Genotype-Phenotype Correlation of Tracheal Cartilaginous Sleeves andFgfr2Mutations in Mice

Objectives To characterize tracheal cartilage morphology in mouse models of fibroblast growth factor receptor (Fgfr2)-related craniosynostosis syndromes. To establish relationships between specificFgfr2mutations and tracheal cartilaginous sleeve (TCS) phenotypes in these mouse models. Methods Postnatal day 0 knock-in mouse lines with disease-specific genetic variations in theFgfr2gene (Fgfr2(C342Y/C342Y),Fgfr2(C342Y/+),Fgfr2(+/Y394C),Fgfr2(+/S252W), andFgfr2(+/P253R)) as well as line-specific controls were utilized. Tracheal cartilage morphology as measured by gross analyses, microcomputed tomography (mu CT), and histopathology were compared using Chi-squared and single-factor analysis of variance statistical tests. Results A greater proportion of rings per trachea were abnormal inFgfr2(C342Y/+)tracheas (63%) thanFgfr2(+/S252W)(17%),Fgfr2(+/P253R)(17%),Fgfr2(+/Y394C)(12%), and controls (10%) (P < .001 for each vs.Fgfr2(C342Y/+)). TCS segments were found only inFgfr2(C342Y/C342Y)(100%) andFgfr2(C342Y/+)(72%) tracheas. Cricoid and first-tracheal ring fusion was noted in allFgfr2(C342Y/C342Y)and 94% ofFgfr2(C342Y/+)samples. TheFgfr2(C342Y/C342Y)andFgfr2(C342Y/+)groups were found to have greater areas and volumes of cartilage than other lines on gross analysis and mu CT. Histologic analyses confirmed TCS among theFgfr2(C342Y/C342Y)andFgfr2(C342Y/+)groups, without appreciable differences in cartilage morphology, cell size, or density; no histologic differences were observed among otherFgfr2lines compared to controls. Conclusion This study found TCS phenotypes only in theFgfr2(C342Y)mouse lines. These lines also had increased tracheal cartilage compared to other mutant lines and controls. These data support further study of theFgfr2mouse lines and the investigation of otherFgfr2variants to better understand their role in tracheal development and TCS formation. Level of Evidence NALaryngoscope, 2020

Automated summary

This study found TCS phenotypes only in the Fgfr2 (C342Y) mouse lines, which also had increased tracheal cartilage compared to other mutant lines and controls. These data support further study of the Fgfr2 mouse lines and other Fgfr2 variants to better understand their role in tracheal development and TCS formation.