Achondroplasia is the most common form of human dwarfism caused by mutations in the FGFR3 receptor tyrosine kinase. Current therapy begins at 2 years of age and improves longitudinal growth but does not address the cranial malformations including midface hypoplasia and foramen magnum stenosis, which lead to significant otolaryngeal and neurologic compromise. A recent clinical trial found partial restoration of cranial defects with therapy starting at 3 months of age, but results are still inconclusive. The benefits of achondroplasia therapy are therefore controversial, increasing skepticism among the medical community and patients. We used a mouse model of achondroplasia to test treatment protocols aligned with human studies. Early postnatal treatment (from day 1) was compared with late postnatal treatment (from day 4, equivalent to ~5 months in humans). Animals were treated with the FGFR3 inhibitor infigratinib and the effect on skeleton was thoroughly examined. We show that premature fusion of the skull base synchondroses occurs immediately after birth and leads to defective cranial development and foramen magnum stenosis in the mouse model to achondroplasia. This phenotype appears significantly restored by early infigratinib administration when compared with late treatment, which provides weak to no rescue. In contrast, the long bone growth is similarly improved by both early and late protocols. We provide clear evidence that immediate postnatal therapy is critical for normalization of skeletal growth in both the cranial base and long bones and the prevention of sequelae associated with achondroplasia. We also describe the limitations of early postnatal therapy, providing a paradigm-shifting argument for the development of prenatal therapy for achondroplasia.

The article provides clear evidence that achondroplasia should be treated immediately after birth, not only to increase height (appendicular growth), but more importantly to prevent defective cranial skeletogenesis and associated severe neurological complications. Although later treatment promotes growth of the long bones (achondroplasia patients grow taller), the defective head skeleton that forms before and/or early after birth cannot be restored if therapy is not started immediately after birth. We also describe the limitations of postnatal treatment and make a strong case for the development of prenatal therapy for achondroplasia, which appears necessary for a comprehensive treatment of this condition.

Czech Center for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences CZ 25250 Vestec Czech Republic

Department of Biology Faculty of Medicine Masaryk University CZ 62500 Brno Czech Republic

Department of Histology and Embryology Faculty of Medicine Masaryk University CZ 62500 Brno Czech Republic

Department of Orthopaedic Surgery Human Genetics and Obstetrics and Gynecology University of California Los Angeles Los Angeles CA 90095 United States

Institute of Animal Physiology and Genetics of the of the Czech Academy of Sciences CZ 60200 Brno Czech Republic

Institute of Medical Science University of Tokyo Tokyo 108 8639 Japan

International Clinical Research Center St Anne's University Hospital CZ 65691 Brno Czech Republic

RIBOMIC Inc Tokyo 108 0071 Japan

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Orioli  IM, Castilla  EE, Barbosa-Neto  JG. The birth prevalence rates for the skeletal dysplasias. J Med Gene PubMed DOI PMC

Hoover-Fong  JE, Schulze  KJ, Alade  AY, et al.  Growth in achondroplasia including stature, weight, weight-for-height and head circumference from CLARITY: achondroplasia natural history study-a multi-center retrospective cohort study of achondroplasia in the US. Orphanet J Rare Di PubMed DOI PMC

Srikumaran  U, Woodard  EJ, Leet  AI, Rigamonti  D, Sponseller  PD, Ain  MC. Pedicle and spinal canal parameters of the lower thoracic and lumbar vertebrae in the achondroplast population. Spine (Phila Pa 1976 PubMed DOI

He  L, Horton  W, Hristova  K. Physical basis behind achondroplasia, the most common form of human dwarfism. J Biol Che PubMed DOI PMC

Murakami  S, Balmes  G, McKinney  S, Zhang  Z, Givol  D, de Crombrugghe  B. Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype. Genes De PubMed DOI PMC

Qi  H, Jin  M, Duan  Y, et al.  FGFR3 induces degradation of BMP type I receptor to regulate skeletal development. Biochim Biophys Act PubMed DOI PMC

Krejci  P, Prochazkova  J, Bryja  V, et al.  Fibroblast growth factor inhibits interferon gamma-STAT1 and interleukin 6-STAT3 signaling in chondrocytes. Cell Signa PubMed DOI PMC

Fafilek  B, Balek  L, Bosakova  MK, et al.  The inositol phosphatase SHIP2 enables sustained ERK activation downstream of FGF receptors by recruiting Src kinases. Sci Signa PubMed DOI PMC

Kunova Bosakova  M, Varecha  M, Hampl  M, et al.  Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies. Hum Mol Gene PubMed DOI PMC

Raucci  A, Laplantine  E, Mansukhani  A, Basilico  C. Activation of the ERK1/2 and p38 mitogen-activated protein kinase pathways mediates fibroblast growth factor-induced growth arrest of chondrocytes. J Biol Che PubMed DOI

Krejci  P, Prochazkova  J, Smutny  J, et al.  FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence. Bon PubMed DOI PMC

Matsushita  T, Wilcox  WR, Chan  YY, et al.  FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Gene PubMed DOI PMC

Campbell  J, Legare  JM, Piatt  J, et al.  Achondroplasia natural history study (CLARITY): 60-year experience with hydrocephalus in achondroplasia from four skeletal dysplasia centers. J Neurosurg Pediat PubMed DOI

Hecht  JT, Butler  IJ, Scott  CI. Long-term neurological sequelae in achondroplasia. Eur J Pediat PubMed DOI

Hecht  JT, Butler  IJ. Neurologic morbidity associated with achondroplasia. J Child Neuro PubMed DOI

Horton  WA, Hall  JG, Hecht  JT. Achondroplasia PubMed DOI

Collins  WO, Choi  SS. Otolaryngologic manifestations of achondroplasia. Arch Otolaryngol Head Neck Sur PubMed DOI

Pauli  RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Di PubMed DOI PMC

Wendt  DJ, Dvorak-Ewell  M, Bullens  S, et al.  Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J Pharmacol Exp The PubMed DOI

Savarirayan  R, Irving  M, Day  J. C-type natriuretic peptide analogue therapy in children with achondroplasia. Reply PubMed DOI

Yasoda  A, Komatsu  Y, Chusho  H, et al.  Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Me PubMed DOI

Kimura  T, Bosakova  M, Nonaka  Y, et al.  An RNA aptamer restores defective bone growth in FGFR3-related skeletal dysplasia in mice. Sci Transl Me PubMed DOI

Savarirayan  R, De Bergua  JM, Arundel  P, et al.  Infigratinib in children with achondroplasia: the PROPEL and PROPEL 2 studies. Ther Adv Musculoskelet Di PubMed DOI PMC

Savarirayan  R, Tofts  L, Irving  M, et al.  Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lance PubMed DOI

Willyard  C. Is a boost to height a boost to health?  Dwarfism therapies spark controversy PubMed DOI

Savarirayan  R, Wilcox  WR, Harmatz  P, et al.  Vosoritide therapy in children with achondroplasia aged 3-59 months: a multinational, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Child Adolesc Healt PubMed DOI

Wang  Y, Spatz  MK, Kannan  K, et al.  A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. Proc Natl Acad Sci US PubMed DOI PMC

Sakai  K, Miyazaki  J. A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission. Biochem Biophys Res Commu PubMed DOI

Gonzalez Lopez  M, Huteckova  B, Lavicky  J, et al.  Spatiotemporal monitoring of hard tissue development reveals unknown features of tooth and bone development. Sci Ad PubMed DOI PMC

Bouxsein  ML, Boyd  SK, Christiansen  BA, Guldberg  RE, Jepsen  KJ, Müller  R. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Re PubMed DOI

Passos-Bueno  MR, Wilcox  WR, Jabs  EW, Sertié  AL, Alonso  LG, Kitoh  H. Clinical spectrum of fibroblast growth factor receptor mutations. Hum Muta PubMed DOI

Wei  X, Thomas  N, Hatch  NE, Hu  M, Liu  F. Postnatal craniofacial skeletal development of female C57BL/6NCrl mice. Front Physio PubMed DOI PMC

Dutta  S, Sengupta  P. Men and mice: relating their ages. Life Sc PubMed DOI

Demuynck  B, Flipo  J, Kaci  N, et al.  Low-dose infigratinib increases bone growth and corrects growth plate abnormalities in an achondroplasia mouse model. J Bone Miner Re PubMed DOI

Di Rocco  F, Biosse Duplan  M, Heuzé  Y, et al.  FGFR3 mutation causes abnormal membranous ossification in achondroplasia. Hum Mol Gene PubMed DOI

Calandrelli  R, Panfili  M, D’Apolito  G, et al.  Quantitative approach to the posterior cranial fossa and craniocervical junction in asymptomatic children with achondroplasia. Neuroradiolog PubMed DOI

Morice  A, Taverne  M, Eché  S, et al.  Craniofacial growth and function in achondroplasia: a multimodal 3D study on 15 patients. Orphanet J Rare Di PubMed DOI PMC

Smith  TD, McMahon  MJ, Millen  ME, et al.  Growth and development at the sphenoethmoidal junction in perinatal primates. Anat Rec (Hoboken PubMed DOI

Smith  TD, Reynolds  RL, Mano  N, et al.  Cranial synchondroses of primates at birth. Anat Rec (Hoboken PubMed DOI

Madeline  LA, Elster  AD. Suture closure in the human chondrocranium: CT assessment. Radiolog PubMed DOI

Schneider  H, Faschingbauer  F, Schuepbach-Mallepell  S, et al.  Prenatal correction of X-linked hypohidrotic ectodermal dysplasia. N Engl J Me PubMed DOI