Changes in FGFR2 amino-acid residue Asn549 lead to Crouzon and Pfeiffer syndrome with hydrocephalus

Caroline Apra,Corinne Collet,Eric Arnaud,Federico Di Rocco

doi:10.3934/genet.2016.4.205

Caroline Apra, Corinne Collet + Show 2 more

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https://doi.org/10.3934/genet.2016.4.205

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Abstract

AbstractMutations in Fibroblast Growth Factor Receptor II (FGFR2) have been identified in patients with Crouzon and Pfeiffer syndrome, among which rare mutations of the intracellular tyrosine kinase domain. Correlating subtle phenotypes with each rare mutation is still in progress. In Necker-Enfants Malades Hospital, we identified three patients harboring three different pathogenic variants of the same amino acid residue Asn-549 located in this domain: in addition to a very typical crouzonoid appearance, they all developed clinically relevant hydrocephalus, which is an inconstant feature of Crouzon and Pfeiffer syndrome. Overall, FGFR2 tyrosine kinase domain mutations account for 5/67 (7.4%) cases in our hospital. We describe a novel mutation, p.Asn549Ser, and new cases of p.Asn549His and p.Asn549Thr mutations, each reported once before. Our three cases of Asn-549 mutations, alongside with rare previously reported cases, show that these patients are at higher risk of hydrocephalus. Clinical and imaging follow-up, with possible early surgery, may help prevent secondary intellectual disability.

Highlights

Craniosynostosis is a cranial malformation occurring in approximately 1 in 2500 live births
From a cohort of patients affected by craniofacial syndromes, we identified three patients with missense mutations affecting the same amino acid Asn549, located in the FGFR2 tyrosine kinase (TK) domain, we discuss their molecular mechanism and compare their phenotypes
Mutations affecting FGFR2 TK domain are a subgroup of FGFR2 mutations found in syndromic craniosynostoses

Summary

Introduction

Craniosynostosis is a cranial malformation occurring in approximately 1 in 2500 live births. FGFR2 (Fibroblast Growth Factor Receptor 2) is a key gene involved in craniosynostosis syndromes such as Crouzon and Pfeiffer syndromes. It codes for a membrane receptor with three extracellular immunoglobulin(Ig)-like domains, a transmembrane domain and an intracellular tyrosine kinase (TK) domain. Rare mutations affect the intracellular TK domain of FGFR2 with subsequent constitutive activation [9,11]. From a cohort of patients affected by craniofacial syndromes, we identified three patients with missense mutations affecting the same amino acid Asn549, located in the FGFR2 TK domain, we discuss their molecular mechanism and compare their phenotypes

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