Craniosynostosis among children with X-linked hypophosphatemia: A systematic review and meta-analysis

Abstract

Background

X-linked hypophosphatemia (XLH) is a rare genetic disorder caused by PHEX gene variants, leading to elevated FGF23 levels and impaired phosphate reabsorption, resulting in abnormal bone growth. Skull abnormalities, including craniosynostosis, are often reported in children with XLH, but the true prevalence of craniosynostosis among children with XLH is unknown.

Methods

We performed a systematic review and meta-analysis to estimate craniosynostosis prevalence in children with XLH. We searched PubMed, Embase, and Web of Science for cohort studies or large case series published before June 2024. Eligible studies included at least ten children with XLH and reported craniosynostosis prevalence without selection based on skull abnormalities. Pooled prevalence was calculated using a random-effects model, with heterogeneity assessed.

Results

Of 517 studies initially identified, ten studies with 461 patients met the criteria for inclusion. The pooled prevalence of craniosynostosis among children with XLH was 22 % (95 % confidence interval (CI) 9.0 % to 44 %) with significant heterogeneity across studies (I² = 88.5 %, p < 0.01). This prevalence is far greater than the prevalence of craniosynostosis in the general pediatric population, which is estimated to be one in 2100–2500 births. We confirmed an expected female predominance among children with XLH (median 65.9 % female, interquartile range [IQR] 53.7 % to 68.4 %) but not among children with XLH and craniosynostosis (median 42 % female, range 21 % to 48 %).

Conclusion

Craniosynostosis is more common among children with XLH compared to the general pediatric population and may be disproportionately common among males. Increased vigilance for craniosynostosis is warranted for children with XLH.