ESSENTIALS OF DIAGNOSIS
Disproportionately tall stature, thoracic deformity, and joint laxity or contractures.
Ectopia lentis and myopia.
Aortic root dilation and dissection; mitral valve prolapse.
Mutation in FBN1, the gene encoding fibrillin-1.
Marfan syndrome, a systemic connective tissue disease, has an autosomal dominant pattern of inheritance. It is characterized by abnormalities of the skeletal, ocular, and cardiovascular systems; spontaneous pneumothorax; dural ectasia; and striae atrophicae. Of most concern is disease of the ascending aorta, which begins as a dilated aortic root. Histology of the aorta shows diffuse medial degeneration. Mitral valve prolapse is common and frequently leads to regurgitation.
Affected patients are typically tall, with particularly long arms, legs, and digits (arachnodactyly). However, there can be wide variability in the clinical presentation. Commonly, scoliosis and anterior chest deformity, such as pectus excavatum, are present. Ectopia lentis is present in about half of patients; severe myopia is common and retinal detachment can occur. Mitral valve prolapse is seen in more than half of patients. Aortic root dilation is common and leads to aortic regurgitation or dissection with rupture. To diagnose Marfan syndrome, people with an affected relative need features in at least two systems. People with no family history need features in the skeletal system, two other systems, and one of the major criteria of ectopia lentis, dilation of the aortic root or aortic dissection or a pathogenic variant in FBN1.
Pathogenic variants in the fibrillin gene (FBN1) on chromosome 15 cause Marfan syndrome. Nonetheless, no simple laboratory test is available to support the diagnosis in questionable cases because related conditions may also be due to defects in fibrillin. The pathogenesis of Marfan syndrome involves aberrant regulation of transforming growth factor (TGF)-beta activity. Pathogenic variants in either of two receptors for TGF-beta (TGFBR1 and TGFBR2) can cause conditions that resemble Marfan syndrome in terms of aortic aneurysm and dissection and autosomal dominant inheritance. Mutations in more than two dozen other genes can predispose adults to thoracic aortic aneurysm and dissection.
There is prenatal and presymptomatic diagnosis for patients in whom the molecular defect in FBN1 has been found.
Children with Marfan syndrome require regular ophthalmologic surveillance to detect ectopia lentis, correct visual acuity and thus prevent amblyopia, and annual orthopedic consultation for diagnosis of scoliosis at an early enough stage so that bracing might delay progression. Patients of all ages require echocardiography at least annually to monitor aortic root diameter and mitral valve function. Long-term beta-adrenergic blockade, titrated to individual tolerance but enough to produce a negative inotropic effect (eg, atenolol, 1–2 mg/kg orally daily), retards the rate ...