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Marfan Syndrome.

Authors

Dietz HC.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.
2001 Apr 18 [updated 2014 Jun 12].

Excerpt

DISEASE CHARACTERISTICS:

Marfan syndrome is a systemic disorder of connective tissue with a high degree of clinical variability. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. FBN1 pathogenic variants associate with a broad phenotypic continuum, ranging from isolated features of Marfan syndrome to neonatal presentation of severe and rapidly progressive disease in multiple organ systems. Myopia is the most common ocular feature; displacement of the lens from the center of the pupil, seen in approximately 60% of affected individuals, is a hallmark feature. People with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and early cataract formation. The skeletal system involvement is characterized by bone overgrowth and joint laxity. The extremities are disproportionately long for the size of the trunk (dolichostenomelia). Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum). Scoliosis is common and can be mild or severe and progressive. The major sources of morbidity and early mortality in the Marfan syndrome relate to the cardiovascular system. Cardiovascular manifestations include dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population.

DIAGNOSIS/TESTING:

Marfan syndrome is a clinical diagnosis based on family history and the observation of characteristic findings in multiple organ systems. Ectopia lentis and aortic aneurysm are given special significance in the diagnosis of Marfan syndrome because of their relative specificity or frequency and clinical significance, respectively. Marfan syndrome is caused by mutation of FBN1. The sensitivity of molecular genetic testing of FBN1 is substantial yet incomplete for unknown reasons; it may be explained by atypical location or character of FBN1 pathogenic variants in some individuals (e.g., large deletions or promoter mutations) or to locus heterogeneity.

MANAGEMENT:

Treatment of manifestations: Comprehensive management by a multidisciplinary team including a geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon is strongly recommended. Eyeglasses for most eye problems; rare need for surgical removal of a dislocated lens with implantation of an artificial lens (preferably after growth is complete). Surgical stabilization of the spine for scoliosis and repair of pectus deformity (largely for cosmetic indications). Orthotics and arch supports can lessen leg fatigue and muscle cramps associated with pes planus. Surgical repair of the aorta when the maximal measurement approaches 5.0 cm in adults or older children, the rate of increase of the aortic root diameter approaches 1.0 cm per year, or progressive and severe aortic regurgitation occurs. For younger children, aortic root surgery should be considered once: (1) the rate of increase of the aortic root diameter approaches 1.0 cm per year, or (2) there is progressive and severe aortic regurgitation. Severe and progressive mitral valve regurgitation with attendant ventricular dysfunction is the leading indication for cardiovascular surgery in children with Marfan syndrome. Afterload-reducing agents can improve cardiovascular function when congestive heart failure is present. Prevention of primary manifestations: Medications that reduce hemodynamic stress on the aortic wall, such as beta blockers, are generally initiated at diagnosis or for progressive aortic dilatation. Other antihypertensive agents can be used if beta blockers are not tolerated; however, evidence as to their efficacy and safety in Marfan syndrome is under investigation. Prevention of secondary complications: Subacute bacterial endocarditis prophylaxis for dental work with the presence of mitral or aortic valve regurgitation. Surveillance: Annual ophthalmologic examination; annual echocardiography to monitor the status of the ascending aorta when aortic dimensions are small and/or the rate of aortic dilation is slow; more frequent examinations are indicated when the aortic root diameter exceeds approximately 4.5 centimeters in adults, rates of aortic dilation exceed approximately 0.5 cm per year, and significant aortic regurgitation is present; intermittent surveillance of the entire aorta with CT or MRA scans beginning in young adulthood. Agents/circumstances to avoid: Contact sports, competitive sports, and isometric exercise; activities that cause joint injury or pain; agents that stimulate the cardiovascular system, including decongestants and caffeine; agents that cause vasoconstriction, including triptans; LASIK correction of refractive errors; breathing against resistance or positive pressure ventilation in those with a documented predisposition for pneumothorax. Evaluation of relatives at risk: Echocardiography in relatives suspected of having Marfan syndrome and in apparently unaffected relatives if findings are subtle in the index case. Pregnancy management: Pregnant women with Marfan syndrome should be followed by a high-risk obstetrician both during pregnancy and through the immediate postpartum period. In women with Marfan syndrome who anticipate pregnancy or become pregnant, beta blockers should be continued, but some other classes of medications such as ACE inhibitors or angiotensin receptor blockers should be stopped because of the risk for fetal loss and birth defects. Cardiovascular imaging with echocardiography every two to three months during pregnancy to monitor aortic root size and growth. Monitoring should continue in the immediate postpartum period due to an increased risk for aortic dissection. Therapies under investigation: Use of angiotensin receptor blockers such as losartan is under intensive investigation because of the dramatic protection against aortic growth seen in mouse models. Multiple prospective trials have shown that the combination of beta blockers and losartan affords better protection against aortic root enlargement than beta blockers alone in both children and adults with Marfan syndrome.

GENETIC COUNSELING:

Marfan syndrome is inherited in an autosomal dominant manner. Approximately 75% of individuals with Marfan syndrome have an affected parent; approximately 25% of probands with Marfan syndrome have a de novo mutation. The risk to the sibs of the proband depends on the status of the parents. If a parent is affected, the risk is 50%. If an affected child is born to clinically unaffected parents, it is likely that the child has a de novo mutation, and the risk to sibs is far less than 50% but above the population risk because of reported (but rare) cases of somatic and germline mosaicism. The children of an individual with Marfan syndrome are at 50% risk of inheriting the mutant allele and the disorder. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

PMID:
20301510
[PubMed]
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