Clinical and genetic characteristics of rare variants of acromelic skeletal dysplasias caused by mutations in the FBN1 gene

BACKGROUND: Geleophysic dysplasia and acromicric dysplasia are rare hereditary diseases characterized by dwarfism and dysplastic skeletal features. In the literature, only a few cases of geleophysic dysplasia and acromicric dysplasia caused by mutations in the FBN1 gene are described. CLINICAL CASES: A description of the clinical and genetic characteristics of three female patients with acromelic dysplasias caused by three types of missense mutations in the FBN1 gene is presented. In two patients, on the basis of clinical manifestations and radiographic examination, acromicric dysplasia, and in one patient geleophysic dysplasia were diagnosed. It was shown that all identified mutations were localized in exons of the FBN1 gene encoding the amino acid sequence of the fifth domain, which has homology with transforming growth factor-beta. DISCUSSION: We have analyzed the clinical and genetic correlations to confirm the previously stated hypothesis about the occurrence of a severe phenotype of geleophysic dysplasia in patients with the c.5206T C mutation. This mutation is characterized by the replacement of cysteine by arginine in the position of the polypeptide chain leading to moderate clinical manifestations of acromicric dysplasia in patients with the c.5284 G A (p. Gly1762Ser). It was shown that the previously undescribed substitution c.5177G A (p.Gly1726Asp and another previously described mutation in this codon resulted in the replacement of glutamine with valine. This mutation causes the appearance of a less pronounced phenotype of AD. CONCLUSIONS: Based on the results of the examination of three Russian patients and analysis of clinical and radiographic parameters described in the literature, we reported that mutations in the FBN1 gene disrupted the amino acid sequence of the fifth like transforming growth factor-beta domain of fibrillin type 1. Importantly, these mutations are responsible for the occurrence of geleophysic dysplasia and acromicric dysplasia. However, the most severe clinical manifestations were observed in patients with mutations leading to the substitution of cysteine for arginine at the position of the polypeptide chain 1736. This may lead to affecting the transforming growth factor-beta signaling pathway.

Acromesomelic and Acromelic Dysplasias/Dysostoses

This chapter discusses acromesomelic and acromelic dysplasias/dysostoses and related disorders and includes discussion on acromesomelic dysplasias (Maroteaux type), Grebe dysplasia, brachydactyly A1, brachydactyly B, brachydactyly C, brachydactyly D, brachydactyly E, brachydactyly (Christian type), tricho-rhino-phalangeal dysplasia (type 1), tricho-rhino-phalangeal dysplasia (type 2), acrocapitofemoral dysplasia, Albright hereditary osteodystrophy, acrodysostosis, geleophysic dysplasia, acromicric dysplasia, Myhre syndrome, and SOFT syndrome. Each discussion includes major radiographic features, major clinical findings, genetics, major differential diagnoses, and a bibliography.

Three cases of Japanese acromicric/geleophysic dysplasia with FBN1 mutations: a comparison of clinical and radiological features

Acromicric dysplasia (AD) and geleophysic dysplasia (GD) are rare skeletal dysplasias characterized by short stature, acromelia, joint contracture, hepatomegaly, hoarseness and respiratory distress. Compared with GD, AD presents with milder clinical and radiological features. Radiological findings of AD and GD consist of shortened tubular bones of the hands and feet, and deformed capital femoral epiphyses. The genetic cause of AD and some cases of GD was shown to be mutations in the transforming growth factor (TGF) β-binding protein-like domain 5 of the fibrillin 1 gene (

Leri’s pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis

ObjectivesLeri’s pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis.Methods and resultsWhole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-β pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p.Ser71Thr, could confer protection against disease (p<1×10−5).ConclusionsOur work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-β/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing ‘TGF-β-pathies’ group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill–Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.