The developmental bases of cleft lip and cleft palate: cellular and molecular mechanisms

Craniofacial development relies on proper growth and fusion during embryogenesis of initially distinct collections of mesenchyme derived from the cranial neural crest, covered by an epithelial lining of ectodermal origin. Fusion between these facial primordia implicates formation of an epithelial seam resulting from adherence and fusion between lining epithelia, and its subsequent removal to generate mesenchymal continuity. These embryonic processes involve a complex array of morphogenetic events requiring coordinated cell migration, survival, proliferation, death, patterning, adhesion, and differentiation, involving both the mesenchymal core and the primitive epithelial covering. Perturbation of any of these developmental events can lead to orofacial cleft phenotypes. Cleft lip and cleft palate are the most common congenital head deformities and, in general, among the commonest inborn defects. Indeed, due to the complexity of lip and palate development, the possibility of errors is a real event, therefore their relatively elevate frequency is not surprising. Understanding the pathogenesis of these malformations requires a thorough knowledge of the biological mechanisms underlying normal craniofacial embryogenesis and how they can be disturbed during development. An important contribution to our understanding of the fusion processes occurring in the orofacial district has come from studies on the role of the periderm in the adhesion between embryonic structures. This review summarises the normal morphogenesis of the upper lip/primary palate and secondary palate, as well as the mechanisms of aberrant development leading to cleft lip and palate, with particular attention to the role of the periderm, and cellular and molecular aspects of developmental pathogenesis.