EPOS

European Paediatric Ophthalmological Society

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10 Analysis of Fibroblast Growth Factor Receptors in syndromic and isolated craniosynostoses

Schindler S.¹, Preising M.N.¹, Friedrich M.², Wagener H.¹, Lorenz B.²
Dept. of Paediatric Ophthalmology, Strabismology and Ophthalmogenetics, Clinic and oliclinic for Neurosurgery, Clinic and Policlinic for Maxillofacial Surgery, University of Regensburg, Germany

Purpose: To differentiate syndromic and isolated forms of craniosynostoses on a molecular genetic level and to identify the underlying mutations in isolated craniosynostoses.

Material and Methods: 3 index cases with syndromic craniosynostosis and 11 index cases with isolated craniosynostosis were screened for mutations in the Fibroblast Growth Factor Receptors (FGFR) 1 - 3. Mutation screening focused on exon 5 of FGFR1, exon IIIa and IIIc for FGFR2, and exon 7 and 9 - 11 for FGFR3, regions known to be involved in craniosynostoses. DNA was extracted from peripheral venous blood and bone samples obtained at suture surgery to identify tissue specific mosaics. Single Strand Conformation Polymorphism (SSCP) analysis was carried out. PCR products showing aberrant banding patterns were subjected to direct sequencing and subsequent restriction endonuclease digestion if possible to confirm the mutation.

Results: 4 patients with sagittalstenosis, 5 patients with trigonocephaly, 1 patient with plagiocephaly, and 1 patient with unclassified craniosynostosis were screened without identification of mutations. Mutation screening in the 3 patients with syndromic craniosynostosis revealed a C342S mutation in exon IIIc of FGFR2 in 2 patients diagnosed as Morbus Crouzon on clinical grounds.

Conclusion: Clinically unequivocal M. Crouzon cases could be correlated with mutations in the FGFR2 exon IIIc. This result corroborates the notion that FGFR2 is the major site of mutations in M. Crouzon. Position Cys 342 turns out to be a hotspot in this syndromic craniosynostosis. No mutation could be shown in the cases with isolated craniosynostosis implicating no involvement of FGFR domains known for syndromic craniosynostoses in these disorders. Further screening of exons not involved in syndromic craniosynostoses and of the TWIST and MSX2 gene will complete the project.