Late embryonic skull anomalies in mice carrying the Fgfr2 W290R Crouzon mutation

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FGFR2 has two major isoforms, IIIb and IIIc, generated through alternative splicing with their own temporal, spatial, and ligand‐binding specificities. Dysregulated signaling of both IIIb and IIIc isoforms of Fgfr2 contribute to the phenotypic changes seen in Crouzon patients carrying the W290R mutation. Previous postnatal studies of mice carrying a Fgfr2W290R/+ mutation have shown that heterozygote mutant mice were similar in shape at birth to their unaffected littermates but presented with dome shaped skulls, shortened snouts, and variable nasal‐septal defects leading to relatively decreased anterior‐posterior skull lengths by 8 weeks of age. In this study, we acquired microCT images of the heads of Fgfr2+/W290R mice at embryonic day 17.5 (E17.5). Using a calcium hydroxyapatite phantom, we used a threshold for bone (80 mg/cm3), and landmarked the skulls of the nine Fgfr2+/W290R and nine Fgfr2+/+ specimens in Avizo 9.4. Euclidean Distance Matrix Analysis (EDMA) and Principal Components Analysis (PCA) were performed to identify and statistically test for morphological differences between these groups. PCA results indicate a phenotypic separation of unaffected and mutant individuals, while EMDA results specify the localized differences responsible for group separation. This analysis shows that relative to Fgfr2+/+ specimens, Fgfr2+/W290R specimens present with a more rounded, domed vault with the largest magnitude differences at the most posterior aspect of the head. Additionally, at E17.5, no reduction in snout length was noted in Fgfr2+/W290R mice. Our results indicate the initiation of craniofacial dysmorphology by E17.5 in Fgfr2+/W290R mice, with the vault being most affected.Support or Funding InformationR01‐DE019638, R01‐DE018234, R01‐DE022988; R01 DE027677, P01 HD078233