Chronic hypophosphatemia leading to the diagnosis of autosomal recessive hypophosphatemic rickets type 2 caused by a novel pathogenic variant in ENPP1.

Abstract

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a rare metabolic bone disorder caused by biallelic loss-of-function variants in ENPP1, the gene encoding for Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), an enzyme essential for generating extracellular pyrophosphate, a key endogenous inhibitor of ectopic calcification. The clinical spectrum of ENPP1 deficiency varies widely, and recognition in adulthood is challenging due to phenotypic heterogeneity and overlap with more common metabolic bone and parathyroid disorders. We describe two brothers in their late 40s with a novel homozygous ENPP1 splice-site pathogenic variant (c.1437 + 1G > C) presenting with chronic hypophosphatemia, elevated serum PTH, extra-skeletal calcifications, and markedly abnormal bone microarchitecture on high-resolution peripheral quantitative computed tomography (HR-pQCT). Brother 1 exhibited long-standing hypophosphatemia, ossification of the posterior longitudinal ligament, conductive hearing loss, congenital hip dysplasia, and aortic valve calcification. Brother 2 presented with progressive myelopathy and spinal stenosis, and underwent parathyroidectomy for presumed normocalcemic primary hyperparathyroidism. Postoperative hypoparathyroidism led to initiation of calcitriol and calcium supplementation, and subsequent nephrolithiasis. Both patients demonstrated FGF23-mediated renal phosphate wasting, low-normal 1,25-dihydroxyvitamin D, elevated parathyroid hormone and normocalcemia, favored to represent secondary rather than primary hyperparathyroidism, and significant abnormalities in cortical and trabecular bone parameters by HR-pQCT. These cases highlight diagnostic pitfalls in adult-onset ARHR2, including delayed recognition of FGF23-mediated phosphate wasting and misdiagnosis as primary hyperparathyroidism. Accurate genetic diagnosis is essential because ARHR2 clinically mimics X-linked hypophosphatemia, underscoring the need for early recognition to guide safe and effective treatment.