The multiple endocrine neoplasia type 1 (MEN1) syndrome was initially described in 1954 as Wermer’s syndrome. Dr Paul Wermer reported on a syndrome in which adenomatosis of the anterior pituitary, parathyroid, and pancreatic islets was observed in a family in which the father and four of nine siblings were affected.¹ He postulated that this syndrome was likely inherited as an autosomal dominant disease and that these patients commonly also suffered from ulcers of the stomach and duodenum. It is now widely known that MEN1 consists of a constellation of multiglandular parathyroid disease, neuroendocrine tumors of the gastroenteropancreatic system, anterior pituitary adenomas, and other associated nonendocrine manifestations such as facial angiofibromas.

The MEN1 syndrome develops in 1/20,000 to 1/40,000 individuals² and is inherited in an autosomal dominant fashion. Primary hyperparathyroidism is the most common and earliest manifestation in MEN1 patients, presenting in 80% to 100% by age 40. Gastrin-secreting tumors (gastrinomas) are the major cause of morbidity and mortality with the MEN1 syndrome and about 50% of MEN1 patients develop gastrinomas by age 50.^3,4,5 Insulinomas are present in 10% to 35% of MEN1 patients and are often benign and solitary. Most of the anterior pituitary tumors are prolactinomas which are present in 20% to 50% of MEN1 patients, although there are also reports of growth hormone-, corticotropin-, and thyrotropin-secreting pituitary tumors.⁸

The multiple endocrine neoplasia type 1 occurs as a result of a loss of function of a tumor suppressor gene, MEN1, located on chromosome 11q13.⁶ The development of this disorder follows the “two-hit hypothesis” whereby two genetic mutations, or “hits,” on both alleles result in loss of function. The first mutation is inherited in the germline and present in every cell; this confers susceptibility to disease. The second is a somatic mutation in a cell located in the target tissue resulting in tumor formation. The MEN1 gene contains 10 exons encoding a 610-amino acid protein called menin.⁶ Menin is known to play an important role in the regulation of gene transcription, cell cycle progression, apoptotic pathways, DNA processing and repair, cytoskeletal integrity, and genome stability. There have been more than 1330 diverse mutations reported in the MEN1 gene as a result of nonsense, missense, frameshift, deletions, and RNA splicing defects.⁷

The multiple endocrine neoplasia type 1 is inherited as an autosomal dominant disorder, so the diagnosis of MEN1 has important implications for other family members because first-degree relatives have an approximately 50% risk of developing the disease. Studies have noted about 10% of germline MEN1 mutations arise de novo and about 30% of patients have no detectable mutations.⁸ MEN1 genetic testing should be performed in (1) a patient with two or more MEN1-associated endocrine tumors; (2) asymptomatic or symptomatic first-degree relatives of a known MEN1 mutation carrier; and (3) and patients with suspicious or atypical MEN1, which includes patients with parathyroid adenomas occurring before age 30 and multigland parathyroid disease.⁹ Some groups suggest that relatives of a patient with known MEN1 mutation should be offered MEN1 gene testing prior to any biochemical or radiographic tests in order to avoid multiple tests and decrease financial costs.⁹

Primary hyperparathyroidism is the most common abnormality of patients with MEN1 occurring in approximately 90% of patients.⁹ Patients present with hypercalcemia on routine lab draw, nephrolithiasis, osteitis fibrosa cystica, or abdominal pain. Biochemical analysis reveals hypercalcemia with elevated parathyroid hormone (PTH) level. Patients with MEN1 have an earlier age of onset (20 to 25 years vs. 55 years) and greater bone mineral density loss than patients with sporadic primary hyperparathyroidism. Preoperative workup includes biochemical analysis alone; preoperative imaging is of limited benefit as all glands are diseased and a full-neck exploration is standard of care. Surgery is the elective therapeutic approach to hyperparathyroidism in MEN1 and the goals of surgery are (1) to permanently correct the hypercalcemia, (2) to avoid permanent hypocalcemia, and (3) to facilitate a future surgery of possible recurrences. Surgical treatment involves either subtotal parathyroidectomy with removal of 3.5 glands, leaving a small portion of parathyroid tissue on its native pedicle, OR total parathyroidectomy with autotransplantation of parathyroid tissue to a remote location (usually the brachioradialis muscle). The preferred surgical procedure for primary hyperparathyroidism in MEN1 syndrome has been a source of controversy among surgeons. Subtotal parathyroidectomy is associated with persistent or recurrent hypercalcemia within 10 to 12 years of surgery in 40% to 60% of patients.¹⁰ For total parathyroidectomy with autotransplantation, recurrent hypercalcemia can be observed in more than 50% of patients with MEN1. However, excision of transplanted parathyroid tissue in the forearm can be accomplished under local anesthesia with lower morbidity compared to a reexploration in the neck.¹¹ A higher rate of permanent hypocalcemia following total parathyroidectomy has been reported.¹² Therefore, many groups currently recommend a subtotal parathyroidectomy with transcervical thymectomy.^9,13