Progress toward understanding craniofacial malformations

Significant advances in the study of the human face have revealed the genet ic and gene-environment bases of numerous common and rare craniofacial diso rders. Classification of craniofacial malformations based on clinical pheno types is sometimes quite different from the genetic findings of patients. D ifferent mutations in a single gene can cause distinct syndromes, and mutat ions in different genes can cause the same syndrome. The extracellular sign aling molecule SHH, fibroblast growth factor receptors, and transcription f actors GLI3, MSX2, and TWIST are discussed as examples of molecules involve d in interrelated signal transduction networks regulating craniofacial deve lopment. Progress in the understanding of normal and abnormal craniofacial development, through the study of morphoregulatory signaling pathways, has benefited from multifactorial approaches recommended 40 years ago at the Na tional Institute of Dental Research-sponsored landmark Gatlinburg Conferenc e. The utilization of biochemistry, protein structure analyses, tissue cult ure, and animal model systems for developmental genetics has resulted in re markable scientific advances. The evolutionary conservation of morphoregula tory pathways has revealed the homology of genes associated with human cran iofacial malformations and their counterparts that regulate the morphogenes is of fruit flies. The continued investments in basic, translational, and p atient-oriented research regarding normal and abnormal craniofacial develop ment will translate into substantial improvements in the prevention, diagno sis, and treatment of craniofacial diseases and disorders.