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.544CT in exon 6 that results in replacement of arginine at position 182 by tryptophan (R182W) and c.575CT 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.