A 38-year-old woman has recurrent nephrolithiasis and is found to have serum calcium 11.2 mg/dL, phosphate 2.1 mg/dL, PTH 142 pg/mL, and 24-hour urinary calcium 480 mg. The most likely diagnosis and its molecular mechanism involves:
- A Familial hypocalciuric hypercalcemia — CaSR gain-of-function mutation
- B Primary hyperparathyroidism — clonal expansion from MENIN or CCND1 mutation ✓
- C Sarcoidosis — ectopic PTHrP secretion
- D Malignancy — PTHrP acting via PTH receptor 1
Explanation
High PTH with hypercalcemia, hypophosphatemia, and markedly elevated 24-hour urinary calcium (> 400 mg) strongly indicates primary hyperparathyroidism, most commonly caused by a single parathyroid adenoma driven by cyclin D1 (CCND1) overexpression or MEN1 gene (MENIN) loss-of-function. Familial hypocalciuric hypercalcemia features a CaSR loss-of-function (not gain-of-function) and low urine calcium (< 200 mg/24h). Sarcoidosis causes hypercalcemia via 1-alpha-hydroxylase in macrophages, not PTHrP. In humoral hypercalcemia of malignancy PTH is suppressed while PTHrP is elevated.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
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Written and medically reviewed by the StethoPrep medical team.