Marfan syndrome--current medical and genetic knowledge: how to treat and when.

Marfan syndrome (MFS), first described 100 years ago, remains a clinical diagnosis. Two out of 3 major systems (ocular, cardiac, skeletal) must be classically affected, to avoid overdiagnosis. Diagnosis may be confirmed by linkage to the dominantly inherited gene MFS-1 on 15q21, or by discovering the family mutation. Either technique may be used for prenatal diagnosis. Modern medical and surgical management is prolonging life, by on average, 13 years, with postoperative 20 year survival rate 65%. Beta-blocker therapy slows aortic root dilatation, and elective surgery is offered at ascending aorta diameter > or = 5 cm. Known associations with early death include new mutation, family history of dissection < 5 cm, male sex, and emergency surgery where the death rate is 5 times higher than in elective surgery. Pregnancy bears a 1% risk of fatal complication, and this risk rises with increasing aortic root diameter. Caesarean section at 38 weeks gestation should be offered if aortic root diameter is greater than 4.5 cm. Gene mapping reveals almost every mutation to be unique, interfering with multimerization of fibrillin monomers, or interactions with other connective tissue elements. Neonatal MFS is caused by mutations in exons 24-32, in calcium-binding EGF-like sequences. Mutations affecting cysteines or amino acids critical for calcium binding in other EGF-like domains, or deletions of complete EGF-like domains, generally lead to classical MFS phenotypes, as do mutations in TGF receptor-like domains. Heterogeneity has been reported with a second locus (MFS-2) on chromosome 3 in one French pedigree.