Familial Nephrocalcinosis Associated With Heterozygous SLC34A1 and TRPV5 Variants Presenting With Elevated 1,25-Dihydroxyvitamin D

Nephrocalcinosis is frequently associated with inherited disturbances of calcium-phosphate metabolism and renal tubular transport. Variants affecting renal phosphate reabsorption or distal tubular calcium handling may result in hypercalciuria, nephrolithiasis, and progressive renal calcification. The SLC34A1 gene encodes the sodium-phosphate cotransporter NaPi-IIa in the proximal tubule, and loss-of-function variants can cause renal phosphate wasting with inappropriate activation of 1α-hydroxylase, leading to elevated 1,25-dihydroxyvitamin D. The TRPV5 gene encodes a calcium-selective channel in the distal nephron and is essential for transcellular calcium reabsorption. We report a familial nephrocalcinosis phenotype in a 30-year-old woman and her 2-year-old daughter. The mother presented with bilateral flank pain, dysuria, palpitations, and fatigue. Laboratory evaluation demonstrated suppressed parathyroid hormone (PTH 9.6 pg/mL), serum calcium at the upper limit of normal (9.7 mg/dL), normal phosphate (3.1 mg/dL), chronically low 25-hydroxyvitamin D (24 ng/mL), and elevated 1,25-dihydroxyvitamin D, suggesting PTH-independent calcitriol excess. Nephrocalcinosis had previously been detected in the child. Targeted next-generation sequencing revealed a heterozygous splice-region variant in SLC34A1 (NM_003052.5:c.644+5G>C) and a heterozygous missense variant in TRPV5 (NM_019841.7:c.1849G>A; p.Gly617Arg) in both individuals. This case is presented as a hypothesis-generating report. Although both variants are classified as variants of uncertain significance, the shared genotype and characteristic biochemical profile suggest a potential disturbance of renal phosphate and calcium handling that may contribute to familial nephrocalcinosis and PTH-independent elevation of active vitamin D. However, definitive causal inferences cannot be established without additional evidence including segregation analysis in extended family members, functional studies, and comprehensive biochemical characterization.