Genetics of craniofacial development and malformation

Embryology, evolution and mouse genetics are shaping our understanding of the development of the head — the most anatomically sophisticated part of the body — and are shedding light on human craniofacial disorders. Human craniofacial disorders arise owing to alterations to specific embryological processes, such as to brain patterning, cell migration, tissue fusion and bone differentiation. The major craniofacial disorders fall into several categories, according to their pattern of malformations, and include: holoprosencephaly, cleft lip and palate, skull vault malformations (such as craniosynostosis), and malformations of the first and second branchial arches, which underlie branchio-oto-renal and Treacher Collins syndromes. Loss-of-function mouse mutants are identifying the types of genes that underlie these categories of malformation and are providing functional insights into the genes that are required for normal craniofacial development. The classes of genes that underlie these disorders range from transcription factors and signalling molecules, the loss of which cause distinct patterning defects, to genes that are required for cell migration and cell proliferation. The most common mechanism that gives rise to craniofacial defects in mice and humans is haploinsufficieny, although gain-of-function mutations in the fibroblast growth factor receptor genes underlie most human craniosynostosis syndromes, such as Apert and Pfeiffer syndromes. Studies of craniofacial malformations show that they often arise from subtle alterations in cell division in the cranial mesenchyme rather than from basic patterning defects. This finding is likely to make it very difficult to identify the genetic determinants of normal variation in facial appearance.