A model for the pharmacological treatment of crouzon syndrome

Neurosurgery. 2006 Jul;59(1):210-5; discussion 210-5. doi: 10.1227/01.NEU.0000224323.53866.1E.

Abstract

Objective: Crouzon syndrome is caused by mutations in fibroblast growth factor receptor 2 (FGFR2) leading to constitutive activation of receptors in the absence of ligand binding. The syndrome is characterized by premature fusion of the cranial sutures that leads to abnormal cranium shape, restricted brain growth, and increased intracranial pressure. Surgical remodeling of the cranial vault is currently used to treat affected infants. The purpose of this study was to develop a pharmacological strategy using tyrosine kinase inhibition as a novel treatment for craniosynostotic syndromes caused by constitutive FGFR activation.

Methods: Characterization of cranial suture fusion in Fgfr2 mutant mice, which carry the most common Crouzon mutation, was performed using micro-computed tomographic analysis from embryogenesis through maturation. Whole calvarial cultures from wild-type and Fgfr2 mice were established and cultured for 2 weeks in the presence of dimethyl sulfoxide control or PD173074, an FGFR tyrosine kinase inhibitor. Paraffin sections were prepared to show suture morphology and calcium deposition.

Results: In untreated Fgfr2 cultures, the coronal suture fused bilaterally with loss of overlap between the frontal bone and parietal bone. Calvaria treated with PD173074 (2 micromol/L) showed patency of the coronal suture and were without evidence of any synostosis.

Conclusion: We report the successful use of PD173074 to prevent in vitro suture fusion in a model for Crouzon syndrome. Further studies are underway to develop an in vivo treatment protocol as a novel therapeutic modality for FGFR associated craniosynostotic syndromes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cranial Sutures / diagnostic imaging
  • Cranial Sutures / drug effects
  • Cranial Sutures / embryology
  • Cranial Sutures / physiopathology
  • Craniofacial Dysostosis / diagnostic imaging
  • Craniofacial Dysostosis / drug therapy*
  • Craniofacial Dysostosis / genetics*
  • Craniofacial Dysostosis / physiopathology
  • Cysteine
  • Disease Models, Animal
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Pyrimidines / therapeutic use*
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics*
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Tissue Culture Techniques
  • Tomography, X-Ray Computed
  • Tyrosine

Substances

  • PD 173074
  • Pyrimidines
  • Receptors, Fibroblast Growth Factor
  • Tyrosine
  • Receptor, Fibroblast Growth Factor, Type 2
  • Cysteine