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Difficulty: HardPediatric Endocrine Disorders

An 18-month-old boy is evaluated in the pediatric clinic for progressive bowing of his legs and a waddling gait. The parents note that he began walking independently at 14 months of age, but his leg bowing has worsened since then. He was exclusively breastfed until 6 months, after which appropriate solid foods were introduced. He receives daily multivitamin drops containing 400 IU of cholecalciferol. His height is at the 3rd percentile, and his weight is at the 25th percentile. Physical examination reveals frontal bossing, widening of the wrists, and pronounced genu varum. Laboratory studies show:

Laboratory TestResultReference Range
Serum calcium9.4 mg/dL8.8-10.8 mg/dL
Serum phosphorus2.2 mg/dL3.5-6.0 mg/dL
Alkaline phosphatase780 U/L150-400 U/L
Parathyroid hormone42 pg/mL10-65 pg/mL
25-hydroxyvitamin D40 ng/mL20-50 ng/mL

Which of the following is the most likely underlying pathophysiology of this patient's condition?

  1. Excessive action of fibroblast growth factor 23Answer
  2. B
    Inadequate dietary intake and cutaneous synthesis of cholecalciferol
  3. C
    Deficient activity of the renal 1-alpha-hydroxylase enzyme
  4. D
    End-organ resistance to parathyroid hormone signaling
  5. E
    Physiologic alignment variation of the lower extremities

Answer

The condition is driven by the excessive action of fibroblast growth factor 23, which represents the pathophysiology of X-linked hypophosphatemia.
The correct answer accurately describes the pathophysiology of X-linked hypophosphatemia (XLH), the most common form of hereditary rickets. XLH is caused by an inactivating mutation in the PHEX gene. This mutation leads to an overproduction and excessive systemic action of fibroblast growth factor 23 (FGF23). FGF23 acts on the kidneys to severely decrease the reabsorption of phosphate in the proximal tubule, leading to profound hypophosphatemia. Furthermore, FGF23 inhibits the 1-alpha-hydroxylase enzyme, preventing the expected compensatory rise in 1,25-dihydroxyvitamin D. The classic laboratory profile—low phosphorus, elevated alkaline phosphatase, and normal serum calcium, normal 25-hydroxyvitamin D, and normal parathyroid hormone—strongly differentiates XLH from nutritional rickets.

Step-by-Step Solution

1
Evaluate the clinical presentation.
The patient has short stature, frontal bossing, wrist widening, and severe genu varum, which collectively establish the clinical syndrome of rickets.
To identify the overarching clinical syndrome before interpreting specific laboratory data.
2
Analyze the laboratory values.
The labs reveal normal serum calcium, normal 25-hydroxyvitamin D, and normal parathyroid hormone, but significantly low serum phosphorus and highly elevated alkaline phosphatase.
To differentiate the specific etiology of rickets (e.g., nutritional vs. genetic).
3
Synthesize the clinical and laboratory findings.
Isolated hypophosphatemia in the setting of normal vitamin D and normal parathyroid hormone points to a primary defect in renal phosphate reabsorption rather than a nutritional deficiency.
To arrive at the diagnosis of hereditary hypophosphatemic rickets, most commonly X-linked hypophosphatemia (XLH).
4
Identify the underlying pathophysiology of the diagnosis.
XLH is caused by a PHEX gene mutation, leading to the overproduction and excessive action of fibroblast growth factor 23 (FGF23), which aggressively promotes renal phosphate excretion.
To answer the specific question asked in the stem regarding pathophysiology.

Key Concept

X-linked hypophosphatemia (XLH) presents with clinical signs of rickets and isolated hypophosphatemia due to excessive FGF23 action, with characteristically normal serum calcium, normal 25-hydroxyvitamin D, and normal or mildly elevated parathyroid hormone.
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Topics

Pediatric Endocrine Disorders

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