Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive disorder characterized by hypophosphatemia, rickets, hyperphosphaturia, elevated 1,25(OH)2D, and hypercalciuria. Mutations in SLC34A3, the gene encoding the sodium-dependent cotransporter NPT2c, have previously been described as a cause of HHRH. Here, we describe two male siblings with rickets and hypercalciuric nephrolithiasis born to unrelated parents, and their response to oral phosphate supplementation and growth hormone therapy. Whole exome sequencing of the oldest brother, and polymerase chain reaction and Sanger sequence analysis of the identified SLC34A3 mutations, was performed for confirmation and to evaluate his siblings and parents. Serum and urine biochemical parameters of mineral homeostasis before and after therapy were evaluated. Whole exome sequencing analysis identified a previously reported heterozygous deletion SLC34A3.g.2259-2359del101bp on the maternal allele, and a novel heterozygous single nucleotide deletion SLC34A3.c.671delT on the paternal allele of the two affected brothers. The parents and the unaffected brother are heterozygous carriers. Recombinant human growth hormone (rHGH) plus oral phosphate in one affected brother improved the renal phosphate leak and resulted in accelerated linear growth superior to that seen with oral phosphate supplementation alone in the other affected brother. Our case study is the first to demonstrate that rHGH can be considered in addition to oral supplementation with phosphorus to improve linear growth in patients with this disorder, and suggests that renal phosphate reabsorption in response to rHGH is NPT2c-independent.

Mutations in the SLC34A3 gene, encoding the sodium/phosphate cotransporter 2C (NPTIIc), induce decreased renal phosphate reabsorption, hypophosphatemia, decreased fibroblast growth factor 23 and parathyroid hormone, and increased 1,25-dihydroxyvitamin D (1,25[OH]2D) levels. The complete phenotype is characterized by hypophosphatemia, hypercalciuria, and nephrolithiasis/nephrocalcinosis, leading to chronic kidney disease and osteoporosis in adults. We report a 15-year-old boy referred for nephrocalcinosis. The patient demonstrated hypercalcemia, hypercalciuria, normal serum phosphate level, normal tubular phosphate reabsorption, and increased serum 1,25(OH)2D level with suppressed serum parathyroid hormone. Compound heterozygous mutations in SLC34A3 were found. Hydrochlorothiazide failed to decrease calciuria. Fluconazole, an inhibitor of 1α-hydroxylase, was effective in normalizing calciuria without decreasing glomerular filtration rate. We conclude that children with SLC334A3 mutations can present with a less-typical phenotype, having normal serum phosphate levels and normal renal phosphate reabsorption. Genetic abnormalities of NPTIIc should be considered in cases of increased 1,25(OH)2D levels without mutations in CYP24A1. The utility of fluconazole to decrease 1,25(OH)2D levels requires confirmation in larger studies.

Circulating inorganic phosphate exhibits a remarkable daily oscillation based on food intake. In humans and rodents, the daily oscillation in response to food intake may be coordinated to control the intestinal absorption, renal excretion, cellular shifts, and extracellular concentration of inorganic phosphate. However, mechanisms regulating the resulting oscillation are unknown. Here we investigated the roles of the sodium phosphate cotransporter SLC34 (Npt2) family and nicotinamide phosphoribosyltransferase (Nampt) in the daily oscillation of plasma inorganic phosphate levels. First, it is roughly linked to urinary inorganic phosphate excretion. Second, expression of renal Npt2a and Npt2c, and intestinal Npt2b proteins also exhibit a dynamic daily oscillation. Analyses of Npt2a, Npt2b, and Npt2c knockout mice revealed the importance of renal inorganic phosphate reabsorption and cellular inorganic phosphate shifts in the daily oscillation. Third, experiments in which nicotinamide and a specific Nampt inhibitor (FK866) were administered in the active and rest phases revealed that the Nampt/NAD+ system is involved in renal inorganic phosphate excretion. Additionally, for cellular shifts, liver-specific Nampt deletion disturbed the daily oscillation of plasma phosphate during the rest but not the active phase. In systemic Nampt+/- mice, NAD levels were significantly reduced in the liver, kidney, and intestine, and the daily oscillation (active and rest phases) of the plasma phosphate concentration was attenuated. Thus, the Nampt/NAD+ system for Npt2 regulation and cellular shifts to tissues such as the liver play an important role in generating daily oscillation of plasma inorganic phosphate levels.