Craniosynostosis (also called craniostensosis) results from a premature fusion of the cranial sutures, which consist of fibrous connective tissue that connects the bones of the cranium. Craniosynostosis may occur as an isolated birth defect or as part of a syndrome. The major cranial sutures are the coronal sutures, which separate the frontal and parietal bones; the sagittal suture, which separates the parietal bones; the metopic suture, which separates the frontal bones; and the lambdoid sutures, which separate the parietal and occipital bones. The main functions of these sutures is to facilitate deformation of the skull during passage through the birth canal and to facilitate growth of the cranium to accommodate rapid brain growth during early childhood. Typically, cranial sutures close in early adulthood with the exception of the metopic suture, which closes in early childhood. Craniosynostosis may affect 1 or more of these sutures, and premature fusion of these sutures can have a host of consequences including increased risk for raised intracranial pressure, abnormal cranial shape, and distortion of craniofacial structures, which may affect breathing patterns, vision, and hearing. Moreover, syndromic forms of craniosynostosis may be characterized by other skeletal abnormalities and involvement of other organ systems.
PATHOGENESIS AND EPIDEMIOLOGY
Craniosynostosis affects approximately 1 in 2000 to 1 in 2500 live births, and the sagittal suture is the most common suture involved. Craniosynostosis may occur in isolation (“nonsyndromic forms”) or within the context of a genetic syndrome (“syndromic form”). Nonsyndromic forms account for about 75% of cases, and these nonsyndromic forms may have genetic and/or environmental causes. Known environmental risk factors include teratogens (eg, valproic acid or methotrexate) and factors that constrain the growth of the developing fetus (eg, multiparity and macrosomia). In the nonsyndromic forms, genetic factors are more likely to contribute to isolated bilateral or unilateral coronal craniosynostosis as compared to other sutures. A recent study has implicated a 2-locus model (eg, variants in SMAD6 and BMP2) to explain a subset of nonsyndromic midline craniosynostosis. Approximately 15% of craniosynostosis occurs in the setting of 1 of more than 150 recognizable genetic syndromes. Pathogenic variants in over 50 genes have been associated with either nonsyndromic or syndromic forms of craniosynostosis. The most common syndromic forms are caused by pathogenic variants in FGFR1, FGFR2, FGFR3, and TWIST. Although autosomal dominant inheritance is the most common pattern observed in genetic forms of craniosynostosis (eg, FGFR1, FGFR2, FGFR3), autosomal recessive and X-linked forms (eg, EFNB1) exist. When inherited, many of these syndromic forms of craniosynostosis are associated with reduced penetrance and/or variable expressivity within families.
Craniosynostosis results in a failure of growth in the plane perpendicular to the prematurely fused suture, and to accommodate, excessive growth occurs in the plane parallel to the prematurely fused suture. This abnormal growth leads to recognizable patterns of skull growth that allows for ...