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

Area of Science:

• Genetics and rare diseases
• Endocrinology and metabolism
• Pediatric bone disorders

Background:

• Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) involves renal phosphate wasting and potential vascular calcification.
• Phosphate supplementation, a common treatment, may exacerbate calcification risk by increasing the calcium-phosphate product.

Purpose of the Study:

• Expand the known phenotype of ARHR2 and heterozygous ENPP1 variant carriers.
• Evaluate safety concerns associated with phosphate supplementation in ARHR2 patients.

Main Methods:

• Longitudinal follow-up of a pediatric ARHR2 patient over 11 years.
• Assessment of skeletal and extraskeletal manifestations, including response to phosphate supplementation.
• Phenotypic analysis of four heterozygous family members to explore carrier implications.

Main Results:

• A homozygous ENPP1 variant (c.2677G>T, p.(Glu893*)) was identified in the ARHR2 patient.
• The patient developed progressive skeletal symptoms and vascular calcifications after phosphate supplementation.
• Heterozygous family members exhibited mild metabolic alterations, suggesting a potential subclinical phenotype.

Conclusions:

• Accurate genetic diagnosis is crucial for managing ARHR2.
• Phosphate supplementation carries significant vascular calcification risks in ARHR2.
• Future therapies should focus on safe phosphate correction, possibly via combined strategies or enzyme replacement, with essential cardiovascular monitoring.