Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder which has been reported in over 120 individuals. Although the prognosis for typical CCA is good, a small number of infants with a severe, lethal form of CCA have been reported. These individuals have died from the sequelae of structural visceral anomalies, including interrupted aortic arch and duodenal atresia. While CCA has been linked to FBN2, the fibrillin gene on chromosome 5, no FBN2 mutations have been reported in CCA patients to date. Here we report a FBN2 mutation resulting in mis-splicing of exon 34, in a mother and daughter with CCA. While the mother exhibited the typical CCA phenotype with arachnodactyly, joint contractures and abnormal pinnae, her daughter exhibited the markedly more severe CCA phenotype, with additional visceral cardiac and gastrointestinal anomalies that led to death in infancy. RT-PCR studies suggest that the mother is a somatic mosaic for the mutation. However, all of the daughter's cells harbor the mutation. These data prove that FBN2 mutations can cause CCA, and also demonstrate phenotypic variability due to a dosage effect of a particularly deleterious FBN2 mutation. Based on the early expression pattern of fibrillin-2 during mouse embryogenesis, it is hypothesized that FBN2 mutations lead to visceral malformations by interfering with normal elastogenesis.
|Original language||English (US)|
|Journal||Journal of Investigative Medicine|
|State||Published - Jan 1 1996|
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)