Two variants in SLC34A3 in a patient with X-linked hypophosphatemia: a diagnostic and therapeutic dilemma.

X-linked hypophosphatemia (XLH) is the most prevalent form of hereditary rickets due to pathogenic variants in the PHEX gene. Since 2018, a treatment with burosumab, which inhibits the activity of fibroblast growth factor 23 (FGF23), has been approved for XLH patients. In contrast, hereditary hypophosphatemic rickets with hypercalciuria (HHRH), caused by pathogenic variants in the SLC34A3 gene, exhibits a similar increase in urinary phosphate excretion due to abnormal function of the renal phosphate transporter; however, FGF23 levels are elevated in XLH but low in HHRH, whereas the levels of biologically active 1,25(OH)₂ vitamin D show the opposite pattern. We present a case of a female patient with XLH due to PHEX deletion, who is also a carrier of two pathogenic variants in the SLC34A3 gene in cis- verified through long-read sequencing. Given these distinct pathophysiological mechanisms and the potential influence of even heterozygous SLC34A3 variants on the clinical phenotype, this case underscores the need to screen WES/WGS data in patients with XLH not only for PHEX variants, but also for variants in other phosphate-regulating genes before initiating burosumab therapy, particularly when biochemical parameters are inconsistent with "classical" XLH.