Closing the Gap: Genetic and Genomic Continuum from Syndromic to Nonsyndromic Craniosynostoses

Abstract

Craniosynostosis, a condition that includes the premature fusion of one or multiple cranial sutures, is a relatively common birth defect in humans and the second most common craniofacial anomaly after orofacial clefts. There is a significant clinical variation among different sutural synostoses as well as significant variation within any given single-suture synostosis. Craniosynostosis can be isolated (i.e., nonsyndromic) or occurs as part of a genetic syndrome (e.g., Crouzon, Pfeiffer, Apert, Muenke, and Saethre-Chotzen syndromes). Approximately 85 % of all cases of craniosynostosis are nonsyndromic. Several recent genomic discoveries are elucidating the genetic basis for nonsyndromic cases and implicate the newly identified genes in signaling pathways previously found in syndromic craniosynostosis. Published epidemiologic and phenotypic studies clearly demonstrate that nonsyndromic craniosynostosis is a complex and heterogeneous condition supporting a strong genetic component accompanied by environmental factors that contribute to the pathogenetic network of this birth defect. Large population, rather than single-clinic or hospital-based studies is required with phenotypically homogeneous subsets of patients to further understand the complex genetic, maternal, environmental, and stochastic factors contributing to nonsyndromic craniosynostosis. Learning about these variables is a key in formulating the basis of multidisciplinary and lifelong care for patients with these conditions.

Keywords: Coronal synostosis; Craniosynostosis; Genome wide association study; Sagittal synostosis; Suture; Whole exome sequencing.

Fig. 1

Variation in cranial vault shape depicted by three-dimensional computed tomography (CT) reconstructions of infants with various types of single-suture craniosynostosis (superior and inferior (i.e., ectocranial) views; anterior aspect of skull at top, posterior aspect of skull at bottom). Those pictured are cases of single-suture craniosynostosis from our archive of 3D CT images and include skulls of infants with a sagittal craniosynostosis; b bicoronal, right unicoronal, and left unicoronal craniosynostoses (from top to bottom); c metopic craniosynostosis; d bilateral, right unilateral, and left unilateral lambdoidal craniosynostoses (from top to bottom); e unaffected individual. The black arrow heads indicate the sutures that are prematurely closed. Though most attention has been focused on cranial vault shape, the cranial base and facial skeleton are also dysmorphic in craniosynostosis conditions. Not to scale