NORD gratefully acknowledges Hal Dietz, MD, Victor A. McKusick Professor of Medicine and Genetics, Institute of Genetic Medicine, Investigator, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, for assistance in the preparation of this report.
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 especially 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 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 during growth.
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. 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). Some individuals may develop widening of the main artery of the lungs (pulmonary artery dilatation). If left untreated, the various heart abnormalities associated with Marfan syndrome can cause life-threatening complications such as rupture of the aorta and congestive heart failure.
Individuals with Marfan syndrome 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 (ectopia lentis) away from the center of the eyeball. Ectopia lentis may occur at birth or later in life and may remain stable or become progressively worse.
Additional symptoms affecting the eyes include an abnormally flat cornea (the clear 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 cataracts or glaucoma. If left untreated, eye abnormalities can result in vision loss.
In addition to the more common symptoms discussed above, individuals with Marfan syndrome may develop 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.
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 (stria atrophicae) on certain areas 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 allows external bulging 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 a mutations 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.
Marfan syndrome is inherited as an autosomal dominant condition. 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. In approximately 25-30 percent of Marfan syndrome cases, this mutation 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.
Marfan syndrome has been linked to defects or disruptions (mutations) of the fibrillin-1 (FBN1) gene. Not everyone who has a mutation of this gene develops the symptoms of Marfan syndrome.
Investigators have determined that most cases (> 95%) of Marfan syndrome occur due to defined mutation of the FBN1 gene located on the long arm (q) of chromosome 15 (15q21.1). 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 segments (called bands) that are numbered. For example, “chromosome 15q21.1” refers to band 21.1 on the long arm of chromosome 15. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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, connective tissue may be weak. Fibrillin-1 also influences the activity of a molecule that instructs cells how to behave (growth factor) called transforming growth factor-β (TGF-β).
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 the added feature of problems with learning (intellectual disability). SGS is caused by mutations in another gene that regulates TGF-β activity called SKI.
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.
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.
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.
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 or remodeling of the natural aortic valve). Studies are underway to assess the durability of valve-sparing procedures.
Surgery to repair or replace the mitral valve in individuals who experience severe mitral valve regurgitation may become necessary as well. 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 may also be corrected through surgical reattachment.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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 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
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) 614-2256 (fax)
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