptoms sometimes associated with MAS include gastroesophageal reflux, gastrointestinal polyps, inflammation of the pancreas (pancreatitis), and several abnormalities of the heart (cardiac abnormalities). Such abnormalities include a faster than normal heart rate (tachycardia), high output heart failure, and aortic root dilatation.Although the term tumor may be used to describe fibrous dysplasia lesions, these growths are benign (non-cancerous). Only in extremely rare cases, likely less than 1% of patients, have these lesions become cancerous (malignant transformation). These malignant tumors (osteosarcomas) developed in individuals who had been radiated for bone pain; a treatment option that has been abandoned.Individuals may also be at an increased risk of developing breast cancer or tumors of the liver, bile duct or pancreas. Some reports suggest that this increased risk is more likely in individuals with growth hormone excess. Thyroid cancer and testicular cancer have also been reported in individuals with MAS in extremely rare instances.
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McCune Albright Syndrome
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Causes of McCune Albright Syndrome
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McCune-Albright syndrome is caused by a mutation in a gene called GNAS1. This gene mutation occurs after fertilization of the embryo (somatic mutation) and is therefore not inherited, nor will affected individuals pass the mutation on to their children. Affected individuals have some cells with a normal copy of this gene and some cells with the abnormal gene (mosaic pattern). The variability of symptoms of MAS is due, in part, to the ratio of healthy cells to abnormal cells. Researchers do not know why these somatic mutations occur; they appear to develop randomly for unknown reasons (sporadically).The GNAS1 gene is located on the long arm (q) of chromosome 20 (20q13.2) Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 20q13.2” refers to band 13.2 on the long arm of chromosome 20. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The GNAS1 gene creates (encodes) a subunit of a protein known as a G-protein. In MAS, a gain-of-function mutation in the GNAS1 gene results in continuous activation of this G-protein. In turn, there is an overproduction of a molecule known as cyclic adenosine monophosphate (cAMP), which is involved in various chemical processes of the body.Overproduction of cAMP contributes to the development of symptoms. For example, cAMP is involved in the change (differentiation) of osteoblasts in bone. Osteoblasts are immature bone-forming cells that form new bone. The human skeleton is living tissue that is constantly changing (remodeling). It is believed that MAS involves increased bone turnover. Bone turnover is a normal process in which bone gradually breaks down (bone resorption) and then reforms. Bone turnover involves osteoblasts and cells that control bone resorption (osteoclasts). The interaction between osteoclasts and osteoblasts determines how bone reforms. The interaction is a complex process that involves many factors. Improper differentiation of osteoblasts due to mutation of the GNAS1 gene is believed to contribute to the development of fibrous dysplasia in individuals with MAS.When a GNAS1 mutation affects skin or endocrine cells, the additional characteristic symptoms of MAS can develop.
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Causes of McCune Albright Syndrome. McCune-Albright syndrome is caused by a mutation in a gene called GNAS1. This gene mutation occurs after fertilization of the embryo (somatic mutation) and is therefore not inherited, nor will affected individuals pass the mutation on to their children. Affected individuals have some cells with a normal copy of this gene and some cells with the abnormal gene (mosaic pattern). The variability of symptoms of MAS is due, in part, to the ratio of healthy cells to abnormal cells. Researchers do not know why these somatic mutations occur; they appear to develop randomly for unknown reasons (sporadically).The GNAS1 gene is located on the long arm (q) of chromosome 20 (20q13.2) Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 20q13.2” refers to band 13.2 on the long arm of chromosome 20. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The GNAS1 gene creates (encodes) a subunit of a protein known as a G-protein. In MAS, a gain-of-function mutation in the GNAS1 gene results in continuous activation of this G-protein. In turn, there is an overproduction of a molecule known as cyclic adenosine monophosphate (cAMP), which is involved in various chemical processes of the body.Overproduction of cAMP contributes to the development of symptoms. For example, cAMP is involved in the change (differentiation) of osteoblasts in bone. Osteoblasts are immature bone-forming cells that form new bone. The human skeleton is living tissue that is constantly changing (remodeling). It is believed that MAS involves increased bone turnover. Bone turnover is a normal process in which bone gradually breaks down (bone resorption) and then reforms. Bone turnover involves osteoblasts and cells that control bone resorption (osteoclasts). The interaction between osteoclasts and osteoblasts determines how bone reforms. The interaction is a complex process that involves many factors. Improper differentiation of osteoblasts due to mutation of the GNAS1 gene is believed to contribute to the development of fibrous dysplasia in individuals with MAS.When a GNAS1 mutation affects skin or endocrine cells, the additional characteristic symptoms of MAS can develop.
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McCune Albright Syndrome
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Affects of McCune Albright Syndrome
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McCune-Albright syndrome affects males and females in equal numbers. Precocious puberty is more common in females. The disorder is estimated to affect 1 in 100,000 to 1 in 1,000,000 individuals in the general population. Because the disorder is difficult to diagnose, affected individuals may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of MAS in the general population.
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Affects of McCune Albright Syndrome. McCune-Albright syndrome affects males and females in equal numbers. Precocious puberty is more common in females. The disorder is estimated to affect 1 in 100,000 to 1 in 1,000,000 individuals in the general population. Because the disorder is difficult to diagnose, affected individuals may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of MAS in the general population.
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McCune Albright Syndrome
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Related disorders of McCune Albright Syndrome
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Symptoms of the following disorders can be similar to those of McCune-Albright syndrome. Comparisons may be useful for a differential diagnosis.Fibrous dysplasia (FD) is a rare bone disorder. Some individuals with a mutation in the GNAS1 gene may develop FD, but not the other characteristic symptoms of MAS. FD may only affect one solitary bone (monostotic disease) or the disorder can be widespread, affecting multiple bones throughout the body (polyostotic disease). The severity of the disorder can vary greatly from one person to another. Any part of the skeleton can be affected, but the long bones of the legs, the bones of the face and skull (craniofacial area), and the ribs are most often affected. FD is usually diagnosed in children or young adults, but mild cases may go undiagnosed until adulthood. In some cases, FD may not require treatment; in other cases, certain medications and surgical procedures may be recommended. (For more information on this disorder, choose “fibrous dysplasia” as your search term in the Rare Disease Database.)Neurofibromatosis type 1 is a rare genetic disorder characterized by the appearance of light brown discolorations (“cafe-au-lait” spots) on the skin; freckling, particularly under the arms (axillary) and/or in the area of the groin (inguinal); multiple benign tumors of the nerves and skin; benign tumor-like nodules on the colored portion of the eyes (iris Lisch nodules); and/or, in some cases, slow-growing tumors of the optic nerve (or optic chiasm). Affected individuals may also have an abnormally large head (macrocephaly), widely spaced eyes (ocular hypertelorism), short stature, abnormal sideways curvature of the spine (scoliosis), and/or other skeletal abnormalities. Some individuals with neurofibromatosis type 1 may also have learning disabilities and speech impairment. Additional physical abnormalities may also be present in many cases. Neurofibromatosis type 1 is an autosomal dominant genetic disorder. Cases in which a positive family history has not been found are thought to represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose “neurofibromatosis type 1” as your search term in the Rare Disease Database.)Cherubism is a rare disorder characterized by displacement of normal bone tissue with areas of fibrous growth (fibrous dysplasia) within the upper and/or lower jaw bones (maxilla and/or mandible) on both sides of the face (bilateral). This causes abnormal expansion of the jaw bones, unusual chubbiness and swelling of the face, and, in severe cases, “upturning” of the eyes. In some cases, fibrous dysplasia may also occur in other bones of the body, particularly the ribs. Some affected individuals may also exhibit other abnormalities such as multiple, patchy areas of dark pigmentation (cafe-au-lait spots) and/or several warty birthmarks (nevi) on the skin. Symptoms usually become apparent in the third or fourth year of life. Cherubism is thought to be inherited as an autosomal dominant genetic trait with variable expressivity and penetrance. Whereas 100% of affected males with a defective gene for cherubism will exhibit the characteristics typically associated with the disorder (high penetrance), only 50 to 75% of females with the disease gene demonstrate symptoms of the disease (reduced penetrance). Mutations in the SH3BP2 gene are associated with approximately 80% of individuals with cherubism.Additional disorders may have specific symptoms that are similar to those seen in MAS including non-ossifying fibromas, idiopathic central precocious puberty, congenital adrenal hyperplasia, ovarian neoplasm, osteofibrous dysplasia, Proteus syndrome, Russell-Silver syndrome, and Mazabraud syndrome. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of McCune Albright Syndrome. Symptoms of the following disorders can be similar to those of McCune-Albright syndrome. Comparisons may be useful for a differential diagnosis.Fibrous dysplasia (FD) is a rare bone disorder. Some individuals with a mutation in the GNAS1 gene may develop FD, but not the other characteristic symptoms of MAS. FD may only affect one solitary bone (monostotic disease) or the disorder can be widespread, affecting multiple bones throughout the body (polyostotic disease). The severity of the disorder can vary greatly from one person to another. Any part of the skeleton can be affected, but the long bones of the legs, the bones of the face and skull (craniofacial area), and the ribs are most often affected. FD is usually diagnosed in children or young adults, but mild cases may go undiagnosed until adulthood. In some cases, FD may not require treatment; in other cases, certain medications and surgical procedures may be recommended. (For more information on this disorder, choose “fibrous dysplasia” as your search term in the Rare Disease Database.)Neurofibromatosis type 1 is a rare genetic disorder characterized by the appearance of light brown discolorations (“cafe-au-lait” spots) on the skin; freckling, particularly under the arms (axillary) and/or in the area of the groin (inguinal); multiple benign tumors of the nerves and skin; benign tumor-like nodules on the colored portion of the eyes (iris Lisch nodules); and/or, in some cases, slow-growing tumors of the optic nerve (or optic chiasm). Affected individuals may also have an abnormally large head (macrocephaly), widely spaced eyes (ocular hypertelorism), short stature, abnormal sideways curvature of the spine (scoliosis), and/or other skeletal abnormalities. Some individuals with neurofibromatosis type 1 may also have learning disabilities and speech impairment. Additional physical abnormalities may also be present in many cases. Neurofibromatosis type 1 is an autosomal dominant genetic disorder. Cases in which a positive family history has not been found are thought to represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose “neurofibromatosis type 1” as your search term in the Rare Disease Database.)Cherubism is a rare disorder characterized by displacement of normal bone tissue with areas of fibrous growth (fibrous dysplasia) within the upper and/or lower jaw bones (maxilla and/or mandible) on both sides of the face (bilateral). This causes abnormal expansion of the jaw bones, unusual chubbiness and swelling of the face, and, in severe cases, “upturning” of the eyes. In some cases, fibrous dysplasia may also occur in other bones of the body, particularly the ribs. Some affected individuals may also exhibit other abnormalities such as multiple, patchy areas of dark pigmentation (cafe-au-lait spots) and/or several warty birthmarks (nevi) on the skin. Symptoms usually become apparent in the third or fourth year of life. Cherubism is thought to be inherited as an autosomal dominant genetic trait with variable expressivity and penetrance. Whereas 100% of affected males with a defective gene for cherubism will exhibit the characteristics typically associated with the disorder (high penetrance), only 50 to 75% of females with the disease gene demonstrate symptoms of the disease (reduced penetrance). Mutations in the SH3BP2 gene are associated with approximately 80% of individuals with cherubism.Additional disorders may have specific symptoms that are similar to those seen in MAS including non-ossifying fibromas, idiopathic central precocious puberty, congenital adrenal hyperplasia, ovarian neoplasm, osteofibrous dysplasia, Proteus syndrome, Russell-Silver syndrome, and Mazabraud syndrome. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of McCune Albright Syndrome
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The diagnosis of McCune-Albright syndrome may be suspected at birth based upon identification of the characteristic skin pigmentations (cafe-au-lait spots). However, in many cases, the disorder may not be suspected until late infancy or childhood when precocious puberty develops or when bone deformities become obvious. A diagnosis may be confirmed based upon characteristic physical findings (i.e., association of characteristic skin, bone, and endocrine abnormalities), a detailed patient history, thorough clinical evaluation, and specialized tests including x-ray studies and blood tests.Clinical Testing and Workup
A complete body survey should be performed for the characteristic cafe-au-lait spots, and x-ray studies should be combined with bone scans to evaluate the presence and extent of fibrous dysplasia. Blood tests may reveal elevated hormone levels (e.g., estrogen, testosterone, cortisol, thyroid hormone, growth hormone, prolactin, somatomedin C) and evidence of abnormally increased bone activity (elevated alkaline phosphatase).Specialized imaging techniques may be used to evaluate bone. Such imaging techniques include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. The abnormal tissue in FD resembles ground glass when seen on x-ray. These tests may be used to determine how extensively bones are affected.A bone scan, also known as bone scintigraphy, is used to determine the extent of bone disease. During this test, a harmless radioactive dye is injected into the affected bone. A special camera that can track the dye as it travels through bone is used to create a picture of the skeleton and determine all affected areas. Bone biopsy is the surgical removal and microscopic examination of a small sample of affected tissue. A bone biopsy can reveal characteristic changes to bone that occur in individuals with FD and may be necessary to distinguish a FD lesion from other types of growths or tumors if it is unclear after an x-ray.A highly sensitive, specific form of polymerase chain reaction (PCR) has been used to detect somatic mutations of the GNAS1 gene that characterize MAS. PCR is a laboratory test that has been described as a form of “photocopying.” It enables researchers to enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely analyze DNA and more easily identify genes and genetic changes (mutations). In MAS, a specific form of PCR testing can detect activating mutations of GNAS1 in peripheral blood cells. However, because only some cells in the body are affected by the mutation, a normal test would not rule out MAS, and so this test is not frequently used in clinical diagnosis.
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Diagnosis of McCune Albright Syndrome. The diagnosis of McCune-Albright syndrome may be suspected at birth based upon identification of the characteristic skin pigmentations (cafe-au-lait spots). However, in many cases, the disorder may not be suspected until late infancy or childhood when precocious puberty develops or when bone deformities become obvious. A diagnosis may be confirmed based upon characteristic physical findings (i.e., association of characteristic skin, bone, and endocrine abnormalities), a detailed patient history, thorough clinical evaluation, and specialized tests including x-ray studies and blood tests.Clinical Testing and Workup
A complete body survey should be performed for the characteristic cafe-au-lait spots, and x-ray studies should be combined with bone scans to evaluate the presence and extent of fibrous dysplasia. Blood tests may reveal elevated hormone levels (e.g., estrogen, testosterone, cortisol, thyroid hormone, growth hormone, prolactin, somatomedin C) and evidence of abnormally increased bone activity (elevated alkaline phosphatase).Specialized imaging techniques may be used to evaluate bone. Such imaging techniques include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. The abnormal tissue in FD resembles ground glass when seen on x-ray. These tests may be used to determine how extensively bones are affected.A bone scan, also known as bone scintigraphy, is used to determine the extent of bone disease. During this test, a harmless radioactive dye is injected into the affected bone. A special camera that can track the dye as it travels through bone is used to create a picture of the skeleton and determine all affected areas. Bone biopsy is the surgical removal and microscopic examination of a small sample of affected tissue. A bone biopsy can reveal characteristic changes to bone that occur in individuals with FD and may be necessary to distinguish a FD lesion from other types of growths or tumors if it is unclear after an x-ray.A highly sensitive, specific form of polymerase chain reaction (PCR) has been used to detect somatic mutations of the GNAS1 gene that characterize MAS. PCR is a laboratory test that has been described as a form of “photocopying.” It enables researchers to enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely analyze DNA and more easily identify genes and genetic changes (mutations). In MAS, a specific form of PCR testing can detect activating mutations of GNAS1 in peripheral blood cells. However, because only some cells in the body are affected by the mutation, a normal test would not rule out MAS, and so this test is not frequently used in clinical diagnosis.
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Therapies of McCune Albright Syndrome
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TreatmentThe treatment of McCune-Albright syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, orthopedic surgeons, endocrinologists, dermatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Although MAS is not inherited, genetic counseling may be of benefit for affected individuals and their families.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as extent of the disease; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Fibrous dysplasia associated with MAS has been treated with drugs known as bisphosphonates such as pamidronate or alendronate. These drugs reduce bone turnover by inhibiting bone resorption. Calcium and vitamin D may be given along with the drug. Some affected individuals respond favorably to such therapy with the main benefit being decreased bone pain. Other affected individuals do not respond to therapy with bisphosphonates or relapse after an initial period of improvement. Relapse of bone pain is more common. Stronger bisphosphonate medications such as zoledronic acid may be used in such cases and may be most effective in improving bone pain.Surgery is sometimes used to treat fibrous dysplasia, although most physicians recommend a conservative strategy. Surgery should be undertaken only for lesions that causing difficulty in some way. Surgery may be undertaken to correct disfigurement or deformity, to correct limb length discrepancy, to eradicate symptomatic lesions (e.g. those causing pain and/or compressing a nerve), to treat specific complications such as scoliosis, or to prevent fracture.Exercises designed to strengthen the muscles surrounding fibrous dysplasia lesions may be recommended and may help to reduce the risk of fracture.In mild cases, females experiencing precious puberty may not require treatment, but only observation. Drug therapy may be required if females experience progressive precious puberty. Such drugs include letrozole, which is an aromatase inhibitor and has a long history of safety for the treatment of precocious puberty in MAS. These drugs block the conversion of androgens to estrogen. No drugs have been shown to be completely effective to-date. In some cases, males experiencing precious puberty may be treated with aromatase inhibitors. Additional drugs are being studied for the treatment of precious puberty in individuals with MAS.Precocious puberty in MAS is known as gonadotropin-independent. Gonadotropins are hormones such as follicle stimulating hormone and luteinizing hormone that are produced by the pituitary gland during puberty and regulate various actions involved in puberty. Most cases of precocious puberty (e.g. those not associated with MAS) are known as central precocious puberty or gonadotropin-dependent precious puberty and can be successfully treated with gonadotropin-releasing hormone, a hormone that, when used regularly, decreases the amount of these hormones released by the pituitary gland. This drug is not effective in most cases of MAS. However, in some affected females, central precocious puberty can develop as a secondary condition and can be successfully treated by long-acting gonadotropin-releasing hormone analogues.Hyperthyroidism may also be treated with drug therapy, specifically thionamides, which inhibit the production of thyroid hormones. Most individuals with MAS respond favorably to this therapy. However, hyperthyroidism in MAS is often persistent and some physicians recommend surgical removal of the thyroid (thyroidectomy) followed by radioactive iodine ablation. Iodine is a chemical element used by the thyroid to synthesize thyroid hormones. Nearly all of the iodine in a person’s blood is absorbed by thyroid tissue. Radioactive iodine therapy destroys any thyroid tissue that remains after a near-total thyroidectomy. After these procedures, individuals must take hormone replacement therapy for the remainder of their lives to replace the hormones normally produced by the thyroid.Growth hormone excess may be treated by drugs known as long-acting somatostatin analogues such as octreotide or bromocriptine. This class of drugs inhibits the production of growth hormone. A growth hormone receptor antagonist, pegvisomant, has also been used to treat growth hormone excess, although somatostatins have generally proven more effective, particularly in children. If medication does not work, surgical removal of the pituitary gland and the destruction of pituitary tissue using radiation (radiotherapy) may be necessary.In some cases Cushing’s syndrome can resolve on its own. Drugs that suppress the production of cortisol may be used and have been effective even in severe cases. However, Cushing’s syndrome can potentially be a severe complication of MAS and may not respond to drug therapy and some physicians consider the surgical removal of the adrenal glands (adrenalectomy) the treatment of choice. Individuals who undergo an adrenalectomy will receive hormone replacement therapy.Individuals with rickets or osteomalacia due to hypophosphatemia may require treatment with oral phosphorous supplementation and calcitriol, an activated vitamin-D metabolite. Whether children who have hypophosphatemia, but do not have signs of rickets require treatment is debated. Some physicians recommend that individuals with markedly low serum phosphate levels should be treated.
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Therapies of McCune Albright Syndrome. TreatmentThe treatment of McCune-Albright syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, orthopedic surgeons, endocrinologists, dermatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Although MAS is not inherited, genetic counseling may be of benefit for affected individuals and their families.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as extent of the disease; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Fibrous dysplasia associated with MAS has been treated with drugs known as bisphosphonates such as pamidronate or alendronate. These drugs reduce bone turnover by inhibiting bone resorption. Calcium and vitamin D may be given along with the drug. Some affected individuals respond favorably to such therapy with the main benefit being decreased bone pain. Other affected individuals do not respond to therapy with bisphosphonates or relapse after an initial period of improvement. Relapse of bone pain is more common. Stronger bisphosphonate medications such as zoledronic acid may be used in such cases and may be most effective in improving bone pain.Surgery is sometimes used to treat fibrous dysplasia, although most physicians recommend a conservative strategy. Surgery should be undertaken only for lesions that causing difficulty in some way. Surgery may be undertaken to correct disfigurement or deformity, to correct limb length discrepancy, to eradicate symptomatic lesions (e.g. those causing pain and/or compressing a nerve), to treat specific complications such as scoliosis, or to prevent fracture.Exercises designed to strengthen the muscles surrounding fibrous dysplasia lesions may be recommended and may help to reduce the risk of fracture.In mild cases, females experiencing precious puberty may not require treatment, but only observation. Drug therapy may be required if females experience progressive precious puberty. Such drugs include letrozole, which is an aromatase inhibitor and has a long history of safety for the treatment of precocious puberty in MAS. These drugs block the conversion of androgens to estrogen. No drugs have been shown to be completely effective to-date. In some cases, males experiencing precious puberty may be treated with aromatase inhibitors. Additional drugs are being studied for the treatment of precious puberty in individuals with MAS.Precocious puberty in MAS is known as gonadotropin-independent. Gonadotropins are hormones such as follicle stimulating hormone and luteinizing hormone that are produced by the pituitary gland during puberty and regulate various actions involved in puberty. Most cases of precocious puberty (e.g. those not associated with MAS) are known as central precocious puberty or gonadotropin-dependent precious puberty and can be successfully treated with gonadotropin-releasing hormone, a hormone that, when used regularly, decreases the amount of these hormones released by the pituitary gland. This drug is not effective in most cases of MAS. However, in some affected females, central precocious puberty can develop as a secondary condition and can be successfully treated by long-acting gonadotropin-releasing hormone analogues.Hyperthyroidism may also be treated with drug therapy, specifically thionamides, which inhibit the production of thyroid hormones. Most individuals with MAS respond favorably to this therapy. However, hyperthyroidism in MAS is often persistent and some physicians recommend surgical removal of the thyroid (thyroidectomy) followed by radioactive iodine ablation. Iodine is a chemical element used by the thyroid to synthesize thyroid hormones. Nearly all of the iodine in a person’s blood is absorbed by thyroid tissue. Radioactive iodine therapy destroys any thyroid tissue that remains after a near-total thyroidectomy. After these procedures, individuals must take hormone replacement therapy for the remainder of their lives to replace the hormones normally produced by the thyroid.Growth hormone excess may be treated by drugs known as long-acting somatostatin analogues such as octreotide or bromocriptine. This class of drugs inhibits the production of growth hormone. A growth hormone receptor antagonist, pegvisomant, has also been used to treat growth hormone excess, although somatostatins have generally proven more effective, particularly in children. If medication does not work, surgical removal of the pituitary gland and the destruction of pituitary tissue using radiation (radiotherapy) may be necessary.In some cases Cushing’s syndrome can resolve on its own. Drugs that suppress the production of cortisol may be used and have been effective even in severe cases. However, Cushing’s syndrome can potentially be a severe complication of MAS and may not respond to drug therapy and some physicians consider the surgical removal of the adrenal glands (adrenalectomy) the treatment of choice. Individuals who undergo an adrenalectomy will receive hormone replacement therapy.Individuals with rickets or osteomalacia due to hypophosphatemia may require treatment with oral phosphorous supplementation and calcitriol, an activated vitamin-D metabolite. Whether children who have hypophosphatemia, but do not have signs of rickets require treatment is debated. Some physicians recommend that individuals with markedly low serum phosphate levels should be treated.
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Overview of McKusick Type Metaphyseal Chondrodysplasia
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SummaryMcKusick type metaphyseal chondrodysplasia, also known as cartilage-hair hypoplasia (CHH), is a rare inherited disorder marked by unevenly short arms and legs (short-limbed dwarfism), increased joint mobility (hypermobility), and fine silky hair. In McKusick type metaphyseal chondrodysplasia, cartilage forms improperly at the large (bulbous) end portions (metaphyses) of the long bones in the arms and legs (metaphyseal chondrodysplasia). In addition, most affected individuals have impaired function of the immune system (immunodeficiency), which causes them to get more infections. Individuals with McKusick type metaphyseal chondrodysplasia can have low levels of red blood cells (anemia). Some individuals also experience difficulties in the absorption of nutrients from their food (intestinal malabsorption) and have increased risks for cancer. The most common types of cancer seen in McKusick type metaphyseal chondrodysplasia are non-Hodgkin lymphoma, squamous cell carcinoma and leukemia. The symptoms of McKusick type metaphyseal chondrodysplasia vary between affected individuals, even within the same family. McKusick type metaphyseal chondrodysplasia is inherited in an autosomal recessive pattern.IntroductionMcKusick type metaphyseal chondrodysplasia was first described in 1965 in the Old Order Amish population. Originally, the syndrome was believed to be characterized by unevenly short arms and legs (short limbed dwarfism), fine and light-colored hair (hypotrichosis), low levels of red blood cells (anemia), and problems with the immune system (immunodeficiency). Now, McKusick type metaphyseal chondrodysplasia is considered to be a spectrum of disorders that includes metaphyseal dysplasia without hypotrichosis (MDWH), cartilage hair hypoplasia (CHH) with metaphyseal dysplasia and hypotrichosis, and a more severe form called anauxetic dysplasia (AD). McKusick type metaphyseal chondrodysplasia has now been reported in around 700 individuals, and has been extensively studied in the Finnish population. The symptoms of McKusick type metaphyseal chondrodysplasia are highly variable, even among individuals of the same family. The variability in symptoms seen among affected individuals is not well understood at this time.
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Overview of McKusick Type Metaphyseal Chondrodysplasia. SummaryMcKusick type metaphyseal chondrodysplasia, also known as cartilage-hair hypoplasia (CHH), is a rare inherited disorder marked by unevenly short arms and legs (short-limbed dwarfism), increased joint mobility (hypermobility), and fine silky hair. In McKusick type metaphyseal chondrodysplasia, cartilage forms improperly at the large (bulbous) end portions (metaphyses) of the long bones in the arms and legs (metaphyseal chondrodysplasia). In addition, most affected individuals have impaired function of the immune system (immunodeficiency), which causes them to get more infections. Individuals with McKusick type metaphyseal chondrodysplasia can have low levels of red blood cells (anemia). Some individuals also experience difficulties in the absorption of nutrients from their food (intestinal malabsorption) and have increased risks for cancer. The most common types of cancer seen in McKusick type metaphyseal chondrodysplasia are non-Hodgkin lymphoma, squamous cell carcinoma and leukemia. The symptoms of McKusick type metaphyseal chondrodysplasia vary between affected individuals, even within the same family. McKusick type metaphyseal chondrodysplasia is inherited in an autosomal recessive pattern.IntroductionMcKusick type metaphyseal chondrodysplasia was first described in 1965 in the Old Order Amish population. Originally, the syndrome was believed to be characterized by unevenly short arms and legs (short limbed dwarfism), fine and light-colored hair (hypotrichosis), low levels of red blood cells (anemia), and problems with the immune system (immunodeficiency). Now, McKusick type metaphyseal chondrodysplasia is considered to be a spectrum of disorders that includes metaphyseal dysplasia without hypotrichosis (MDWH), cartilage hair hypoplasia (CHH) with metaphyseal dysplasia and hypotrichosis, and a more severe form called anauxetic dysplasia (AD). McKusick type metaphyseal chondrodysplasia has now been reported in around 700 individuals, and has been extensively studied in the Finnish population. The symptoms of McKusick type metaphyseal chondrodysplasia are highly variable, even among individuals of the same family. The variability in symptoms seen among affected individuals is not well understood at this time.
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Symptoms of McKusick Type Metaphyseal Chondrodysplasia
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Unevenly short arms and legs (short limbed dwarfism) are the most common features in McKusick type metaphyseal chondrodysplasia and are seen in around 100% of affected individuals. Increased inward curvature of the lower spine (lumbar lordosis) and increased side curvature of the rest of the spine (scoliosis) also cause shorter heights in affected individuals. Median height is estimated to be around 4 feet 3 inches in men and 4 feet 0 inches in women. In individuals with the more severe form, anauxetic dysplasia (AD), the median height is less than 2 feet 10 inches.Increased joint mobility (hypermobility) has been reported in 87% of affected individuals. The joints in the hands and feet are most commonly affected. However, increased joint mobility can also be present in the knees, which can lead to a bowlegged appearance (varus leg deformity) in around 77% of affected individuals. Fine, sparse, and silky hair (hypotrichosis) is seen in around 90% of individuals with McKusick type metaphyseal chondrodysplasia. In most individuals, the hair also tends to be blonde or light colored. About 15% of affected individuals have complete hair loss (alopecia), which includes the scalp, eyelashes, eyebrows, and body hair.Decreased red blood cell production (anemia) has been reported in about 80% of affected individuals. The decreased red blood cell production ranges from mild to severe, and usually goes away on its own by childhood. Persistent decreased red cell production has only been reported in 6% of individuals. Decreased white blood cell production (lymphopenia) and decreased immune cell production lead to decreased immunity (immunodeficiency) in around 88% of affected individuals. Decreased immunity leads to an increased rate of infections in approximately 35-65% of affected individuals. Most infections occur during infancy or childhood, and ear and lung infections appear to be the most common. Also, chickenpox can be severe.The risk for cancer in McKusick type metaphyseal chondrodysplasia is estimated to be around 11%. Most cancers tend to be diagnosed under 44 years old. The most common cancers are non-Hodgkin lymphoma, squamous cell carcinoma, leukemia, and Hodgkin lymphoma. The reason why individuals with McKusick type metaphyseal chondrodysplasia have increased risks for cancer is unclear at this time. However, it does not appear to be related to decreased immune cell production (immunodeficiency).In about 8% of individuals, their intestines have difficulty absorbing nutrients from food (intestinal malabsorption). Intestinal malabsorption presents as diarrhea, and decreased ability to gain weight (failure to thrive) in the newborn period. Most of the intestinal symptoms appear within the first two years of life. Also, some individuals have Hirschsprung’s disease, an absence of nerve cells in the intestine, which presents with constipation from birth.Other features seen in McKusick type metaphyseal chondrodysplasia include decreased sperm production (spermatogenesis) and intellectual disability.
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Symptoms of McKusick Type Metaphyseal Chondrodysplasia. Unevenly short arms and legs (short limbed dwarfism) are the most common features in McKusick type metaphyseal chondrodysplasia and are seen in around 100% of affected individuals. Increased inward curvature of the lower spine (lumbar lordosis) and increased side curvature of the rest of the spine (scoliosis) also cause shorter heights in affected individuals. Median height is estimated to be around 4 feet 3 inches in men and 4 feet 0 inches in women. In individuals with the more severe form, anauxetic dysplasia (AD), the median height is less than 2 feet 10 inches.Increased joint mobility (hypermobility) has been reported in 87% of affected individuals. The joints in the hands and feet are most commonly affected. However, increased joint mobility can also be present in the knees, which can lead to a bowlegged appearance (varus leg deformity) in around 77% of affected individuals. Fine, sparse, and silky hair (hypotrichosis) is seen in around 90% of individuals with McKusick type metaphyseal chondrodysplasia. In most individuals, the hair also tends to be blonde or light colored. About 15% of affected individuals have complete hair loss (alopecia), which includes the scalp, eyelashes, eyebrows, and body hair.Decreased red blood cell production (anemia) has been reported in about 80% of affected individuals. The decreased red blood cell production ranges from mild to severe, and usually goes away on its own by childhood. Persistent decreased red cell production has only been reported in 6% of individuals. Decreased white blood cell production (lymphopenia) and decreased immune cell production lead to decreased immunity (immunodeficiency) in around 88% of affected individuals. Decreased immunity leads to an increased rate of infections in approximately 35-65% of affected individuals. Most infections occur during infancy or childhood, and ear and lung infections appear to be the most common. Also, chickenpox can be severe.The risk for cancer in McKusick type metaphyseal chondrodysplasia is estimated to be around 11%. Most cancers tend to be diagnosed under 44 years old. The most common cancers are non-Hodgkin lymphoma, squamous cell carcinoma, leukemia, and Hodgkin lymphoma. The reason why individuals with McKusick type metaphyseal chondrodysplasia have increased risks for cancer is unclear at this time. However, it does not appear to be related to decreased immune cell production (immunodeficiency).In about 8% of individuals, their intestines have difficulty absorbing nutrients from food (intestinal malabsorption). Intestinal malabsorption presents as diarrhea, and decreased ability to gain weight (failure to thrive) in the newborn period. Most of the intestinal symptoms appear within the first two years of life. Also, some individuals have Hirschsprung’s disease, an absence of nerve cells in the intestine, which presents with constipation from birth.Other features seen in McKusick type metaphyseal chondrodysplasia include decreased sperm production (spermatogenesis) and intellectual disability.
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Causes of McKusick Type Metaphyseal Chondrodysplasia
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McKusick type metaphyseal chondrodysplasia is inherited in an autosomal recessive pattern. Genetic disorders are determined by the status of two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of a non-working gene for the same trait, one from each parent. If an individual inherits one working gene and one non-working gene, the person will be a carrier for the disorder but usually will not show symptoms. The risk for two carrier parents to both pass on a non-working 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 working genes from both parents is 25%. The risks are the same for males and females.Some individuals with McKusick type metaphyseal chondrodysplasia have parents who are related by blood (consanguineous). Parents who are close blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, which increases their risk to have children with a recessive genetic disorder.Scientists have determined that McKusick type metaphyseal chondrodysplasia is caused by genetic changes (mutations) in the mitochondrial RNA-processing endoribonuclease (RMRP) gene. More than 90 different disease causing changes (pathogenic mutations) have been reported. The reason why gene changes (mutations) in the RMRP gene cause the symptoms associated with the disorder is still unclear at this time. However, current research suggests that the disorder may be caused by increased rates of cell death (apoptosis) in affected individuals.
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Causes of McKusick Type Metaphyseal Chondrodysplasia. McKusick type metaphyseal chondrodysplasia is inherited in an autosomal recessive pattern. Genetic disorders are determined by the status of two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of a non-working gene for the same trait, one from each parent. If an individual inherits one working gene and one non-working gene, the person will be a carrier for the disorder but usually will not show symptoms. The risk for two carrier parents to both pass on a non-working 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 working genes from both parents is 25%. The risks are the same for males and females.Some individuals with McKusick type metaphyseal chondrodysplasia have parents who are related by blood (consanguineous). Parents who are close blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, which increases their risk to have children with a recessive genetic disorder.Scientists have determined that McKusick type metaphyseal chondrodysplasia is caused by genetic changes (mutations) in the mitochondrial RNA-processing endoribonuclease (RMRP) gene. More than 90 different disease causing changes (pathogenic mutations) have been reported. The reason why gene changes (mutations) in the RMRP gene cause the symptoms associated with the disorder is still unclear at this time. However, current research suggests that the disorder may be caused by increased rates of cell death (apoptosis) in affected individuals.
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Affects of McKusick Type Metaphyseal Chondrodysplasia
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McKusick type metaphyseal chondrodysplasia affects both males and females in equal proportions. The disease has been reported in about 700 individuals. The most severe form, anauxetic dysplasia (AD) is rare, and has been reported in less than 10 individuals. Affected individuals have been reported in multiple populations. However, McKusick type metaphyseal chondrodysplasia is more common in the Old Order Amish population with an estimated incidence of between 1: 1,000 and 1: 2,000 and the Finnish population with an estimated incidence of 1: 23,000. A disease causing genetic change that arose many generations ago (founder mutation), g.70A>G, is present in 100% of Old Order Amish individuals, 92% of Finnish individuals, and 48% of non-Finnish individuals.
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Affects of McKusick Type Metaphyseal Chondrodysplasia. McKusick type metaphyseal chondrodysplasia affects both males and females in equal proportions. The disease has been reported in about 700 individuals. The most severe form, anauxetic dysplasia (AD) is rare, and has been reported in less than 10 individuals. Affected individuals have been reported in multiple populations. However, McKusick type metaphyseal chondrodysplasia is more common in the Old Order Amish population with an estimated incidence of between 1: 1,000 and 1: 2,000 and the Finnish population with an estimated incidence of 1: 23,000. A disease causing genetic change that arose many generations ago (founder mutation), g.70A>G, is present in 100% of Old Order Amish individuals, 92% of Finnish individuals, and 48% of non-Finnish individuals.
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Related disorders of McKusick Type Metaphyseal Chondrodysplasia
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Symptoms of the following disorders may be similar to those of McKusick type metaphyseal chondrodysplasia. Comparisons may be useful for a differential diagnosis:Shwachman-Diamond syndrome (SDS) is an extremely rare inherited condition that affects around 1: 77,000 newborns. Shwachman Diamond syndrome is characterized by decreased intestinal absorption of nutrients (intestinal malabsorption) and abnormal function of the pancreas (pancreatic insufficiency). The bones of individuals with SDS do not develop normally, especially in their ribs, arms, and leg bones (metaphyseal dysostosis). This can lead to shortened heights. Individuals with SDS also have thickening of their ribs and connective tissue (costochondral thickening), causing their ribs to be abnormally short. Additionally, decreased bone marrow production leads to decreased blood cell production (pancytopenia) in most affected individuals. Shwachman-Diamond syndrome is inherited as an autosomal recessive trait, and is believed to be caused by inheriting two genetic changes (mutations) in the SBDS gene. (For more information on this disorder, choose “Shwachman” as your search term in the Rare Disease Database).Schmid type metaphyseal chondrodysplasia is a very rare inherited condition characterized by shortened height and unevenly short arms and legs (short-limed dwarfism). Other symptoms associated with this condition include flaring of the bones in the lower rib cage, bowed legs (varus leg deformity) and leg pain. Due to changes in the legs and hips, affected children often walk with a waddling gait. Schmid type metaphyseal chondrodysplasia is inherited as an autosomal dominant trait, and is believed to be caused by inheriting a single genetic change (mutation) in the COL10A1 gene. (For more information on this disorder, choose “Schmid” as your search term in the Rare Disease Database.)Jansen type metaphyseal chondrodysplasia is an extremely rare inherited disorder characterized by shortened height and unevenly short arms and legs (short-limbed dwarfism). This disorder is characterized by improper formation of the cartilage at the end portions (metaphyses) of the long bones (metaphyseal chondrodysplasia). Improper cartilage development may also occur in the bones of the hands and feet (metacarpals and metatarsals). Affected children may experience stiffness in certain joints, short fingers (brachydactyly), and atypical curvature of the spine (kyphoscoliosis). Additionally, individuals with Jansen type metaphyseal chondrodysplasia may have high levels of calcium in their blood (hypercalcemia). Jansen type metaphyseal chondrodysplasia is inherited as an autosomal dominant trait, and is believed to be caused by inheriting a single genetic change (mutation) in the PTH gene. (For more information on this disorder choose “Jansen Type Metaphyseal Chondrodysplasia” as your search term in the Rare Disease Database.)Schimke immunosseous dysplasia (SIOD) is an extremely rare inherited disorder that affects around 1: 1,000,000 to 1: 3,000,000 births. SIOD is characterized by shortened height, progressive steroid-resistant kidney disease (nephropathy), and decreased immune cell production (immunodeficiency). SIOD has been divided into an infantile, severe early-onset form, and a juvenile mild late-onset form. SIOD is inherited as an autosomal recessive trait, and is believed to be caused by inherited two genetic changes (mutations) in the SMARCAL1 gene. (For more information on this disorder choose “Schimke Immuno-Osseous Dysplasia” as your search term in the Rare Disease Database.)
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Related disorders of McKusick Type Metaphyseal Chondrodysplasia. Symptoms of the following disorders may be similar to those of McKusick type metaphyseal chondrodysplasia. Comparisons may be useful for a differential diagnosis:Shwachman-Diamond syndrome (SDS) is an extremely rare inherited condition that affects around 1: 77,000 newborns. Shwachman Diamond syndrome is characterized by decreased intestinal absorption of nutrients (intestinal malabsorption) and abnormal function of the pancreas (pancreatic insufficiency). The bones of individuals with SDS do not develop normally, especially in their ribs, arms, and leg bones (metaphyseal dysostosis). This can lead to shortened heights. Individuals with SDS also have thickening of their ribs and connective tissue (costochondral thickening), causing their ribs to be abnormally short. Additionally, decreased bone marrow production leads to decreased blood cell production (pancytopenia) in most affected individuals. Shwachman-Diamond syndrome is inherited as an autosomal recessive trait, and is believed to be caused by inheriting two genetic changes (mutations) in the SBDS gene. (For more information on this disorder, choose “Shwachman” as your search term in the Rare Disease Database).Schmid type metaphyseal chondrodysplasia is a very rare inherited condition characterized by shortened height and unevenly short arms and legs (short-limed dwarfism). Other symptoms associated with this condition include flaring of the bones in the lower rib cage, bowed legs (varus leg deformity) and leg pain. Due to changes in the legs and hips, affected children often walk with a waddling gait. Schmid type metaphyseal chondrodysplasia is inherited as an autosomal dominant trait, and is believed to be caused by inheriting a single genetic change (mutation) in the COL10A1 gene. (For more information on this disorder, choose “Schmid” as your search term in the Rare Disease Database.)Jansen type metaphyseal chondrodysplasia is an extremely rare inherited disorder characterized by shortened height and unevenly short arms and legs (short-limbed dwarfism). This disorder is characterized by improper formation of the cartilage at the end portions (metaphyses) of the long bones (metaphyseal chondrodysplasia). Improper cartilage development may also occur in the bones of the hands and feet (metacarpals and metatarsals). Affected children may experience stiffness in certain joints, short fingers (brachydactyly), and atypical curvature of the spine (kyphoscoliosis). Additionally, individuals with Jansen type metaphyseal chondrodysplasia may have high levels of calcium in their blood (hypercalcemia). Jansen type metaphyseal chondrodysplasia is inherited as an autosomal dominant trait, and is believed to be caused by inheriting a single genetic change (mutation) in the PTH gene. (For more information on this disorder choose “Jansen Type Metaphyseal Chondrodysplasia” as your search term in the Rare Disease Database.)Schimke immunosseous dysplasia (SIOD) is an extremely rare inherited disorder that affects around 1: 1,000,000 to 1: 3,000,000 births. SIOD is characterized by shortened height, progressive steroid-resistant kidney disease (nephropathy), and decreased immune cell production (immunodeficiency). SIOD has been divided into an infantile, severe early-onset form, and a juvenile mild late-onset form. SIOD is inherited as an autosomal recessive trait, and is believed to be caused by inherited two genetic changes (mutations) in the SMARCAL1 gene. (For more information on this disorder choose “Schimke Immuno-Osseous Dysplasia” as your search term in the Rare Disease Database.)
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Diagnosis of McKusick Type Metaphyseal Chondrodysplasia
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Due to the high degree of variability in symptoms among affected individuals, there are no formal diagnostic criteria for McKusick type metaphyseal chondrodysplasia. In most cases, a clinical diagnosis can be made by the second or third year of life. Newborn screening for severe combined immunodeficiency (SCID) can identify some individuals with McKusick type metaphyseal chondrodysplasia due to their low levels of immune cells (immunodeficiency). Diagnosing the disorder clinically requires a thorough physical exam, a detailed patient medical history, and a variety of advanced skeletal imaging techniques. A diagnosis of McKusick type metaphyseal chondrodysplasia should be suspected in individuals with unevenly short arms and legs (short-limbed dwarfism) and thinning of the shafts of the long bones (metaphyseal dysplasia). Full skeletal X-rays with views of the spine can be done to look for the characteristic cupped appearance at the end portions of the long bones (metaphyses).Children who are diagnosed with McKusick type metaphyseal chondrodysplasia should receive a complete immunology evaluation to determine if impaired T cell or B cell function (immunodeficiency) is present. Additionally, blood tests should be done to detect low levels of red (anemia) and or white blood cells (lymphopenia).Genetic TestingMcKusick type metaphyseal chondrodysplasia can also be diagnosed through genetic testing. Reading through (sequencing) the RMRP gene and looking for mutations can be done to confirm the diagnosis in individuals who have symptoms. The identification of two disease causing genetic changes (pathogenic mutations) in RMRP confirms a clinical diagnosis of McKusick type metaphyseal chondrodysplasia. Most individuals with a clinical diagnosis will be found to have two genetic changes (mutations) upon reading through (sequencing) the RMRP gene. However, if only one mutation is found upon sequencing the gene, another test can be done to look for small pieces of missing or extra DNA (deletions and duplications). No deletions or duplications have been reported thus far.In individuals of Old Order Amish or Finnish ancestry, targeted genetic testing should be done first to search for the g.70A>G mutation that is present in 100% of Amish and 92% of Finnish individuals.
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Diagnosis of McKusick Type Metaphyseal Chondrodysplasia. Due to the high degree of variability in symptoms among affected individuals, there are no formal diagnostic criteria for McKusick type metaphyseal chondrodysplasia. In most cases, a clinical diagnosis can be made by the second or third year of life. Newborn screening for severe combined immunodeficiency (SCID) can identify some individuals with McKusick type metaphyseal chondrodysplasia due to their low levels of immune cells (immunodeficiency). Diagnosing the disorder clinically requires a thorough physical exam, a detailed patient medical history, and a variety of advanced skeletal imaging techniques. A diagnosis of McKusick type metaphyseal chondrodysplasia should be suspected in individuals with unevenly short arms and legs (short-limbed dwarfism) and thinning of the shafts of the long bones (metaphyseal dysplasia). Full skeletal X-rays with views of the spine can be done to look for the characteristic cupped appearance at the end portions of the long bones (metaphyses).Children who are diagnosed with McKusick type metaphyseal chondrodysplasia should receive a complete immunology evaluation to determine if impaired T cell or B cell function (immunodeficiency) is present. Additionally, blood tests should be done to detect low levels of red (anemia) and or white blood cells (lymphopenia).Genetic TestingMcKusick type metaphyseal chondrodysplasia can also be diagnosed through genetic testing. Reading through (sequencing) the RMRP gene and looking for mutations can be done to confirm the diagnosis in individuals who have symptoms. The identification of two disease causing genetic changes (pathogenic mutations) in RMRP confirms a clinical diagnosis of McKusick type metaphyseal chondrodysplasia. Most individuals with a clinical diagnosis will be found to have two genetic changes (mutations) upon reading through (sequencing) the RMRP gene. However, if only one mutation is found upon sequencing the gene, another test can be done to look for small pieces of missing or extra DNA (deletions and duplications). No deletions or duplications have been reported thus far.In individuals of Old Order Amish or Finnish ancestry, targeted genetic testing should be done first to search for the g.70A>G mutation that is present in 100% of Amish and 92% of Finnish individuals.
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Therapies of McKusick Type Metaphyseal Chondrodysplasia
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Treatment
The treatment of McKusick type metaphyseal chondrodysplasia is often directed toward the specific symptoms that are found in an affected individual. Treatment requires the collaboration of a team of specialists. Pediatricians, physicians who specialize in treating skeletal disorders (orthopedists), physicians who diagnose and treat skin disorders (dermatologists), physicians who specialize in immune disorders (immunologists), physicians who specialize in blood disorders (hematologists), physicians who specialize in intestinal disorders (gastroenterologists), dental specialists, speech therapists, dieticians, physical therapists, and other health care professionals may all be involved in the treatment of affected individuals.Corrective bone surgeries (osteotomies) may be done in late childhood or adolescence for excessive leg bowing (varus deformities). Physical therapy may also be used to help treat skeletal complications, like the limited range of motion in the elbows and legs. Growth hormones have not been shown to be effective in treating the shortened height associated with McKusick type metaphyseal chondrodysplasia.For treating immunodeficiency, antiviral treatments, antibiotic therapies, immunoglobulin replacement therapy and bone marrow transplantations have all been shown to decrease rates of infection. Physicians may also recommend that certain vaccinations be avoided.Physicians may regularly monitor affected individuals for the blood symptoms (neutropenia, anemia, lymphopenia) associated with the condition. Individuals with a severe decrease in blood cell production are often treated with recurrent blood cell transfusions. Removing excess iron from the blood (iron chelation therapy) has been shown to improve outcomes in individuals who require recurrent red blood cell transfusions.No specific recommendations for reducing cancer risks are available at this time. However, physicians may closely monitor affected individuals to ensure early detection and treatment.Individuals with Hirschsprung’s disease may require surgery during early childhood to remove the damaged portion of the colon. In some cases, before this procedure is performed, a temporary opening for the colon may be made in the abdominal wall (colostomy) to allow passage of feces from the body.Genetic counseling is recommended for all affected individuals and their families.
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Therapies of McKusick Type Metaphyseal Chondrodysplasia. Treatment
The treatment of McKusick type metaphyseal chondrodysplasia is often directed toward the specific symptoms that are found in an affected individual. Treatment requires the collaboration of a team of specialists. Pediatricians, physicians who specialize in treating skeletal disorders (orthopedists), physicians who diagnose and treat skin disorders (dermatologists), physicians who specialize in immune disorders (immunologists), physicians who specialize in blood disorders (hematologists), physicians who specialize in intestinal disorders (gastroenterologists), dental specialists, speech therapists, dieticians, physical therapists, and other health care professionals may all be involved in the treatment of affected individuals.Corrective bone surgeries (osteotomies) may be done in late childhood or adolescence for excessive leg bowing (varus deformities). Physical therapy may also be used to help treat skeletal complications, like the limited range of motion in the elbows and legs. Growth hormones have not been shown to be effective in treating the shortened height associated with McKusick type metaphyseal chondrodysplasia.For treating immunodeficiency, antiviral treatments, antibiotic therapies, immunoglobulin replacement therapy and bone marrow transplantations have all been shown to decrease rates of infection. Physicians may also recommend that certain vaccinations be avoided.Physicians may regularly monitor affected individuals for the blood symptoms (neutropenia, anemia, lymphopenia) associated with the condition. Individuals with a severe decrease in blood cell production are often treated with recurrent blood cell transfusions. Removing excess iron from the blood (iron chelation therapy) has been shown to improve outcomes in individuals who require recurrent red blood cell transfusions.No specific recommendations for reducing cancer risks are available at this time. However, physicians may closely monitor affected individuals to ensure early detection and treatment.Individuals with Hirschsprung’s disease may require surgery during early childhood to remove the damaged portion of the colon. In some cases, before this procedure is performed, a temporary opening for the colon may be made in the abdominal wall (colostomy) to allow passage of feces from the body.Genetic counseling is recommended for all affected individuals and their families.
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Overview of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency
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MCT8-specific thyroid hormone cell transporter deficiency (MCT8 deficiency) is a genetic disorder characterized by severe intellectual disability, an impaired ability to speak, low muscle tone (hypotonia), disorganized movements and specific thyroid test abnormalities.Except for poor muscle tone, most affected infants appear to develop normally during the first months of life. However, by about two months of age, an affected infant may seem weak and be unable to hold up their head. Due to hypotonia, severely reduced motor development and other abnormalities, affected children very rarely develop the ability to walk and when they do, it is with a shuffling gait. Associated features often include underdevelopment (hypoplasia) and decreasing (atrophy) of muscle tissue; weakness and stiffness of the legs (spastic paraplegia) with exaggerated reflexes (hyperreflexia) and relatively slow, involuntary, purposeless (dyskinetic) movements. Writhing movements (athetoid movements) and/or other movement abnormalities are less common. Affected individuals may also have characteristic features of the skull and face. MCT8 deficiency is an X-linked genetic disorder.
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Overview of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency. MCT8-specific thyroid hormone cell transporter deficiency (MCT8 deficiency) is a genetic disorder characterized by severe intellectual disability, an impaired ability to speak, low muscle tone (hypotonia), disorganized movements and specific thyroid test abnormalities.Except for poor muscle tone, most affected infants appear to develop normally during the first months of life. However, by about two months of age, an affected infant may seem weak and be unable to hold up their head. Due to hypotonia, severely reduced motor development and other abnormalities, affected children very rarely develop the ability to walk and when they do, it is with a shuffling gait. Associated features often include underdevelopment (hypoplasia) and decreasing (atrophy) of muscle tissue; weakness and stiffness of the legs (spastic paraplegia) with exaggerated reflexes (hyperreflexia) and relatively slow, involuntary, purposeless (dyskinetic) movements. Writhing movements (athetoid movements) and/or other movement abnormalities are less common. Affected individuals may also have characteristic features of the skull and face. MCT8 deficiency is an X-linked genetic disorder.
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Symptoms of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency
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MCT8 deficiency is primarily characterized by severe intellectual disability, hypotonia and movement abnormalities. As mentioned above, an affected infant typically appears to develop normally (except for hypotonia) until about 2 months of age, when they may seem to have generalized weakness and be unable to hold up their head. Family members have described this feature as “limber neck.” Due to low muscle tone, weakness, severely reduced motor development and/or other factors, affected children are unable to walk or walk with great difficulty. Associated findings may include underdevelopment (hypoplasia) and decreasing (atrophy) of various skeletal (voluntary) muscles; an impaired ability to coordinate certain voluntary movements (ataxia); weakness and stiffness of the legs (spastic paraplegia) with associated hyperreflexia and involuntary, rapid, repeated involuntary contractions and relaxations of the legs (clonus). Movement abnormalities are common and include dyskinetic attacks or relatively slow, writhing movements (athetoid movements) and/or other movement abnormalities. Typical dyskinetic attacks last a few minutes or less and consist of body extension, opening of the mouth and stretching or flexing of the limbs. They are usually triggered by physical and emotional stimuli such as changing diapers or clothes. While these episodes are commonly interpreted as being seizures, true epilepsy is uncommon.As noted earlier, infants and children with the disorder are also affected by severe intellectual disability and delays in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor delay). In addition, affected children are unable to speak, or rarely, acquire garbled speech. Children with MCT8 deficiency are generally good natured and have agreeable behavior.As adults, affected individuals may have a generalized decrease of muscle (atrophy), permanent fixation of multiple small and large joints in various fixed postures (joint contractures) and/or decreased reflex reactions (hyporeflexia).Individuals with MCT8 deficiency may also have characteristic craniofacial features and/or additional skeletal abnormalities. The head is usually of normal size but may be narrow at the temples (bitemporal narrowing). The face may appear long and thin with large, poorly developed ears. Some people with MCT8 deficiency have side-to-side curvature of the spine (scoliosis); depression of the breastbone (“funnel chest” or pectus excavatum) and/or foot abnormalities.
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Symptoms of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency. MCT8 deficiency is primarily characterized by severe intellectual disability, hypotonia and movement abnormalities. As mentioned above, an affected infant typically appears to develop normally (except for hypotonia) until about 2 months of age, when they may seem to have generalized weakness and be unable to hold up their head. Family members have described this feature as “limber neck.” Due to low muscle tone, weakness, severely reduced motor development and/or other factors, affected children are unable to walk or walk with great difficulty. Associated findings may include underdevelopment (hypoplasia) and decreasing (atrophy) of various skeletal (voluntary) muscles; an impaired ability to coordinate certain voluntary movements (ataxia); weakness and stiffness of the legs (spastic paraplegia) with associated hyperreflexia and involuntary, rapid, repeated involuntary contractions and relaxations of the legs (clonus). Movement abnormalities are common and include dyskinetic attacks or relatively slow, writhing movements (athetoid movements) and/or other movement abnormalities. Typical dyskinetic attacks last a few minutes or less and consist of body extension, opening of the mouth and stretching or flexing of the limbs. They are usually triggered by physical and emotional stimuli such as changing diapers or clothes. While these episodes are commonly interpreted as being seizures, true epilepsy is uncommon.As noted earlier, infants and children with the disorder are also affected by severe intellectual disability and delays in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor delay). In addition, affected children are unable to speak, or rarely, acquire garbled speech. Children with MCT8 deficiency are generally good natured and have agreeable behavior.As adults, affected individuals may have a generalized decrease of muscle (atrophy), permanent fixation of multiple small and large joints in various fixed postures (joint contractures) and/or decreased reflex reactions (hyporeflexia).Individuals with MCT8 deficiency may also have characteristic craniofacial features and/or additional skeletal abnormalities. The head is usually of normal size but may be narrow at the temples (bitemporal narrowing). The face may appear long and thin with large, poorly developed ears. Some people with MCT8 deficiency have side-to-side curvature of the spine (scoliosis); depression of the breastbone (“funnel chest” or pectus excavatum) and/or foot abnormalities.
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Causes of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency
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MCT8 deficiency is caused by a change (pathogenic variant or mutation) in the MCT8 (SLC16A2) gene leading to an altered structure and function of the MCT8 protein. So far, 210 distinct MCT8 gene variants have been identified in patients with MCT8 deficiency. The severity of clinical symptoms can vary depending on the type of gene variant.The abnormal MCT8 protein is unable to transport thyroid hormones produced by the thyroid gland into the brain. The lack of thyroid hormones in the brain before birth and in early childhood affects brain development. The excess T3 thyroid hormone in the blood can increase metabolism (hypermetabolism), so more calories are needed for an affected child to gain weight.MCT8 deficiency is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene but affected females have been reported. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all 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 children.
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Causes of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency. MCT8 deficiency is caused by a change (pathogenic variant or mutation) in the MCT8 (SLC16A2) gene leading to an altered structure and function of the MCT8 protein. So far, 210 distinct MCT8 gene variants have been identified in patients with MCT8 deficiency. The severity of clinical symptoms can vary depending on the type of gene variant.The abnormal MCT8 protein is unable to transport thyroid hormones produced by the thyroid gland into the brain. The lack of thyroid hormones in the brain before birth and in early childhood affects brain development. The excess T3 thyroid hormone in the blood can increase metabolism (hypermetabolism), so more calories are needed for an affected child to gain weight.MCT8 deficiency is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene but affected females have been reported. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all 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 children.
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Affects of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency
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MCT8 deficiency is a rare inherited disorder that affects mostly males. More than 300 families have been identified with 210 different MCT8 gene variants. The frequency of MCT8 deficiency among people with intellectual disability is not known, though estimated to occur in 1 in 70,000 newborns.
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Affects of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency. MCT8 deficiency is a rare inherited disorder that affects mostly males. More than 300 families have been identified with 210 different MCT8 gene variants. The frequency of MCT8 deficiency among people with intellectual disability is not known, though estimated to occur in 1 in 70,000 newborns.
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Related disorders of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency
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Symptoms of the following disorders may be similar to those of MCT8 deficiency. Comparisons may be useful for a differential diagnosis:Angelman syndrome (AS) is a rare genetic neurological disorder characterized by severe developmental delays and learning disabilities; the absence or near absence of speech; an inability to coordinate voluntary movements (ataxia) and tremulous, jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling, often at inappropriate times. Additional symptoms may occur in some patients including seizures, sleep disorders and feeding difficulties. Some affected children may have distinctive facial features. AS is caused by deletion of or abnormal expression of the UBE3A gene. Most cases of AS appear to occur spontaneously. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)Juberg-Marsidi syndrome is an extremely rare X-linked genetic disorder that is fully expressed in males only and is apparent at birth or during the first few weeks of life. Affected children have severe intellectual disability; delays in reaching developmental milestones (e.g., crawling, walking, etc.); muscle weakness; low muscle tone (hypotonia) and/or delayed bone growth as well as growth delay, resulting in short stature. Affected infants also have hearing loss; underdevelopment of the genitals and/or characteristic head and facial features such as a small head (microcephaly), a flat (depressed) nasal bridge and eye (ocular) abnormalities. The range and severity of symptoms varies from person to person. (For more information on this disorder, choose “Juberg Marsidi” as your search term in the Rare Disease Database.)Renpenning syndrome is one of the X-linked intellectual disability disorders that mostly affects males. It is characterized by intellectual disability that can be severe, short stature, a small head circumference (microcephaly) and small testes. Renpenning syndrome is caused by variants in the PQBP1 gene and is inherited in an X-linked pattern.L1 syndrome is a genetic condition occurring in males that usually includes hydrocephalus, intellectual disability, spasticity of legs and clasped (adducted) thumbs. L1 syndrome is caused by variants in the L1CAM gene. The variable types of L1 syndrome were once thought to be different diseases, but all the following conditions are now known to be caused by variants in the L1CAM gene:X-linked hydrocephalus with stenosis of aqueduct of Sylvius (HSAS) is characterized by severe hydrocephalus that often begins prenatally, adducted (clasped) thumbs, spasticity and severe intellectual disability. HASA syndrome is characterized by mild to moderate intellectual disability, aphasia (delayed speech), hypotonia that progresses to spasticity, adducted thumbs and variable widening of the third ventricle in the brain. X-linked complicated hereditary spastic paraplegia type 1 is characterized by spastic paraplegia (shuffling gait), mild to moderate intellectual disability and normal findings on MRI of the brain. X-linked complicated corpus callosum agenesis is characterized by variable spastic paraplegia, mild to moderate intellectual disability and abnormalities in the corpus callosum of the brain. (For more information on this disorder, choose “L1 syndrome” as your search term in the Rare Disease Database.)Pelizaeus-Merzbacher disease (PMD) is a rare X-linked genetic disorder affecting the central nervous system that is associated with abnormalities of the white matter of the brain. Symptoms develop due to lack of fatty covering of nerve cells (myelin sheath). Many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum and/or brain stem. Symptoms may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, loss of motor abilities and the slow progressive deterioration of intellectual function. PMD disease is associated with variants in the PLP1 gene. Some individuals with MCT8 deficiency have been incorrectly diagnosed as having PMD. (For more information on this disorder, choose “Pelizeaus-Merzbacher” as your search term in the Rare Disease Database.)There are additional congenital disorders that may be characterized by X-linked intellectual disability and occur in association with movement abnormalities, psychomotor delay and/or other features similar to those associated with MCT8 deficiency. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database).
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Related disorders of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency. Symptoms of the following disorders may be similar to those of MCT8 deficiency. Comparisons may be useful for a differential diagnosis:Angelman syndrome (AS) is a rare genetic neurological disorder characterized by severe developmental delays and learning disabilities; the absence or near absence of speech; an inability to coordinate voluntary movements (ataxia) and tremulous, jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling, often at inappropriate times. Additional symptoms may occur in some patients including seizures, sleep disorders and feeding difficulties. Some affected children may have distinctive facial features. AS is caused by deletion of or abnormal expression of the UBE3A gene. Most cases of AS appear to occur spontaneously. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)Juberg-Marsidi syndrome is an extremely rare X-linked genetic disorder that is fully expressed in males only and is apparent at birth or during the first few weeks of life. Affected children have severe intellectual disability; delays in reaching developmental milestones (e.g., crawling, walking, etc.); muscle weakness; low muscle tone (hypotonia) and/or delayed bone growth as well as growth delay, resulting in short stature. Affected infants also have hearing loss; underdevelopment of the genitals and/or characteristic head and facial features such as a small head (microcephaly), a flat (depressed) nasal bridge and eye (ocular) abnormalities. The range and severity of symptoms varies from person to person. (For more information on this disorder, choose “Juberg Marsidi” as your search term in the Rare Disease Database.)Renpenning syndrome is one of the X-linked intellectual disability disorders that mostly affects males. It is characterized by intellectual disability that can be severe, short stature, a small head circumference (microcephaly) and small testes. Renpenning syndrome is caused by variants in the PQBP1 gene and is inherited in an X-linked pattern.L1 syndrome is a genetic condition occurring in males that usually includes hydrocephalus, intellectual disability, spasticity of legs and clasped (adducted) thumbs. L1 syndrome is caused by variants in the L1CAM gene. The variable types of L1 syndrome were once thought to be different diseases, but all the following conditions are now known to be caused by variants in the L1CAM gene:X-linked hydrocephalus with stenosis of aqueduct of Sylvius (HSAS) is characterized by severe hydrocephalus that often begins prenatally, adducted (clasped) thumbs, spasticity and severe intellectual disability. HASA syndrome is characterized by mild to moderate intellectual disability, aphasia (delayed speech), hypotonia that progresses to spasticity, adducted thumbs and variable widening of the third ventricle in the brain. X-linked complicated hereditary spastic paraplegia type 1 is characterized by spastic paraplegia (shuffling gait), mild to moderate intellectual disability and normal findings on MRI of the brain. X-linked complicated corpus callosum agenesis is characterized by variable spastic paraplegia, mild to moderate intellectual disability and abnormalities in the corpus callosum of the brain. (For more information on this disorder, choose “L1 syndrome” as your search term in the Rare Disease Database.)Pelizaeus-Merzbacher disease (PMD) is a rare X-linked genetic disorder affecting the central nervous system that is associated with abnormalities of the white matter of the brain. Symptoms develop due to lack of fatty covering of nerve cells (myelin sheath). Many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum and/or brain stem. Symptoms may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, loss of motor abilities and the slow progressive deterioration of intellectual function. PMD disease is associated with variants in the PLP1 gene. Some individuals with MCT8 deficiency have been incorrectly diagnosed as having PMD. (For more information on this disorder, choose “Pelizeaus-Merzbacher” as your search term in the Rare Disease Database.)There are additional congenital disorders that may be characterized by X-linked intellectual disability and occur in association with movement abnormalities, psychomotor delay and/or other features similar to those associated with MCT8 deficiency. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database).
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MCT8-Specific Thyroid Hormone Cell Transporter Deficiency
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Diagnosis of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency
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The diagnosis of MCT8 deficiency may be suspected in infants with low muscle tone (hypotonia) and poor head control that causes the head to droop (limber neck). Although hypotonia and muscle weakness may be obvious during early infancy, other symptoms (e.g., dyskinetic attacks, spastic paraplegia, etc.) may not become apparent until late infancy. Therefore, the disorder may not be diagnosed until childhood, based upon a thorough clinical evaluation, detailed patient history and specialized tests.Thyroid hormone testing is necessary to determine if MCT8 deficiency is a possible diagnosis. If results show elevated serum triiodothyronines (T3) and reduced reverse T3 concentrations, molecular genetic testing is indicated to determine if a MCT8 gene variant is present. In addition, serum thyroxine (T4) level tends to be low, and thyrotropin (TSH) may be slightly elevated.
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Diagnosis of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency. The diagnosis of MCT8 deficiency may be suspected in infants with low muscle tone (hypotonia) and poor head control that causes the head to droop (limber neck). Although hypotonia and muscle weakness may be obvious during early infancy, other symptoms (e.g., dyskinetic attacks, spastic paraplegia, etc.) may not become apparent until late infancy. Therefore, the disorder may not be diagnosed until childhood, based upon a thorough clinical evaluation, detailed patient history and specialized tests.Thyroid hormone testing is necessary to determine if MCT8 deficiency is a possible diagnosis. If results show elevated serum triiodothyronines (T3) and reduced reverse T3 concentrations, molecular genetic testing is indicated to determine if a MCT8 gene variant is present. In addition, serum thyroxine (T4) level tends to be low, and thyrotropin (TSH) may be slightly elevated.
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MCT8-Specific Thyroid Hormone Cell Transporter Deficiency
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Therapies of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency
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Treatment
The treatment of MCT8 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, neurologists, specialists who assess and treat skeletal abnormalities (orthopedists), speech-language pathologists, physical therapists and/or other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.Specific therapies for the treatment of MCT8 deficiency are symptomatic and supportive. Affected individuals who have scoliosis may be treated with orthopedic braces, physical therapy and/or other orthopedic measures. When abnormal depression of the breastbone (pectus excavatum) is present, corrective surgery may be recommended in some patients.Early intervention is important to ensure that children with MCT8 deficiency reach their potential. Special services that may be beneficial include special remedial education, special social support, physical therapy and/or other medical, social and/or vocational services.
Genetic counseling is recommended for affected individuals and their families.
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Therapies of MCT8-Specific Thyroid Hormone Cell Transporter Deficiency. Treatment
The treatment of MCT8 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, neurologists, specialists who assess and treat skeletal abnormalities (orthopedists), speech-language pathologists, physical therapists and/or other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.Specific therapies for the treatment of MCT8 deficiency are symptomatic and supportive. Affected individuals who have scoliosis may be treated with orthopedic braces, physical therapy and/or other orthopedic measures. When abnormal depression of the breastbone (pectus excavatum) is present, corrective surgery may be recommended in some patients.Early intervention is important to ensure that children with MCT8 deficiency reach their potential. Special services that may be beneficial include special remedial education, special social support, physical therapy and/or other medical, social and/or vocational services.
Genetic counseling is recommended for affected individuals and their families.
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MCT8-Specific Thyroid Hormone Cell Transporter Deficiency
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nord_770_0
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Overview of MDR3 Deficiency
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Summary MDR3 deficiency is a rare genetic disorder that predominantly affects the liver. The disorder represents a spectrum of diseases that can range from mild to severe. The main symptom is interruption or suppression of the flow of bile from the liver (cholestasis). In addition, affected individuals may be prone to forming gallstones. Cholestasis in MDR3 deficiency occurs due to defects within the liver (intrahepatic), although the defects can also lead to injury of the bile ducts outside the liver (extrahepatic). Cholestasis can cause yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, growth deficiency, easy bleeding, rickets and persistent itchiness. Symptoms may be present in the neonatal period rather than at birth (congenital) or, in many cases, may not appear until childhood or even middle age when the disorder manifests as intrahepatic cholestasis of pregnancy, gallstone disease, or jaundice and scarring of the liver (cirrhosis). MDR3 deficiency is caused by mutations of the ABCB4 gene and appears to follow autosomal recessive inheritance in most patients. However, autosomal dominant inheritance may occur in some patients.Introduction The terminology used to describe MDR3 deficiency can be confusing. The term can be applied to several disorders including progressive familial intrahepatic cholestasis (PFIC) type 3, benign recurrent intrahepatic cholestasis (BRIC), low phospholipid associated cholelithiasis (LPAC) syndrome, adult biliary fibrosis or cirrhosis, and certain cases of intrahepatic cholestasis of pregnancy (ICP), of drug induced cholestasis (DIC) and of transient neonatal cholestasis (TNC). These disorders are all caused by mutations of the ABCB4 gene and resulting deficiency of MDR3.There is a spectrum of disease in PFIC3. At the severe end of the spectrum the disease is progressive and leads to end-stage liver disease necessitating liver transplantation in childhood. At the other end of the spectrum is a much milder disease that may be very responsive to ursodeoxycholic acid (UDCA).
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Overview of MDR3 Deficiency. Summary MDR3 deficiency is a rare genetic disorder that predominantly affects the liver. The disorder represents a spectrum of diseases that can range from mild to severe. The main symptom is interruption or suppression of the flow of bile from the liver (cholestasis). In addition, affected individuals may be prone to forming gallstones. Cholestasis in MDR3 deficiency occurs due to defects within the liver (intrahepatic), although the defects can also lead to injury of the bile ducts outside the liver (extrahepatic). Cholestasis can cause yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, growth deficiency, easy bleeding, rickets and persistent itchiness. Symptoms may be present in the neonatal period rather than at birth (congenital) or, in many cases, may not appear until childhood or even middle age when the disorder manifests as intrahepatic cholestasis of pregnancy, gallstone disease, or jaundice and scarring of the liver (cirrhosis). MDR3 deficiency is caused by mutations of the ABCB4 gene and appears to follow autosomal recessive inheritance in most patients. However, autosomal dominant inheritance may occur in some patients.Introduction The terminology used to describe MDR3 deficiency can be confusing. The term can be applied to several disorders including progressive familial intrahepatic cholestasis (PFIC) type 3, benign recurrent intrahepatic cholestasis (BRIC), low phospholipid associated cholelithiasis (LPAC) syndrome, adult biliary fibrosis or cirrhosis, and certain cases of intrahepatic cholestasis of pregnancy (ICP), of drug induced cholestasis (DIC) and of transient neonatal cholestasis (TNC). These disorders are all caused by mutations of the ABCB4 gene and resulting deficiency of MDR3.There is a spectrum of disease in PFIC3. At the severe end of the spectrum the disease is progressive and leads to end-stage liver disease necessitating liver transplantation in childhood. At the other end of the spectrum is a much milder disease that may be very responsive to ursodeoxycholic acid (UDCA).
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MDR3 Deficiency
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Symptoms of MDR3 Deficiency
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The age of onset, severity and specific symptoms of MDR3 deficiency can vary greatly from one person to another. In some cases (mainly PFIC3, TNC3), cholestasis may be present in newborns (neonatal period). Individuals with mild forms of this disorder may not develop symptoms until young adulthood or middle age where MDR3 deficiency may manifest as mild abnormalities in liver blood tests, gallstones, jaundice and/or itching during pregnancy, or as scarring of the liver and/or yellowing of the eyes and skin. Cholestasis is the characteristic finding for MDR3 deficiency. Cholestasis is defined as reduction of the flow of bile from the liver. The formation of bile is one of the main functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), lipids (bile salts, phospholipids, cholesterol), and other materials including an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, fat soluble vitamins, and other nutrients and it aids in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body. In MDR3 deficiency cholestasis, this interruption or suppression usually begins during the first few months of life. Affected infants have episodes of cholestasis followed by disease-free periods. However, eventually cholestasis progresses to become a permanent condition. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body. The initial symptoms associated with MDR3 deficiency may be jaundice, pale stools and/or hepatomegaly, which can be present during the neonatal period rather than at birth (congenital). Affected infants may also experience mild or moderate itching (pruritus) starting at about 9 months of age. Itching can cause irritability and skin abrasions due to constant scratching. Yellowing of the skin, mucous membranes and whites of the eyes (jaundice) is often present. Initially jaundice may come and go, but eventually it may continually persist. Additional symptoms common to liver disease such as an abnormally large liver and spleen (hepatosplenomegaly) may also occur. Another symptom associated with MDR3 deficiency is impairment of the ability of the digestive system to properly absorb fat, fat soluble vitamins and other nutrients (malabsorption). Malabsorption leads to vitamin deficiency and eventually results in failure to thrive, growth deficiency, bleeding episodes such as repeated nosebleeds, an abnormal susceptibility to bruising, and rickets. Vitamin K deficiency can lead to severe even life-threatening problems with bleeding and as such careful monitoring of this issue is important. Rickets is a bone disorder with characteristic growth plate abnormalities and progressive softening of the bone structure. It can lead to a predisposition to fractures. MDR3 deficiency eventually progresses to cause serious life-threatening complications including high blood pressure of the vein of that carries blood from the intestines to the liver (portal hypertension), scarring of the liver (cirrhosis) and, eventually, liver failure. This process can occur rapidly or more slowly, ranging from the neonatal period to before adulthood. Additional symptoms that may affect individuals with MDR3 deficiency include the development of gallstones. Gallstones, also known as cholelithiasis, can cause obstruction and/or inflammation of the gallbladder (cholecystitis), which can result in cramping pain in the upper abdomen, fever and jaundice. Stones and/or sludge found within the liver (as opposed to the usual location in the gallbladder) is an uncommon problem and fairly specific to MDR3 deficiency. Although many cases of MDR3 deficiency occur during infancy or childhood, some individuals with mutations of the ABCB4 gene do not develop symptoms until young adulthood or middle age. For example, some adults may develop jaundice and scarring of the liver (fibrosis or cirrhosis) during middle age. In some cases the liver disease may look like sclerosing cholangitis a disease often seen in individuals with inflammatory bowel disease. In the setting of MDR3 disease the bile duct injury is mostly inside the liver. In other cases, some adults with mutations of the ABCB4 gene develop a specific type of cholesterol gallstone disease called low phospholipid associated cholelithiasis (LPAC). LPAC syndrome is characterized by inflammation of the gallbladder, inflammation of the bile ducts, intrahepatic gallstone disease and may result in inflammation of the pancreas (pancreatitis). In this condition there is a predisposition to the development of stones within the liver itself, which is different than the typical situation where the stones develop in the gallbladder. Because the problem is not localized to the gallbladder, problems can persist even after the surgical removal of the gallbladder. Onset of symptoms is younger than 40 years of age. Some females with mutations of the ABCB4 gene may develop a condition known as intrahepatic cholestasis of pregnancy (ICP). This condition is characterized by cholestasis, itching and, in some cases, jaundice that develops during pregnancy, usually during the third trimester. The symptoms resolve without treatment (spontaneously) after the pregnancy (postpartum). Generally, females who develop ICP do not exhibit symptoms before pregnancy and do not develop chronic liver damage. It is important to note that individuals with MDR3 deficiency might experience during their life different features of the various MDR3 deficiency diseases.
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Symptoms of MDR3 Deficiency. The age of onset, severity and specific symptoms of MDR3 deficiency can vary greatly from one person to another. In some cases (mainly PFIC3, TNC3), cholestasis may be present in newborns (neonatal period). Individuals with mild forms of this disorder may not develop symptoms until young adulthood or middle age where MDR3 deficiency may manifest as mild abnormalities in liver blood tests, gallstones, jaundice and/or itching during pregnancy, or as scarring of the liver and/or yellowing of the eyes and skin. Cholestasis is the characteristic finding for MDR3 deficiency. Cholestasis is defined as reduction of the flow of bile from the liver. The formation of bile is one of the main functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), lipids (bile salts, phospholipids, cholesterol), and other materials including an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, fat soluble vitamins, and other nutrients and it aids in the elimination of excess cholesterol, bilirubin, waste, and toxins from the body. In MDR3 deficiency cholestasis, this interruption or suppression usually begins during the first few months of life. Affected infants have episodes of cholestasis followed by disease-free periods. However, eventually cholestasis progresses to become a permanent condition. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body. The initial symptoms associated with MDR3 deficiency may be jaundice, pale stools and/or hepatomegaly, which can be present during the neonatal period rather than at birth (congenital). Affected infants may also experience mild or moderate itching (pruritus) starting at about 9 months of age. Itching can cause irritability and skin abrasions due to constant scratching. Yellowing of the skin, mucous membranes and whites of the eyes (jaundice) is often present. Initially jaundice may come and go, but eventually it may continually persist. Additional symptoms common to liver disease such as an abnormally large liver and spleen (hepatosplenomegaly) may also occur. Another symptom associated with MDR3 deficiency is impairment of the ability of the digestive system to properly absorb fat, fat soluble vitamins and other nutrients (malabsorption). Malabsorption leads to vitamin deficiency and eventually results in failure to thrive, growth deficiency, bleeding episodes such as repeated nosebleeds, an abnormal susceptibility to bruising, and rickets. Vitamin K deficiency can lead to severe even life-threatening problems with bleeding and as such careful monitoring of this issue is important. Rickets is a bone disorder with characteristic growth plate abnormalities and progressive softening of the bone structure. It can lead to a predisposition to fractures. MDR3 deficiency eventually progresses to cause serious life-threatening complications including high blood pressure of the vein of that carries blood from the intestines to the liver (portal hypertension), scarring of the liver (cirrhosis) and, eventually, liver failure. This process can occur rapidly or more slowly, ranging from the neonatal period to before adulthood. Additional symptoms that may affect individuals with MDR3 deficiency include the development of gallstones. Gallstones, also known as cholelithiasis, can cause obstruction and/or inflammation of the gallbladder (cholecystitis), which can result in cramping pain in the upper abdomen, fever and jaundice. Stones and/or sludge found within the liver (as opposed to the usual location in the gallbladder) is an uncommon problem and fairly specific to MDR3 deficiency. Although many cases of MDR3 deficiency occur during infancy or childhood, some individuals with mutations of the ABCB4 gene do not develop symptoms until young adulthood or middle age. For example, some adults may develop jaundice and scarring of the liver (fibrosis or cirrhosis) during middle age. In some cases the liver disease may look like sclerosing cholangitis a disease often seen in individuals with inflammatory bowel disease. In the setting of MDR3 disease the bile duct injury is mostly inside the liver. In other cases, some adults with mutations of the ABCB4 gene develop a specific type of cholesterol gallstone disease called low phospholipid associated cholelithiasis (LPAC). LPAC syndrome is characterized by inflammation of the gallbladder, inflammation of the bile ducts, intrahepatic gallstone disease and may result in inflammation of the pancreas (pancreatitis). In this condition there is a predisposition to the development of stones within the liver itself, which is different than the typical situation where the stones develop in the gallbladder. Because the problem is not localized to the gallbladder, problems can persist even after the surgical removal of the gallbladder. Onset of symptoms is younger than 40 years of age. Some females with mutations of the ABCB4 gene may develop a condition known as intrahepatic cholestasis of pregnancy (ICP). This condition is characterized by cholestasis, itching and, in some cases, jaundice that develops during pregnancy, usually during the third trimester. The symptoms resolve without treatment (spontaneously) after the pregnancy (postpartum). Generally, females who develop ICP do not exhibit symptoms before pregnancy and do not develop chronic liver damage. It is important to note that individuals with MDR3 deficiency might experience during their life different features of the various MDR3 deficiency diseases.
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MDR3 Deficiency
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Causes of MDR3 Deficiency
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MDR3 deficiency occurs due to disruption or changes (mutations) of the ABCB4 gene. This mutation is thought to be inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females. In general MDR3 disease behaves as an autosomal recessive condition, requiring the presence of mutations in both copies of the gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some cases, MDR3 related disease process occur in individuals with only one altered ABCB4 gene. Therefore, in some people, MDR3 deficiency can act like an autosomal dominant disease. The ABCB4 gene creates (encodes) a protein known as multidrug resistance protein 3 (MDR3). Mutations in the ABCB4 gene result in absence or low levels of functional MDR3 enzyme leading to decreased level of phospholipids in bile and an abnormality in bile ducts. Individuals with no residual enzyme activity have severe forms of MDR3 deficiency. Individuals with mild forms of the MDR3 deficiency have varying degrees of enzyme activity and of subsequent phospholipid concentrations in bile. In all untreated patients with MDR3 deficiency, serum GGT activity is elevated.
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Causes of MDR3 Deficiency. MDR3 deficiency occurs due to disruption or changes (mutations) of the ABCB4 gene. This mutation is thought to be inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females. In general MDR3 disease behaves as an autosomal recessive condition, requiring the presence of mutations in both copies of the gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some cases, MDR3 related disease process occur in individuals with only one altered ABCB4 gene. Therefore, in some people, MDR3 deficiency can act like an autosomal dominant disease. The ABCB4 gene creates (encodes) a protein known as multidrug resistance protein 3 (MDR3). Mutations in the ABCB4 gene result in absence or low levels of functional MDR3 enzyme leading to decreased level of phospholipids in bile and an abnormality in bile ducts. Individuals with no residual enzyme activity have severe forms of MDR3 deficiency. Individuals with mild forms of the MDR3 deficiency have varying degrees of enzyme activity and of subsequent phospholipid concentrations in bile. In all untreated patients with MDR3 deficiency, serum GGT activity is elevated.
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MDR3 Deficiency
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Affects of MDR3 Deficiency
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MDR3 deficiency affects males and females in equal numbers. The exact incidence and prevalence of MDR3 deficiency is unknown. Concerning PFIC3, fewer than 500 cases have been reported in the medical literature. Because milder forms of MDR3 deficiency often go unrecognized or misdiagnosed, it is difficult to determine the disorder’s true frequency in the general population.
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Affects of MDR3 Deficiency. MDR3 deficiency affects males and females in equal numbers. The exact incidence and prevalence of MDR3 deficiency is unknown. Concerning PFIC3, fewer than 500 cases have been reported in the medical literature. Because milder forms of MDR3 deficiency often go unrecognized or misdiagnosed, it is difficult to determine the disorder’s true frequency in the general population.
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MDR3 Deficiency
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Related disorders of MDR3 Deficiency
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Symptoms of the following disorders can be similar to those of MDR3 deficiency. Comparisons may be useful for a differential diagnosis. Extrahepatic causes of cholestasis are ruled out by liver ultrasonography or magnetic resonance cholangiography. Biliary atresia is a rare gastrointestinal disorder characterized by destruction or rarely, absence of all or a portion of the extrahepatic bile duct. The bile duct is a tube that allows the passage of bile from the liver into the gallbladder and, eventually, the small intestine. In biliary atresia, destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected newborns (neonates) have yellowing of the skin and whites of the eyes (jaundice), pale, gray (discolored) stools and abnormal enlargement of the liver (hepatomegaly). Eventually, infants develop additional symptoms such as itching and scarring of the liver (cirrhosis). In some cases, additional anatomical abnormalities (asplenia or polysplenia syndrome) may be present. The exact cause of biliary atresia is unknown. Biliary atresia is a form of cholestasis where GGT is high, like in MDR3 disease and many other forms of cholestasis. (For more information on this disorder, choose “biliary atresia” as your search term in the Rare Disease Database.) Metabolic disorders are a group of disorders in which certain enzymes required to “metabolize” or breakdown various substances in the body (e.g., carbohydrates, proteins, fats) are missing or reduced. Many of these enzymes are crucial in the production of energy. Absence or deficiency of critical enzymes causes substances to build up in the body potentially damaging various organs. Various metabolic diseases are associated with liver dysfunction similar to that found in MDR3 deficiency. In addition, other genetic disorders like alpha-1-antitrypsin deficiency and cystic fibrosis may be similar to MDR3 deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Several rare disorders may involve the liver, causing signs and symptoms that are similar to those found in MDR3 deficiency. These disorders include sclerosing cholangitis and Alagille syndrome. They generally have additional signs and symptoms that can distinguish them from MDR3 deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Wilson disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter. Copper is excreted in bile and as such can accumulate in the liver of individuals with MDR3 deficiency and in some people MDR3 deficiency has been misdiagnosed as Wilson Disease. (For more information on these disorders, choose “as your search term in the Rare Disease Database.)
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Related disorders of MDR3 Deficiency. Symptoms of the following disorders can be similar to those of MDR3 deficiency. Comparisons may be useful for a differential diagnosis. Extrahepatic causes of cholestasis are ruled out by liver ultrasonography or magnetic resonance cholangiography. Biliary atresia is a rare gastrointestinal disorder characterized by destruction or rarely, absence of all or a portion of the extrahepatic bile duct. The bile duct is a tube that allows the passage of bile from the liver into the gallbladder and, eventually, the small intestine. In biliary atresia, destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected newborns (neonates) have yellowing of the skin and whites of the eyes (jaundice), pale, gray (discolored) stools and abnormal enlargement of the liver (hepatomegaly). Eventually, infants develop additional symptoms such as itching and scarring of the liver (cirrhosis). In some cases, additional anatomical abnormalities (asplenia or polysplenia syndrome) may be present. The exact cause of biliary atresia is unknown. Biliary atresia is a form of cholestasis where GGT is high, like in MDR3 disease and many other forms of cholestasis. (For more information on this disorder, choose “biliary atresia” as your search term in the Rare Disease Database.) Metabolic disorders are a group of disorders in which certain enzymes required to “metabolize” or breakdown various substances in the body (e.g., carbohydrates, proteins, fats) are missing or reduced. Many of these enzymes are crucial in the production of energy. Absence or deficiency of critical enzymes causes substances to build up in the body potentially damaging various organs. Various metabolic diseases are associated with liver dysfunction similar to that found in MDR3 deficiency. In addition, other genetic disorders like alpha-1-antitrypsin deficiency and cystic fibrosis may be similar to MDR3 deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Several rare disorders may involve the liver, causing signs and symptoms that are similar to those found in MDR3 deficiency. These disorders include sclerosing cholangitis and Alagille syndrome. They generally have additional signs and symptoms that can distinguish them from MDR3 deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) Wilson disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter. Copper is excreted in bile and as such can accumulate in the liver of individuals with MDR3 deficiency and in some people MDR3 deficiency has been misdiagnosed as Wilson Disease. (For more information on these disorders, choose “as your search term in the Rare Disease Database.)
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MDR3 Deficiency
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nord_770_5
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Diagnosis of MDR3 Deficiency
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A diagnosis of MDR3 deficiency should be suspected in infants and children with evidence of cholestasis and/or chronic liver disease when the serum gGTP levels are elevated. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history, and a variety of tests. Clinical Testing and Work-Up
Tests used to help diagnose MDR3 deficiency include measuring serum levels of bilirubin, bile salts, and gamma-glutamyltransferase (GGT). Molecular genetic testing for mutations in the ABCB4 gene is available on a clinical basis and can confirm the diagnosis. Microscopic examination of liver tissue (biopsy) and MDR3 immunostaining may be performed to aid in diagnosis and to detect the presence of cirrhosis. If bile can be collected during ERCP or surgery, a biliary lipid analysis could be performed. The decrease in biliary phospholipid supports the diagnosis and the level of the residual concentration is potentially helpful for prognosis.
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Diagnosis of MDR3 Deficiency. A diagnosis of MDR3 deficiency should be suspected in infants and children with evidence of cholestasis and/or chronic liver disease when the serum gGTP levels are elevated. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history, and a variety of tests. Clinical Testing and Work-Up
Tests used to help diagnose MDR3 deficiency include measuring serum levels of bilirubin, bile salts, and gamma-glutamyltransferase (GGT). Molecular genetic testing for mutations in the ABCB4 gene is available on a clinical basis and can confirm the diagnosis. Microscopic examination of liver tissue (biopsy) and MDR3 immunostaining may be performed to aid in diagnosis and to detect the presence of cirrhosis. If bile can be collected during ERCP or surgery, a biliary lipid analysis could be performed. The decrease in biliary phospholipid supports the diagnosis and the level of the residual concentration is potentially helpful for prognosis.
| 770 |
MDR3 Deficiency
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nord_770_6
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Therapies of MDR3 Deficiency
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Treatment
Ursodeoxycholic acid (UDCA) therapy is effective in some patients (especially those with milder disease) and should be part of the initial treatment options for affected individuals. Restoring vitamins and nutrients lost through malabsorption may also be necessary. At a minimum fat-soluble vitamin levels should be monitored to identify deficiency in affected individuals. Other treatments are directed toward the specific symptoms (e.g. itching) or complications (e.g. cirrhosis, gallbladder stone disease) that are apparent in each individual. Treatment options include surgery (e.g. cholecystectomy [gallbladder removal]), but this may not be completely effective due to the on-going risk of stone formation within the liver. Some individuals do not respond to UDCA therapy and may require a liver transplant. Nearly all affected individuals who have undergone liver transplantation have demonstrated dramatic improvement of symptoms. However, a liver transplantation carries risk and may result in post-operative complications. Also, after a liver transplant, affected individuals typically are required to take medication life-long for immunosuppression. Genetic counseling is recommended for affected individuals and their families.
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Therapies of MDR3 Deficiency. Treatment
Ursodeoxycholic acid (UDCA) therapy is effective in some patients (especially those with milder disease) and should be part of the initial treatment options for affected individuals. Restoring vitamins and nutrients lost through malabsorption may also be necessary. At a minimum fat-soluble vitamin levels should be monitored to identify deficiency in affected individuals. Other treatments are directed toward the specific symptoms (e.g. itching) or complications (e.g. cirrhosis, gallbladder stone disease) that are apparent in each individual. Treatment options include surgery (e.g. cholecystectomy [gallbladder removal]), but this may not be completely effective due to the on-going risk of stone formation within the liver. Some individuals do not respond to UDCA therapy and may require a liver transplant. Nearly all affected individuals who have undergone liver transplantation have demonstrated dramatic improvement of symptoms. However, a liver transplantation carries risk and may result in post-operative complications. Also, after a liver transplant, affected individuals typically are required to take medication life-long for immunosuppression. Genetic counseling is recommended for affected individuals and their families.
| 770 |
MDR3 Deficiency
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nord_771_0
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Overview of Measles
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Measles is a highly contagious viral disease occurring primarily in children. This disease is characterized by fever, cough, acute nasal mucous membrane discharge (coryza), inflammation of the lining of the eyelids (conjunctivitis), a spreading rash, and eruption of small, irregular, bright red spots (Koplik's spots) on the inner cheeks in the mouth with a minute bluish or white speck in the center of each.It is often difficult to avoid exposure to measles because it can be contracted from someone whose symptoms have not yet appeared. Measles is not contagious four days after appearance of the rash.As a result of vaccination to prevent measles, all cases that now occur in the United States have been brought from other countries. Measles continues to be a significant public health problem in developing countries, with 30-40 million cases per year. Most reported cases are from Africa.
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Overview of Measles. Measles is a highly contagious viral disease occurring primarily in children. This disease is characterized by fever, cough, acute nasal mucous membrane discharge (coryza), inflammation of the lining of the eyelids (conjunctivitis), a spreading rash, and eruption of small, irregular, bright red spots (Koplik's spots) on the inner cheeks in the mouth with a minute bluish or white speck in the center of each.It is often difficult to avoid exposure to measles because it can be contracted from someone whose symptoms have not yet appeared. Measles is not contagious four days after appearance of the rash.As a result of vaccination to prevent measles, all cases that now occur in the United States have been brought from other countries. Measles continues to be a significant public health problem in developing countries, with 30-40 million cases per year. Most reported cases are from Africa.
| 771 |
Measles
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nord_771_1
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Symptoms of Measles
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Measles usually begins like a common cold after a seven to fourteen day incubation period, with sinus congestion, a runny nose, a cough, and red, irritated eyes. Two days later, although often unnoticed, Koplik's spots (small red spots with blueish-white specks in the center) form inside the mouth opposite the molars. After four days of these worsening symptoms, a telltale rash appears first on the face and neck, then on the trunk, arms and legs. Patients may have some degree of sensitivity to light. After two to four days of listlessness, the rash, cough, stuffiness and red eyes (conjunctivitis) abruptly improve. If no complications have set in, measles has run its course by the tenth day.Measles patients can have lowered resistance to infections such as bronchitis, ear infections, or other bacterial infections. Possible direct complications may include pneumonia and inner ear infections such as otitis media and mastoiditis that can possibly lead to deafness. Approximately 1 in 1,000 people with measles develop inflammation of the brain (encephalitis) that can result in mental retardation. Approximately 1 in 1,000 people die from measles. Measles virus may also be associated with subacute sclerosing panencephalitis (SSPE), a slow virus infection. (Slow viruses may stay dormant in humans for extended periods of time, then for reasons yet unknown, may become reactivated.) SSPE is a chronic brain disease of children and adolescents that can occur months to years (usually years) after an attack of measles. SSPE can cause intellectual deterioration, convulsive seizures, coma and motor abnormalities. (For more information on this disorder, choose “SSPE” as your search term in the Rare Disease Database.)
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Symptoms of Measles. Measles usually begins like a common cold after a seven to fourteen day incubation period, with sinus congestion, a runny nose, a cough, and red, irritated eyes. Two days later, although often unnoticed, Koplik's spots (small red spots with blueish-white specks in the center) form inside the mouth opposite the molars. After four days of these worsening symptoms, a telltale rash appears first on the face and neck, then on the trunk, arms and legs. Patients may have some degree of sensitivity to light. After two to four days of listlessness, the rash, cough, stuffiness and red eyes (conjunctivitis) abruptly improve. If no complications have set in, measles has run its course by the tenth day.Measles patients can have lowered resistance to infections such as bronchitis, ear infections, or other bacterial infections. Possible direct complications may include pneumonia and inner ear infections such as otitis media and mastoiditis that can possibly lead to deafness. Approximately 1 in 1,000 people with measles develop inflammation of the brain (encephalitis) that can result in mental retardation. Approximately 1 in 1,000 people die from measles. Measles virus may also be associated with subacute sclerosing panencephalitis (SSPE), a slow virus infection. (Slow viruses may stay dormant in humans for extended periods of time, then for reasons yet unknown, may become reactivated.) SSPE is a chronic brain disease of children and adolescents that can occur months to years (usually years) after an attack of measles. SSPE can cause intellectual deterioration, convulsive seizures, coma and motor abnormalities. (For more information on this disorder, choose “SSPE” as your search term in the Rare Disease Database.)
| 771 |
Measles
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nord_771_2
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Causes of Measles
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Measles is caused by a paramyxovirus. The disease is highly contagious and can be transmitted from four days before the rash begins. The virus lives in the mucus in the nose and throat of an infected person and is spread into the air when the infected person sneezes or coughs.
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Causes of Measles. Measles is caused by a paramyxovirus. The disease is highly contagious and can be transmitted from four days before the rash begins. The virus lives in the mucus in the nose and throat of an infected person and is spread into the air when the infected person sneezes or coughs.
| 771 |
Measles
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