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


  • This study was funded in part by the Centers for Disease Control and Prevention, the National Science Foundation, the National Institutes of Health, a Children's Miracle Network Endowed Chair, and the American Recovery and Reinvestment Act: K23 DE00462, R03 DE016342, R01 DE016886, M01-RR00052, R01 DE018500, 3R01 DE18500-02S1, R01 DE022988; 5R01 DD000350, BCS 0725227.



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.


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.


Our results confirm a strong correspondence between genotype and facial phenotype for AS and MS with severity of facial dysmorphology diminishing from Apert FGFR2S252W to Apert FGFR2P253R 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.


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. Birth Defects Research (Part A) 100:250–259, 2014. © 2014 Wiley Periodicals, Inc.