FBN2 mutations identified in congenital contractural arachnodactyly patients with aortic root dilatation. S.G. Carmical, P. Gupta, D.M. Milewicz, E.A. Putnam. Internal Med/Medical Genetics, Univ of Texas Medical School, Houston, TX.

   Congenital contractural arachnodactyly (CCA or Beals syndrome) is an autosomal dominant disorder phenotypically similar to Marfan syndrome (MFS). CCA results from mutations in the FBN2 gene encoding fibrillin-2, while MFS results from mutations in the FBN1 gene encoding fibrillin-1. Features of CCA include dolicholstenomelia, arachnodactyly, scoliosis, congenital joint contractures and abnormal ear helices, but not aortic root dilatation (ARD). Neonatal MFS (nMFS) patients have many of these features, but also have valvular problems and ARD leading to early death. We have identified five patients with classic CCA with ARD. Using FBN2 intron-based, exon-specific primers for exons 23-33, genomic DNA was amplified and then screened by SSCP analysis. Two novel FBN2 mutations have been identified. The first patient (previously reported) had congenital scoliosis, arachnodactyly and joint contractures, and was initially thought to have nMFS when she developed progressive aortic root dilatation at age 2 years. A FBN2 mutation resulting in the missplicing of exon 31 was detected in the mRNA, and confirmed (G->C at +1 of intron 31) using the exon-specific primers. The second patient was diagnosed with CCA at birth and developed ARD at age 18 months. A FBN2 mutation in exon 28 (C1239R) was identified in the genomic DNA from this patient. We have also identified a putative mutation in FBN2 exon 33 in a third CCA patient who has ARD detected at age 6 years, which we are confirming. The fourth patient at age 12 years had a severely dilated ascending aorta. The fifth patient (30 years old) had mild ARD (3.9 cm) and mitral valve prolapse. This familial case has been linked to FBN2 using a polymorphic marker within the gene. None of the patients have undergone aortic surgery or are known to have dissected their aorta. In summary, ARD is a feature of CCA but has not been demonstrated to result in life-threatening aortic disease.