Genetic and developmental pathways causing midface hypoplasia

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DESCRIPTION (provided by applicant): Craniosynostosis is among the most clinically significant craniofacial anomalies and is characterized by the pathologic premature fusion of one or more cranial sutures, the regions of non-mineralized mesenchyme separating the cranial bones. Midfacial hypoplasia is a prominent but understudied co-morbidity of craniosynostosis as well as a common clinical problem as an isolated anomaly. Although advances have been made in our understanding of the molecular pathogenesis of syndromic craniosynostosis, little is understood about the biologic effects of these mutations or the pathogenesis of associated midfacial hypoplasia. Our project will utilize state of the art genome sequencing technologies to identify genetic causes and the perturbed downstream molecular pathways in patients and new mouse mutants that co-present with midfacial hypoplasia and craniosynostosis. In addition, we propose to utilize a combination of unique and powerful transgenic mouse lines to aid in characterization of the cellular and developmental basis of midface hypoplasia in the various mouse models. These studies will provide significant new insight into the genetic pathways and cellular mechanisms important for normal facial suture biology, midfacial outgrowth, and dysmorphology. Ultimately, it is hoped that a greater understanding of the pathogenesis of midfacial hypoplasia will lead to improvements in effectiveness and timing of the clinical and surgical management of patients. PUBLIC HEALTH RELEVANCE: The causes and mechanisms underlying the clinical presentation of craniosynostosis-associated midfacial hypoplasia remains poorly understood, despite the significance of the clinical problem. The vast majority of biologic research has focused on the pathogenesis of calvarial bone fusion while ignoring the co-morbid association of midfacial hypoplasia, which often leads to life threatening airway compromise and the need for extensive reconstructive orthognathic surgery. Closing these gaps in our knowledge of the pathogenesis of craniofacial synostosis is vital to the development of appropriate, evidence-based care for this patient population.