Second case of Beare–Stevenson syndrome with an FGFR2 Ser372Cys mutation

Fonseca, Renata; Costa-Lima, Marcelo Aguiar; Cosentino, Viviana; Orioli, Iêda M.

doi:10.1002/ajmg.a.32176

Cited by 21 publications

(12 citation statements)

References 16 publications

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“…Craniosynostosis occurs in 1 in 2,500 newborns across all ethnicities and is present in more than 100 human skeletal syndromes (10)(11)(12)(13). The FGF receptor (FGFR) mutations that underlie the genetic basis of BSS are FGFR2 Y375C and S372C (human FGFR2 IIIc protein NP_000132.3) of the juxtamembrane domain (4,(14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

Wang¹,

Zhou²,

Oberoi³

et al. 2012

J. Clin. Invest.

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Beare-Stevenson cutis gyrata syndrome (BSS) is a human genetic disorder characterized by skin and skull abnormalities. BSS is caused by mutations in the FGF receptor 2 (FGFR2), but the molecular mechanisms that induce skin and skull abnormalities are unclear. We developed a mouse model of BSS harboring a FGFR2 Y394C mutation and identified p38 MAPK as an important signaling pathway mediating these abnormalities. Fgfr2 +/Y394C mice exhibited epidermal hyperplasia and premature closure of cranial sutures (craniosynostosis) due to abnormal cell proliferation and differentiation. We found ligand-independent phosphorylation of FGFR2 and activation of p38 signaling in mutant skin and calvarial tissues. Treating Fgfr2 +/Y394C mice with a p38 kinase inhibitor attenuated skin abnormalities by reversing cell proliferation and differentiation to near normal levels. This study reveals the pleiotropic effects of the FGFR2 Y394C mutation evidenced by cutis gyrata, acanthosis nigricans, and craniosynostosis and provides a useful model for investigating the molecular mechanisms of skin and skull development. The demonstration of a pathogenic role for p38 activation may lead to the development of therapeutic strategies for BSS and related conditions, such as acanthosis nigricans or craniosynostosis.

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Section: Introductionmentioning

confidence: 99%

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

Wang¹,

Zhou²,

Oberoi³

et al. 2012

J. Clin. Invest.

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“…Two cases harbored a c.1115C¡G transversion (9,14) located in the carboxyl-terminal end of the linker region between the immunoglobulin III-like (Iglll) and transmembrane domains of the protein, and 9 cases harbored a c.1124A¡G transition (4,(8)(9)(10)(11)(12)(13) located in the transmembrane region of the protein. In 2 patients, no FGFR2 mutations were detected, suggesting further genetic heterogeneity (9).…”

Section: Discussionmentioning

confidence: 99%

“…BSS cases are sporadic, and a paternal age effect has been suggested (4,7,8). Molecular analysis of BSS cases has revealed two closely spaced mutations in exon 11 of the FGFR2 gene: c.1115C¡G (S372C) in 2 patients and c.1124C¡G (Y375C) in 9 patients (4,6,(8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Beare-Stevenson cutis gyrata syndrome: A new case of a c.1124C↷G (Y375C) mutation in the FGFR2 gene

Fonseca

Costa-Lima²,

Pereira³

et al. 2008

Mol Med Rep

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“…Missense mutations in FGFR 2 in these syndromic forms of craniosynostosis are clustered around the third immunoglobulin-like domain or within the tyrosine kinase domains [Katoh, 2009;Jezela-Stanek and Krajewska-Walasek, 2013]. CS is typically caused by mutations in FGFR2 exons 8 and 10, BSS is typically caused by 1 of 2 recurrent mutations in exon 11 of FGFR2 (Tyr375Cys and Ser372Cys); however, a deletion involving FGFR2 exon 8 has also been described in patients with typical features of BSS [Przylepa et al, 1996;Roscioli et al, 2001;Eun et al, 2007;Fonseca et al, 2008;Slavotenik et al, 2009] ( Table 1 ). CS is much more common (1 in 60,000 live births) than BSS, where fewer than 20 cases have been reported [Slavotenik et al, 2009].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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Second case of Beare–Stevenson syndrome with an FGFR2 Ser372Cys mutation

Cited by 21 publications

References 16 publications

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

Beare-Stevenson cutis gyrata syndrome: A new case of a c.1124C↷G (Y375C) mutation in the FGFR2 gene

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

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