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A model for the pharmacological treatment of crouzon syndrome.
Neurosurgery 2006; 59(1):210-5; discussion 210-5N

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.

Authors+Show Affiliations

Division of Plastic Surgery and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. cperlyn@molecool.wustl.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

16823318

Citation

Perlyn, Chad A., et al. "A Model for the Pharmacological Treatment of Crouzon Syndrome." Neurosurgery, vol. 59, no. 1, 2006, pp. 210-5; discussion 210-5.
Perlyn CA, Morriss-Kay G, Darvann T, et al. A model for the pharmacological treatment of crouzon syndrome. Neurosurgery. 2006;59(1):210-5; discussion 210-5.
Perlyn, C. A., Morriss-Kay, G., Darvann, T., Tenenbaum, M., & Ornitz, D. M. (2006). A model for the pharmacological treatment of crouzon syndrome. Neurosurgery, 59(1), pp. 210-5; discussion 210-5.
Perlyn CA, et al. A Model for the Pharmacological Treatment of Crouzon Syndrome. Neurosurgery. 2006;59(1):210-5; discussion 210-5. PubMed PMID: 16823318.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A model for the pharmacological treatment of crouzon syndrome. AU - Perlyn,Chad A, AU - Morriss-Kay,Gillian, AU - Darvann,Tron, AU - Tenenbaum,Marissa, AU - Ornitz,David M, PY - 2006/7/11/pubmed PY - 2006/8/2/medline PY - 2006/7/11/entrez SP - 210-5; discussion 210-5 JF - Neurosurgery JO - Neurosurgery VL - 59 IS - 1 N2 - 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. SN - 1524-4040 UR - https://www.unboundmedicine.com/medline/citation/16823318/A_model_for_the_pharmacological_treatment_of_crouzon_syndrome_ L2 - https://academic.oup.com/neurosurgery/article-lookup/doi/10.1227/01.NEU.0000224323.53866.1E DB - PRIME DP - Unbound Medicine ER -