A Genetic-Pathophysiological Framework for Craniosynostosis

Abstract

Craniosynostosis, the premature fusion of one or more cranial sutures of the skull, provides a paradigm for investigating the interplay of genetic and environmental factors leading to malformation. Over the past 20 years molecular genetic techniques have provided a new approach to dissect the underlying causes; success has mostly come from investigation of clinical samples, and recent advances in high-throughput DNA sequencing have dramatically enhanced the study of the human as the preferred "model organism." In parallel, however, we need a pathogenetic classification to describe the pathways and processes that lead to cranial suture fusion. Given the prenatal onset of most craniosynostosis, investigation of mechanisms requires more conventional model organisms; principally the mouse, because of similarities in cranial suture development. We present a framework for classifying genetic causes of craniosynostosis based on current understanding of cranial suture biology and molecular and developmental pathogenesis. Of note, few pathologies result from complete loss of gene function. Instead, biochemical mechanisms involving haploinsufficiency, dominant gain-of-function and recessive hypomorphic mutations, and an unusual X-linked cellular interference process have all been implicated. Although few of the genes involved could have been predicted based on expression patterns alone (because the genes play much wider roles in embryonic development or cellular homeostasis), we argue that they fit into a limited number of functional modules active at different stages of cranial suture development. This provides a useful approach both when defining the potential role of new candidate genes in craniosynostosis and, potentially, for devising pharmacological approaches to therapy.

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

“…The evidence supporting this conclusion is extremely strong with highly significant P values along with very strong prior biological support of the role of these pathways in craniosynostosis (1,5). These findings provide strong genetic evidence linking the biology underlying non-syndromic and syndromic forms of craniosynostosis.…”

“…As discussed above, mutations that cause rare syndromic forms of craniosynostosis in humans and in mouse cluster in developmental signaling pathways that converge on promotion of osteoblast differentiation and bone formation (5). These are encompassed by the Ras/ERK, Wnt, BMP, hedgehog, ephrin, STAT, and retinoic acid signaling pathways (5).…”

“…Many genes have been implicated in human syndromic craniosynostoses, with at least 40 showing significant statistical support or having been identified in more than one study (5). Many genes have also been implicated by studies of mouse genetics (4,(6)(7)(8)(9).…”

“…These genes are involved in signaling pathways that converge on promotion of osteoblast differentiation and bone formation. The most prominent of these are the Ras/ERK, bone morphogenetic protein (BMP), and Wnt pathways, with ephrin, smoothened/hedgehog, STAT, and retinoic acid signaling pathways being implicated at lower frequency (5). Examples include gain-of-function (GOF) mutations in FGF receptors 1-3, which present with craniosynostosis of any or all sutures with variable hypertelorism, proptosis, midface abnormalities, and syndactyly, and loss-of-function (LOF) mutations in TGFBR1/2 that present with craniosynostosis in conjunction with severe cardiac/vascular abnormalities and other extracranial defects.…”

Activation of the IGF1 pathway mediates changes in cellular contractility and motility in single-suture craniosynostosis

“…Craniosynostosis divides into syndromic and non-syndromic forms, with syndromic forms defined as those with recognizable patterns of craniofacial and non-craniofacial malformations. A number of mutations are associated with syndromic craniosynostosis (Fitzpatrick, 2013;Sharma et al, 2013;Twigg et al, 2013;Twigg and Wilkie, 2015). However, the biological basis for the majority of cases of non-syndromic singlesuture craniosynostosis (SSC) remains unknown.…”