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.
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.
|Yu, Kai; Deng, Mei; Naluai-Cecchini, Theresa et al. (2017) Differences in Oral Structure and Tissue Interactions during Mouse vs. Human Palatogenesis: Implications for the Translation of Findings from Mice. Front Physiol 8:154|
|Shaffer, John R; Li, Jinxi; Lee, Myoung Keun et al. (2017) Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment. Am J Hum Genet 101:913-924|
|Palmer, Kristina; Fairfield, Heather; Borgeia, Suhaib et al. (2016) Discovery and characterization of spontaneous mouse models of craniofacial dysmorphology. Dev Biol 415:216-227|
|Cox, Timothy C (2015) Utility and limitations of animal models for the functional validation of human sequence variants. Mol Genet Genomic Med 3:375-82|
|Aneja, D; Vora, S R; Camci, E D et al. (2015) Automated Detection of 3D Landmarks for the Elimination of Non-Biological Variation in Geometric Morphometric Analyses. Proc IEEE Int Symp Comput Based Med Syst 2015:78-83|
|Vora, Siddharth R; Camci, Esra D; Cox, Timothy C (2015) Postnatal Ontogeny of the Cranial Base and Craniofacial Skeleton in Male C57BL/6J Mice: A Reference Standard for Quantitative Analysis. Front Physiol 6:417|
|Cox, Timothy C; Camci, Esra D; Vora, Siddharth et al. (2014) The genetics of auricular development and malformation: new findings in model systems driving future directions for microtia research. Eur J Med Genet 57:394-401|
|Turner, Eric E; Cox, Timothy C (2014) Genetic evidence for conserved non-coding element function across species-the ears have it. Front Physiol 5:7|
|Rolfe, S M; Camci, E D; Mercan, E et al. (2013) A new tool for quantifying and characterizing asymmetry in bilaterally paired structures. Conf Proc IEEE Eng Med Biol Soc 2013:2364-7|
|Cox, Timothy C; Luquetti, Daniela V; Cunningham, Michael L (2013) Perspectives and challenges in advancing research into craniofacial anomalies. Am J Med Genet C Semin Med Genet 163C:213-7|