A 9-year-old boy has severe short stature and fasting hypoglycemia. Serum growth hormone is markedly elevated, serum IGF-1 is very low, and he fails to respond to exogenous growth hormone therapy. What is the most likely defect?
- A Mutation of the growth hormone receptor causing GH insensitivity ✓
- B GHRH receptor mutation causing pituitary hypoplasia
- C IGF-1 gene deletion with intact GH receptor signaling
- D Hypothalamic GHRH deficiency
Correct answer: A. Mutation of the growth hormone receptor causing GH insensitivity
Explanation
Laron syndrome results from loss-of-function mutations in the growth hormone receptor. The liver cannot generate IGF-1, so IGF-1 is low, and loss of negative feedback drives GH very high. Because the defect is downstream of the receptor ligand interaction, giving more GH achieves nothing, whereas recombinant IGF-1 works. GHRH receptor mutation or hypothalamic GHRH deficiency would produce low GH with low IGF-1, the opposite pattern. An IGF-1 gene deletion would show low IGF-1 but preserved GH responsiveness.
Reference: Williams Textbook of Endocrinology, 14th ed.
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