Craniofacial development is a complex process involving several signaling pathways, including the one regulated by the TGF-beta (TGF-β) superfamily of growth factors. Isoforms of TGF-β play a vital part in embryonic development, notably in craniofacial patterning. Consequently, pathogenic variants in their coding genes may result in a variety of orofacial and craniofacial malformations. Here, we review the impact of genetic variability of TGF-β signaling biomarkers in major disorders, including palatal and lip clefts, dental anomalies, and craniofacial syndromes, such as the Loeys-Dietz syndrome (LDS) and Camurati-Engelmann disease. Cleft lip and cleft palate are associated with missense mutations in the TGFB1 and TGFB3 genes, while mutations in the LTBP3 gene encoding TGF-β binding protein 3 may cause selective tooth agenesis. Oligodontia may also be caused by TGFB1-inactivating mutations and/or by variations in the GREM2 gene, which disrupt the activity of gremlin 2, a TGF-β/bone morphogenetic protein (BMP4) signaling antagonist. CED may be caused by mutations in the TGFB1 gene, while the TGF-β-related genetic background of LDS consists mostly of TGFBR1 and TGFBR2 mutations, which may also impact the above syndromes' vascular manifestations. The potential utility of the TGF-β signaling pathway factors as biomarkers that correlate genetics with clinical outcome of craniofacial malformations is discussed.
Keywords: BMP; Cleft lip; Cleft palate; Craniofacial defects; Loeys-Dietz syndrome; Orofacial genetics; SMAD; TGF-β; Tooth agenesis.
© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.