MARFAN SYNDROME
Marfan syndrome is an autosomal dominantly inherited disorder of connective tissue that is caused by a genetic defect in the FBN1 gene located on chromosome 15. The disorder leads to a defect in the fibrillin-1 protein, which is a component of the extracellular matrix of connective tissue. The defect leads to many clinical findings in the cardiovascular, ocular, skeletal, integumentary, and respiratory systems. The diagnosis is made based on multiple criteria that include major and minor features of the syndrome. Cardiovascular disease is a major cause of morbidity and mortality in this syndrome.
Clinical
Findings: Marfan syndrome has an estimated incidence of approximately 1 per 7500
people. It affects all populations and has no gender differential. Many of the
manifestations of the syndrome are present at the time of birth. As the child
grows, the findings become more evident and the severity may worsen. The
diagnosis of Marfan syndrome does not imply any specific prognosis, because the
syndrome has a range of clinical manifestations. On one end of the spectrum is
the patient with life-threatening disease, and at the other end is the patient
who has only the musculoskeletal clinical features of the syndrome.
Many
skeletal anomalies can be seen, including arachnodactyly, pectus excavatum,
scoliosis, pes planus, high palate, and an increased lower body to upper body
ratio. The most striking features are tall stature, thin body habitus, long
arms, and disproportionate lower- to-upper body ratio.
Cutaneous
findings of Marfan syndrome may be subtle. The presence of striae distensae is
almost universal. Adipose tissue is decreased, and patients often appear
extremely thin. Elastosis perforans serpiginosa is seen with a high incidence
in Marfan syndrome and is caused by the extrusion of abnormal elastic tissue
through the epidermis. Ocular involvement often leads to an upward displacement
of the lens (ectopia lentis). Myopia is often seen, as well as a decreased
ability to constrict the pupil.
The
respiratory and cardiovascular systems are commonly affected. Pulmonary blebs
can be seen in an apical location. The blebs may spontaneously rupture, causing
a pneumothorax. Severity of involvement of the cardiovascular system is the
best prognostic indicator in Marfan syndrome. Prolapse of the mitral valve,
aortic root dilation, and early-onset calcification of the mitral valve anulus
are a few of the cardiovascular findings. The leading cause of mortality is
rupture of an aortic aneurysm or aortic dissection.
Pathogenesis:
Fibrillin-1
is a glycoprotein found in a wide range of connective tissues. Fibrillin-1 is
required for proper elasticity and strength properties of the extracellular
matrix. Many hundreds of mutations have been reported in the gene that encodes
fibrillin-1. There is a wide phenotypic variability in Marfan syndrome, due in
some part to the different mutations of the gene but also to other, as yet
undescribed factors. This leads to a large variation in phenotype among
individuals with the same genotypic mutation.
Defects in
the fibrillin-1 protein lead to a decreased ability to bind to calcium. This
ultimately manifests as abnormalities of the microfibrils throughout the
connective tissue. These abnormal microfibrils are more susceptible to
degradation by matrix metalloproteinases, and when they occur within the
connective tissue lining of the vascular walls, the lining’s elastic and
strength properties are compromised. This may lead to dilation, increased
stiffness, aneurysm, and eventual dissection of arterial walls, with the aorta being the most commonly
affected vessel.
Treatment:
All
patients with Marfan syndrome should be monitored directly by a cardiologist
and a cardiothoracic surgeon as needed. Routine echocardiograms and evaluations
for aortic aneurysms are required. β-Blockade has been shown
to be helpful to decrease mean arterial pressure. This reduces the pressure on the weakened vessel walls
and subsequently decreases the likelihood of arterial dilation, dissection, and
aneurysms.
Calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors are second-line agents. Patients with Marfan syndrome who are closely followed and treated promptly may live a normal life span. They must be educated to avoid strenuous physical activity and contact sports. Surgery to repair aortic dilation and aneurysm is required once the caliber of the aorta reaches 5.0 cm or if the rate of enlargement is greater than 0.5 cm/year. Ocular disease should be evaluated and treated promptly by an ophthalmologist.
