Craniofacial development involves several complex tissue movements including several fusion processes to form the frontonasal and maxillary structures, including the upper lip and palate. Each of these movements are controlled by many different factors that are tightly regulated by several integral morphogenetic signaling pathways. Subject to both genetic and environmental influences, interruption at nearly any stage can disrupt lip, nasal, or palate fusion and result in a cleft. Here, we discuss many of the genetic risk factors that may contribute to the presentation of orofacial clefts in patients, and several of the key signaling pathways and underlying cellular mechanisms that control lip and palate formation, as identified primarily through investigating equivalent processes in animal models, are examined.

During craniofacial development, defective growth and fusion of the upper lip and/or palate can cause orofacial clefts (OFCs), which are among the most common structural birth defects in humans. The developmental basis of OFCs includes morphogenesis of the upper lip, primary palate, secondary palate, and other orofacial structures, each consisting of diverse cell types originating from all three germ layers: the ectoderm, mesoderm, and endoderm. Cranial neural crest cells and orofacial epithelial cells are two major cell types that interact with various cell lineages and play key roles in orofacial development. The cellular basis of OFCs involves defective execution in any one or several of the following processes: neural crest induction, epithelial‐mesenchymal transition, migration, proliferation, differentiation, apoptosis, primary cilia formation and its signaling transduction, epithelial seam formation and disappearance, periderm formation and peeling, convergence and extrusion of palatal epithelial seam cells, cell adhesion, cytoskeleton dynamics, and extracellular matrix function. The latest cellular and developmental findings may provide a basis for better understanding of the underlying genetic, epigenetic, environmental, and molecular mechanisms of OFCs.

Orofacial clefts (OFCs) are among the most common birth defects and impart a significant burden on afflicted individuals and their families. It is increasingly understood that many nonsyndromic OFCs are a consequence of extrinsic factors, genetic susceptibilities, and interactions of the two. Therefore, understanding the environmental mechanisms of OFCs is important in the prevention of future cases. This review examines the molecular mechanisms associated with environmental factors that either protect against or increase the risk of OFCs. We focus on essential metabolic pathways, environmental signaling mechanisms, detoxification pathways, behavioral risk factors, and biological hazards that may disrupt orofacial development.