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

Abstract

BackgroundFBN1 (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 presentationTwo 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.ConclusionThe 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.

Assembly assay identifies a critical region of human fibrillin-1 required for 10–12 nm diameter microfibril biogenesis

“…Subtle details explaining the spectrum of milder cases of MFS are still to be determined. The R2726W substitution has been reported in several cases of mild MFS with isolated skeletal symptoms [ 70 – 72 ]. In COS-1 cells, this substitution reduces, but does not abolish, cleavage of the C-terminal propeptide [ 73 ], suggesting that FBN1 levels in these cases are higher than the threshold required for a complete MFS phenotype, and that a kinetic defect underlies mild disease.…”

Echocardiography of Marfan's Syndrome Patient with New Gene Mutation of FBN1 with 13-year Follow-up

“…(2) Aortic insufficiency; (3) mitral valve prolapse; (4) biphasic murmurs can be heard at apex of heart [2]. The disease may also affect other organs, such as lung, eye, dura, hard jaw, etc [3,4].…”

An enormous Italian pedigree of Marfan syndrome with a novel mutation in the FBN1 gene

“…Interstitial fibrosis in the apices is a rare phenomenon among affected individuals which has been described as an extreme example of MFS manifestation. In contrast, restriction on the pulmonary system has commonly seen in MFS patients which causes by skeletal abnormalities such as pectus deformities and scoliosis 14 …”

“…In contrast, restriction on the pulmonary system has commonly seen in MFS patients which causes by skeletal abnormalities such as pectus deformities and scoliosis. 14 Evaluation of cardiovascular complications has an important value due to the direct involvement of the mentioned difficulties in the affected individuals' survival. The cardiovascular complications could express in severe forms including aortic aneurysm, aortic ectasia, mitral and aortic valvular regurgitation with acute aortic dissection.…”