Description of a novel mutation causing hereditary hypophosphatemic rickets with hypercalciuria in two adolescent boys and response to recombinant human growth hormone

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive disorder characterized by hypophosphatemia, rickets, hyperphosphaturia, elevated 1,25(OH) 2 D, 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