Facing up to the challenges of advancing Craniofacial Research

Abstract

Craniofacial anomalies are among the most common human birth defects and have considerable functional, aesthetic, and social consequences. The early developmental origin as well as the anatomical complexity of the head and face render these tissues prone to genetic and environmental insult. The establishment of craniofacial clinics offering comprehensive care for craniofacial patients at a single site together with international research networks focused on the origins and treatment of craniofacial disorders has led to tremendous advances in our understanding of the etiology and pathogenesis of congenital craniofacial anomalies. However, the genetic, environmental, and developmental sources of many craniofacial disorders remain unknown. To overcome this problem and further advance craniofacial research, we must recognize current challenges in the field and establish priority areas for study. We still need (i) a deeper understanding of variation during normal development and within the context of any disorder, (ii) improved genotyping and phenotyping and understanding of the impact of epigenetics, (iii) continued development of animal models and functional analyses of genes and variants, and (iv) integration of patient derived cells and tissues together with 3D printing and quantitative assessment of surgical outcomes for improved practice. Only with fundamental advances in each of these areas will we be able to meet the challenge of translating potential therapeutic and preventative approaches into clinical solutions and reduce the financial and emotional burden of craniofacial anomalies.

Rare syndromes of the head and face: mandibulofacial and acrofacial dysostoses

“…Careful phenotypic and genotypic analysis is clinically necessary in advancing treatment, personalized care, and most importantly prevention of these congenital diseases. Although many facial dysostoses present with similar and overlapping phenotypes, their etiology, developmental history, and genetics may require different treatment regimes . For example, although mutations in either Tcof1 , Polr1c , or Polr1d lead to TCS, successful treatment and/or prevention may depend on the specific underlying genetic mutation.…”

“…For example, although mutations in either Tcof1 , Polr1c , or Polr1d lead to TCS, successful treatment and/or prevention may depend on the specific underlying genetic mutation. A thorough understanding of the distinct signals, switches and mechanisms which regulate both, normal development and disease is still needed …”

“…Although many facial dysostoses present with similar and overlapping phenotypes, their etiology, developmental history, and genetics may require different treatment regimes. 93 For example, although mutations in either Tcof1, Polr1c, or Polr1d lead to TCS, successful treatment and/or prevention may depend on the specific underlying genetic mutation. A thorough understanding of the distinct signals, switches and mechanisms which regulate both, normal development and disease is still needed.…”

Nonlinear gene expression‐phenotype relationships contribute to variation and clefting in the A/WySn mouse

“…While group‐level analysis may be sufficient for understanding how fully penetrant phenotypes develop, most birth defects have some amount of variable penetrance . Lack of understanding of the variation within craniofacial disease has been identified as a challenge to overcome within the field . Developing precision medicine requires having an understanding of the trajectory of disease development in an individual .…”

“…[38][39][40] Lack of understanding of the variation within craniofacial disease has been identified as a challenge to overcome within the field. 41 Developing precision medicine requires having an understanding of the trajectory of disease development in an individual. 8 In order to reach that goal, we must understand how each individual differs from the population and how these partially penetrant traits arise.…”