Marfan: excessive flexibility that puts the heart at risk

If you are tall and very flexible with large hands, you must ask yourself the question of Marfan syndrome, an inherited disease, which affects the connective tissue. Connective tissue provides part of the structure of many organs (skeleton, heart, arteries, eyes, lungs, etc.) and its anomaly makes them fragile. The symptoms are very varied from one patient to another, including within the same family, but the most feared risk is that of a dilation of the artery that leaves the heart, the aorta ascending, with a risk of rupture and sudden death.

The problem most often relates to a gene called FBN1 on chromosome 15, but can result from abnormalities in other genes. It is hereditary and is transmitted in a dominant way, that is to say that it only takes one affected gene to be sick. Children can therefore be affected in one in 2 cases, in both men and women, and this is the whole point of family screening, because the problems of this disease can be compensated or prevented.

Evocative signs

Because of the great variability in the expression of symptoms, and the progressiveness of their appearance, the diagnosis remains complicated at any age. The general appearance and the very great flexibility (hyperlaxity) can suggest the diagnosis of this disease which would affect approximately 12,000 people in France.

It is, in fact, most often people of great size, with excessive length of the hands and fingers (arachnodactyly), joint hypermobility (hyperlaxity of the articular ligaments) with supranormal joint movement and repeated sprains, a deformation of the spine like scoliosis and kyphosis, a deformity of the thorax (in boat hull, pectus carinatum, or with a hollow in the sternum, pectus excavatum). The mouth is marked by hypotrophy of the lower jaw (micrognathism) and an arched palate deformation.

The disease can affect the eyes with myopia which is accompanied by retinal detachments and, more suggestive, a displacement of the lens (ectopia or dislocation). Cataracts and glaucoma are earlier.

The skin is affected with fragility and stretch marks sometimes from childhood. The lungs are also affected by fragility with the formation of bubbles (emphysema) and a risk of rupture of these bubbles (pneumothorax, often recurrent).

A vital risk linked to the heart and blood vessels

The heart and blood vessels are also affected and do most of the prognosis of the disease with, when left unchecked, a risk of sudden death.

There is in fact a progressive dilation and weakening of the part of the aorta which comes out of the heart, the ascending aorta. This dilation is the result of the lower resistance of this vessel to the “knocks” produced by the heart (which has an alternating function): it appears fairly early a dilation of the aorta which exposes a high risk of rupture of the wall. of this aorta (aortic dissection).

Aortic dilation can, moreover, cause a leakage of the aortic valve (which prevents the return of blood from the aorta to the heart) and dilation of the heart with also an insufficiency of the mitral valve. This valve dilation and insufficiency can be complicated by heart rhythm disturbances, infection (endocarditis) and heart failure).

Hyperlaxity and hyper-fragility

In the vast majority of cases, Marfan syndrome is caused by mutations in the FBN1 gene, a gene that codes for the production of fibrillin-1, an essential protein in connective tissue. Fibrillin 1 allows, in fact, the organization of elastin fibers in connective tissue. Its anomaly is therefore the cause of greater elasticity of the connective tissue, but also of greater fragility. Frontier forms are secondary to mutations in other genes (TGFBR2, SMAD3, ACTA2, etc.).

The diagnosis is based on clinical signs and family history, but due to the extremely variable clinical picture between patients, the diagnosis is often difficult to establish. To improve it, international diagnostic criteria have been established (the Ghent criteria) based on a score of major and / or minor clinical signs.

An affected person has a 50% risk of transmitting the disease causing mutation. This is therefore the whole point of the family diagnosis. Genetic prenatal diagnosis is technically possible in families in which the mutation has been identified (trophoblast or placenta biopsy). It is not without risk for pregnancy and must be discussed on a case-by-case basis between the parents and the specialist doctor. A preimplantation diagnosis is also possible in the event of IVF.

Compensatory and preventive treatment

The support must be done in a expert center because it must be multidisciplinary with the intervention of different specialists (cardiologists, geneticists, rheumatologists, ophthalmologists, pediatricians and radiologists).

Its main objective is to limit the dilation of the ascending aorta thanks to drugs which will reduce the importance of the pulse wave at the exit of the heart: beta-blockers. Despite this treatment, the aorta should be monitored regularly by echocardiograms in order to suggest replacement of the aortic valve and of the aortic root when dilation poses a risk of dissection.

Different medical and surgical solutions are also available to prevent or compensate for abnormalities of the skeleton (stabilization of scoliosis by a corset or surgery, repair of thoracic deformities), of the eyes (laser, replacement of the dislocated lens), of the mouth (orthodontics ), lungs. Treatment is otherwise symptomatic.

Aortic involvement determines the prognosis of the disease. With regular monitoring of the aorta and heart, as well as adequate care, patients now have a life expectancy close to that of the general population: life expectancy has increased by 30 years over the years. Last 30 years.