1 - Embryonic origins of lower jaw pathologies in FGFR-related craniosynostosis: Morphometric insights from mouse models of Apert and Crouzon syndromes

Poster Board Number: 1
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Co-authors:

Frederick Foster - Postdoctoral Researcher, Anthropology, The Pennsylvania State University; Nishchal Sapkota - Graduate Research Assistant, University of Notre Dame; Yeija Zhang - University of Notre Dame; Yuhan Hsi - The Pennsylvania State University; Mizuho Kawasaki - The Pennsylvania State University; Abigail Coupe - The Pennsylvania State University; Danny Chen - The University of Notre Dame; Joan Richtsmeier - The Pennsylvania State University; Kazuhiko Kawasaki - The Pennsylvania State University; Susan Motch Perrine - The Pennsylvania State University

Abstract Body :Fibroblast growth factor receptor 2 (FGFR2) mutations are causative for Apert and Crouzon syndromes that produce distinct phenotypes characterized by craniosynostosis and midface hypoplasia. Recent studies of FGFR2 mutations suggest that differences in mandibular morphology are also characteristic of these syndromes. We sought to determine whether differences in lower jaw morphology were present prenatally. We examined critical timepoints in embryonic (E) development in Meckel’s cartilage (MC) (E14.5, E16.5) and mandible (E16.5) development in Fgfr2(+/P253R) Apert syndrome (E14.5 n = 6, E16.5 = 6 ) and Fgfr2cC342Y/+ Crouzon syndrome mouse models (E14.5 n = 6, E16.5 n =7), and their unaffected littermates: Fgfr2+/+, (E14.5 n = 4, E16.5 = 5), and Fgfr2c+/+, (E14.5 n = 7, E16.5 n = 4), respectively. Machine learning facilitated automatic cartilage segmentation from phosphotungstic acid-enhanced micro-CT images and the subsequent creation of 3D models of MC in Avizo 3D (v. 2021.2). The 3D coordinates of six anatomical landmarks for MC were collected for all specimens using 3D Slicer (v. 5.2.2 and 5.6.1). MicroCT scans thresholded for bone were used to create 3D models of the hemi-mandibles and 3D coordinates of eight anatomical landmarks were then collected. Euclidean Distance Matrix Analysis (EDMA) and Growth Difference Matrix Analysis (GDMA) were used to determine morphometric differences within the Apert and Crouzon mouse models at each age, and differences in growth. EDMA revealed statistically significant morphological differences between affected specimens carrying the mutations of interest and unaffected littermates within each model. In MC, the Fgfr2+/P253R Apert syndrome mice demonstrated shorter length and width measurements at E14.5, but by E16.5 these differences were localized to the symphysis and length of the right rod. The MC of Fgfr2cC342Y/+ Crouzon syndrome mice showed differences in symphysis length and left malleus length relative to Fgfr2c+/+ mice at E14.5 but no differences by E16.5. Growth of MC from E14.5 and E16.5 showed significant differences between the Fgfr2+/P253R Apert syndrome mice and their unaffected littermates. No significant MC growth differences were detected between the Fgfr2cC342Y/+ Crouzon syndrome mice and their unaffected littermates. At E16.5, the mid and anterior portion of the mandible in the Fgfr2+/P253R Apert syndrome mice was significantly smaller compared to unaffected littermates, while the mandibles of the Fgfr2cC342Y/+ Crouzon mice were relatively larger relative to their unaffected littermates. Results indicate that MC and mandibular dysmorphology is visible in both Apert and Crouzon mouse models in early embryogenesis, but that MC and mandibles do not necessarily follow the same pattern of dysmorphogenesis.