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About the Authors
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Publication acknowledgements: We thank Renée Shediac, Wayne Pan and Dominique Kelly (BioMarin Pharmaceutical Inc.) for administrative and logistical support. The initial meeting of the Consensus panel was sponsored by BioMarin Pharmaceutical Inc., which provided logistical assistance. They had no influence or input regarding the content of this Consensus Statement.
Author contributions: All authors researched data for the article. All authors contributed substantially to the discussion of content. R.S. and S.O.F wrote the article. All authors reviewed and/or edited the manuscript before submission.
Ethics declarations: Competing interests: R.S. has received consulting fees and grants from BioMarin and was an investigator in clinical trials for achondroplasia for BioMarin. I.A. has received honorarium from BioMarin and Ascendis Pharma; travel expenses from Ascendis Pharma, Eurordis, Kyowa Kirin and ERN BOND; personal fees from BioMarin and Ascendis Pharma; and non-financial support from Ascendis Pharma, Eurordis, Kyowa Kirin and ERN BOND. W.A.R.B. has received honoraria, consulting fees and travel expenses from BioMarin. M.B. has received consulting fees and grants from BioMarin, Ascendis, Therachon, QED and Alexion, grants from BioMarin, Ascendis, Therachon, QED, Medlife, SOBI and Shire, and was an investigator in BioMarin clinical trials for achondroplasia. J.C. has received personal fees from BioMarin. P.C. has received support from Ascendis and Pfizer for local enrolment in company-led achondroplasia natural history studies. M.C. has received honoraria from BioMarin and is an investigator in achondroplasia trials by BioMarin, Ascendis, QED and Pfizer. M.D.P. has received personal fees and grants from BioMarin. V.F. has received grants and personal fees from BioMarin. M.G. has received honoraria from BioMarin. L.H. has received a grant to Karolinska Institute from BioMarin to work with achondroplasia data and consultant fees from BioMarin, Ascendis and Kyowa Kirin. J.H.F. has received consulting fees from BioMarin, Therachon and Ascendis, grants from BioMarin, and is an investigator in BioMarin clinical trials for achondroplasia. A.L-G. has received honoraria, consulting fees, and travel expenses from BioMarin and was an investigator in BioMarin clinical trials for achondroplasia. M.I. has received consulting fees from BioMarin and was an investigator in BioMarin clinical trials for achondroplasia. J.L. has received grants and personal fees from BioMarin. W.M. has served on advisory boards for LPA, BioMarin, and MPS and has received consulting fees, honoraria and travel expenses from BioMarin. K.M. has served as a BioMarin advisory board member and has received personal fees from BioMarin. K.M. has received consulting fees and grants from BioMarin and was an investigator in BioMarin clinical trials for achondroplasia. G.M. has received honoraria from BioMarin and is involved in the Dreambird study (Therachon/Pfizer) and the Silverbird study (recifercept) for which he receives payments from Pfizer. A.O. has received personal fees, non-financial support, support with manuscript preparation, and travel fees and subsistence for initial expert meetings from BioMarin and served as a reader for imaging in a BioMarin clinical trial for achondroplasia. A.O. has also received grants from Alexion and is involved with the Alexion Research project: Development of dREAMS. K.O. has received honoraria from BioMarin and was an investigator in a BioMarin clinical trial for achondroplasia. J.P. has received fees for board membership and travel from BioMarin. C.R. serves on the advisory board of OIF, EDS, and SDMC and has received consulting fees from BioMarin, Ascendis, Alexion, and Mereo and provided contracted research to BioMarin, Nextcure, and OIF. C.R. is also a member of the speaker’s bureau for BioMarin and Alexion. D.T. has received honoraria and travel expenses from BioMarin relating to his participation on advisory panels in relation to a project seeking to define best practice guidelines for individuals with achondroplasia. N.Y. was an investigator in the BioMarin clinical trial for achondroplasia and has nothing additional to disclose. The remaining authors declare no competing interests.
The cellular mechanism of disease in achondroplasia
a | A growth plate chondrocyte with wild-type fibroblast growth factor receptor 3 (FGFR3) signalling that is ligand (FGF) dependent. In this scenario, only ligand-dependent activation of the RAS–RAF1–MEK1/2–ERK1/2 pathway (otherwise known as RAS–MAPK pathway) occurs. Consequently, the proliferation and differentiation of chondrocytes are able to occur along with matrix synthesis and bone growth. b | A growth plate chondrocyte with a common missense mutation in the transmembrane domain (red rectangle) of FGFR3. This mutation enables activation of the RAS–MAPK pathway that is both ligand (FGF) dependent and independent, with consequent excess inhibition of chondrocyte proliferation and differentiation, leading to impaired matrix synthesis and bone growth.