A 32-year-old man found on routine screening to have serum calcium 11.2 mg/dL shows phosphate 2.8 mg/dL, mildly elevated PTH, and 24-hour urinary calcium of 60 mg. His father was incidentally noted to have mild hypercalcemia years ago. What is the underlying defect?

• A Loss-of-function mutation of the calcium-sensing receptor in the parathyroid gland ✓
• B Inactivating mutation of claudin-16 in the thick ascending limb
• C Gain-of-function mutation of the calcium-sensing receptor causing reduced set point
• D Autonomous secretion of PTH from a single parathyroid adenoma

Explanation

Familial hypocalciuric hypercalcemia results from loss-of-function CaSR mutations in both parathyroid chief cells and renal tubules. The shifted calcium set point maintains PTH secretion despite hypercalcemia, while impaired renal calcium reabsorption causes hypocalciuria, here under 100 mg/day. A parathyroid adenoma would produce hypercalciuria, which excludes option D. Claudin-16 mutation causes familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

Reference: Williams Textbook of Endocrinology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.