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Activating FGFR3 mutations in human result in achondroplasia (ACH), the most frequent form of dwarfism, where cartilages are severely disturbed causing long bones, cranial base and vertebrae defects. Because mandibular development and growth rely on cartilages that guide or directly participate to the ossification process, we investigated the impact of FGFR3 mutations on mandibular shape, size and position. By using CT scan imaging of ACH children and by analyzing  Fgfr3 Y367C/+    mice, a model of ACH, we show that  FGFR3  gain-of-function mutations lead to structural anomalies of primary (Meckel’s) and secondary (condylar) cartilages of the mandible, resulting in mandibular hypoplasia and dysmorphogenesis. These defects are likely related to a defective chondrocyte proliferation and differentiation and pan-FGFR tyrosine kinase inhibitor NVP-BGJ398 corrects Meckel’s and condylar cartilages defects  ex vivo.  Moreover, we show that low dose of NVP-BGJ398 improves  in vivo  condyle growth and corrects dysmorphologies in  Fgfr3 Y367C/+    mice, suggesting that postnatal treatment with NVP-BGJ398 mice might offer a new therapeutic strategy to improve mandible anomalies in ACH and others FGFR3-related disorders.

Meckel’s and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible