SUN-744 - A Novel BRCA2-Associated Form of FGF23-Mediated Hypophosphatemic Rickets: Clinical, Biochemical, and Genetic Evidence

Background: Hypophosphatemic rickets (HR) is a heterogeneous group of disorders characterized by renal phosphate wasting, impaired bone mineralization, and elevated fibroblast growth factor 23 (FGF23). While most cases are linked to mutations in PHEX, FGF23, DMP1, or ENPP1, a subset remains genetically unexplained. Emerging data suggest that pathways classically associated with DNA repair, including BRCA2 signaling, may influence phosphate homeostasis.

Case Presentation: We report an 11.2-year-old prepubertal boy evaluated after a low-impact comminuted femoral fracture. He exhibited short stature, severe microcephaly, marked osteopenia, osteoporosis (lumbar spine DEXA Z-score −2.0 SDS), and a profoundly reduced Bone Health Index (−3.9 SDS), evident since early childhood. Biochemical evaluation revealed severe FGF23-mediated phosphaturia (FEPO₄ 44%), suppressed PTH, hypercalciuria, dissociation between 25(OH)D and undetectable 1,25(OH)₂D despite vitamin D repletion, and markedly elevated FGF23 (257 IU). Renal function was normal. Tumor-induced osteomalacia was excluded by whole-body MRI and hematologic evaluation.
Whole-exome sequencing identified no known pathogenic variants in canonical HR genes. Analysis of variants of uncertain significance revealed a novel missense variant in BRCA2, two trans AXIN variants (one de novo), a heterozygous GDF5 variant explaining digital skeletal anomalies, and a heterozygous PHACTR1 variant potentially accounting for microcephaly.
Intervention and Outcome: Treatment with burosumab (40 mg s.c. every 2 weeks) normalized phosphaturia and PTH and improved mineral metabolism. Due to initial worsening of bone density (DEXA Z-score −2.5 SDS at 6 months), adjunctive therapy with calcium, cholecalciferol, oxandrolone, and alendronate was introduced, resulting in dramatic improvement in bone mineral density (final Z-score −1.1 SDS), growth velocity, and near-complete radiographic resolution of osteopenia, although cortical thickness indices remained low.

Conclusion: This case supports the existence of a novel form of FGF23-mediated hypophosphatemic rickets potentially linked to BRCA2 pathway dysfunction. Given emerging evidence that BRCA2 signaling intersects with Klotho–FGF23 regulation and reports of elevated FGF23 in BRCA2 carriers, BRCA2 may act as a disease modifier or causative factor in rare, genetically complex HR. Functional studies are warranted to elucidate this newly proposed link between cancer predisposition pathways and phosphate metabolism.

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