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 leaflets are also abnormal and mitral prolapse and regurgitation may be present, often with elongated chordae tendineae, which on occasion may rupture.
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 found. Ectopia lentis is present in about half of patients; severe myopia is common and retinal detachment can occur. Mitral valve prolapse is seen in about 85% 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. Patients with homocystinuria due to cystathionine beta-synthase deficiency also have dislocated lenses, tall, disproportionate stature, and thoracic deformity. They tend to have below normal intelligence, stiff joints, and a predisposition to arterial and venous occlusive disease. Males with Klinefelter syndrome do not show the typical ocular or cardiovascular features of Marfan syndrome and are generally sporadic occurrences in the family.
Mutations 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 nature of the FBN1 mutation has little predictive value in terms of prognosis. The pathogenesis of Marfan syndrome involves aberrant regulation of transforming growth factor (TGF)-beta activity. Mutations 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 correct ...