Missense mutations in FBN1 exons 41 and 42 cause Weill-Marchesani syndrome with thoracic aortic disease and Marfan syndrome

Abstract

Mutations in FBN1 cause a range of overlapping but distinct conditions including Marfan syndrome (MFS), Weill-Marchesani syndrome (WMS), familial thoracic aortic aneurysms/dissections (FTAAD), acromicric dysplasia (AD), and geleophysic dysplasia (GD). Two forms of acromelic dysplasia, AD and GD, characterized by short stature, brachydactyly, reduced joint mobility, and characteristic facies, result from heterozygous missense mutations occurring in exons 41 and 42 of FBN1; missense mutations in these exons have not been reported to cause MFS or other syndromes. Here we report on probands with MFS and WMS who have heterozygous FBN1 missense mutations in exons 41 and 42, respectively. The proband with WMS has ectopia lentis, short stature, thickened pinnae, tight skin, striae atrophicae, reduced extension of the elbows, contractures of the fingers and toes, and brachydactyly and has a missense mutation in exon 42 of FBN1 (c.5242T>C; p.C1748R). He also experienced a previously unreported complication of WMS, an acute thoracic aortic dissection. The second proband displays classic characteristics of MFS, including ectopia lentis, skeletal features, and aortic root dilatation, and has a missense mutation in exon 41 of FBN1 (c.5084G>A; p.C1695Y). These phenotypes provide evidence that missense mutations in exons 41 and 42 of FBN1 lead to MFS and WMS in addition to AD and GD and also suggest that all individuals with pathogenic FBN1 mutations in these exons should be assessed for thoracic aortic disease and ectopia lentis. Further studies are necessary to elucidate the factors responsible for the different phenotypes associated with missense mutations in these exons of FBN1.

Keywords: acromicric dysplasia; aortic aneurysm; aortic dissection; ectopia lentis; geleophysic dysplasia.

Figure 1. Clinical features and pedigree of Weill-Marchasani family, Patient 1

(A) Aneurysm and dissection of the ascending thoracic aorta. The left panel show a Chest CT with contrast of the 38-year-old proband in the WMS family (Person III-1) demonstrating an aneurysm of the ascending aorta measuring 47 mm. The right panel is a Chest CT with contrast of the WMS proband (person III-1) showing the transverse aortic arch with a luminal flap visualized, demarcating the aortic dissection. (B) Clinical features observed in the WMS family. Short stature observed in the proband’s father (Person II-3) and sister (Person III-3) and brachydactyly observed in the proband’s father (Person II-3) and sister (Person III-3). Written consent was obtained for publication of these images. (C) Pedigree of WMS family with p.C1748R mutation in exon 42 of FBN1. The disease status of individuals is indicated in the figure legend. The horizontal line above the symbol indicates an examination by a medical geneticist. The presence (+/−) of the FBN1 mutation is indicated below the symbol.

Figure 2. Clinical features and pedigree of the MFS family, Patient 2

(A) Tall stature observed in proband with MFS (Person II-1) and facial features, which include dolichocephaly, enopthalmos and mild malar hypoplasia. Written consent was obtained for publication of these images. (B) Pedigree of MFS family with p.C1695Y mutation in exon 41 of FBN1. The disease status of individuals is as indicated in the figure legend. The horizontal line above the symbol indicates an examination by a medical geneticist. Age of death is documented below the symbol. The presence (+/−) or absence (−/−) of the FBN1 mutation is indicated below the symbol.