Quantification of facial skeletal shape variation in fibroblast growth factor receptor-related craniosynostosis syndromes

Abstract

Background: fibroblast growth factor receptor (FGFR) -related craniosynostosis syndromes are caused by many different mutations within FGFR-1, 2, 3, and certain FGFR mutations are associated with more than one clinical syndrome. These syndromes share coronal craniosynostosis and characteristic facial skeletal features, although Apert syndrome (AS) is characterized by a more dysmorphic facial skeleton relative to Crouzon (CS), Muenke (MS), or Pfeiffer syndromes.

Methods: Here we perform a detailed three-dimensional evaluation of facial skeletal shape in a retrospective sample of cases clinically and/or genetically diagnosed as AS, CS, MS, and Pfeiffer syndrome to quantify variation in facial dysmorphology, precisely identify specific facial features pertaining to these four syndromes, and further elucidate what knowledge of the causative FGFR mutation brings to our understanding of these syndromes.

Results: Our results confirm a strong correspondence between genotype and facial phenotype for AS and MS with severity of facial dysmorphology diminishing from Apert FGFR2(S252W) to Apert FGFR2(P253R) to MS. We show that AS facial shape variation is increased relative to CS, although CS has been shown to be caused by numerous distinct mutations within FGFRs and reduced dosage in ERF.

Conclusion: Our quantitative analysis of facial phenotypes demonstrate subtle variation within and among craniosynostosis syndromes that might, with further research, provide information about the impact of the mutation on facial skeletal and nonskeletal development. We suggest that precise studies of the phenotypic consequences of genetic mutations at many levels of analysis should accompany next-generation genetic research and that these approaches should proceed cooperatively.

Keywords: diagnosis; genotype-phenotype correspondence; midfacial retrusion; morphogenesis; suture fusion.

Copyright © 2014 Wiley Periodicals, Inc.

Figures

FIGURE 1

Genotype phenotype correspondence in FGFR-related craniosynostosis syndromes. A: Placement of the syndromic cases and unaffected individuals on PC1 and PC2 in the shape space (principal components analysis of the Procrustes shape coordinates) when analyzing all landmarks and semilandmarks measured on the facial skeleton. B: Shape changes associated with PC1 when analyzing the facial skeleton. The warped facial skeleton in red corresponds to the facial shape of the FGFR2S252W group while the warped facial skeleton in gray corresponds to the facial shape of the unaffected individuals.

FIGURE 2

Facial phenotypic variation of patients genetically and/or clinically diagnosed with AS, CS, MS, or PS. A: Placement of the syndromic cases and unaffected individuals on PC1 and PC2 in the shape space (principal components analysis of the Procrustes shape coordinates) when analyzing all landmarks and semilandmarks measured on the facial skeleton. Filled circles: patients genetically diagnosed; open circles: patients clinically diagnosed. B: Lateral, anterior and inferior views of the mean shape differences between the facial skeleton of AS, MS, PS, CS and unaffected individuals. Colors represent the magnitude of shape differences between the consensus shape (PAS) of each syndrome (AS, MS, PS, or CS) and the unaffected PAS computed as the difference of the vertex positions of corresponding vertices in both triangular meshes.