Dataset Information

Atypical Skin Manifestations in FGFR2-Related Craniosynostosis Syndromes Broaden the Phenotypic Spectrum.

ABSTRACT: Crouzon syndrome (CS) and Beare-Stevenson syndrome (BSS) are craniosynostosis syndromes caused by mutations in the fibroblast growth factor 2 (FGFR2) gene. CS is more common (1 in 60,000 live births) than BSS, where fewer than 20 individuals have been reported. The cardinal features of BSS are craniosynostosis, cutis gyrata, acanthosis nigricans, skin furrows, skin tags, anogenital anomalies, and a prominent umbilical stump. Previously described individuals with BSS have typically had mutations in exon 11 of FGFR2. Here, we present 2 patients with CS who have significant skin manifestations and some phenotypic overlap with BSS. De novo mutations in exon 8 of FGFR2 were identified in both; one is a mutation (c.799T>C; p.Ser267Pro) previously identified in individuals with CS and the other a novel in-frame deletion (c.820_824delinsTT; p.Val274_Glu275delinsLeu). No mutations in exon 11 of FGFR2, where previously reported BSS mutations have been located, were identified. This case expands the phenotypic spectrum of CS and highlights the overlap between conditions caused by mutations in FGFR2.

SUBMITTER: LeBlanc S

PROVIDER: S-EPMC6006653 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Atypical Skin Manifestations in <i>FGFR2</i>-Related Craniosynostosis Syndromes Broaden the Phenotypic Spectrum.

LeBlanc Shannon S David David D Colley Alison A Buckley Michael M Roscioli Tony T Barnett Christopher C

Molecular syndromology 20180424 3

Crouzon syndrome (CS) and Beare-Stevenson syndrome (BSS) are craniosynostosis syndromes caused by mutations in the fibroblast growth factor 2 (<i>FGFR2</i>) gene. CS is more common (1 in 60,000 live births) than BSS, where fewer than 20 individuals have been reported. The cardinal features of BSS are craniosynostosis, cutis gyrata, acanthosis nigricans, skin furrows, skin tags, anogenital anomalies, and a prominent umbilical stump. Previously described individuals with BSS have typically had mut ...[more]

PMID: 29928180

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Project description:One diagnostic feature of craniosynostosis syndromes is mandibular dysgenesis. Using three mouse models of Apert, Crouzon and Pfeiffer craniosynostosis syndromes, we investigated how embryonic development of the mandible is affected by fibroblast growth factor receptor 2 (Fgfr2) mutations. Quantitative analysis of skeletal form at birth revealed differences in mandibular morphology between mice carrying Fgfr2 mutations and their littermates that do not carry the mutations. Murine embryos with the mutations associated with Apert syndrome in humans (Fgfr2+/S252W and Fgfr2+/P253R ) showed an increase in the size of the osteogenic anlagen and Meckel's cartilage (MC). Changes in the microarchitecture and mineralization of the developing mandible were visualized using histological staining. The mechanism for mandibular dysgenesis in the Apert Fgfr2+/S252W mouse resulting in the most severe phenotypic effects was further analyzed in detail and found to occur to a lesser degree in the other craniosynostosis mouse models. Laser capture microdissection and RNA-seq analysis revealed transcriptomic changes in mandibular bone at embryonic day 16.5 (E16.5), highlighting increased expression of genes related to osteoclast differentiation and dysregulated genes active in bone mineralization. Increased osteoclastic activity was corroborated by TRAP assay and in situ hybridization of Csf1r and Itgb3 Upregulated expression of Enpp1 and Ank was validated in the mandible of Fgfr2+/S252W embryos, and found to result in elevated inorganic pyrophosphate concentration. Increased proliferation of osteoblasts in the mandible and chondrocytes forming MC was identified in Fgfr2+/S252W embryos at E12.5. These findings provide evidence that FGFR2 gain-of-function mutations differentially affect cartilage formation and intramembranous ossification of dermal bone, contributing to mandibular dysmorphogenesis in craniosynostosis syndromes.This article has an associated First Person interview with the joint first authors of the paper.

Dataset Information

Atypical Skin Manifestations in FGFR2-Related Craniosynostosis Syndromes Broaden the Phenotypic Spectrum.

Publications

Atypical Skin Manifestations in <i>FGFR2</i>-Related Craniosynostosis Syndromes Broaden the Phenotypic Spectrum.

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