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Difficulty: MediumFormulating a Differential Diagnosis

Match each patient presentation of hypercalcemia to the most likely underlying diagnosis based on the clinical and laboratory findings.

  • A 58-year-old man with a heavy smoking history, a central lung mass, hypercalcemia, and a suppressed intact parathyroid hormone level.Squamous cell carcinoma of the lung
  • A 32-year-old woman with a chronic cough, bilateral hilar lymphadenopathy, hypercalcemia, and an elevated 1,25-dihydroxyvitamin D level.Sarcoidosis
  • A 68-year-old woman with severe back pain, normocytic anemia, renal insufficiency, hypercalcemia, and a negative radionuclide bone scan.Multiple myeloma
  • A 45-year-old asymptomatic man with mild hypercalcemia, a high-normal intact parathyroid hormone level, and a urine calcium-to-creatinine clearance ratio of 0.005.Familial hypocalciuric hypercalcemia

Answer

The correct pairings link each specific clinical and laboratory presentation of hypercalcemia to its distinct pathophysiologic mechanism: the central lung mass with suppressed PTH matches squamous cell carcinoma of the lung; hilar lymphadenopathy with elevated 1,25-dihydroxyvitamin D matches sarcoidosis; anemia, renal failure, and a negative bone scan matches multiple myeloma; and normal/high PTH with a very low urine calcium ratio matches familial hypocalciuric hypercalcemia.
Each presentation highlights a unique diagnostic pathway for hypercalcemia. Squamous cell carcinoma drives it via ectopic PTHrP. Sarcoidosis drives it via macrophage-mediated 1-alpha-hydroxylase activity leading to high 1,25-dihydroxyvitamin D. Multiple myeloma produces local cytokines causing purely lytic bone lesions that are characteristically negative on a standard bone scan. FHH stems from a calcium-sensing receptor mutation leading to low urinary calcium excretion despite a normal or high PTH.

Step-by-Step Solution

1
Evaluate the intact parathyroid hormone (PTH) level to determine if the hypercalcemia is PTH-mediated or non-PTH-mediated.
Patients 1, 2, and 3 have suppressed PTH (non-PTH-mediated). Patient 4 has a high-normal PTH (PTH-mediated or receptor-mediated).
The PTH level is the critical initial branch point in formulating a differential diagnosis for hypercalcemia.
2
Analyze the specific clinical findings in the patients with non-PTH-mediated hypercalcemia.
Patient 1's lung mass suggests PTHrP production (squamous cell carcinoma). Patient 2's high 1,25-vitamin D and hilar adenopathy suggest extrarenal hydroxylation (sarcoidosis). Patient 3's negative bone scan despite bone pain, renal failure, and anemia suggests purely lytic lesions (multiple myeloma).
Differentiating malignancy and granulomatous disease relies on recognizing specific ectopic hormone production and distinct patterns of organ involvement.
3
Differentiate the etiology of the patient with normal/high PTH (Patient 4).
The remarkably low urine calcium-to-creatinine clearance ratio (< 0.01) distinguishes the presentation from primary hyperparathyroidism.
Familial hypocalciuric hypercalcemia involves a mutated calcium-sensing receptor, requiring a higher serum calcium to suppress PTH and leading to avid renal calcium reabsorption, which definitively separates it from primary hyperparathyroidism.

Key Concept

Formulating a differential diagnosis for hypercalcemia relies on interpreting intact parathyroid hormone levels alongside specific regulatory hormones (e.g., 1,25-dihydroxyvitamin D) and distinguishing clinical/radiologic findings.
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Formulating a Differential Diagnosis

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