SLC34A1 – Idiopathic Infantile Hypercalcemia

Idiopathic infantile hypercalcemia (IIH) is a rare disorder of PTH-independent hypercalcemia presenting in early infancy with severe hypercalcemia, hypercalciuria, nephrocalcinosis, dehydration, vomiting, and failure to thrive. While CYP24A1 mutations underlie IIH type 1, autosomal recessive variants in SLC34A1 encoding the renal sodium–phosphate cotransporter NaPi-IIa have been established as the cause of IIH type 2.

Genetic evidence supporting a definitive association includes homozygosity mapping in four consanguineous families and 12 sporadic IIH cases revealing autosomal recessive SLC34A1 mutations in 16 unrelated probands (16 probands (PMID:26047794)). Segregation in affected sibships and compound heterozygous case reports further corroborate inheritance.

The variant spectrum encompasses loss-of-function alleles (nonsense, frameshift, splice-site) and hypomorphic missense changes. Notably, the recurrent truncating variant c.1156C>T (p.Gln386Ter) has been identified in multiple probands. Additional novel compound heterozygotes (c.1337G>A, c.1483C>T) expand the allelic series (PMID:30943683).

Functional studies demonstrate that mutant NaPi-IIa fails to reach the apical membrane in Xenopus oocytes and OK cells, abolishing phosphate transport. Slc34a1–knockout mice recapitulate hypophosphatemia, elevated 1,25-dihydroxyvitamin D, and hypercalcemia, confirming loss-of-function as the pathogenic mechanism ([PMID:26047794]).

Case reports of antenatal diagnosis and early postnatal management highlight the value of genetic confirmation for targeted therapy, including phosphate supplementation and vitamin D restriction, preventing severe complications (PMID:38753084).

Collectively, over 30 unrelated IIH type 2 cases, robust segregation, and concordant in vitro and animal model data fulfill ClinGen criteria for a definitive gene–disease relationship. Key Take-home: SLC34A1 genotyping is essential for accurate diagnosis and precision management of infantile hypercalcemia.

References

• Journal of the American Society of Nephrology • 2016 • Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia PMID:26047794
• Annals of Pediatric Endocrinology & Metabolism • 2019 • Infantile hypercalcemia with novel compound heterozygous mutation in SLC34A1 encoding renal sodium-phosphate cotransporter 2a: a case report. PMID:30943683
• Pediatric Nephrology • 2024 • Antenatal presentation and early postnatal treatment of infantile hypercalcemia type 2. PMID:38753084

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