Clinical Scenario:
A 7-year-old boy presents with progressive bowing of both legs and poor growth. He has a history of recurrent renal colic, and renal ultrasound shows bilateral nephrocalcinosis. Examination reveals widened wrists and genu varum.
Investigations show:
- Serum phosphate: low
- Serum calcium: normal
- ALP: elevated
- PTH: low-normal
- 25-OH vitamin D: normal
- 1,25-(OH)₂ vitamin D: markedly elevated
- Urinary phosphate excretion: increased
- Urinary calcium excretion: markedly increased
What is the most likely diagnosis?
A. Hereditary hypophosphatemic rickets with hypercalciuria
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: A. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)
Explanation
HHRH is an autosomal-recessive phosphate-wasting disorder caused by biallelic SLC34A3/NPT2c defects. Loss of proximal tubular phosphate reabsorption causes hypophosphatemia and rickets. Unlike XLH, FGF23 is appropriately suppressed, resulting in increased 1,25-(OH)₂D, increased intestinal calcium absorption and hypercalciuria, which can lead to nephrocalcinosis or renal stones.
Why the other options are incorrect:
- B. Nutritional vitamin D deficiency: Would typically have low 25-OH vitamin D and does not explain the characteristic renal phosphate wasting with marked hypercalciuria.
- C. VDDR1A: Caused by CYP27B1/1α-hydroxylase deficiency, producing low 1,25-(OH)₂D rather than markedly elevated levels.
- D. VDDR2A: Caused by vitamin D receptor resistance; 1,25-(OH)₂D is elevated, but the characteristic combination of renal phosphate wasting and hypercalciuria points toward HHRH. Alopecia would also support VDDR2A.
- E. XLH: Also causes renal phosphate wasting and hypophosphatemia, but is an FGF23-mediated disorder. In HHRH, 1,25-(OH)₂D is typically elevated and hypercalciuria/nephrocalcinosis is a major distinguishing clue.
High-yield clue
Hypophosphatemic rickets + renal phosphate wasting + hypercalciuria/nephrocalcinosis + ↑1,25-(OH)₂D → HHRH.
Reference:
Bergwitz C, Miyamoto K-I. Hereditary hypophosphatemic rickets with hypercalciuria: pathophysiology, clinical presentation, diagnosis and therapy. Pflugers Arch. 2019;471:149–163.
