A report of three families with FBN1-related acromelic dysplasias and review of literature for genotype-phenotype correlation in geleophysic dysplasia

Abstract

Acromelic dysplasia is a heterogeneous group of rare skeletal dysplasias characterized by distal limb shortening. Weill-Marchesani syndrome (WMS), Geleophysic dysplasia (GD) and Acromicric dysplasia (AD) are clinically distinct entities within this group of disorders and are characterized by short stature, short hands, stiff joints, skin thickening, facial anomalies, normal intelligence and skeletal abnormalities. Mutations of the Fibrillin-1 (FBN1) gene have been reported to cause AD, GD and related phenotypes. We reported three families with acromelic short stature. FBN1 analysis showed that all affected individuals carry a heterozygous missense mutation c.5284G>A (p.Gly1762Ser) in exon 42 of the FBN1 gene. This mutation was previously reported to be associated with GD. We reviewed the literature and compared the clinical features of the patients with FBN1 mutations to those with A Distintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2) mutations. We found that tip-toeing gait, long flat philtrum and thin upper upper lip were more consistently found in GD patients with ADAMTSL2 mutations than in those with FBN1 mutations. The results have shed some light on the phenotype-genotype correlation in this group of skeletal disorders. A large scale study involving multidisciplinary collaboration would be needed to consolidate our findings.