-Related Marfan Syndrome

CLINICAL CHARACTERISTICS

-related Marfan syndrome (Marfan syndrome), a systemic disorder of connective tissue with a high degree of clinical variability, comprises a broad phenotypic continuum ranging from mild (features of Marfan syndrome in one or a few systems) to severe and rapidly progressive neonatal multiorgan disease. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. Ocular findings include myopia (>50% of affected individuals); ectopia lentis (seen in approximately 60% of affected individuals); and an increased risk for retinal detachment, glaucoma, and early cataracts. Skeletal system manifestations include bone overgrowth and joint laxity; disproportionately long extremities for the size of the trunk (dolichostenomelia); overgrowth of the ribs that can push the sternum in (pectus excavatum) or out (pectus carinatum); and scoliosis that ranges from mild to severe and progressive. The major morbidity and early mortality in Marfan syndrome relate to the cardiovascular system and include dilatation of the aorta at the level of the sinuses of Valsalva (predisposing to aortic tear and rupture), mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Severe and prolonged regurgitation of the mitral and/or aortic valve can predispose to left ventricular dysfunction and occasionally heart failure. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population.

DIAGNOSIS/TESTING: The diagnosis of Marfan syndrome is established in a proband (by definition a person without a known family history of Marfan syndrome) who has an pathogenic variant known to be associated with Marfan syndrome and EITHER of the following: Aortic root enlargement (z score ≥2.0). Ectopia lentis.

MANAGEMENT

Comprehensive management by a multidisciplinary team including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon is strongly recommended. Treatment typically includes spectacle correction for refractive errors and, sometimes, surgical removal of a dislocated lens with artificial lens implantation (preferably after growth is complete). Glaucoma, cataracts, and retinal detachment are treated in the standard fashion per an ophthalmologist. Scoliosis may require bracing or surgical stabilization; repair of pectus deformity is largely cosmetic. Functional deficits or pain associated with protusio acetabulae may respond to physical therapy, analgesics, or anti-inflammatory medications. Orthotics and arch supports can lessen leg fatigue, joint pain, and muscle cramps associated with pes planus. Dental crowding may be addressed through orthodontia and a palatal expander may be considered in some cases. Surgical repair of the aorta is indicated either when the maximal measurement of the aortic root approaches 5.0 cm in adults or older children, when the rate of increase of the aortic root diameter approaches 0.5-1.0 cm per year, or if there is progressive and severe aortic regurgitation. For younger children, aortic root surgery should be considered once: (1) the rate of increase of the aortic root diameter approaches 0.5-1.0 cm per year, or (2) there is progressive and severe aortic regurgitation. Severe and progressive mitral valve regurgitation with attendant ventricular dysfunction requires immediate attention of a cardiologist or cardiothoracic surgeon and 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. Standard treatment for hernias and pneumothorax is recommended. There are no known effective therapies for symptomatic dural ectasia. Medications that reduce hemodynamic stress on the aortic wall, such as beta-blockers or angiotensin receptor blockers (ARBs), are routinely prescribed. This therapy should be managed by a cardiologist or clinical geneticist familiar with its use. Therapy is generally initiated at the time of diagnosis with Marfan syndrome at any age or upon appreciation of progressive aortic root dilatation even in the absence of a definitive diagnosis. Measurement of length/height/weight at each visit. Ophthalmologic examination annually or as clinically indicated. Clinical assessment for chest wall deformities and scoliosis at each visit until skeletal maturity, although severe scoliosis may require ongoing surveillance in adulthood. At least annual dental evaluation, including orthodontia, as indicated. Echocardiography annually when aortic dimensions are small and the rate of aortic dilatation is slow; more frequent than annual examinations are indicated when the aortic root diameter exceeds approximately 4.5 cm in adults, rates of aortic dilatation exceed approximately 0.3 cm per year, or significant aortic regurgitation is present. Intermittent surveillance of the entire aorta with CT or MRA scans beginning in young adulthood or at least annually in anyone with a history of aortic root replacement or dissection. / Contact sports, competitive sports, and isometric exercise; activities that cause joint injury or pain; agents that stimulate the cardiovascular system, including decongestants and excessive 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; fluoroquinolone antibiotics, which may exacerbate the predisposition for aneurysm and dissection; classes of antihypertensive agents (e.g., calcium channel blockers, ACE inhibitors) where there is an absence of direct evidence for their efficacy or safety in individuals with Marfan syndrome. It is recommended that the genetic status of at-risk relatives of any age be clarified so that affected individuals can undergo routine surveillance for early detection of medically significant complications, particularly potentially life-threatening cardiac manifestations. Genetic status of at-risk relatives can be established EITHER: By molecular genetic testing if the pathogenic variant in the family is known; OR. In those with a rigorously defined family history of Marfan syndrome, by the presence of ONE OR MORE of the following: Ectopia lentis. A systemic score ≥7. Aortic root dilatation (z score ≥2.0 for individuals age ≥20 years or z score ≥3.0 for those age <20 years). An individual with Marfan syndrome should consider pregnancy only after appropriate counseling from a clinical geneticist or cardiologist familiar with this condition, a genetic counselor, and a high-risk obstetrician because of the risk of more rapid dilation of the aorta or aortic dissection during pregnancy, delivery, or in the immediate postpartum period. Cardiovascular imaging with echocardiography should be performed every two to three months during pregnancy to monitor aortic root size and growth. Monitoring should continue in the immediate postpartum period because of the increased risk for aortic dissection. Individuals with Marfan syndrome who anticipate pregnancy or become pregnant should continue use of beta-blockers; however, some other classes of medications such as ARBs should be discontinued because of the increased risk for fetal loss, oligohydramnios, and abnormal development, often related to second- and third-trimester exposure.

GENETIC COUNSELING

Marfan syndrome is inherited in an autosomal dominant manner. Approximately 75% of individuals with Marfan syndrome have an affected parent; approximately 25% have a pathogenic variant. Each child of an individual with Marfan syndrome has a 50% chance of inheriting the pathogenic variant and the disorder. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.