Presentation and outcome in carriers of pathogenic variants in SLC34A1 and SLC34A3 encoding sodium-phosphate transporter NPT 2a and 2c

Brunkhorst M; Brunkhorst L; Martens H; Papizh S; Besouw M; Grasemann C; Turan S; Sikora P; Chromek M; Cornelissen E; Fila M; Lilien M; Allgrove J; Neuhaus TJ; Eltan M; Espinosa L; Schnabel D; Gokce I; Gonzalez-Rodriguez JD; …Haffner D

doi:10.1530/ey.22.5.3

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 5.3 | DOI: 10.1530/ey.22.5.3

ESPEYB25 5. Bone, Growth Plate and Mineral Metabolism Advances in Clinical Practice (6 abstracts)

5.3. Presentation and outcome in carriers of pathogenic variants in SLC34A1 and SLC34A3 encoding sodium-phosphate transporter NPT 2a and 2c

Brunkhorst M , Brunkhorst L , Martens H , Papizh S , Besouw M , Grasemann C , Turan S , Sikora P , Chromek M , Cornelissen E , Fila M , Lilien M , Allgrove J , Neuhaus TJ , Eltan M , Espinosa L , Schnabel D , Gokce I , González-Rodríguez JD & …Haffner D

Kidney International, 2025. 107(1), 116-129. https://doi.org/10.1016/j.kint.2024.08.035

Brief Summary: This multicentre retrospective study analysed the clinical, biochemical and genetic data of 113 patients from 90 families with pathogenic variants in the SLC34A1 or SLC34A3 genes. The study revealed distinct, yet partially overlapping, phenotypes in biallelic carriers of SLC34A1 and SLC34A3, as well as limited efficacy of phosphate treatment in improving outcomes. Furthermore, the study found an increased risk of chronic kidney disease in adult patients with biallelic SLC34A3 variants.

Commentary: Phosphate homeostasis is regulated by the renal sodium-phosphate transporters NPT2a (encoded by the SLC34A1 gene) and NPT2c (encoded by the SLC34A3 gene). Pathogenic variants in these genes are a rare cause of phosphate wasting. Biallelic variants in SLC34A1 have historically been associated with infantile hypercalcemia-2 (IH2), whereas biallelic variants in SLC34A3 cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). This study represents the largest cohort to date investigating the presentation and long-term outcomes of individuals with pathogenic or likely pathogenic variants in these genes.

This study detailed the distinct phenotypic differences between biallelic SLC34A1 and SLC34A3 carriers. SLC34A1 variant carriers typically present in infancy with symptoms of hypercalcemia (such as polyuria, failure to thrive, vomiting, constipation) and nephrocalcinosis. In contrast, SLC34A3 variant carriers usually present in childhood or adulthood with hypophosphatemic rickets and less frequent nephrocalcinosis. The study also highlights that adult biallelic SLC34A3 carriers have a 6-fold increased risk of chronic kidney disease compared to the general population. While both groups share a common biochemical pattern of elevated 1,25(OH)2D and alkaline phosphatase levels, suppressed parathyroid hormone, and hypercalciuria, the study reports that phosphate treatmentonly partially improves clinical and biochemical features and may even lead to increased PTH levels, potentially exacerbating renal phosphate loss. The study also suggests that heterozygous carriers, previously thought to be unaffected, might exhibit milder phenotypes and an increased risk of renal calcification.