Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter:...

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.

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.

We used PCR to analyze the SLC34A3 gene in the proband and members of his family.

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.

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.