Most Common Cause of Hypercalcemia in MEN1
Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia in MEN1 patients, occurring in 95% of cases and typically presenting as multiglandular parathyroid adenomas or hyperplasia. 1, 2
Clinical Presentation and Frequency
- PHPT is the most frequent hormonal manifestation of MEN1, present in 95% of patients, making it the predominant cause of elevated calcium levels in this population 1, 2, 3
- The disease penetrance for PHPT in MEN1 carriers is substantial: 45% by age 30,82% by age 50, and 96% by age 70 2, 3
- Unlike sporadic PHPT where 80% of cases are due to a single adenoma, MEN1-associated PHPT typically involves multiglandular disease (multiple adenomas or hyperplasia) affecting approximately 15-20% of all PHPT cases 4
Pathophysiology
- The underlying mechanism involves pathogenic variants in the MEN1 tumor-suppressor gene on chromosome 11q13, which encodes the protein menin 2, 3
- This genetic defect leads to autonomous overproduction of parathyroid hormone (PTH), resulting in hypercalcemia regardless of serum calcium levels 1
- The hyperplastic parathyroid tissue in MEN1 has a shifted calcium set-point compared to normal tissue, explaining the persistent hypercalcemia 5
Important Clinical Distinctions
- Parathyroid carcinoma is rare in MEN1 (<1% of PHPT cases generally), though case reports document its occurrence even in multiple glands simultaneously 4, 6
- PHPT in MEN1 must be differentiated from familial hypocalciuric hypercalcemia (FHH), as FHH patients should avoid operative treatment while MEN1 patients require surgical intervention 7
- The calcium-creatinine clearance ratio can help distinguish between these conditions 7
Surveillance and Early Detection
- Surveillance should begin in childhood as 17% of MEN1-associated tumors are diagnosed before age 21, with tumors documented as early as 5 years of age 2
- Routine monitoring of calcium and phosphorus levels is essential for early detection 1
- Early identification through surveillance is critical, as delays in diagnosis are associated with increased morbidity and mortality 2
Common Pitfall
The primary pitfall is failing to screen for other MEN1-associated tumors (pancreatic neuroendocrine tumors, pituitary adenomas) when hyperparathyroidism is identified, especially in young patients 2. Once PHPT is diagnosed in the context of MEN1, comprehensive evaluation for the other major constituent tumors is mandatory 1.