Iatrogenic Pan-Craniosynostosis Due to Alkaline Phosphatase Enzyme Replacement Therapy Using Asfotase Alfa for Hypophosphatasia

Hypophosphatasia is a relatively rare congenital bone metabolic disease, occurring in approximately 1 in 100,000 to 150,000 births. It is diagnosed in infancy by low bone calcification, rickets-like symptoms visible on X-ray, and decreased serum alkaline phosphatase (ALP) levels in the blood. Prognosis varies by type, and while treatment has not been long established, ALP enzyme replacement therapy has been developed and has achieved improved outcomes since 2015. Pan-craniosynostosis, as an unfavorable side effect of this symptomatic therapy, is not well known even among experienced craniofacial surgeons, likely because it is often regarded as part of the bone transformation process, especially when the unusual discrepancy between a hard cranium and fragile limb bones is observed, or is overlooked due to poor prognosis. The author's purpose is to present rare experiences of two cases of pan-craniosynostosis considered to be iatrogenic after the therapy for hypophosphatasia. Some reports in Japan indicate that this iatrogenic complication may appear in 15.3% of cases after treatment. As craniofacial surgeons, we need to recognize this causal relationship between hypophosphatasia treatment and craniosynostosis.