ESPE Yearbook of Paediatric Endocrinology

In Brief: Autosomal recessive hypophosphatemic rickets type 1 (ARHR1) is caused by inactivating pathogenic variants in the DMP1 gene. Fibroblast growth factor 23 (FGF23) concentration is elevated, which causes hypophosphatemic rickets. This study showed benefits of burosumab (Crysvita), a humanized monoclonal antibody to FGF23, on biochemical and clinical outcomes in two patients with ARHR1.

Commentary: ARHRs are rare, heritable renal phosphate-wasting disorders that arise from overexpression of the bone-derived phosphaturic hormone FGF23 leading to impaired bone mineralization (rickets and osteomalacia). Inactivating mutations in Dentin matrix protein 1 (DMP1) give rise to ARHR type 1 (ARHR1). Short stature, prominent bowing of the legs, fractures/pseudofractures, and severe enthesopathy are prominent in this patient population. Traditionally, treatment consists of oral phosphate replacement and calcitriol, but this approach is limited by modest efficacy and potential renal and gastrointestinal side effects.

The advent of burosumab (Crysvita), a fully humanized monoclonal antibody to FGF23, to treat X-linked hypophosphatemia and tumour-induced osteomalacia, offers a unique opportunity to evaluate its safety and efficacy in patients with ARHR1. This study reports monthly administration of burosumab to two brothers (age 42 and 52 years old) affected by ARHR1, resulting in normalized serum phosphate, pseudofracture healing, diminished fatigue, less bone pain, and reduced incapacity arising from the extensive enthesopathy and soft tissue fibrosis/calcification that characterizes this disorder. No adverse effects were reported.

This report highlights the beneficial biochemical and clinical outcomes of burosumab in patients with ARHR1. A multicenter cohort study is needed to fully assess its safety and long-term efficacy in this patient population, albeit the rarity of this disorder will undoubtedly pose a major obstacle to such an endeavour.