Marfan syndrome (MFS), a multisystem autosomal-dominant disorder, is characterized by mutations of the
fibrillin-1 (FBN1) gene and by abnormal patterns of synthesis, secretion, and matrix deposition of the
fibrillin protein. To determine the sensitivity and specificity of
fibrillin protein abnormalities in the diagnosis of MFS, we studied dermal fibroblasts from 57 patients with classical MFS, 15 with equivocal MFS, 8 with single-organ manifestations, and 16 with other connective tissue disorders including
homocystinuria and
Ehlers-Danlos syndrome. Abnormal
fibrillin metabolism was identified in 70 samples that were classified into four different groups based on quantitation of
fibrillin synthesis and matrix deposition. Significant correlations were found for phenotypic features including
arachnodactyly,
striae distensae, cardiovascular manifestations, and
fibrillin groups II and IV, which included 70% of the MFS patients. In addition, these two groups were associated with shortened "event-free" survival and more severe cardiovascular complications than groups I and III. The latter included most of the equivocal MFS/single manifestation patients with
fibrillin abnormalities. Our results indicate that
fibrillin defects at the
protein level per se are not specific for MFS, but that the drastically reduced
fibrillin deposition, caused by a dominant-negative effect of abnormal
fibrillin molecules in individuals defined as groups II and IV, is of prognostic and possibly diagnostic significance.