Vertebrate skeletogenesis is a unique and complex process, consisting of creating a structure with more than two hundred pieces of bone and cartilage. This process is particularly important in the head, whereby an assortment of neural crest and mesoderm derived cartilages and bones give rise to the cranial and facial components of the skull, thus creating a customised body frame that is essential for protecting the brain as well as fixing the position of all facial features.
Just as with any mechanism, craniofacial skeletogenesis can be disrupted, leading to compromised structural function and mental wellbeing of the affected individual. Apart from the psychological strain sustained on individuals with facial deformities, the inadequate accommodation of the brain due to restricted development of the cranium could lead to a compromised mental function or even death (Padmanabhan et al. 2011). Despite our increased understanding of the means by which certain gene disturbances can cause cranial skeletal abnormalities, there continues to be a therapeutic and diagnostic challenge in dealing with abnormalities stemming from cranial malformations.
Crouzon syndrome is a manifestation of such abnormalities; first described by a French neurosurgeon Octave Crouzon in 1912, it is known as an autosomal dominant genetic disorder with high penetrance and variable expressivity (Dahl 1976; Rutland et al. 1995). Genetic studies concerning this syndrome have identified numerous mutations in fibroblast growth factor receptors (FGFR), amongst which, mutations in FGFR2 are thought to be the key causative factor in this disorder (Fries & Katowitz 1990). Notably, non-familial cases comprise approximately 30% of all cases of Crouzon syndrome.
With an incidence of 1 in 25,000 live births (Cohen et al. 1988), this syndrome is characterised by the premature fusion of the coronal sutures, and in some case other sutures (sagittal) of the cranium (Prasad et al. 2013). Sutures are strong fibrous bands of tissue that connect the bones of the skull to one another. During infancy, the patency of the sutures are important for optimum brain growth. However, the premature fusion of sutures, leads to restricted growth potential of the calvarial bones, giving rise to various deformities (Fig. 1).
Abnormalities in Crouzon syndrome exacerbate with growth. The premature cranial fusion often extend to the skull base giving rise to the characteristic exophthalmos (shallow orbits), midfacial and maxillary hypoplasia (Hlongwa 2009). In addition, Crouzon patients may present with intra oral indicators, such as mandibular prognathism (outward projecting jaw) and palatine abnormalities. Together, cranial, facial and intraoral abnormalities result in an increasing disparity in the facial appearance of Crouzon patients, with the possibility of adversely affecting the surrounding neurological circuitries including the optic nerve (Gorlin et al. 1990). Rarely, patients show neural tube defect such as spina bifida, although it is unclear whether this is associated with the syndrome (Rekate 1993).
Figure 1 | Diagrammatical representation of normal sutures in the skull (A), skull with sagittal synostosis (B), and skull with coronal synostosis (C). Sagittal suture synostosis results in elongation of the head anteroposteriorly; the opposite is true for coronal suture synostosis where there is widening of the coronal dimension and shortening of the antero-posterior extent of the head (Adapted from Swenker & Uijl 2010).
The hallmark feature of Crouzon syndrome is craniosynostosis; this condition involves the premature ossification of one or more of the fibrous sutures in the infant’s skull leading to a change in the growth pattern of this structure (Fig. 1)(Slater et al. 2008). This change involves the compensatory growth of the skull in the direction parallel to the closed suture, rather than a perpendicular growth due to the restriction nature of the fused suture. This compensation may or may not be effective in providing the necessary space for the growing brain; regardless of its effectiveness, all patients display abnormal head shape and disparity in their facial features. In cases where this compensation is not effective in allowing for adequate brain growth, craniosynostosis leads to increased intracranial pressure, where apart from the significant mortality rate associated with it, it also poses a risk to the mental and visual development of the patient as well as causing sleeping and eating impairments (Gault et al. 1992).
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