Genetic advances in craniosynostosis

Abstract

Craniosynostosis, the premature ossification of one or more skull sutures, is a clinically and genetically heterogeneous congenital anomaly affecting approximately one in 2,500 live births. In most cases, it occurs as an isolated congenital anomaly, that is, nonsyndromic craniosynostosis (NCS), the genetic, and environmental causes of which remain largely unknown. Recent data suggest that, at least some of the midline NCS cases may be explained by two loci inheritance. In approximately 25-30% of patients, craniosynostosis presents as a feature of a genetic syndrome due to chromosomal defects or mutations in genes within interconnected signaling pathways. The aim of this review is to provide a detailed and comprehensive update on the genetic and environmental factors associated with NCS, integrating the scientific findings achieved during the last decade. Focus on the neurodevelopmental, imaging, and treatment aspects of NCS is also provided.

Keywords: craniofacial; craniosynostosis; gene mutations; malformation; skull sutures.

Figure 1

Craniofacial features and three-dimensional computed tomography images of individuals with craniosynostosis. (A–C) Nonsyndromic sagittal craniosynostosis. (D–F) Nonsyndromic metopic craniosynostosis. (G–I) Nonsyndromic unilateral right coronal craniosynostosis. (J–L) Nonsyndromic bilateral coronal craniosynostosis. (M–O) Nonsyndromic unilateral left lambdoid craniosynostosis. (P–R) Nonsyndromic bilateral lambdoid craniosynostosis. (S–W) Images of individuals with Muenke syndrome demonstrate extreme clinical variability and overlap of the milder cases with nonsyndromic coronal craniosynostosis. (X) Mild case of Saethre-Chotzen syndrome resembles unicoronal craniosynostosis. The images on the bottom row demonstrate the need of molecular testing of the coronal cases for proper diagnosis.

Figure 2. Craniosynostosis gene network

The diagram shows known and predicted interactions among candidate genes implicated in the etiopathogenesis of craniosynostosis, discussed in the different sections (see text for details). The network was drawn using String (version 10.0) license-free software (http://string-db.org/), using the “molecular action” display format. Rounded nodes refer to gene/protein symbol included in the query; small nodes are for proteins with unknown 3D structure, while large nodes are for those with known structures. The lines connecting nodes represent the most relevant and best characterized types of protein-protein association within the networking genes, according to the following color codes: green = activation, red = inhibition, blue = binding, violet= catalysis, pink= post-translation modification, black= reaction, yellow= transcriptional regulation. Grey lines symbolize predicted links based on literature search (i.e. genes/proteins are co-mentioned in PubMed abstracts). Thicker lines represent stronger associations between proteins. The line ending shape represents the effect (whenever applicable) of the molecular action: arrow end= positive, transverse line end= negative, ball end= unspecified. The interactions were automatically integrated in the network by the software, with the medium confidence value set at 0.0400 (i.e. a 40% probability that a predicted link exists between two enzymes in the same metabolic map in the KEGG database: http://www.genome.jp/kegg/pathway.html). Additional interactions among ERF, RUNX2, FGFR1-3, GLI3 and BMP2, were added manually, given their functional implication in the molecular background described in this review.