Insights into the development of molecular therapies for craniosynostosis

Abstract

<jats:p>For the past 2 decades, clinical and basic science researchers have gained significant insights into the molecular and genetic pathways associated with common forms of craniosynostosis. This has led to invaluable information for families and physicians in their attempts to understand the heterogeneity of craniosynostosis. Genetic mutations have been identified in the fibroblast growth factor receptors (FGFRs) as well as in other targets, including TWIST1, BMP, and RUNX2. Greater understanding of these and other pathways has led to the development of innovative approaches for applying medical therapies to the treatment of craniosynostosis, in particular by maintaining suture patency. In this article, the authors discuss the molecular pathophysiological mechanisms underlying various forms of craniosynostosis. They also highlight recent developments in the field of molecular craniosynostosis research with the hope of identifying targets for medical therapies that might augment the results of surgical intervention.</jats:p>

Clinical genetics of craniosynostosis

“…Importantly, markers are now becoming available to mark murine sutural cells at different stages of differentiation including Gli1 [58], Prrx1 [59] and Axin2 [60*]. A detailed understanding of the complex processes underlying normal sutural homeostasis may eventually lead to medical preventions or therapies for craniosynostosis [61]. For the time being, however, surgery continues to be the mainstay of treatment, although lack of consensus about timing and surgical approaches remains a persisting issue in this field [62].…”

Craniosynostosis - Recognition, clinical characteristics, and treatment

“…To date, mutations in 57 genes have been identified as an underlying cause of craniosynostosis. These genes and transcription factors are fundamental in the skull morphogenesis and, among others, include the FGFR genes, TWIST, MSX2, bone morphogenetic protein (BMP) genes, TGFB2, ERF of ETS transcription factor family, RUNX2, EFNB1, FAM20C, and LMX1B gene [40][41][42][43].…”

A Higher Proportion of Craniosynostosis Genes Are Cancer Driver Genes

“…The involvement of FGF (fibroblast growth factor), FGFR (fibroblast growth factor receptor), and MAPK/ERK signaling pathways in CRS has long been discussed in the literature (Marie et al, 2005; Shukla et al, 2007; Kim et al, 2015; Kosty and Vogel, 2015; Pfaff et al, 2016; Timberlake et al, 2017). However, our top hit gene-set is KEGG’s cancer pathway, and this link between CRS and cancer is to our knowledge rarely discussed in the literature.…”