The multiple endocrine neoplasia (MEN) syndromes are rare autosomal-dominant conditions that predispose affected individuals to benign and malignant tumors of the pituitary, thyroid, parathyroids, adrenals, endocrine pancreas, paraganglia, or nonendocrine organs.

Four major forms of MEN, which are autosomal dominant disorders, are recognized and referred to as:

  1. MEN type 1 (MEN1), due to menin mutations.
  2. MEN2 (previously MEN2A) due to mutations of a tyrosine kinase receptor encoded by the rearranged during transfection (RET) protoncogene.
  3. MEN3 (previously MEN2B) due to RET mutations.
  4. MEN4 due to cyclin-dependent kinase inhibitor (CDNK1B) mutations.

 

MEN type 1 (MEN1)

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare hereditary endocrine cancer syndrome characterized primarily by tumors of the parathyroid glands (95% of cases), endocrine gastroenteropancreatic (GEP) tract (30-80% of cases), and anterior pituitary (15-90% of cases). Other endocrine and non-endocrine neoplasms including adrenocortical and thyroid tumors, visceral and cutaneous lipomas, meningiomas, facial angiofibromas and collagenomas, and thymic, gastric, and bronchial carcinoids also occur. The phenotype of MEN1 is broad, and over 20 different combinations of endocrine and non-endocrine manifestations have been described MEN1 should be suspected in patients with an endocrinopathy of two of the three characteristic affected organs, or with an endocrinopathy of one of these organs plus a first-degree relative affected by MEN1 syndrome.

Many endocrine tumors in MEN1 are benign and cause symptoms by overproduction of hormones or local mass effects, while other MEN1 tumors are associated with an elevated risk for malignancy. About one third of patients affected with MEN1 will die early from an MEN1-related cancer or associated malignancy. Entero-pancreatic gastrinomas and thymic and bronchial carcinoids are the leading cause of morbidity and mortality.

Associated endocrine tumors

Patients most often present with multiple tumors of the parathyroids, anterior pituitary adenomas, and tumors of the neuroendocrine cells in the GEP tract, which constitute the “typical” clinical features of this syndrome.

Parathyroid glands

PHPT is the most common endocrinopathy in MEN1, affecting nearly 100% of patients by age 50. It is the first endocrine MEN1 manifestation in 90% of patients and may be recognized as early as age 8 in rare cases. MEN1 hyperparathyroidism can be differentiated from sporadic hyperthyroidism by its earlier age of onset (typically between 20 and 25 years of age versus 50 years). Moreover, unlike the single adenomas of sporadic PHPT, PHPT in MEN1 is characterized by multiglandular hyperplasia and usually all parathyroids are affected.

Anterior pituitary tumors

Anterior pituitary adenomas have been reported to occur in 15 to 90% of MEN1 patients. They are the first manifestation of MEN1 in 25% of sporadic and 10% of familial cases. MEN1 anterior pituitary adenomas are usually single. They are invasive only in 10-15% of cases, and malignant degeneration is a very rare event. Symptoms depend on both the secreted pituitary hormone and/or compressive effects due to size of the tumor. Pituitary macroadenomas may compress optic chiasm causing bitemporal hemianopia and other visual field defects, blurred vision and headaches, or they compress the adjacent normal pituitary tissue inducing hypopituitarism. Approximately 60% of MEN1-associated pituitary tumors secrete prolactin (prolactinomas), 25% secrete GH, 3% secrete adenocorticotrophin (ACTH) causing hypercortisolism, and the others seem to be non-functional. The frequency of plurihormonal-secreting tumors is higher in MEN1 than in sporadic isolated pituitary tumors.

Prolactinomas

These prolactin-secreting tumors (with or without simultaneous GH over-secretion) are the most common pituitary tumors in MEN1, and symptoms include galactorrhoea, amenorrhoea, and infertility in women and hypogonadism, sexual dysfunction, reduction of libido, impotence, and, more rarely, gynecomastia in men.

GH-secreting tumors

The GH-secreting tumors are the second most frequent MEN1 anterior pituitary tumors after prolactinomas. The increased secretion of GH is responsible for the development of gigantism in children and acromegaly in adults.

Gastroenteropancreatic (GEP) tract neuroendocrine tumors

Endocrine GEP tumors occur in about 30-80% of MEN1 patients and are the second most frequent clinical manifestation of MEN1. Unlike sporadic GEP tumors, they are characterized by multiple nodular lesions that develop usually a decade earlier than their sporadic counterparts. The multiple adenomas, scattered throughout the whole pancreas, may be very numerous (up to 100 in some cases) and range in size from microadenomas slightly larger than unaffected islets to macroadenomas larger than 0.5 cm. Two thirds of these tumors produce excessive amounts of hormones (gastrin, insulin, somatostatin, glucagons, neurotensin, or vasoactive intestinal polypeptide (VIP)) and are associated with distinct clinical syndromes. The most common functional pancreatic tumors are gastrinomas (54%) and insulinomas (15%). Non-functional tumors and insulinomas are located within the pancreas, while gastrinomas are often found in the soft tissue around the pancreas and in the duodenal submucosa, but not in the mucosa where the gastrin-producing G cells are located.

Gastrinomas

These gastrin-secreting tumors represent about 54% of all functional GEP endocrine tumors in MEN1. Ninety percent are located in the duodenum. Zollinger-Ellison syndrome (ZES) refers to the constellation of clinical findings associated with increased gastric acid production caused by gastrin. Manifestations of ZES include esophagitis, vomiting, epigastric abdominal pain, chronic diarrhea, duodenal ulcers especially in the usual location of the second and third portion, jejunal ulcers, and weight loss. Gastrinomas in MEN1 are frequently multiple and most of them are malignant, with half having metastasized before diagnosis. Malignant gastrinomas represent the major cause of morbidity and mortality in MEN1 patients, principally due to duodenal and jejunal ulcers that may perforate. Poor prognosis is associated with primary pancreatic gastrinomas (more aggressive than duodenal gastrinomas, as suggested by their larger size and greater risk for hepatic metastasis), liver metastases, ectopic Cushing syndrome, and very high gastrin level. Nodal metastases do not seem to negatively influence prognosis.

Insulinomas

These β-islet cell insulin-secreting tumors arise in about 10% of MEN1 patients, often in association with gastrinomas. They usually occur in the third decade of life, one decade earlier than onset of sporadic insulinomas. MEN1 insulinomas can occur as single or multiple macroadenomas of about 1-4 cm in diameter and are almost always benign. Patients with MEN1 insulinoma present with hypoglycaemia that develops after a fast or exertion and improves after glucose intake. Unlike many patients with sporadic insulinoma, MEN1 patients with insulinomas are usually not obese.

Glucagonomas

These α-islet cell glucagon-secreting tumors have been reported in few MEN1 patients. They usually are a single macroadenoma larger than 3 cm. Glucagonomas can manifest with skin rash (necrolytic migratory erythema, venous thrombosis, anemia, diarrhea, anorexia, weight loss, stomatitis, hyperglycaemia, glucose intolerance, and hyperglucagonaemia.

VIPomas

These vasoactive intestinal peptide (VIP)-secreting tumors occur as WDHA syndrome characterized by watery diarrhea, hypokalaemia, and achlorhydria . VIPomas have been reported in only a few MEN1 patients.

PPomas

These tumors secrete pancreatic polypeptide (PP) and have been recognized in some MEN1 cases. Increased PP secretion has no known clinical significance.

Non-functional GEP tract tumors

These tumors are frequent in MEN1 syndrome affecting about 20% of patients.

Other MEN1-associated endocrine tumors

Adreno-cortical tumors

Adreno-cortical tumors, involving one or both adrenal glands, affect about 20-40% of MEN1 patients, usually occurring later in the course of the disease. The great majority of these tumors are non-functional and exhibit an indolent clinical course. However, rare functional adrenal cortical tumors secrete ACTH, and they are associated with elevated serum concentrations of cortisol, causing primary hypercortisolism, primary hyperaldosteronism, and Cushing’s syndrome.

Pheochromocytoma

This tumor affects less than 1% of all MEN1 patients and it is always unilateral. However, it is appropriate to measure urinary catecholamine values prior to surgery to diagnose and treat a MEN1-associated pheochromocytoma and to avoid dangerous and potentially lethal blood pressure peaks during surgery.

Thyroid tumors

Thyroid tumors, consisting of adenoma, colloid goitres, and carcinomas have been reported to occur in over 25% of MEN1 patients. Nevertheless, the prevalence of thyroid disorders in the general population is high thus association of thyroid lesions in MEN1 patients may be incidental and not significant.

MEN1-associated non-endocrine tumors

Carcinoid tumors

These tumors are estimated to occur in about 10% of MEN1 patients and may be located in the gastrointestinal tract (type II gastric enterochromaffin-like (ECL) cells), the pancreas, the bronchi, or the thymus. Thymic carcinoids are more prevalent in males than in females, while bronchial carcinoids are more prevalent in females than in males. Cigarette smoking appears to be a risk factor for bronchial carcinoids . Most carcinoids are clinically silent. Thymic carcinoids may be aggressive and lethal, particularly in males who are smokers. Most bronchial carcinoids behave indolently, but there have been reported cases of local mass effects, metastasis and recurrence after resection. Rarely thymic, bronchial and gastric carcinoids over-secrete ACTH, calcitonin, GHRH, serotonin, or histamine and rarely cause the carcinoid syndrome associated with flushing attacks and dyspnoea.

Collagenomas and facial angiofibromas

Collagenomas have been reported in >70% of MEN1 patients and they present as multiple, skin-coloured, sometimes hypopigmented cutaneous nodules. They manifest symmetrically arranged on the trunk, neck, and upper limbs. They are typically asymptomatic, roundish, firm-elastic and can range from few millimetres to several centimetres in size. Multiple facial angiofibromas have been observed in 40-90% of MEN1 patients. Half of patients with angiofibromas have five or more. They are benign tumors comprising blood vessels and connective tissue, and they consist of acneiform papules that do not regress and that may extend across the vermillion border of the lips.

Lipomas

Lipomas may occur in 20-30% of MEN1 patients. They are generally multiple benign fatty tissue tumors and can be subcutaneous or, rarely, visceral. Lesions, often multiple, can be small or large and cosmetically disturbing. When surgically removed they usually do not recur.

Leiomyomas

Leiomyomas of the esophagus, uterus, or rectum can occasionally occur in MEN1 patients. They are benign neoplasms derived from smooth muscle.

Central nervous system tumors: meningiomas and ependymomas

Meningiomas have been reported in about 8% of MEN1 patients, typically presenting later in life. Few cases of spinal ependymomas have been rarely (about 1% of patients) associated with MEN1 syndrome and with abnormalities at the 11q13 locus. Whether meningiomas or ependymomas occur with increased frequency in MEN1 patients compared to the general normal population is unclear.

 Diagnosis

Clinical diagnostic criteria for MEN1 syndrome include the presence of two endocrine tumors that are parathyroid, pituitary, or GEP tract tumors. Biochemical testing detects an increased serum concentration of parathyroid hormone and calcium in primary hyperparathyroidism, increased serum concentrations of prolactin from a prolactinoma, and increased serum concentrations of gastrin, insulin, and VIP from tumors of the GEP tract. Prolactinomas are imaged by MRI, neuroendocrine tumors (NETs) are detected by somatostatin receptor scintigraphy, and pancreatic endocrine tumors are detected by endoscopic ultrasound. Molecular genetic testing of MEN1, the only gene in which pathogenic variants are known to cause MEN1 syndrome, detects a heterozygous MEN1 pathogenic variant in approximately 80%-90% of probands with familial MEN1 syndrome and in approximately 65% of simplex cases (i.e., a single occurrence of MEN1 syndrome in the family).

Management

Treatment of manifestations: Hyperparathyroidism is treated with subtotal parathyroidectomy and cryopreservation of parathyroid tissue or total parathyroidectomy and autotransplantation of parathyroid tissue; calcimimetics are used to treat primary hyperparathyroidism in those for whom surgery is contraindicated or has failed; prior to surgery, bone antiresorptive agents are used to reduce hypercalcemia and limit bone resorption. Prolactinomas are treated with dopamine agonists (cabergoline being the drug of choice). Growth hormone-secreting tumors causing acromegaly are treated by transsphenoidal surgery; medical therapy for growth hormone-secreting tumors includes somatostatin analogs, octreotide, and lanreotide. ACTH-secreting pituitary tumors associated with Cushing syndrome are surgically removed; non-secreting pituitary adenomas are treated by transsphenoidal surgery. Proton pump inhibitors or H2-receptor blockers reduce gastric acid output caused by gastrinomas. Surgery is indicated for insulinoma and most other pancreatic tumors. Long-acting somatostatin analogs can control the secretory hyperfunction associated with carcinoid syndrome. Surgical removal of adrenocortical tumors that exceed 3.0 cm in diameter can prevent malignancy.

Prevention of primary manifestations: Thymectomy may prevent thymic carcinoid in males, particularly in smokers.

Prevention of secondary complications: Measure PTH and/or serum calcium to assess for hypoparathyroidism following subtotal or total parathyroidectomy. Measure urinary catecholamines prior to surgery to diagnose and treat a pheochromocytoma to avoid blood pressure peaks during surgery.

Surveillance: Serum concentrations of calcium from age eight years, gastrin from age 20 years, and prolactin from age five years; abdominal CT or MRI from age 20 years and head MRI from age five years. Consider fasting serum PTH concentration and yearly chest CT.

Evaluation of relatives at risk: Because early detection affects management, molecular genetic testing is offered to at-risk members of a family in which a germline MEN1 pathogenic variant has been identified.

Pregnancy management: Women with primary hyperparathyroidism from any cause are at increased risk of developing preeclampsia; infants born to women with primary hyperparathyroidism should be monitored for postnatal hypocalcemia.