There are three well-characterized, inherited pluriglandular disorders in which several endocrine glands simultaneously undergo neoplastic transformation and become hyperfunctional. All these disorders are genetically transmitted in an autosomal dominant fashion. These disorders are MEN-1, MEN-2A, and MEN-2B.

MEN-1 consists of hyperplasia or neoplastic transformation of the parathyroid glands, pancreatic islets, and pituitary.

MEN-2A consists of hyperplasia or neoplastic transformation of the thyroid parafollicular cells (medullary thyroid carcinoma [MTC]), parathyroid glands, and adrenal medulla (pheochromocytoma).

MEN-2B consists of hyperplasia or neoplastic transformation of the thyroid parafollicular cells (MTC) and adrenal medulla (pheochromocytoma) with concomitant development of mucosal neuromas.

The cells that comprise many endocrine organs are able to decarboxylate various amino acids and convert the molecules to amines or peptides that act as hormones or neurotransmitters. These cells have been classified as amine precursor uptake and decarboxylation (APUD) cells and are considered to be embryologically of neuroectodermal origin. APUD cells contain markers of their common neuroendocrine origin, including neuron-specific enolase and chromogranin A. Neoplastic transformation of APUD cells long after organogenesis is complete appears to result from a germline mutation (loss of a tumor suppressor gene in MEN-1 or mutation of a protooncogene to an oncogene in MEN-2A and MEN-2B) in a gene that is expressed only in neuroectodermal cells. When neuroectodermal cells later migrate to specific developing organs, the genetic mutation similarly is distributed to those organs. This explains the common mutations manifested in this class of neuroendocrine tumors (NETs).

This is the eponym for the MEN-1 syndrome. Wermer first recognized the association of parathyroid hyperplasia, multicentric pituitary tumors, and pancreatic islet-cell tumors in several kindreds and described the syndrome in 1954. Although neoplastic transformation occurs most commonly in the parathyroid glands, pituitary, and pancreas, hyperplastic adrenal cortical and nodular thyroid disorders have been described. Carcinoid tumors, especially involving the foregut (thymus, lung, stomach, and duodenum), are uncommon but also have been reported in MEN-1 syndrome.

Wermer syndrome is the most common form of MEN. Its prevalence is estimated to vary between 2 and 20 per 100,000 population. The syndrome is characterized by a high degree of penetrance; expression increases with age.

No. Hyperparathyroidism associated with MEN-1 results from hyperplasia of all four glands, whereas sporadic primary hyperparathyroidism is usually characterized by adenomatous change in a single gland. Hyperparathyroidism is the most common and earliest manifestation of MEN-1, and it occurs in 80% to 95% of cases. It has been described in patients as young as 17 years and develops in nearly all patients with MEN-1 by age 40 years.

Hyperplasia of parathyroid glands affected by MEN-1 results from expansion of multiple cell clones, whereas sporadic parathyroid adenomas result from activation of a single cell clone. A mitogenic factor, similar to basic fibroblast growth factor (bFGF), has been found in MEN-1. The factor may originate from the pituitary and specifically stimulate angiogenesis of parathyroid cells. Complications of MEN-1 hyperparathyroidism are similar to those of sporadic hyperparathyroidism; they include nephrolithiasis, osteoporosis, mental status changes, and muscular weakness.

Therapy of both sporadic adenomas and MEN-1–associated hyperplastic glands depends on surgical resection. In sporadic primary hyperparathyroidism, removal of the solitary adenoma is curative in 95% of cases. In MEN-1–associated hyperplasia, at least 3.5 hyperplastic glands must be resected to restore normocalcemia. Only 75% of patients are normocalcemic postoperatively; 10% to 25% of patients are rendered hypoparathyroid. Unfortunately, the parathyroid remnants in the patient with MEN-1 have a great propensity to regenerate; 50% of patients become hypercalcemic again within 10 years of surgery. This recurrence rate dictates that surgery be delayed until complications of hypercalcemia are imminent or gastrin levels are elevated, as discussed later. Recurrence may be treated surgically or with cinacalcet, which acts at the calcium-sensing receptor, to reduce parathyroid hormone (PTH) secretion.

Neoplastic transformation of the pancreatic islet cells is the second most common manifestation of MEN-1, and it occurs in approximately 66% to 80% of cases. These pancreatic NETs are commonly referred to as PNETs.

PNETs in MEN-1 syndrome are usually multicentric and are often capable of elaborating several peptides and biogenic amines. They are, by convention, classified on the basis of the clinical syndrome produced by the predominant secretory product. This group of tumors characteristically progresses from hyperplasia to malignancy with metastases, thus making curative resection unlikely. PNETs may arise from normal islet cells (eutopic) or cells that are not normal constituents of the adult pancreas (ectopic).

Gastrinomas are the most common functional PNETs in MEN-1 syndrome (47%–78% of cases). They are ectopic tumors; G cells are normally present in the fetal pancreas only. Gastrinomas also may occur independently of MEN-1 (only 15%–48% of all patients with a gastrinoma are later found to have MEN-1). Gastrinomas associated with MEN-1 are multiple and often extrapancreatic, occurring in the duodenal wall and retroperitoneal lymphatics.

Excessive gastrin secretion by these tumors causes prolific production of gastric acid with resultant duodenal and jejunal ulcers and diarrhea. Basal acid output exceeds 15 mmol/hour, and basal fasting serum gastrin levels usually exceed 300 pg/mL.

Hypergastrinemia also may result from any condition that stimulates normal gastrin secretion (hypercalcemia) or that interferes with normal gastric acid production and feedback to the G cells (achlorhydria, gastric outlet obstruction, retained antrum with a Billroth II procedure, vagotomy, and the use of histamine-2 [H₂] blockers and proton pump inhibitors). Hyperparathyroidism (see questions 8 and 9) can therefore falsely elevate serum gastrin levels.

A secretin stimulation test may aid in the differentiation of gastrinomas from other hypergastrinemic states; serum gastrin levels in patients with gastrinomas increase by at least 200 pg/mL. More information about gastrinomas is included in Chapter 53.

Insulinomas are the second most common PNET in the MEN-1 syndrome (12%–36% of islet-cell tumors) and the most common eutopic type. Persistent or disordered insulin secretion causes severe hypoglycemia; inappropriately elevated concentrations of insulin, proinsulin, and C-peptide are present in the serum. Insulinomas associated with MEN-1 syndrome are more frequently multicentric and malignant than are the sporadic tumors. Approximately 1% to 5% of all patients with an insulinoma are eventually discovered to have MEN-1. An excellent discussion of the diagnosis and therapy of insulinomas is found in Chapter 53.

Pancreatic tumors less frequently associated with MEN-1 include glucagonomas, somatostatinomas, and vasoactive intestinal polypeptide–secreting tumors (VIPomas). Associated syndromes and therapy are also described in Chapter 53.

Multicentric gastrinomas are rarely cured surgically (10%–15% of cases). Fortunately, symptoms of hypergastrinemia can be pharmacologically controlled with administration of an H₂ blocker, proton pump inhibitor, or octreotide. Because metastases to the liver become increasingly common when gastrinomas exceed 2 cm in diameter, most surgeons reserve excision for tumors smaller than 2 cm. Gastrinomas express surface receptors for somatostatin, thus potentiating the use of somatostatin-receptor scintigraphy in combination with annual magnetic resonance imaging (MRI) and computed tomography (CT) surveillance to monitor tumor progression.

Insulinomas, unlike gastrinomas, produce devastating hypoglycemia, which is difficult to counteract medically. Without effective long-term pharmacotherapy, surgical resection of the tumor is required in most patients. Fortunately, when the largest tumor is excised, many of the patient’s symptoms are ameliorated. Localization is accomplished preoperatively with endoscopic ultrasonography, MRI or CT, or comparison of insulin levels in the right hepatic vein following selective infusion of the intrapancreatic arteries with calcium gluconate. Intraoperative ultrasonography may also assist precise localization at the time of surgery.

Pituitary tumors occur in 50% to 71% of patients with MEN-1. These tumors may result either from neoplastic transformation of anterior pituitary cells with clonal expansion to a tumor or from excessive stimulation of the pituitary by ectopically produced hypothalamic releasing factors elaborated by carcinoids or pancreatic islet cells.

Prolactinomas, the most common pituitary tumors associated with MEN-1, constitute 60% of the total. The symptoms of hyperprolactinemia (galactorrhea and amenorrhea in women; impotence in men) are the third most common manifestation of MEN-1. The tumors are typically multicentric and large but respond to dopamine agonists, such as bromocriptine. In earlier series, many pituitary tumors described as chromophobe adenomas were, in reality, prolactinomas that contained sparse, poorly staining secretory granules. These tumors are also discussed in Chapter 20.

The second most commonly encountered pituitary tumor type is the growth hormone–producing tumor, which is reported in 10% to 25% of patients. Overproduction of growth hormone results in gigantism in children and acromegaly in adults. The tumors are often multicentric and may result from secretion of growth hormone–releasing hormone by pancreatic or carcinoid tumors. Diagnosis and therapy are described in Chapter 21.

Corticotropin (ACTH)-producing tumors that cause Cushing syndrome may be associated with MEN-1. Such tumors result from neoplastic transformation of the pituitary or elaboration of corticotropin-releasing hormone by pancreatic or carcinoid tumors. Diagnosis and therapy are described in Chapter 23.

The gene predisposing to the development of MEN-1 (MEN-1 susceptibility gene) is located on the long arm of chromosome 11 (11q13) and encodes a protein known as menin, which functionally acts as a tumor suppressor. To date 1133 germline mutations have been discovered, thus rendering genetic screening extremely challenging. The cellular function of menin is complex; menin regulates transcription and genome stability. The proband inherits an allele predisposing to MEN-1 from the affected parent, whereas a normal allele is passed down from the unaffected parent. The gene for this tumor suppressor is unusually susceptible to mutation. If a somatic mutation later inactivates the normal allele, suppressor function is lost, thereby permitting hyperplasia of the gland to occur.

The three means of diagnosing MEN-1 are as follows:

Clinical: Two or more MEN-1–associated tumors

Familial: Patient with one MEN-1–associated tumor and a first-degree relative with MEN-1

Genetic: An asymptomatic carrier of MEN-1 mutation (no biochemical manifestations)

Carriers of the genetic defect must first be clinically identified, the extent of their organ involvement determined, and their family screened for additional carriers of one of the MEN-1 mutations. As mentioned earlier, multiple mutations in the gene coding for menin have been described in patients with MEN-1 and may be used to identify carriers of the disorder. Although mutational analysis was previously restricted to research laboratories, clinical testing for mutations in the MEN-1 gene is now available to detect disease within affected kindreds.

Asymptomatic carriers of the MEN-1 mutation should be screened for biochemical and anatomic evidence of tumors. Manifestations of MEN-1 syndrome have been reported as early as 5 years of age; therefore, for patients at risk, endocrine screening should be considered at that time. Nearly all people at risk develop the disorder by the age of 40 years; screening may be unnecessary in family members older than 50 years who are proved to be disease free.

In known mutant gene carriers, annual testing for calcium, PTH, prolactin, insulin-like growth factor-I (IGF-I), chromogranin A, fasting gastrin, fasting glucose, and insulin levels is recommended. MRI of the pituitary and CT of the abdomen is recommended every 12 to 36 months.

This is the eponym for MEN-2A. In 1961, Sipple recognized and described a patient who died of an intracerebral aneurysm and was found at autopsy to have MTC, pheochromocytomas, and hyperparathyroidism. This disorder is inherited in an autosomal dominant fashion and exhibits a high degree of penetrance and variable expressivity. It is less common than MEN-1 syndrome.

No. MTC results from malignant transformation of the parafollicular cells (or C cells) that normally elaborate calcitonin and are scattered throughout the thyroid gland. MTC accounts for 2% to 10% of all thyroid malignant tumors. The sporadic form of MTC, as described in Chapter 37, is more common (75% of all MTC), occurs in a solitary form (<20% multicentric), and metastasizes to local lymphatics, lung, bone, and liver early in the course of disease (metastasis may occur with primary tumors <1 cm in diameter). Sporadic MTC occurs more commonly in an older population (peak age, 40–60 years) and is usually located in the upper two thirds of the gland.

MTC associated with MEN-2A is multicentric (90% at the time of diagnosis), occurs at a younger age than sporadic MTC (as young as 2 years), and generally has a better prognosis than the sporadic form. MTC occurs in nearly 95% of all cases of MEN-2A and is usually the first tumor to appear.

Calcitonin or other peptides elaborated by the tumor may cause secretory diarrhea that is present in 4% to 7% of patients at the time of diagnosis but develops in 25% to 30% during the course of the disease.

Parafollicular cells in patients with MEN-2A characteristically progress through a state of C-cell hyperplasia to nodular hyperplasia to malignant degeneration over a variable period. It is imperative that patients at risk be diagnosed while still in the C-cell hyperplasia stage; total thyroidectomy precludes malignant degeneration and metastases.

Detection of C-cell hyperplasia is facilitated by the pentagastrin stimulation test. MTC also expresses peptides and hormones not commonly elaborated by parafollicular cells, including somatostatin, thyrotropin-releasing hormone, vasoactive intestinal peptide, proopiomelanocortin, carcinoembryonic antigen, and neurotensin.

Pheochromocytomas occur in 50% to 70% of cases of MEN-2A and are bilateral in up to 84% of patients. Compared with the sporadic form, pheochromocytomas associated with MEN-2A secrete greater amounts of epinephrine. Hypertension is therefore less common, and urinary excretion of catecholamines may become supranormal later in the course of the disease.

Surgical resection is indicated, but controversy surrounds the need for prophylactic resection of contralateral uninvolved adrenals, 50% of which develop pheochromocytomas within 10 years of the original surgical procedure. The diagnosis and management of pheochromocytomas are discussed in Chapter 28.

MEN-2A is caused by an activating mutation of the RET protooncogene located on chromosome 10q11.2. The gene codes for a receptor tyrosine kinase that phosphorylates and activates enzymes critical to cellular development. The ligand that normally activates the tyrosine kinase is glial cell–derived neurotropic factor (GDNF). When GDNF binds, two receptors bind together (homodimerization), and phosphorylation of enzymes occurs downstream. Mutation of the RET protooncogene to an oncogene results in constitutive activation of the enzyme, thus causing unregulated phosphorylation of other critical enzymes. Inheritance of one RET oncogene from one affected parent is sufficient to cause MEN-2A syndrome in children. Five distinct mutations involving exons 10 and 11 have been described in 98% of 203 kindreds with the disorder.

As explained in question 26, screening initially entails the differentiation of gene carriers from uninvolved family members and the subsequent delineation of organ involvement in the affected members. Direct DNA sequencing of the RET oncogene causing MEN-2A is clinically available. With appropriate repeat analysis of positive and negative test results, the assay offers near 100% accuracy in identification of affected individuals. Genetic analysis of the kindred should be performed to identify the specific RET oncogene mutation; characterization of the familial oncogene precludes the need for repetitive biochemical screening of noncarriers in subsequent generations.

Because C-cell hyperplasia has been described in gene carriers as young as 2 years, total thyroidectomy is suggested in affected individuals before age 5 years. An alternative to preemptive thyroidectomy is to perform annual pentagastrin stimulation tests and withhold surgery until a positive result is obtained. Because MEN-2A–associated pheochromocytoma may produce large amounts of epinephrine that do not cause hypertension, annual timed urine collections for catecholamines should be obtained in all gene carriers. Serum levels of calcium should be assessed every 2 years. After the presence of the syndrome has been established, screening for adrenal and parathyroid involvement should continue through life.

MEN-2B syndrome is the association of MTC and pheochromocytoma with multiple mucosal neuromas in an affected individual or kindred. Hyperparathyroidism is not associated with MEN-2B. This syndrome is less common than the MEN-2A and is more commonly sporadic than familial, but if inherited, it is transmitted in an autosomal dominant fashion.

The occurrence of multiple mucosal neuromas on the distal tongue, lips, and eyelids and along the gastrointestinal tract should always raise the possibility of MEN-2B. Other manifestations of MEN-2B include a marfanoid habitus (without ectopia lentis or aortic aneurysms), hypertrophic corneal nerves, and slipped femoral epiphysis.

The MTC associated with this syndrome is more aggressive than other forms; metastatic lesions have been described in infancy. Because of the propensity toward early metastasis, many clinicians advocate that children with the syndrome should undergo total thyroidectomy as soon as surgery can be tolerated. Pheochromocytomas occur in nearly half of all patients and follow a clinical course similar to those in the MEN-2A syndrome.

Overall mortality in MEN-2B is more severe; the average age of death for patients with MEN-2A is 60 years, whereas in patients with MEN-2B, the average age of death is 30 years.

Screening of family members with pentagastrin stimulation for MTC should begin at birth and continue through life if thyroidectomy is deferred. Screening for pheochromocytoma should begin at 5 years and continue for life.

More than 95% of the kindreds with MEN-2B have been found to carry a mutation of the RET protooncogene at codon 918 (exon 16). This oncogene codes for a methionine-to-threonine substitution and results in activation of the innermost tyrosine kinase moiety of the same receptor associated with MEN-2A.

Yes. When the MEN syndromes were initially described, most patients presented with involvement of all the aforementioned organ systems because diagnostic capabilities were limited. At present, early diagnosis of the proband and aggressive screening of the kindred may permit detection of hyperplasia and prompt prophylactic surgery or medical therapy that limits morbidity and mortality.