ESPE Abstracts

Introduction: Serum phosphate concentration is regulated by renal phosphate reabsorption, mediated by sodium–phosphate cotransporters. Germline heterozygous mutations of SLC34A1, encoding for the renal sodium–phosphate cotransporter NPT2, are associated with the autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis type 1. FGF23 acts upon its specific receptor FGFR1 to down-regulate the number of NPT2 luminal channels. In X-linked hypophosphatemic rickets (XLH), PHEX mutations lead to an overproduction of FGF23, which results in renal phosphate wasting by down-regulation of NPT2. We report a unique case of a girl with XLH and an associated SLC34A1 mutation, who showed a poor response to Burosumab.

Clinical case: A 12-year-old Ukrainian girl with a history of vitamin D-resistant hypophosphatemic rickets (VDDR) presented for evaluation following her arrival in Italy in 2022 due to the war in Ukraine. The patient had a clinical diagnosis of VDDR at the age of 3 years and had been treated with calcitriol and oral phosphates since that time. Upon evaluation in Italy, despite conventional treatment she had persistent bone pain, severe varus deformity of the lower limbs and radiographic evidence of rickets (RSS 8/10). She had low serum phosphate and elevated alkaline phosphatase and FGF23 levels (P 2.28 mg/dl, ALP 625 U/L, FGF23 78.6 pg/ml), with inappropriately low urine phosphate reabsorption (TmPO4/GFR 1.93 mg/dL, normal values for age > 3.4). Negative celiac disease screening, normal urinary tract ultrasound. Next-generation sequencing identified a heterozygous variant in the PHEX gene, classified as pathogenic for XLH. A heterozygous variant of unknown significance was also identified in the SLC34A1 gene. Burosumab therapy was therefore initiated in November 2022, starting at a dose of 0.4 mg/kg and gradually increased to 1 mg/kg due to poor response. After one year of Burosumab treatment, the patient's serum FGF23 levels decreased, but her serum phosphate levels remained low with inappropriately low urine phosphate reabsorption: FGF23 30 pg/ml, P 2.49 mg/dL, TmPO4/GFR 2.34 mg/dL (normal values for age > 2.9). Her varus deformity remained unchanged, with a RSS 6/10.

Conclusion: Burosumab is a human monoclonal antibody inactivating FGF23, approved in 2018 for the treatment of XLH. If PHEX gene mutations co-occur with SLC34A1 gene mutations, Burosumab treatment may show limited efficacy in improving phosphate reabsorption, even though FGF23 serum levels normalize. This is because Burosumab targets FGF23, but the mutated NPT2 luminal channels (encoded by SLC34A1) remain dysfunctional and cannot properly reabsorb phosphate from the kidneys.