Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter: Presentation as hypercalciuria and nephrolithiasis

Amanda L. Tencza, Shoji Ichikawa, Anna Dang, David Kenagy, Edward McCarthy, Michael J. Econs, Michael A. Levine

Research output: Contribution to journalArticle

33 Scopus citations


Context: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a metabolic disorder due to homozygous loss-of-function mutations in the SLC34A3 gene encoding the renal type IIc sodium-phosphate cotransporter (NaPi-IIc). The typical presentation is severe rickets and hypophosphatemia, and hypercalciuria is often discovered later or overlooked. Objective: We sought to determine the genetic basis for severe hypercalciuria and nephrolithiasis/nephrocalcinosis in an adolescent male with elevated serum levels of calcitriol but normal serum levels of calcium and phosphorus. Design and Setting: We used PCR to analyze the SLC34A3 gene in the proband and members of his family. Results: The proband was a compound heterozygote for two SLC34A3 missense mutations, a novel c.544C→T in exon 6 that results in replacement of arginine at position 182 by tryptophan (R182W) and c.575C→T in exon 7 that results in replacement of serine at position 192 by leucine (S192L). The R182W and S192L alleles were inherited from the mother and father, respectively, both of whom had hypercalciuria. A clinically unaffected brother was heterozygous for S192L. Conclusion: We report a novel mutation in the SLC34A3 gene in a patient with an unusual presentation of HHRH. This report emphasizes that moderate and severe hypercalciuria can be manifestations of heterozygous or homozygous loss-of-function mutations in the SLC34A3 gene, respectively, providing further evidence for a gene dosage effect in determining the phenotype. HHRH may be an underdiagnosed condition that can masquerade as idiopathic hypercalciuria or osteopenia.

Original languageEnglish (US)
Pages (from-to)4433-4438
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Issue number11
StatePublished - Nov 2009


ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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