Utility of molecular analyses in the exploration of extreme intrafamilial variability in the Marfan syndrome

The diagnosis of Marfan syndrome may be hampered by the existence of very mild and atypical cases as well as by marked intrafamilial variability. In these instances, molecular analysis of the fibrillin-1 gene (FBN1) can be helpful to identify individuals at risk. The underlying molecular mechanism for the clinical variability is presently unknown. We performed clinical and molecular studies in 36 subjects from three unrelated families. Expression studies of both FBN1 alleles were performed and related to the clinical severity. In family 1, an overlapping phenotype between Marfan syndrome (MFS) and Weill-Marchesani syndrome is presented. The diagnosis necessitated molecular studies and clinical examination in first-degree relatives. In family 2, the young proband presented with a phenotype overlapping between MFS and the kyphoscoliotic type of Ehlers-Danlos syndrome. Follow-up over time and identification of a FBN1 mutation allowed confirmation of the diagnosis. Mutation analysis enabled us to identify family members with mild expression. Family 3 illustrates the extensive intrafamilial variability in the clinical severity of MFS. Identification of a FBN1 mutation was helpful to identify subjects with mild expression and for the timely diagnosis in a neonate. In families 2 and 3, the relative expression of both FBN1 alleles was not related to clinical severity. We demonstrated that confirmation of the diagnosis of MFS may require detailed and repeated clinical evaluation and thorough family history taking. FBN1 mutation analysis is supportive for the diagnosis in mild and atypical presentations.