A Case of Chronic Hypophosphatemia Leading to Identification of a Rare Mutation

Introduction: Hypophosphatemia occurs not infrequently in the inpatient setting. Inherited causes should be suspected when it is accompanied by musculoskeletal symptoms or extra-skeletal calcification. Case Description: A 47-year-old Asian man was referred for evaluation of chronic hypophosphatemia. His history included congenital bilateral conductive hearing loss, congenital hip dysplasia requiring childhood surgery and hip arthroplasty at age 39, and ossification of the posterior longitudinal ligament (OPLL) s/p numerous spinal surgeries since age 38. He had a bicuspid aortic valve with moderate calcification and severe stenosis. His brother also had chronic hypophosphatemia and OPLL requiring spinal surgery. Our patient had asymptomatic chronic mild-moderate hypophosphatemia. Further outpatient work-up revealed renal phosphate wasting (TMP/GFR 1.78 mg/dL, ref: >4.2), normal serum calcium and creatinine, elevated FGF23(129 pg/mL, ref:<59), PTH (111 pg/mL, ref: 25-105) and Alkphos (163 U/L, ref: 40-150)). Genetic testing ultimately identified a novel homozygous mutation in Ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1) c.1437+1G>C (splice donor). Discussion: ENPP1 hydrolyzes extracellular ATP to pyrophosphate, an endogenous inhibitor of hydroxyapatite formation. It regulates soft tissue mineralization and vascular endothelial proliferation, while inhibiting extra-skeletal calcification. ENPP1 deficiency results in phenotypes ranging from generalized arterial calcification of infancy to autosomal recessive hypophosphatemic rickets type 2 (ARHR2), and OPLL. Clinically, ARHR2 resembles the more common X-linked hypophosphatemia (XLH) with FGF23-mediated renal phosphate wasting, but diagnosis is often delayed, and treatment differs significantly: Burosumab, a monoclonal antibody inhibiting FGF23 approved for XLH, can potentially exacerbate extra-skeletal calcification in ARHR2. Recombinant ENPP1-Fc enzyme replacement therapy showed promising results in mouse models of ARHR2 and vascular calcification in CKD, and is being studied in humans with ARHR2 and calciphylaxis. In summary, ARHR2 from ENPP1 deficiency causes significant multi-system morbidities, including hypophosphatemia, musculoskeletal complications like rickets and OPLL, and early-onset vascular calcification. Diagnosis requires high clinical suspicion and prompt genetic testing, and burosumab should be avoided in affected patients.