Genomic Screening of Fibroblast Growth-Factor Receptor 2 Reveals a Wide Spectrum of Mutations in Patients with Syndromic Craniosynostosis

Abstract

It has been known for several years that heterozygous mutations of three members of the fibroblast growth-factor-receptor family of signal-transduction molecules-namely, FGFR1, FGFR2, and FGFR3-contribute significantly to disorders of bone patterning and growth. FGFR3 mutations, which predominantly cause short-limbed bone dysplasia, occur in all three major regions (i.e., extracellular, transmembrane, and intracellular) of the protein. By contrast, most mutations described in FGFR2 localize to just two exons (IIIa and IIIc), encoding the IgIII domain in the extracellular region, resulting in syndromic craniosynostosis including Apert, Crouzon, or Pfeiffer syndromes. Interpretation of this apparent clustering of mutations in FGFR2 has been hampered by the absence of any complete FGFR2-mutation screen. We have now undertaken such a screen in 259 patients with craniosynostosis in whom mutations in other genes (e.g., FGFR1, FGFR3, and TWIST) had been excluded; part of this screen was a cohort-based study, enabling unbiased estimates of the mutation distribution to be obtained. Although the majority (61/62 in the cohort sample) of FGFR2 mutations localized to the IIIa and IIIc exons, we identified mutations in seven additional exons-including six distinct mutations of the tyrosine kinase region and a single mutation of the IgII domain. The majority of patients with atypical mutations had diagnoses of Pfeiffer syndrome or Crouzon syndrome. Overall, FGFR2 mutations were present in 9.8% of patients with craniosynostosis who were included in a prospectively ascertained sample, but no mutations were found in association with isolated fusion of the metopic or sagittal sutures. We conclude that the spectrum of FGFR2 mutations causing craniosynostosis is wider than previously recognized but that, nevertheless, the IgIIIa/IIIc region represents a genuine mutation hotspot.

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

“…This situation is similar to two previous studies 15,21 in which mutations were detected in 18/20 and 25/28 Crouzon patients, respectively. In PS, we found 95% of mutations in our cohort of 20 patients.…”

“…14 In 2002, novel mutations in other regions of the receptor including the IgII loop and the tyrosine kinase subdomains TK1 and TK2 have been reported. 15 Likewise, this study demonstrated that in a clinically homogeneous group of CS and PS patients, FGFR2 mutations were detectable in more than 90% of all cases, thus making the existence of an additional major locus very unlikely. 14 A recurrent mutation, A391E, in a third gene, FGFR3, accounts for a peculiar form of CS associating craniosynostosis with acanthosis nigricans also called crouzonodermoskeletal syndrome.…”

“…On the basis of previous studies 15,20 and our own experience, the mutation detection rate appears to depend largely on the accuracy of the original diagnosis and the sensitivity of the detection method. In our study, all patients were examined by the same physicians and complete clinical and radiological data were recorded, so that the criteria for phenotypic classification were highly homogeneous allowing recognition of the Crouzonoid facies.…”

“…A similar percentage was obtained in the Oxford series. 15 In contrast, Cornejo-Roldan et al 20 studying a total of 78 unrelated Pfeiffer patients identified FGFR mutations in only 40 cases (51%). The difference between the three studies could rely on the stringency of clinical diagnosis.…”

FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease

“…Most of the mutations are missense, or small in-frame insertions or deletions that affect the highly conserved extracellular FGFR ligand-binding domain. However, some recently described mutations involve the intracellular tyrosine kinase domain of FGFR2 and presumably function to activate downstream signaling pathways (Kan et al 2002).…”