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Marfan syndrome

  • Marfan syndrome is one of the most common inherited conditions of connective tissue. Prevalance is estimated to be 1 in 5,000 individuals in the UK.
  • Marfan syndrome is a multisystem disorder, most commonly involving the cardiovascular system, eyes, skeleton and lungs. The extent to which different systems are affected can vary from person to person within a family. It can present at any age. Some affected individuals develop signs in infancy. Others do not have symptoms until adulthood. There is a severe neonatal form of the condition.
  • The diagnosis is made on clinical grounds based on fulfilling internationally agreed criteria (Ghent criteria). A DNA test is not always indicated, though if a mutation is identified in the proband, this greatly facilitates risk assessment.
  • Marfan syndrome is an autosomal dominant condition, usually due to mutations in the Fibrillin-1 (FBN1) gene.

Clinical features

Any one or more of the following features should make you consider the diagnosis; the most serious life-threatening complications involve the cardiovascular system.

  • Heart: dilatation/dissection/rupture of the aorta, mitral valve prolapse, family history of sudden early cardiac death.
  • Eyes: myopia/lens dislocation/detached retina.
  • Lungs: spontaneous pneumothorax.
  • Skeleton: tall and thin, long limbs/fingers/toes, spinal curvature, pectus excavatum or carinatum, flexible joints.
  • Connective tissue: recurrent hernias, stretch marks.

Diagnosis

  • In all cases of suspected Marfan syndrome a set of diagnostic criteria (Ghent criteria) are used. These have been internationally agreed and were revised in 2010.
  • Aortic root aneurysm and ectopia lentis (lens dislocation) are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the diagnosis of Marfan syndrome.
  • In the absence of either of these two features, the presence of a FBN1 mutation or a combination of systemic manifestations is required (J Med Genet 2010; 47; 476-485). A diagnosis requires major involvement in at least two organ systems and minor involvement of a third system. However, in families where a pathogenic FBN1 gene mutation has been found, the finding of this mutation in a family member is sufficient for diagnosis.

Major criteria

Major criteria include:

  • an enlarged aorta (main artery);
  • a tear in the aorta;
  • dislocation of the lens of the eye (ectopia lentis);
  • a family history of the syndrome;
  • at least four skeletal problems, such as flat feet or a curved spine (scoliosis); and
  • dural ectasia (enlargement of the lining that surrounds part of the spinal cord).

Minor criteria

Minor criteria include:

  • short-sightedness (myopia);
  • unexplained stretch marks;
  • loose joints;
  • a long, thin face; and
  • a high, arched palate (roof of the mouth).

Genetic basis

  • Marfan syndrome is an autosomal dominant condition, which means that each child of someone with Marfan syndrome has a 50%, or 1 in 2, chance of inheriting the gene alteration that causes the condition.
  • All cases of classical Marfan syndrome appear to be due to mutations in the Fibrillin-1 (FBN1) gene.
  • Seventy-five per cent of affected individuals have inherited the condition from an affected parent; the other 25% of affected individuals have Marfan syndrome because of a new mutation in the FBN1 gene and do not have a family history of the condition.

Clinical management

  • Individuals diagnosed with the condition will need lifelong monitoring and will be followed up by a number of healthcare professionals familiar with the condition, including clinical geneticists, cardiologists, ophthalmologists, orthopaedic surgeons and general paediatricians. All individuals should have an echocardiogram and ophthalmic review annually, more frequently if there is a clinical indication. Complications can be prevented if patients are seen on a regular basis by their various specialists.
  • Active management is important because early detection and treatment of the possible problems can prevent serious complications, improving prognosis and lenghthening lifespan.
  • Current treatment (such as beta blockers and elective surgery) does postpone but cannot prevent aortic complications. Ongoing clinical trials assessing whether losartan treatment leads to a clinically relevant decrease of aortic dilatation in adult patients with Marfan syndrome look promising.
  • Individuals should remain active with aerobic activities performed in moderation, but they should avoid contact sports, long-distance running and weight training. Individuals at risk of recurrent pneumothoraces should also avoid breathing against resistance, such as scuba diving, playing brass instruments.
  • Genetic counselling and family screening.

Genetic testing

Genetic testing can be used:

  • to confirm the diagnosis;
  • to provide information about the genetic status of relatives at risk of Marfan syndrome; and
  • for prenatal diagnosis, though this is unusual and a positive result does not provide prognostic information.

Genetic testing is widely available across the UK and usually provided through specialist clinics or regional genetic centres.

 

This information is intended for educational use and was current in August 2013. For clinical management, it is recommended that local guidelines and protocols are used.