Molecular genetics and biology of craniofacial craniosynostoses

The craniofacial skeleton is made up of the neurocranium, which encases the brain, and the viscerocranium, which includes the bones of the face and cranial base. At birth, the human craniofacial skeleton is comprised of 44 bones that develop via both endochondral and intramembranous ossification, depending on the bone. Undifferentiated mesenchyme separates the bones for varying periods of postnatal life, playing a key role in regulating cranioskeletal growth. Appositional bone growth at the suture margins is regulated by a complex crosstalk between growth factor signaling pathways, some of which function more prominently in specific sutures. In this chapter, we review the embryology and current understanding of the molecular genetic basis of premature fusions (synostosis) of both the calvarial and facial sutures gleaned from genetic studies in humans and model organisms such as the mouse. In addition, we reassess the spectrum of mutations found in FGFR2, the most prominent factor implicated in craniofacial synostosis, and propose a new model for explaining the impact of many of the common amino acid substitutions that result in pathology. Finally, advancements that promise to enable use of mesenchymal stem cells in tissue engineering-based approaches are discussed with respect to prospects for more effective treatment of these craniofacial conditions.