X-linked hypophosphatemia in the presence of a CLDN16 variant: implications for renal handling and disease severity

Abstract

X-linked hypophosphatemia (XLH), a rare genetic disorder caused by PHEX mutations, leads to fibroblast growth factor 23–mediated phosphate wasting, hypophosphatemia, and impaired bone mineralization. We report a 28-year-old woman with XLH carrying a heterozygous PHEX c.1080-1G>A splice-site mutation and a CLDN16 c.165_166delinsC mutation. Diagnosed at 18 months of age, she received long-term phosphate and active vitamin D metabolites, which resulted in secondary hyperparathyroidism, vertebral fractures, and medullary nephrocalcinosis requiring subtotal parathyroidectomy. Although CLDN16 mutation carriers are usually asymptomatic, coexistence of XLH and prolonged phosphate therapy may exacerbate renal magnesium and calcium handling defects, potentially contributing to nephrocalcinosis. Burosumab was initiated for ongoing complications. Before surgery, she was wheelchair dependent due to severe diffuse bone pain. Postoperatively, pain improved and she regained independent ambulation, which further improved after burosumab initiation. Laboratory findings showed partial but sustained improvements in serum phosphate, alkaline phosphatase, and parathyroid hormone levels. Incomplete biochemical normalization may reflect renal tubular acidosis and medullary calcinosis. This case suggests long-term phosphate therapy can adversely affect parathyroid glands and may exacerbate nephrocalcinosis in the presence of tubular vulnerabilities. It supports burosumab as an effective therapeutic option in patients with coexisting renal tubular disorders. © The Author(s) 2026. Published by Oxford University Press on behalf of the Endocrine Society.