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A 24-year-old man is referred after an acute episode of renal colic. Imaging studies show bilateral kidney stones. Metabolic workup is consistent with primary hyperparathyroidism as illustrated by the following laboratory test results:
- Serum calcium = 11.9 mg/dL (2.98 mmol/L) (reference range, 8.2-10.2 mg/dL [2.1-2.6 mmol/L])
- Serum PTH = 112 pg/mL (112 ng/L) (reference range, 10-65 pg/mL [10-65 ng/L])
- Urinary calcium excretion = 400 mg/24 h (10 mmol/d) (reference range, 100-300 mg/24 h [2.5-7.5 mmol/d])
Following a sestamibi scan that shows a “possible” adenoma in the right lower pole, the patient undergoes minimally invasive parathyroidectomy with resection of 1 enlarged parathyroid gland. Pathologic examination confirms a hyperplastic adenoma. Two weeks later, he returns for blood work while taking elemental calcium, 600 mg twice daily.
Laboratory test results 2 weeks after surgery:
- Calcium = 11.8 mg/dL (2.95 mmol/L) (reference range, 8.2-10.2 mg/dL [2.1-2.6 mmol/L])
- Phosphorus = 2.2 mg/dL (0.7 mmol/L) (reference range, 2.3-4.7 mg/dL [0.7-1.5 mmol/L])
- Albumin = 4.2 g/dL (42 g/L) (reference range, 3.5-5.0 g/dL [35-50 g/L])
- PTH = 120 pg/mL (120 ng/L) (reference range, 10-65 pg/mL [10-65 ng/L])
- Serum creatinine = 1.0 mg/dL (88.4 mmol/L) (reference range, 0.6-1.1 mg/dL [53.0-97.2 mmol/L])
Which of the following should you do now?
- Genetic testing for mutations in the calcium-sensing receptor gene (CASR)
- Genetic testing for mutations in the multiple endocrine neoplasia type 1 gene (MEN1)
- 4D CT of the neck
- Another sestamibi scan
- Cessation of calcium supplementation and recheck of laboratory tests in 1 month
Genetic testing for mutations in the multiple endocrine neoplasia type 1 gene (MEN1)
It is critical to think about and screen for MEN1 mutations (Answer B) in all young patients (<30 years) who present with primary hyperparathyroidism. Up to 10% of patients with primary hyperparathyroidism have a familial (germline) mutation. Hereditary syndromes should be suspected in anyone with a personal history of other endocrine tumors (especially pancreatic or pituitary) or a family history of parathyroid disease, renal stones, or pancreatic/pituitary tumors in first-degree relatives. These syndromes should also be suspected and screened for in patients presenting with atypical or multigland parathyroid adenomas at any age. Only 2% to 4% of all patients with primary hyperparathyroidism present with multigland adenomas.
In addition to multiple endocrine neoplasia type 1, other more rare causes of multiorgan syndromic primary hyperparathyroidism include multiple endocrine neoplasia type 2, multiple endocrine neoplasia type 4, and hyperparathyroidism–jaw tumor syndrome. Familial idiopathic primary hyperparathyroidism may be a subtype of hyperparathyroidism–jaw tumor syndrome.
The presence of renal stones and high urinary calcium excretion excludes familial hypocalciuric hypercalcemia caused by an inactivating mutation in the gene encoding the calcium sensing receptor (CASR) (Answer A). Although a 4D CT (Answer C) would be reasonable in an older patient with persistent primary hyperparathyroidism, in this young man, it is mandatory to screen for multiple endocrine neoplasia first because that diagnosis would alter the surgical management and medical follow-up. Another sestamibi scan (Answer D) looking for a second adenoma would not be indicated when all 4 glands may be involved. Calcium supplementation would not be responsible for these laboratory findings, so cessation of this treatment (Answer E) is not necessary.
Pursue the diagnosis of multiple endocrine neoplasia type 1 in young patients presenting with primary hyperparathyroidism.
Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011.
Eastell R, Brandi ML, Costa AG, D’Amour P, Shoback DM, Thakker RV. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3570-3579.
Lassen T, Friis-Hansen L, Rasmussen AK, Knigge U, Feldt-Rasmussen U. Primary hyperparathyroidism in young people. When should we perform genetic testing for multiple endocrine neoplasia 1 (MEN-1)? J Clin Endocrinol Metab. 2014;99(11):3983-3987.