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)