Skeletal manifestations of Marfan syndrome associated to heterozygous R2726W FBN1 variant: sibling case report and literature review

Abstract

Background: FBN1 (15q21.1) encodes fibrillin-1, a large glycoprotein which is a major component of microfibrils that are widely distributed in structural elements of elastic and non-elastic tissues. FBN1 variants are responsible for the related connective tissue disorders, grouped under the generic term of type-1 fibrillinopathies, which include Marfan syndrome (MFS), MASS syndrome (Mitral valve prolapse, Aortic enlargement, Skin and Skeletal findings, Acromicric dysplasia, Familial ectopia lentis, Geleophysic dysplasia 2, Stiff skin syndrome, and dominant Weill-Marchesani syndrome.

Case presentation: Two siblings presented with isolated skeletal manifestations of MFS, including severe pectus excavatum, elongated face, scoliosis in one case, and absence of other clinical features according to Ghent criteria diagnosis, were screened for detection of variants in whole FBN1 gene (65 exons). Both individuals were heterozygous for the R2726W variant. This variant has been previously reported in association with some skeletal features of Marfan syndrome in the absence of both tall stature and non-skeletal features. These features are consistent with the presentation of the siblings reported here.

Conclusion: The presented cases confirm that the R2726W FBN1 variant is associated with skeletal features of MFS in the absence of cardiac or ocular findings. These findings confirm that FBN1 variants are associated with a broad phenotypic spectrum and the value of sequencing in atypical cases.

Fig. 1

Clinical features of the proband and his sister. a, b Clinical phenotype of the proband (II:2) including severe pectus excavatum, scoliosis and some Marfan facial features. c Clinical phenotypes of the proband and his sister (II:3) including facial features

Fig. 2

Family pedigree and molecular characterization of the FBN1 variant. a Family pedigree. Black square and circle indicates the individuals affected (II:2, II:3). b PCR-RFLP analysis of the R2726W FBN1 variant. The 214-bp amplification product was submitted to MspI cleavage. Lines 2 and 3, heterozygous variant (patients II:2 and II:3); lines 3 and 4, wild-type genotype (I:2 and II:1). MspI cleaves a 214-bp fragment into 27- and 187-bp fragments in the presence of the C wild-type allele, whereas the T mutant allele is not cleaved. c The R2726W variant in exon 64 of FBN1. Electropherogram showing the corresponding normal sequence in unaffected family members: a) Mother (I:1), b) brother (II:1), c and d) the C to T heterozygous variant in II:2 and II:3, indicated by the arrow, resulting in the substitution of arginine by tryptophan (R2726W)