Autosomal recessive hypophosphatemic rickets type 2 (ARHR2): Is phosphate supplementation safe?

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is an ultra-rare disorder characterized by renal phosphate wasting and patients may exhibit an increased risk of vascular calcification. Phosphate supplementation, a standard treatment for hypophosphatemic rickets, may further increase this risk by elevating the calcium-phosphate product.

To expand the phenotypic spectrum of ARHR2 and heterozygous ENPP1 variant carriers and to review safety concerns related to phosphate supplementation in affected individuals.

We describe an 11-year follow-up of a pediatric patient with ARHR2, focusing on skeletal and extraskeletal manifestations, particularly the response to a brief period of phosphate supplementation. Additionally, we present a phenotypic analysis of four heterozygous family members, highlighting potential implications of carrier status.

The patient was homozygous for the ENPP1 variant c.2677G > T, p.(Glu893*), exhibited progressive skeletal symptoms, and developed vascular calcifications following phosphate supplementation. Heterozygous family members showed mild alterations in bone and phosphate metabolism, suggesting a possible subclinical phenotype.

This case highlights the complexity of ARHR2 management, the importance of accurate genetic diagnosis, and concerns regarding the safety of phosphate supplementation. Close cardiovascular monitoring is essential, and future therapies should aim to correct phosphate imbalance without increasing calcification risk-potentially through combined treatment strategies or enzyme replacement therapy.