A model for the pharmacological treatment of crouzon syndrome.
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.


CONCLUSIONS
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.
Perlyn
Chad A
CA
Division of Plastic Surgery and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. cperlyn@molecool.wustl.edu
Morriss-Kay
Gillian
G
Darvann
Tron
T
Tenenbaum
Marissa
M
Ornitz
David M
DM
D000818:Animals; D003393:Cranial Sutures / Q000000981:diagnostic imaging / Q000187:drug effects / Q000196:embryology / Q000503:physiopathology; D003394:Craniofacial Dysostosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D003545:Cysteine; D004195:Disease Models, Animal; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D011743:Pyrimidines / Q000627:therapeutic use*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D046509:Tissue Culture Techniques; D014057:Tomography, X-Ray Computed; D014443:Tyrosine
C115711:PD 173074; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D014443:Tyrosine; D051497:Receptor, Fibroblast Growth Factor, Type 2; D003545:Cysteine