ESPE Abstracts

Background: Hypophosphatemic rickets (HR) is most commonly X-linked or autosomal dominant, but autosomal recessive (AR) forms have been described. ARHR1 (DMP1) and ARHR2 (ENPP1) share identical biochemical characteristics of excessive renal phosphate wasting due to increased circulating levels of the phosphatonin FGF23 and low serum levels of 1,25(OH)₂D. By contrast, in hereditary hypophosphatemic rickets with hypercalciuria (HHRH) phosphaturia is due to defects in the renal type 2c sodium phosphate cotransporter encoded by SLC34A3, with suppressed levels of FGF23 and consequently elevated levels of serum 1,25(OH)₂D and urine calcium.

Objective and hypotheses: To use whole exome sequencing (WES) to identify the genetic basis for HR rickets in four kindreds with AR transmission.

Method: We obtained clinical and biochemical data and performed WES for four kindreds.

Results: The three affected boys of family 1 were initially diagnosed with HR based on severe signs of rickets of both knees but with elevated serum 1,25(OH)₂D levels; the parents were healthy first cousins of Arab-Bedouin descent. We identified a known frameshift variant, c.295_296delGG, in DMP1. Affecteds are homozygous, both parents are heterozygous and maternal grandmother is wild type. The affecteds from families 2 and 3 were also suspected to have HR, but they also had borderline to high PTH levels and very low 25(OH)D levels. WES revealed homozygous mutations in ENPP1 in affecteds from family 2 (c.1499A>G:p.H500R) and family 3 (c.755A>G:p.Y252C). In family 4, two children had HR with elevated 1,25(OH)₂D and developed hypercalcemia after moderate vitamin D supplementation; we confirmed a homozygous variant, c.709G>A:p.D237N, in SLC34A3, that cosegregated with the phenotype.

Conclusion: We report 2 novel mutations in ENPP1 and 1 known mutation in DMP1 in patients with ARHR2 and ARHR1, respectively. The HHRH phenotype is further extended by illustrating that patients with SLC34A3 mutations have vitamin D sensitivity that can lead to hypercalcemia.