Paucity of skeletal manifestations in Hispanic families with FBN1 mutations

Abstract

Marfan syndrome (MFS) is an autosomal dominant condition with pleiotropic manifestations involving the skeletal, ocular, and cardiovascular systems. The diagnosis is based primarily on clinical involvement of these and other systems, referred to as the Ghent criteria. We have identified three Hispanic families from Mexico with cardiovascular and ocular manifestations due to novel FBN1 mutations but with paucity of skeletal features. The largest family, hMFS001, had a frameshift mutation in exon 24 (3075delC) identified as the cause of aortic disease in the family. Assessment of eight affected adults revealed no major skeletal manifestation of MFS. Family hMFS002 had a missense mutation (R1530C) in exon 37. Four members fulfilled the criteria for ocular and cardiovascular phenotype but lacked skeletal manifestations. Family hMFS003 had two consecutive missense FBN1 mutations (C515W and R516G) in exon 12. Eight members fulfilled the ocular criteria for MFS and two members had major cardiovascular manifestations, however none of them met criteria for skeletal system. These data suggest that individuals of Hispanic descent with FBN1 mutations may not manifest skeletal features of the MFS to the same extent as Caucasians. We recommend that echocardiogram, ocular examination and FBN1 molecular testing be considered for any patients with possible MFS even in the absence of skeletal features, including Hispanic patients.

Figure 1

Pedigrees of three Hispanic families (hMFS001, hMFS002, and hMFS003) with cardiovascular and ocular complications of MFS due to mutations in FBN1. Closed symbols indicate affected status based on the identified mutation and open symbols indicate unaffected status. Mutation status was inferred for hMFS001 I:1, II:1, II:3, II:6, II:8, III:9, III:21, IV:2, IV:6, IV:9 based on their position in the pedigree and/or history of MFS cardiovascular or ocular complications.

Figure 2

Members of families hMFS001 (top panel) and hMFS003 (bottom panel) showing absence of MFS skeletal features. The proband in hMFS001, III:4, does not have skeletal or facial features of the MFS. She and her two children (IV:4 and IV:5) do not have arachnodactyly. The proband of family hMFS003 (II:8) and his brother (II:3) do not have MFS skeletal features. The son of II:3 (III:4) has a Caucasian mother and does not have skeletal features of MFS. The patients have provided consent for publication of these photographs.