Craniosynostosis, the premature fusion of cranial sutures, represents a significant medical problem with an estimated birth incidence of 1/2500. It is often associated with additional abnormalities including increased intracranial pressure, airway obstruction, impaired vision and hearing, learning disabilities, facial deformities, and adverse psychological effects. Craniosynostosis can occur secondary to abnormal brain development or deformational forces, or due to a genetic cause. The identification of causal mutations has greatly changed our understanding of the previously clinically defined craniosynostosis syndromes. The most common syndromes are thus being redefined at the molecular level by mutations in the genes for the fibroblast growth factor receptors 1, 2 and 3 and the TWIST transcription factor. The hypothesis of this project is that surgical and neurodevelopmental outcome varies depending on the underlying mutation.
The specific aims are: 1) Determine the etiology of unicoronal and bicoronal synostosis by mutational analysis. Standard molecular techniques will be applied, patient samples without identifiable mutation will subsequently be further analyzed in Aim 3. 2) Characterize the surgical and neurodevelopmental outcome of patients with craniosynostosis. Outcome will be assessed through annual postoperative examination; developmental and adaptive function will be measured through age appropriate tools. Results will then be analyzed stratified according to the underlying mutation, identified through Aim 1. 3) Identify novel mutations and genes causing craniosynostosis and delineate their phenotype/genotype correlation. Samples with no identified mutation will be further studied using segregation analysis, mutation screening techniques and extended sequencing.
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