A 34-year-old man is evaluated for an incidental finding of serum calcium 11.2 mg/dL. PTH is 58 pg/mL (normal 15-65), 24-hour urine calcium is 68 mg (low), and calcium-to-creatinine clearance ratio is 0.008. Family history reveals similar asymptomatic hypercalcemia in his father and sibling. Which molecular defect explains this presentation?

• A Autoantibodies against the parathyroid calcium-sensing receptor
• B Activating mutation of the calcium-sensing receptor (CaSR) in the parathyroid and kidney
• C Inactivating mutation of the vitamin D receptor in the parathyroid gland
• D Inactivating mutation of the calcium-sensing receptor (CaSR) in the parathyroid and kidney ✓

Explanation

Familial hypocalciuric hypercalcemia (FHH) is caused by heterozygous inactivating mutations of the calcium-sensing receptor (CaSR). The mutant receptor has reduced sensitivity to extracellular calcium, so a higher serum calcium level is required to suppress PTH release and to promote renal calcium reabsorption. This produces mild hypercalcemia with inappropriately normal or mildly elevated PTH and low urine calcium. Option B (activating CaSR mutation) causes autosomal dominant hypocalcemia, the opposite phenotype. Option C would cause vitamin A resistance and typically presents with hypocalcemia and elevated PTH. Option A describes autoimmune hypoparathyroidism, not FHH.

Reference: Williams Textbook of Endocrinology, 14th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.