Model for the Pharmacologic Treatment of Crouzon Syndrome

Abstract

AbstractOBJECTIVECrouzon syndrome is caused by mutations in 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 skull 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 pharmacologic strategy using tyrosine kinase inhibition as a novel treatment for craniosynostotic syndromes caused by constitutive FGFR activation.METHODSCharacterization of cranial suture fusion in Fgfr2C342Y/+ mutant mice, which carry the most common Crouzon mutation, was performed using MicroCT analysis from embryogenesis through maturation. Whole calvarial cultures from wild-type and Fgfr2C342Y/+ mice were then established and calvaria cultured for 2 weeks in the presence of DMSO control or PD173074, an FGFR tyrosine kinase inhibitor. Paraffin sections were prepared to show suture morphology and calcium deposition.RESULTSIn untreated Fgfr2C342Y/+ cultures, the coronal suture fused bilaterally with loss of overlap between the frontal bone and parietal bone. Calvaria treated with PD173074 (2 (M) 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.