Coronal Craniosynostosis

GENESIS

Coronal craniosynostosis is the second most common type of craniosynostosis, accounting for 20–30% of cases. Constraint-induced unilateral coronal craniosynostosis can be secondary to early descent of the fetal head into a constraining pelvis, aberrant fetal lie, or constraint within a bicornuate uterus. It is known that the majority (67–71%) of unilateral coronal craniosynostosis is right-sided, and this nonrandom predilection may relate to the fact that 67% of vertex presentations are in the left occiput transverse position, with the left coronal suture against the sacral prominence. If the fetal head descends early and is maintained in the most common position (i.e., left occiput transverse), the result may be more constraint across the right coronal suture as it lies against the pubic bone compared with the left coronal suture as it lies against the sacral prominence. This may explain the increased prevalence of right-sided, unilateral coronal craniosynostosis. Nonsyndromic coronal craniosynostosis occurs in 0.94 per 10,000 births, with 61% of cases sporadic and 14.4% of 180 pedigrees familial. Bilateral cases occur much more frequently than unilateral cases, and coronal synostosis is more common in females (male:female ratio, 1:2). The paternal age is significantly older than average (32.7 years), with an average paternal age of 26 to 27 years and the advent of testicular aging at 30 years of age. Most sperm banks discourage donors over 40 years of age. These data have been interpreted as being consistent with autosomal dominant inheritance, with 60% penetrance when the synostosis has a genetic basis.

Defects in postmigratory neural crest cells can result in pre- or postossification defects in the developing craniofacial skeleton and craniosynostosis. When craniosynostosis occurs as part of a syndrome, it is most important to examine the patient carefully for associated anomalies. Evaluation of the limbs, ears, eyes, and cardiovascular system yields the most significant data for diagnosing syndromes associated with craniosynostosis. Limb defects such as syndactyly, brachydactyly, or broad, deviated thumbs and halluces suggest the presence of an associated syndrome. It is also important to examine both parents for digital anomalies, carpal coalition, and/or facial asymmetry because these findings may represent variable expression of an altered gene in a parent.

Bilateral coronal synostosis often lacks sutural ridging and usually has a genetic basis, which suggests that all such patients should be screened for mutations. Among 57 patients with bilateral coronal synostosis, mutations were found in fibroblast growth factor receptor ( FRGR ) genes for all 38 patients who had a syndromic form of craniosynostosis. Among 19 patients with unclassified brachycephaly, mutations in or near exon 9 of FGFR2 were found in four patients, and a common Pro250Arg mutation in exon 7 of FGFR3 was detected in 10 patients. Only five patients (9%) manifested brachycephaly without a detectable mutation in FGFR1 , 2 , or 3 . In a study of 233 individuals, whose previous testing had not identified a causative variant within FGFR1–3 or TWIST1 , pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of ~15% and variants most frequently identified in TCF12 and EFNB1 . These findings suggest that mutation analysis of FGFR1–3 , TWIST1 , TCF12 , and EFNB1 genes should be considered in all patients with coronal synostosis. Tooze et al. describe the expansion and diagnostic yield of gene panels in craniosynostosis.

It is also important to obtain hand and foot radiographs in older children and their parents, because subtle digital changes and carpal/tarsal coalition can be seen in individuals with the Pro250Arg mutation in FGFR3 , even if they lack findings of coronal craniosynostosis. An estimated 10% of patients with unilateral coronal synostosis carry this mutation; some parents carry this mutation but demonstrate few clinical manifestations. In a prospective study of 47 patients with synostotic frontal plagiocephaly (unilateral coronal synostosis), mutations were found in eight patients (17%): two with FGFR2 , three with FGFR3 Pro250Arg, and three with TWIST mutations. Two clinical features were strongly associated with mutation detection: (1) asymmetric brachycephaly with retrusion of both orbital rims; and (2) orbital hypertelorism. More recently, a study by Sharma et al. of 28 bicoronal and 115 unicoronal craniosynostosis cases found a TCF12 gene mutation in 32% of bilateral and 10% of unicoronal cases. In addition, several patients were carriers of a mutation but did not express signs of craniosynostosis. It is also important to emphasize that inability to demonstrate a mutation does not rule out a genetic cause for the craniosynostosis, and not every person with a mutation manifests craniosynostosis.