Achondroplasia: aligning mouse model with human clinical studies shows crucial importance of immediate postnatal start of the therapy

Rico-Llanos G; Spoutil F; Blahova E; Koudelka A; Prochazkova M; Czyrek A; Fafilek B; Prochazka J; Gonzalez Lopez M; Krivanek J; Sedlacek R; Krakow D; Nonaka Y; Nakamura Y; Krejci P

doi:10.1530/ey.22.5.10

5.10

Prev Next

Section Contents Cite

ESPE Yearbook of Paediatric Endocrinology (2025) 22 5.10 | DOI: 10.1530/ey.22.5.10

ESPEYB25 5. Bone, Growth Plate and Mineral Metabolism Novel Treatments (6 abstracts)

5.10. Achondroplasia: aligning mouse model with human clinical studies shows crucial importance of immediate postnatal start of the therapy

Rico-Llanos G , Spoutil F , Blahova E , Koudelka A , Prochazkova M , Czyrek A , Fafilek B , Prochazka J , Gonzalez Lopez M , Krivanek J , Sedlacek R , Krakow D , Nonaka Y , Nakamura Y & Krejci P

Journal of Bone and Mineral Research, (2024). 39(12), 1783-1792. https://doi.org/10.1093/jbmr/zjae173

Brief Summary: This study used a mouse model of achondroplasia to compare the efficacy of early versus late postnatal treatment with the FGFR3 inhibitor,infigratinib. It demonstrated that early intervention is crucial for restoring cranial base development and preventing associated neurological complications. Both early and late treatments improved long bone growth.

Commentary: Achondroplasia (ACH) is the most common form of human dwarfism and is caused by mutations in the FGFR3 receptor. Current therapies, such as C-natriuretic peptide (CNP) analogues and tyrosine kinase inhibitors, mainly aim to increase longitudinal growth. However, they often fail to address early cranial malformationssuch as midface hypoplasia and foramen magnum stenosis. These malformations can lead to significant otolaryngeal and neurological issues, including obstructive sleep apnoea and sudden infant death syndrome. Using a mouse model that recapitulates human ACH pathology, this study compared the effects of treatment initiated immediately after birth (day 1) and later postnatal treatment (day 4, equivalent to ~5 months in humans) with infigratinib, a tyrosine kinase inhibitor.

This study demonstrates that immediate postnatal therapy is essential for normalising skeletal growth in the cranial base and long bones. Specifically, early treatment improved naso-anal length and vertebral growth. Importantly, it also restored defective cranial development, including the fronto-basal angle and the area of the foramen magnum. In contrast, late treatment provided little to no improvement for cranial malformations, although it did promote long bone growth in a similar manner to early treatment. The study also revealed that premature fusion of skull base synchondroses occurs immediately after birth in achondroplasia, resulting in defective cranial development.

These results suggest that children with achondroplasia should receive treatment as early as possible to prevent complications during the early years of life.