Marfan Syndrome

Disease Overview

Marfan syndrome is a genetic disorder that affects connective tissue, which is the material between cells of the body that gives the tissues form and strength. Connective tissue is found all over the body and multiple organ systems may be affected in individuals with Marfan syndrome. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), indentation or protrusion of the chest wall (pectus deformity), dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and tear (dissection) of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse) and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of Marfan syndrome vary greatly from person to person. Marfan syndrome is inherited as an autosomal dominant trait, meaning that only one abnormal copy of the Marfan gene inherited from one parent is sufficient to have the condition. Defects or deletions (pathogenic variants) of the fibrillin-1 (FBN1) gene have been shown to cause Marfan syndrome.

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Synonyms

• MFS

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Signs & Symptoms

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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Causes

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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Affected populations

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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Disorders with Similar Symptoms

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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Diagnosis

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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Standard Therapies

Treatment

The 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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Clinical Trials and Studies

Researchers are studying a variety of drugs including calcium channel blockers (such as amlodipine or verapamil), or angiotensin converting enzyme inhibitors such as enalapril as potential alternative therapies for aortic enlargement in Marfan syndrome. One study in mouse models of Marfan syndrome showed that calcium channel blockers can accelerate aortic growth and increased the risk of aortic tear. While there was preliminary evidence of increased risk in people with Marfan syndrome taking calcium channel blockers, more research is necessary to address this issue and to determine the long-term safety and effectiveness of other potential therapies.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

Contact for additional information about Marfan syndrome:

Hal Dietz, MD
Victor A. McKusick Professor of Medicine and Genetics
Investigator, Howard Hughes Medical Institute
Institute of Genetic Medicine
Departments of Pediatrics, Medicine, and Molecular Biology & Genetics
Johns Hopkins University School of Medicine
733 N. Broadway, BRB 539
Baltimore, MD 21205
(410) 614-0701
(410) 614-2256 (fax)
[email protected]

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References

TEXTBOOKS
Dietz H. Marfan Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:218-9.

Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:1608-9.

Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. W. B. Saunders Co., Philadelphia, PA; 1997:546.

JOURNAL ARTICLES
Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476-485.

Dean JC. Marfan syndrome: clinical diagnosis and management. Eur J Hum Genet. 2007;15:274-33.

Forteza A, Cortina JM, Sanchez V, et al. Aortic valve preservation in Marfan syndrome. Initial experience. Rev Esp Cardiol. 2007;60:471-5.

Ramirez F, Dietz HC. Marfan syndrome: from molecular pathogenesis to clinical treatment. Curr Opin Genet Dev. 2007;17:252-8.

Judge DP, Dietz HC. Marfan’s syndrome. Lancet. 2005;366:1965-76.

Gott VL, Cameron DE, Alejo DE, et al. Aortic root replacement in 271 Marfan patients: a 24-year experience. Ann Thorac Surg. 2002;73:438-43.

Le Parc JM, Molcard S Tubach F, et al. Marfan syndrome and fibrillin disorders. Joint Bone Surg. 2000;67:401-7.

Collod G, Babron M-C, Jondeau G, et al. A second locus for Marfan syndrome maps to chromosome 3p24.2-p25. Nat Genet. 1994;8:264-8.

Dietz HC, Pyeritz RE, Hall BD, et al. The Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352:337-9.

Sakai LY, Keene DR, Engvall E. Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol. 1986;103:2499-509.

INTERNET
Chen H. Genetics of Marfan syndrome. Medscape. Last Update:Jan 07, 2021. https://www.emedicine.com/ped/topic1372.htm Accessed January 21. 2021.

Channell K. Marfan syndrome. Medscape. Last Update Jun 18, 2020.  https://www.emedicine.com/orthoped/topic414.htm Accessed January 21, 2021.

Dietz H. Marfan Syndrome. 2001 Apr 18 [Updated 2017 Oct 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1335/ Accessed January 21, 2021.

Jondeau G.. Marfan syndrome. Orphanet encyclopedia, March 2010. Available at: https://www.orpha.net/consor/cgi-bin/index.php Accessed January 21, 2021.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Marfan Syndrome; MFS. Entry No: 154700. Last Edited 11/27/2019. Available at: https://omim.org/entry/154700 Accessed January 21, 2021.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Loeys-Dietz Syndrome, Type 2B; LDS2B (Marfan Syndrome, Type II, Formerly). Entry No: 610168 Last Updated 07/11/2017. Available at: https://omim.org/entry/610168 Accessed January 21, 2021.

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Programs & Resources

• Assistance Programs
• Patient Organizations
• More Information

RareCare^® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Learn more about Patient Assistance Programs >

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Patient Organizations

The Marfan Foundation

NORD Member

Email: [email protected]

Related Rare Diseases: Shprintzen Goldberg Syndrome, Congenital Contractural Arachnodactyly, Mixed Connective Tissue Disease, ...

https://rarediseases.org/organizations/marfan-foundation/

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National Scoliosis Foundation

Phone: 781-341-8333 Email: [email protected] Fax: 781-341-8333

Related Rare Diseases: Shprintzen Goldberg Syndrome, Ataxia with Vitamin E Deficiency, Marfan Syndrome, ...

https://rarediseases.org/organizations/national-scoliosis-foundation/

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American Heart Association

Phone: 214-784-7212 Email: [email protected] Fax: 214-784-1307

Related Rare Diseases: Recurrent Pericarditis, Tangier Disease, Shprintzen Goldberg Syndrome, ...

https://rarediseases.org/organizations/american-heart-association/

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NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

Phone: 301-495-4484 Email: [email protected] Fax: 301-718-6366

Related Rare Diseases: Chanarin-Dorfman Syndrome, Congenital Myasthenic Syndromes, Arterial Tortuosity Syndrome, ...

https://rarediseases.org/organizations/nih-national-institute-of-arthritis-and-musculoskeletal-and-skin-diseases/

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GADA CANADA

Phone: 905-826-3223 Email: [email protected] Fax: 905-826-2125

Related Rare Diseases: Shprintzen Goldberg Syndrome, Marfan Syndrome, Síndrome de Marfan, ...

https://rarediseases.org/organizations/gada-canada/

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Learn more about Patient Organization & Membership >

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More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

View report

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Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

View report

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

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