Novel NaPi-IIc mutations causing HHRH and idiopathic hypercalciuria in several unrelated families: long-term follow-up in one kindred.

Homozygous and compound heterozygous mutations in SLC34A3, the gene encoding the sodium-dependent co-transporter NaPi-IIc, cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate-wasting resulting in hypophosphatemia, elevated 1,25(OH)(2) vitamin D levels, hypercalciuria, rickets/osteomalacia, and frequently kidney stones or nephrocalcinosis. Similar albeit less severe biochemical changes are also observed in heterozygous carriers, which are furthermore indistinguishable from those encountered in idiopathic hypercalciuria (IH). We now searched for SLC34A3 mutations (exons and introns) in two previously not reported HHRH kindreds, which resulted in the identification of three novel mutations. The affected members of kindred A were compound heterozygous for two different mutations, c.1046_47del and the intronic mutation c.560+23_561-42del, while the index case in kindred B was homozygous for the nonsense SLC34A3 mutation c.1764C>G (p.Y588X). The patient in kindred C was diagnosed with IH because of bilateral medullary nephrocalcinosis, suppressed PTH levels, and hypercalciuria; she was found to have a novel heterozygous c.1571_1880del mutation. The HHRH patients in kindred A were treated for up to 7years with oral phosphate, which led to reversal of hypophosphatemia, hypercalciuria, and prevention or healing of the mild bone abnormalities. PTH levels were normal throughout the observation period, while 1,25(OH)(2) vitamin D levels remained elevated and may thus be helpful for assessing treatment efficacy and patient compliance in HHRH.