Abstract: SA-PO0574
A Red Herring? SLC34A3 Variant of Uncertain Significance in a Woman with Fractures and Kidney Stones
Session Information
- Bones, Stones, and Mineral Metabolism: Research and Cases
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 502 Bone and Mineral Metabolism: Clinical
Authors
- Opare-Addo, Kwasi Asamoah, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Spiardi, Ryan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Ocampo Mascaro, Javier, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Shah, Siddharth P., University of Pennsylvania, Philadelphia, Pennsylvania, United States
Introduction
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder with estimated prevalence of 1/250,000. It results from biallelic variants in the solute carrier family 34-member 3 (SLC34A3) gene which encodes the sodium-dependent phosphate cotransporter 2c in the proximal tubule. While the classic phenotype is linked to a homozygous mutation c.228delC, heterozygous variants may be associated with variable and incompletely understood clinical expression. [1]
Case Description
We report a 36-year-old woman who presented with acute T4–T6 vertebral compression fractures when she fell from a height of 2 stairs. She was 3 months postpartum and actively breastfeeding. Lowest Z score by DXA was -1.6 at L1-4. She reported prior cough-induced rib fracture and multiple toe fractures after minor trauma.
Initial studies showed elevated urine calcium (UCa), 349mg/24h, with normal serum calcium and phosphate, urinary phosphate, intact parathyroid hormone, fibroblast growth factor 23, and 1,25-dihydroxyvitamin D. Repeated UCa was higher, 945 mg/dL, while breastfeeding on hydrochlorothiazide and even higher, 1024 mg/dL, during 2nd pregnancy.
Genetic testing revealed a heterozygous variant of uncertain significance (VUS) in SLC34A3 (c.751G>C; p.Val251Leu). Serial 24-hour urine collections confirmed persistent hypercalciuria despite phosphate supplementation. While hypercalciuria did not improve with short-acting thiazides, it improved drastically to 149 mg/24h with indapamide.
Discussion
Classically, HHRH presents with hypophosphatemia due to renal phosphate wasting with resultant hypercalciuria due to elevated 1,25-dihydroxyvitamin D, and subsequent osteomalacia. Although our patient does not exhibit the full biochemical phenotype, the presence of unexplained hypercalciuria, reduced bone mineral density, fragility fractures, and a SLC34A3 VUS raises the possibility of an atypical presentation. Zhu et al. analyzed SLC34A3 heterozygous variant carriers and showed a wide phenotypic spectrum of bone and renal manifestations. While most carriers did not have disease features, about 11% displayed both bone and renal phenotypes, like our patient. [2].
This case highlights the complex, evolving role of genetics in mineral bone disease, and nuances surrounding VUS. More studies on SLC34A3 heterozygotes are needed to better define their phenotypic spectrum and management