## Vitamin D-Dependent Rickets Type 1 (VDDR Type 1) **Key Point:** VDDR type 1 is caused by deficiency of **1α-hydroxylase**, the enzyme responsible for converting 25-hydroxyvitamin D [25(OH)D] to the active metabolite 1,25-dihydroxyvitamin D [1,25(OH)~2~D] in the proximal tubule of the kidney. ## Pathophysiology 1. **Enzyme defect:** 1α-hydroxylase (CYP27B1) is absent or severely reduced 2. **Result:** Inability to produce active vitamin D metabolite despite normal or elevated 25(OH)D levels 3. **Biochemical findings:** - Low 1,25(OH)~2~D (diagnostic) - Normal or elevated 25(OH)D - Elevated PTH (secondary hyperparathyroidism) - Hypocalcemia and hypophosphatemia ## Clinical Features - Presents in infancy or early childhood (typically 6 months to 2 years) - Severe rickets with hypocalcemia - Seizures or tetany from hypocalcemia - Alopecia (hair loss) is characteristic - Autosomal recessive inheritance ## Management **High-Yield:** Treatment is with **calcitriol (1,25(OH)~2~D)** — bypassing the defective enzyme. Doses are much lower than for nutritional rickets (0.25–2 μg/day) because the active metabolite is being supplied directly. ## Differential from VDDR Type 2 | Feature | VDDR Type 1 | VDDR Type 2 | |---------|-------------|-------------| | Enzyme defect | 1α-hydroxylase | Vitamin D receptor | | 1,25(OH)~2~D level | Low | High (receptor unresponsive) | | Response to calcitriol | Excellent | Poor/absent | | Treatment | Calcitriol | High-dose calcitriol or calcium | **Clinical Pearl:** The key diagnostic clue is **low 1,25(OH)~2~D with normal/high 25(OH)D** — this pattern immediately points to 1α-hydroxylase deficiency. 
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