The prevalence of MFS is about 1 : 5,000 to 1 : 10,000 persons, with no enrichment in particular ethnic or racial groups or by gender. It is caused by mutations in the fibrillin-1 gene, FBN1, and is inherited in an autosomal dominant manner. Recent research indicates that at least part of the pathophysiologic basis of MFS is due to excessive activation of and signaling by transforming growth factor-β that occurs as a result of mutated fibrillin-1.

In 1986, an international group of experts developed clinical criteria for the diagnosis of Marfan syndrome. In 1991, mutations in FBN1 were identified as the basis for MFS; and, in 1996, new diagnostic criteria, the Ghent nosology, were developed. Those criteria included both major and minor defining criteria, with major manifestations including ectopia lentis, aortic root dilatation/dissection, dural ectasia, or a combination of 4 or more of eight skeletal features. The diagnosis of MFS required major involvement of at least two organ systems and minor involvement of a third, but if an individual had an FBN1 mutation associated with MFS or a first-degree relative with an unequivocal diagnosis, the diagnosis could then be made in the context of one major and one minor manifestation. These criteria proved extremely useful but had some limitations and, in 2010, the revised Ghent nosology for the diagnosis of MFS was developed. With these newer criteria, a diagnosis of MFS can be established for a proband not having a family history of MFS in four ways: if there is ectopia lentis and an FBN1 mutation that has been previously associated with aortic enlargement or if there is aortic root enlargement (Z-score ≥ 2, standardized for age and body size) and either ectopia lentis, a pathogenic FBN1 mutation, or a systemic score ≥ 7, with the latter referring to a score based on the combined presence of various physical findings that occur more commonly in persons with MFS. For individuals who have a family history of an unequivocal diagnosis of MFS, a diagnosis can be established if there is ectopia lentis, a systemic score > 7, or aortic root enlargement (with Z-score ≥ 2 for those ≥ 20 years or ≥ 3 for those < 20 years).

These diagnostic criteria highlight key clinical findings in MFS, but there is considerable additional clinical involvement that can commonly occur. Involvement of the eyes is highly variable. Myopia is the most common ocular feature, and often progresses rapidly during childhood. Ectopia lentis of varying degree occurs in about 60% of persons with MFS. Persons with MFS are also at increased risk to develop retinal detachment, glaucoma, and cataracts.

Skeletal manifestations are similarly diverse. Long bone overgrowth and joint laxity are hallmark features with limbs that are disproportionately long relative to the trunk. Scoliosis is common and, sometimes, progressive and severe. Chest wall abnormalities such as pectus excavatum or pectus carinatum are also common but usually not of major clinical significance. Other relatively common skeletal findings include pes planus, an acetabulum that can be excessively deep and susceptible to an accelerated degenerative process, and a high and narrow palate with crowded dentition.

Abnormalities of the cardiovascular system are the major cause of significant morbidity and early mortality if MFS is untreated or treated late in its natural history. These include dilatation of the aorta at the level of the sinuses of Valsalva, predisposition for aortic dissection and rupture, mitral valve prolapse with or without regurgitation, and tricuspid valve prolapse. Each of these findings can be progressive. The risk of aortic dissection becomes significant as its diameter reaches 5 cm; secondary aortic regurgitation can develop as an aortic aneurysm enlarges. Secondary left ventricular dilatation and heart failure can occur with advanced mitral valvular dysfunction. These clinical concerns can be minimized or prevented if diagnosis and appropriate care are provided early in the natural history of MFS.

There are numerous other clinical findings that occur with greater frequency in individuals with MFS. These include striae, inguinal hernias, lung bullae that can predispose to pneumothorax, and characteristic facial features. Stretching of the dural sac in the lumbosacral region—dural ectasia—occurs more frequently in MFS and can cause bone erosion and nerve entrapment and consequent low back and leg pain and, sometimes, additional symptoms.

The age at onset of the cardiovascular, skeletal, and ocular findings varies considerably; some features can be apparent at birth. Similarly, the pace of symptom development is variable, with a small minority of individuals having forms of MFS that are of early onset and that are rapidly progressive.