New insights into craniofacial malformations

Abstract

Development of the human skull and face is a highly orchestrated and complex three-dimensional morphogenetic process, involving hundreds of genes controlling the coordinated patterning, proliferation and differentiation of tissues having multiple embryological origins. Craniofacial malformations that occur because of abnormal development (including cleft lip and/or palate, craniosynostosis and facial dysostoses), comprise over one-third of all congenital birth defects. High-throughput sequencing has recently led to the identification of many new causative disease genes and functional studies have clarified their mechanisms of action. We present recent findings in craniofacial genetics and discuss how this information together with developmental studies in animal models is helping to increase understanding of normal craniofacial development.

Figure 1.

Development of the head and face and recently identified craniofacial genes. An embryo is shown on the left, the arrows represent the patterns of migration of diencephalic (di), anterior and posterior mesencephalic (mes), and rhombencephalic (r1–4) NCCs into the FNP and pharyngeal arches 1 and 2 (PA1, PA2). The dashed arrow indicates movement of mesoderm-derived MSCs to the supra-orbital regulatory centre above the eye. Neural crest-derived craniofacial regions formed from the FNP and PA1 are indicated with the same colours on the head (right). The parietal and occipital bones are mesoderm-derived (pink). The coronal suture contains purely mesoderm-derived cells (red) that have expanded apically from the supra-orbital region. Centrally, the genes discussed in this review are shown, with the embryological site underlying pathogenesis (if known—boxed genes), and the structures affected by mutation, indicated.

Figure 2.

Irf6 regulation and pathways. Interactions involving Irf6 discussed in this review are shown. Sonic hedgehog has a role in correct fusion at the lambdoidal junction through modulation of Wnt signalling and Tfap2a upstream of Irf6 expression (38). A CLP associated SNP (rs642961) and mutation (dupA) within the Irf6 regulatory element MCS9.7 affect expression of Irf6 by disrupting binding of AP-2α (40) and p63 (32), respectively. The dupA mutation also creates a Tcf4/Lef1 binding site. Irf6 regulates expression of both Ripk4 (35), a kinase that can phosphorylate Irf6 (33,34), and Grhl3 (42) in periderm development (9,41).