Knowledge on rare diseases and orphan drugs

The prevalence is estimated at 1/5,000 and there is no difference between sexes.

Symptoms can appear at any age and vary greatly between individuals even within the same family. Cardiovascular involvement is characterized by 1) progressive dilation of the aorta accompanied by an increased risk of aortic dissection, which affects prognosis; the aortic dilation can result in a leaky aortic valve; and 2) mitral insufficiency, which can be complicated by arythmias, endocarditis or cardiac insufficiency. Skeletal involvement is often the first sign of the disease and can include dolichostenomelia (excessive length of extremities), large size, arachnodactyly, joint hypermobility, scoliotic deformations, acetabulum protrusion, thoracic deformity (pectus carinatum or pectus excavatum), dolichocephaly of the anteroposterior axis, micrognathism or malar hypoplasia. Ophthalmic involvement results in axile myopia, which can lead to retinal detachment and lens displacement (ectopia or luxation are characteristic signs). Ocular complications, particularly lens ectopia, can lead to blindness. Cutaneous signs (vergetures), a risk of pneumothorax and dural ectasia can also occur.

In the vast majority of cases, Marfan syndrome is caused by mutations of the FBN1 gene (15q21), which codes for fibrilline-1, a protein essential for connective tissues. Frontier forms have been identified that are secondary to mutations in the TGFBR2 gene located on chromosome 3, which codes for a TGF-beta receptor.

Diagnosis is based on clinical signs and family history. However, as a result of the widely variable clinical picture, the diagnosis can be difficult to establish. International diagnostic criteria (Ghent criteria) based on major and/or minor clinical signs have been established to aid diagnosis.

Differential diagnoses include MASS syndrome, Shprintzen-Goldberg syndrome, mitral valve prolapse, Ehlers-Danlos syndrome and other diseases that present with aortic aneurysm such as Loeys-Dietz syndrome (see these terms).

Prenatal genetic diagnosis is possible for families in which the causal mutation has been identified.

Transmission is autosomal dominant. An affected individual has a 50% risk of transmitting the mutation responsible for the disease. Some sporadic cases have been reported.

Management should be multidisciplinary with consultations from different specialists including cardiologists, geneticists, rheumatologists, ophthalmologists, pediatricians and radiologists. Management should aim to limit aortic dilation (beta-blockers and a reduction in sport activities) and regularly monitor the aorta (annual echocardiograms) in order to allow the aortic root to be replaced before dissection occurs. Surgery can be offered for skeletal anomalies (vertebral column stabilization in the case of scoliosis or reparation of thoracic deformities) and ocular anomalies (laser treatment or replacement of a dislocated lens). Treatment is otherwise symptomatic.

Prognosis depends on the degree of aortic involvement. With regular follow-up and adequate management, patients now have a life expectancy close to that of the general population. Over the last 30 years that life expectancy has increased by 30 years.

Last update: March 2010 - Expert reviewer(s): Pr Guillaume JONDEAU