Clinical Scenario:
A 14-month-old boy presents with delayed walking, poor growth, progressive bowing of the legs and widening of the wrists. He has generalized muscle weakness. He was initially treated with adequate doses of vitamin D for presumed nutritional rickets, but there was no significant clinical or biochemical improvement.
Investigations show:
- Serum calcium: low
- Serum phosphate: low
- ALP: markedly elevated
- PTH: elevated
- 25-OH vitamin D: normal
- 1,25-(OH)₂ vitamin D: markedly low
What is the most likely diagnosis?
A. Hypophosphatasia
B. Nutritional vitamin D deficiency
C. Vitamin D–dependent rickets type 1A
D. Vitamin D–dependent rickets type 2A
E. X-linked hypophosphatemic rickets
Correct answer & Explanation:
Answer: C. Vitamin D–dependent rickets type 1A
Explanation
The combination of clinical rickets, hypocalcemia, hypophosphatemia, markedly elevated ALP, secondary hyperparathyroidism, normal 25-OH vitamin D and low 1,25-(OH)₂D strongly indicates vitamin D–dependent rickets type 1A (VDDR1A).
VDDR1A is an autosomal-recessive disorder caused by biallelic CYP27B1 mutations, resulting in deficiency of renal 1α-hydroxylase. Consequently, 25-OH vitamin D cannot be adequately converted into biologically active 1,25-(OH)₂D (calcitriol).
Why the other options are incorrect
- A. Hypophosphatasia — Incorrect: Hypophosphatasia characteristically causes low ALP, whereas this child has markedly elevated ALP.
- B. Nutritional vitamin D deficiency — Incorrect: Nutritional vitamin D deficiency causes a low 25-OH vitamin D level. Here, 25-OH vitamin D is normal despite adequate treatment.
- D. Vitamin D–dependent rickets type 2A — Incorrect: VDDR2A results from vitamin D receptor (VDR) resistance. Despite impaired vitamin D action, 1,25-(OH)₂D is typically markedly elevated, rather than low. Alopecia is also a classic clinical clue and occurs in approximately half of affected patients.
- E. X-linked hypophosphatemic rickets — Incorrect: XLH is primarily an FGF23-mediated renal phosphate-wasting disorder. Calcium is usually normal, and the biochemical picture is dominated by hypophosphatemia and inappropriate renal phosphate loss rather than hypocalcemia with secondary hyperparathyroidism.
High-yield exam clue
Normal 25-OH vitamin D + low 1,25-(OH)₂D + hypocalcemia + ↑PTH + rickets → VDDR1A
VDDR1A: CYP27B1 / 1α-hydroxylase defect → ↓ calcitriol.
VDDR2A: VDR resistance → ↑ calcitriol ± alopecia.
Reference
Kliegman RM, St Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson Textbook of Pediatrics. 22nd ed. Elsevier; 2023. Chapter 69: Vitamin D Deficiency (Rickets) and Excess.
