Pathogenesis of Hereditary Vitamin-D-Dependent Rickets

TLDR

The study proposes that vitamin‑D‑dependent rickets results from a genetic defect in 25‑hydroxycholecalciferol‑1‑hydroxylase, impairing conversion to active 1α,25‑dihydroxyvitamin D. The authors examined the vitamin‑D metabolite requirements in five patients with vitamin‑D‑dependent rickets. Patients needed large doses of vitamin D2, D3, or 25‑hydroxyvitamin D3 to heal rachitic lesions, whereas a physiologic dose of 1α,25‑dihydroxyvitamin D rapidly resolved symptoms, indicating a defect in conversion to the active metabolite.

Abstract

Requirements of vitamin D2, vitamin D3, 25-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3 were studied in five patients with vitamin-D-dependent rickets, a recessively inherited form of vitamin-D-refractory rickets. Massive doses of vitamin D2 (1.25 to 2.50 mg per day), vitamin D3 (1.25 mg per day) and 25-hydroxyvitamin D3 (0.4 to 0.9 mg per day) were required to heal the rachitic lesions, but minute doses of 1α,25-dihydroxyvitamin D3. (1.0 μg per day) promptly initiated healing. The dosage of 1α,25-dihydroxyvitamin D3 was probably in the physiologic range for the human infant — evidence against target-cell unresponsiveness. Our data suggest that conversion of vitamin D to 25-hydroxyvitamin D was normal in our patients, but that a block was present in subsequent conversion to 1α,25-dihydroxyvitamin D, the active metabolite. We postulate, therefore, that vitamin-D-dependent rickets is an inborn error of vitamin D metabolism due to a genetic defect in 25-hydroxycholecalciferol-1-hydroxylase, the enzyme responsible for the production of 1α,25-dihydroxyvitamin D. (N Engl J Med 289:817–822, 1973)