Fibrillin abnormalities and prognosis in marfan syndrome and related disorders

✍ Scribed by Aoyama, Takeshi ;Francke, Uta ;Gasner, Cheryll ;Furthmayr, Heinz

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: English
• Weight: 843 KB
• Volume: 58
• Category: Article
• ISSN: 0148-7299
• DOI: 10.1002/ajmg.1320580216

✦ Synopsis

Marfan syndrome (MFS), a multisystem autosomal-dominant disorder, is characterized by mutations of the fibrillin-1 (FBNI) 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 syn- drome. 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 I1 and W, 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 111. The latter included most of the equivocal MFSkingle 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 I1 and IV, is of prognostic and possibly diagnostic significance.