Midface and upper airway dysgenesis in FGFR2-related craniosynostosis involves multiple tissue-specific and cell cycle effects

Development. 2018 Oct 5;145(19):dev166488. doi: 10.1242/dev.166488.


Midface dysgenesis is a feature of more than 200 genetic conditions in which upper airway anomalies frequently cause respiratory distress, but its etiology is poorly understood. Mouse models of Apert and Crouzon craniosynostosis syndromes exhibit midface dysgenesis similar to the human conditions. They carry activating mutations of Fgfr2, which is expressed in multiple craniofacial tissues during development. Magnetic resonance microscopy of three mouse models of Apert and Crouzon syndromes revealed decreased nasal passage volume in all models at birth. Histological analysis suggested overgrowth of the nasal cartilage in the two Apert syndrome mouse models. We used tissue-specific gene expression and transcriptome analysis to further dissect the structural, cellular and molecular alterations underlying midface and upper airway dysgenesis in Apert Fgfr2+/S252W mutants. Cartilage thickened progressively during embryogenesis because of increased chondrocyte proliferation in the presence of Fgf2 Oral epithelium expression of mutant Fgfr2, which resulted in a distinctive nasal septal fusion defect, and premature facial suture fusion contributed to the overall dysmorphology. Midface dysgenesis in Fgfr2-related craniosynostosis is a complex phenotype arising from the combined effects of aberrant signaling in multiple craniofacial tissues.

Keywords: Apert syndrome; Crouzon syndrome; Fibroblast growth factor; Midface dysgenesis; Mouse; Nasal cartilage; Suture.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acrocephalosyndactylia / pathology
  • Animals
  • Cartilage / pathology
  • Cell Cycle*
  • Cell Proliferation
  • Chondrocytes / pathology
  • Cranial Sutures / pathology
  • Craniofacial Dysostosis / embryology
  • Craniofacial Dysostosis / pathology
  • Craniosynostoses / embryology*
  • Craniosynostoses / pathology
  • Disease Models, Animal
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / pathology
  • Face / abnormalities*
  • Face / embryology
  • Face / pathology
  • Gene Expression Regulation, Developmental
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Nose / abnormalities
  • Nose / embryology
  • Nose / pathology
  • Organ Specificity*
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
  • Respiratory System Abnormalities / embryology*
  • Respiratory System Abnormalities / pathology*


  • Fgfr2 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 2