AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

First reported in 1963 by Wermer, multiple endocrine neoplasia (MEN) syndromes consist of rare, autosomal dominant mutations in genes that regulate cell growth.¹ Current classification recognizes type 1 MEN and type 2 MEN, with subcategories type 2A MEN (Sipple syndrome) and type 2B MEN. The menin protein produced from the MENIN gene is a tumor suppressor. Loss of this protein allows tumors to arise. Alternatively, Ret protein produced from the RET gene, a proto-oncogene, can be constitutively activated, causing abnormal cell proliferation.²

Type 1 MEN is defined by hyperfunctioning tumors in all 4 parathyroid glands, pancreatic islets (eg, gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor [VIPoma], pancreatic polypeptide–producing tumor [PPoma]), and the anterior pituitary (eg, prolactinoma, somatotropinoma, corticotropinoma, nonfunctioning tumors). Other associated tumors include lipomas, angiofibromas, or those located in the adrenal gland cortex (rarely, in the adrenal medulla).

Type 2A MEN is defined by medullary thyroid carcinoma (MTC), pheochromocytoma (about 50% of cases), and hyperparathyroidism caused by parathyroid gland hyperplasia (about 20% of cases).

Familial MTC is also recognized. Familial MTC is hereditary MTC without other associated endocrinopathies, although adrenomedullary hyperplasia secondary to a germline RET mutation may still be present but undiagnosed.

Type 2B MEN is defined by medullary thyroid cancer and pheochromocytoma. Associated abnormalities include mucosal neuromas, medullated corneal nerve fibers, and marfanoid habitus.

Pathophysiology

The MENIN gene responsible for type 1 MEN is located on chromosome 11 and produces a tumor suppressor protein called menin. The MENIN gene is ubiquitously expressed and is localized to the nucleus of cells. The former term "amine precursor uptake and decarboxylation (APUD) system" is obsolete. Neuroendocrine tumors can derive from various tissues, including the so-called APUD cells, but also arise from pluripotent stem cells of the respective tissue (eg, pituitary tissue). Patients with type 1 MEN possess a germline mutation in the MENIN gene and develop tumors when inactivation of the wild-type allele occurs.

Most tumors arise in the pituitary gland and pancreatic islet cells and most cases of hyperparathyroidism are sporadic. Only a few cases are related to type 1 MEN.

The gene responsible for type 2 MEN is a proto-oncogene called RET. In contrast to MENIN of type 1 MEN, RET is specifically expressed in neural crest–derived cells, such as the C cells in the thyroid gland and the chromaffin cells in the adrenal gland. Whether RET is also expressed in the parathyroid glands remains unknown, especially considering the low rate of hyperparathyroidism in patients with type 2A MEN and the lack of hyperparathyroidism in type 2B MEN. RET encodes the tyrosine kinase RET protein subunit of a cell surface receptor. Activation of RET leads to hyperplasia of target cells in vivo. Subsequent secondary events then lead to tumor formation.

Most cases of MTC and/or pheochromocytoma are sporadic. Only about 10% of cases are hereditary and related to type 2 MEN.

Type 1 multiple endocrine neoplasia

Hyperparathyroidism is the most common manifestation of type 1 MEN (80% of presentations) and results from hyperplasia of all 4 parathyroid glands. Abnormalities of parathyroid hormone (PTH) secretion may affect children younger than 10 years. Islet-cell tumors that secrete predominantly gastrin are called gastrinomas; these tumors frequently metastasize. Children rarely have gastrinomas. Pituitary tumors (eg, as prolactinoma) affect children as young as 5 years. Adrenal involvement includes silent adenomas, adrenocortical hyperplasia, cortisol-secreting adenomas, and, rarely, carcinomas. In addition, pheochromocytomas have been reported in patients with type 1 MEN. Thymic and bronchial carcinoid tumors can be associated with type 1 MEN. Lipomas and angiofibromas may often lead to the diagnosis of type 1 MEN before the endocrine manifestations.

Type 2A multiple endocrine neoplasia (Sipple syndrome)

Type 2A MEN accounts for most cases of type 2 MEN. In general, type 2 MEN affects about 1 in 40,000 individuals, and fewer than 1000 kindreds are known worldwide. C-cell hyperplasia develops early in life and can be viewed as the precursor lesion for MTC, which often arises multifocally and bilaterally. RET germline mutation testing has replaced the pentagastrin and calcium stimulation tests for the diagnosis of C-cell hyperplasia and MTC. This advance is especially important for children, because the stimulation tests were unpleasant, and reference values for calcitonin were not established in children.

In addition, stimulation tests are inaccurate for the diagnosis of MTC, as demonstrated with prophylactic thyroidectomy based on positive results on RET germline mutation tests. In studies, about 50% of patients with a negative pentagastrin result but a positive RET mutation had already developed MTC. These data supported the recommendation to perform prophylactic thyroidectomy with lymph node dissection in children older age 5 years with positive RET mutations. Most commercial RET mutation tests search for only part of the RET proto-oncogene (exons 10, 11, 13, 14, 15, 16) and typically help in identifying 97% of patients with type 2 MEN.

Pheochromocytomas are bilateral in 70% of cases and develop on the background of adrenomedullary hyperplasia secondary to an RET germline mutation. Biochemical manifestations, imaging manifestations, or both occur in about 50% of patients. The peak age at onset is approximately 40 years, but children as young as 10 years are reported. Therefore, annual surveillance for plasma free metanephrines and urinary catecholamines, including fractionated metanephrines, is recommended in children older than 6 years (although collecting 24-h urine samples in children is difficult). In adults with an adrenal incidentaloma and hypertension, measuring plasma chromogranin A in addition to plasma free metanephrines may be helpful.

Less than 25% of patients with type 2A MEN develop frank hyperparathyroidism; this condition is rare in childhood. Reasons for this low prevalence and discrepancy in type 2B MEN are unknown. Although various RET mutations can cause type 2B MEN, those mutations within exon 16 are most often reported in association with hyperparathyroidism.

Type 2B multiple endocrine neoplasia

Type 2B MEN represents about 5% of all cases of type 2 MEN. Patients have some aspects of a distinctive marfanoid phenotype and mucosal neuromas. MTC is relatively aggressive and frequently occurs in childhood. Children as young as 12 months may develop MTC. Therefore, prophylactic thyroidectomy with lymph node dissection is recommended in children younger than 5 years who have a RET germline mutation in exon 16. Pheochromocytomas also occur earlier than in patients with type 2A MEN, and patients have the same features arising in the context of adrenomedullary hyperplasia, multifocality, and often bilateral involvement. In contrast to MTC, which frequently metastasizes, metastatic pheochromocytomas rarely occur in patients with type 2 MEN (0-25%). An important parameter in this setting is the follow-up period and the time of first occurrence or diagnosis.

Carney complex

Carney complex is a distinct rare type of MEN characterized by primary pigmented adrenocortical disease, pituitary adenoma, Sertoli-cell tumors, thyroid nodules, and additional nonendocrine features. The most commonly associated features are cardiac and skin myxomas, melanotic schwannomas, and lentigines.

Frequency

United States

The prevalence in adults is about 0.02-0.2 cases per 1000 population. Data for children are not available.

Mortality/Morbidity

Death related to MEN can be caused by complicated peptic ulcer disease, metastases of endocrine pancreatic tumors, severe hypercalcemia with arrhythmias, metastatic MTC, catecholamine release–related arrhythmias, coronary heart disease, stroke, heart failure, and/or arrhythmias from cardiac myxomas.

• Zollinger-Ellison syndrome (ZES) is the major cause of morbidity and mortality in type 1 MEN.
• In 1998, Doherty et al reported 103 patients with type 1 MEN.³ In this series, 46% of patients died from causes related to their endocrine tumors after a median of 47 years.
• Mortality in type 2B MEN is mainly due to the aggressive nature of MTCs.

Race

No racial predilection is known.

Sex

The male-to-female ratio is 2:1.

Age

Patients with hyperparathyroidism in type 1 MEN most often present at age 20-40 years, but the disease may appear in children younger than 10 years.

• Type 1 MEN can be detected in individuals from kindreds with testing before age 18 years (even younger, if desired). MENIN mutations occur throughout the gene, and new mutations continue to emerge. Mutation screening helps in identifying as many as 85% of patients with type 1 MEN.
• The degree of penetrance of type 1 MEN at age 20 years is about 43%.
• MEN type 2 is highly penetrant and should be diagnosed by RET mutation testing before age 5 years. If mutation tests are positive, subsequent prophylactic thyroidectomy with lymph node dissection is recommended. If a parent has type 2B MEN, earlier diagnosis is recommended for the affected adult's child because the disease is relatively aggressive.
• All MEN syndromes are rare in children.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Type 1 multiple endocrine neoplasia
• • Hyperparathyroidism is most common initial clinical manifestation of type 1 multiple endocrine neoplasia (MEN). Some patients may manifest findings of ZES before they have hyperparathyroidism.
  • Symptoms of gastrinoma may become clinically apparent either with abdominal pain and diarrhea or with complications such as ulcer perforation or bleeding.
• Type 2A multiple endocrine neoplasia
• • All patients develop MTC on the basis of C-cell hyperplasia.
  • About 50% of patients with MTC manifest pheochromocytomas (usually late in life), and 20% of patients have hyperparathyroidism.

Physical

The clinical picture depends on the glands involved and the hormones secreted.

• Type 1 multiple endocrine neoplasia
• • Hyperparathyroidism occurs with mild hypercalcemia and bone abnormalities. Musculoskeletal symptoms have also been observed in adults but rarely in adolescents.
  • Gastrinoma causes diarrhea, abdominal pain due to peptic ulcer disease, and esophagitis.
  • Insulinoma causes hypoglycemia.
  • Glucagonoma can cause hyperglycemia. Rare cases of type 1 MEN are associated with erythema, anemia, diarrhea, or venous thrombosis.
  • Pituitary tumors may cause headaches, visual field defects, and other effects depending on hormone production.
• Type 2A multiple endocrine neoplasia
• • MTC causes one or more firm nodules, which are often associated with enlarged cervical lymph nodes.
  • Pheochromocytomas cause hypertension, sweating, palpitations and tachycardia, headache, emotional lability, nausea, vomiting, polyuria, and polydipsia.
• Type 2B multiple endocrine neoplasia
• • Marfanoid phenotype develops in all patients. Phenotypic characteristics include a slender body build; long and thin extremities; abnormal laxity of joints; and, in many cases, a high-arched palate, pectus excavatum, or pes cavus.
  • The facies is characterized by enlarged thick lips as a result of embedded mucosal neuromas.
  • Neuromas may be found on the surface of the lips, tongue, eyelids, and cornea.
  • Ganglioneuromas may occur at any level of the GI tract, causing constipation or diarrhea due to abnormal control of intestinal motility.
  • MTC may appear within the first year of life.

Causes

• The gene for type 1 MEN has been localized to chromosome band 11q13. It is a tumor suppressor gene that encodes menin, a nuclear protein.
• The gene for type 2 MEN is RET, located on chromosome band 10q11.2. In type 2A MEN, 95% of RET mutations occur in exons 10, 11, and 14. Mechanisms of tumorigenesis in vivo recently elucidated show allelic imbalance between mutant and wild type RET alleles. In type 2B MEN, RET mutations in exon 16 are found in 95% of cases.
• So-called inactivating mutations due to deletions of RET are associated with congenital neurologic defects, such as aganglionic colon (ie, Hirschsprung disease).⁴ Of interest, these mutations also occur on exons 10 and 11 (associated with type 2A MEN).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Mastocytosis
Type 1 multiple endocrine neoplasia (MEN): Gastrinoma, adrenal adenoma, and glucagonomas
Type 2B MEN: Medullary carcinoma of the thyroid, mucosal neuromas, and ganglioneuromas

Other conditions associated with elevated gastrin levels

Massive small-bowel resection
Hypercalcemia
Treatment with histamine 2 (H₂) blockers or proton-pump inhibitors (PPIs), such as omeprazole
Gastric-outlet obstruction

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

Laboratory studies include investigations of the different tumor-expression patterns.

• Gastrinomas (ZES): Serum gastrin levels exceed 115 ng/mL and increase more than 200 ng/mL from baseline after secretin challenge (ie, intravenous injection of 2 U/kg of secretin). Approximately two-thirds of patients have basal gastrin levels of 150-1000 ng/mL.
• Insulinoma
• • Results may reveal fasting hypoglycemia with inappropriately elevated serum insulin, C-peptide, or proinsulin concentrations.
  • When the serum glucose level is less than 60 mg/dL, the serum insulin level should be less than 2 µU/mL. A serum insulin level of less than 2 µU/mL during hypoglycemia is consistent with hyperinsulinism.
  • Additional diagnostic criteria include the following:
  • • Decreased fasting tolerance (defined during a controlled inpatient fast)
    • Inappropriate glycemic response to glucagon challenge when the patient is hypoglycemic (ie, increase in serum glucose level by >30 mg/dL from a baseline of <60 mg/dL within 20 min after 1 mg of glucagon is intravenously or subcutaneously administered)
    • Suppressed lipolysis (free fatty acid concentration <20 mM)
    • Suppressed ketogenesis (undetectable plasma acetoacetate or beta-hydroxybutyrate) when the patient has hypoglycemia
    • Acute insulin response to peripheral venous or intra-arterial calcium challenge (performed at centers including the University of Texas Health Science Center at San Antonio and the Children's Hospital of Philadelphia)
• Glucagonoma: Findings are hyperglycemia with elevated serum glucagon levels.
• Watery diarrhea syndrome: Serum levels of vasoactive intestinal peptide are elevated. Serum K levels may be low.
• Carcinoids: levels of serotonin, urinary 5-hydroxyindoleacetic acid (5-HIAA), calcitonin, and 24-hour urinary free cortisol and corticotropin may be elevated.
• Pituitary tumors: Tests reveal persistent elevation of serum somatotropin (growth hormone [GH]) during oral glucose challenge; serum free or total insulinlike growth factor (IGF)-I level more than 2 standard deviations (for age, sex, and Tanner stage); or elevated serum prolactin levels.
• Type 2 multiple endocrine neoplasia
• • MTC: Patients frequently have elevated calcitonin levels.
  • Pheochromocytoma: Total urine catecholamine excretion exceeds 100-300 μg/d (over 24 h). Serum levels of more than 2000 μg/mL are pathognomonic. Measuring plasma free and urinary fractionated metanephrines with a 24-hour collection is best.

Imaging Studies

• Type 1 multiple endocrine neoplasia
• • Gastrinomas: Somatostatin-receptor scintigraphy (SRS) has a sensitivity of 70-90%, which is more than that of any other imaging procedure. SRS depends on the SSR receptor profile (types 2 and 5, rarely type 3) and tumors size (exceeding 5 mm). Endoscopic ultrasonography can depict tumors in the pancreatic head but rarely in the duodenal wall.
  • Insulinomas: Perform high-resolution CT scanning and MRI first. SRS findings are positive in about 50% of patients. Intraoperative ultrasonography of the pancreas is highly recommended to detect additional tumors.
  • Pituitary tumors: Perform MRI, CT scanning, or both after biochemical evaluation.
• Pheochromocytoma: Radiologic imaging for pheochromocytomas includes CT scanning, MRI, metaiodobenzylguanidine (MIBG) scanning, OctreoScan imaging, and positive emission tomography (PET).
• Nonfunctioning pancreatic endocrine tumors: After type 1 multiple endocrine neoplasia (MEN) is confirmed, perform pancreatic endoscopic ultrasonography to monitor progression of nonfunctioning pancreatic endocrine tumors. Their incidence is high (54.9%), although their clinical significance remains uncertain. Follow-up of lesions discovered should be coordinated with experienced subspecialists.

Histologic Findings

• Parathyroid glands: The glands show hyperplasia and diffuse or nodular proliferations of chief cells, mixed with some oncocytic cells. All glands are involved.
• Pancreas: Numerous microadenomas (mostly in the pancreatic tail) are present. The tumors display a trabecular pattern. Immunohistochemically, tumor cells stain with antibodies directed to pancreatic polypeptide, glucagon, insulin, and gastrin.
• Duodenum: Duodenal tumors are most often gastrinomas in the first part of the duodenum. They stain positive for gastrin and may metastasize to regional lymph nodes.
• Stomach: In the stomach, diffuse hyperplasia of enterochromaffinlike (ECL) cells is found and is associated with tumors of considerable size but rarely of metastatic potential.
• Pituitary: Most tumors are single, are found in the anterior part of the gland, and produce prolactin and/or GH, and, occasionally, corticotropin.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Hypercalcemia: For patients with type 1 multiple endocrine neoplasia (MEN) who have hypercalcemia, surgery is the treatment of choice, including removal of 3.5 parathyroid glands.
• Gastrinoma: The current treatment consists of PPIs to reduce acid hypersecretion.
• Insulinoma: Surgery is the therapy of choice. Unresectable tumors are treated with diazoxide.
• Glucagonoma: Glucagonomas are surgically removed.
• VIPoma: Octreotide controls symptoms (diarrhea) in 80% of patients; however, surgical tumor removal should be attempted.
• Prolactinoma: Prolactinomas are treated with dopamine agonists, such as bromocriptine or cabergoline.
• GH-producing pituitary tumor: These tumors are treated by transsphenoidal surgery; in rare instances, medical therapy with a GH receptor antagonist is recommended.

Surgical Care

• Type 1 multiple endocrine neoplasia with hyperparathyroidism: In patients with type 1 multiple endocrine neoplasia (MEN) who have hyperparathyroidism, surgery is the treatment of choice if any of the following conditions are present:
• • Serum albumin–adjusted serum calcium level is more than 1 mg/dL of the upper limit of the reference range
  • Kidney stones
  • PTH-induced bone disease with a T score of -2.5
  • 24-hour urinary calcium excretion of more than 400 mg
• Type 1 multiple endocrine neoplasia with ZES
• • In patients with type 1 MEN with ZES, parathyroid surgery is indicated even in mild forms of hypercalcemia because serum calcium levels in the reference range are often associated with lower serum gastrin levels and consecutively lower gastric acid secretion (high calcium stimulates gastrin in those patients).
• • Removal of 3.5-4 parathyroid glands controls hypercalcemia. If 4 glands are removed, immediate autograft of parathyroid tissue into the musculature of the nondominant arm is indicated.
  • Some authors recommend taking careful operative notes and marking the residual parathyroid tissue with clips because reoperation in patients with type 1 MEN is likely.
• Gastrinoma
• • The role of surgery in ZES and type 1 MEN remains controversial because cure is only occasionally achieved. Most tumors are multicentric, raising the possibility of recurrence. Surgery may be indicated in patients with positive findings on imaging studies and no distant metastases.
  • Gastrinomas are found in the duodenal wall, in the pancreas, or in lymph nodes.
  • Local tumor excision is preferred, with larger tumors of the pancreatic body or tail removed by distal pancreatectomy. This approach may reduce the risk of subsequent metastatic disease to the liver.
  • Resection of liver metastases may be beneficial.
  • Total pancreatectomy is not indicated because of the deleterious effects of this procedure (eg, pancreatic exocrine insufficiency, diabetes mellitus).
• Insulinoma
• • Insulinomas are single large tumors that can be enucleated.
  • Resection may result in cure, although insulinomas in type 1 MEN may be multicentric.
  • Some authors recommend subtotal pancreatectomy (>80% of the pancreas) in patients with multiple tumors or when the tumor is not localized.
  • Surgical debulking in metastatic disease may reduce hypoglycemia to a certain extent.
  • Intraoperative ultrasonography facilitates tumor identification. Other methods include intraoperative monitoring of plasma glucose and insulin levels.
• VIPoma: In VIPoma, resection of single and multiple tumors is indicated, which may include a pancreatic tail resection.
• Carcinoid tumors: Carcinoid tumors are removed surgically; half of tumors are locally invasive or metastatic, particularly thymic carcinoids.
• Pituitary tumors
• • Transsphenoidal pituitary surgery is aimed at resection of any pituitary mass, particularly in acromegaly.
  • Patients with incomplete resection remain on treatment with dopamine agonists.
• Prolactinoma: Prolactinomas may be large and multicentric. The recurrence rate after surgical removal is high. Medical treatment is now the therapy of choice. Transsphenoidal surgery with external radiation therapy (external beam or gamma knife) is indicated in patients in whom long-term bromocriptine therapy is ineffective.
• Type 2 multiple endocrine neoplasia
• • Total thyroidectomy with radical lymph-node dissection is recommended in patients aged 5 years if a RET germline mutation is identified. All regional lymph nodes must be removed, even if they are not macroscopically suspected. Before any surgery, screening for pheochromocytomas must be performed. For those patients with germline mutations in codons 790/791, the age total thyroidectomy should be performed is controversial. 
  • Pheochromocytomas require surgical excision under alpha-adrenergic blockade, starting 7-10 days before surgery (target blood pressure is 120/80 mm Hg while seated and systolic blood pressure is >90 mm Hg while standing/upright).

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical therapy is directed toward the specific endocrine syndromes.

Drug Category: Somatostatin analogs

Sandostatin acts similarly to the natural hormone somatostatin by suppressing peptide secretion from gastroenteropancreatic tumors.

Drug Category: Gastric acid inhibitors

Gastric acid secretion with PPIs is mandatory to prevent complications of gastric acid hypersecretion. PPIs are safe and cause no adverse effects even after long-term use. The goal is to reduce the basal acid output to levels less than 10 mEq/h 1 hour before the next dose in patients without previous acid-reducing gastric surgery and to kess than 5 mEq/h in patients with previous acid-reducing gastric surgery.

Drug Category: Hyperglycemic agents

These agents inhibit insulin release from the tumor.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• After parathyroid surgery, monitor serum ionized calcium and magnesium levels. Transient hypoparathyroidism frequently develops and requires calcium and vitamin D supplementation. In rare cases, hungry-bone syndrome may ensue, with rapid declines in serum calcium and magnesium levels.
• Somatostatin therapy is indicated particularly in patients with acromegaly in whom surgery did not achieve complete tumor removal. Tumor shrinkage can be expected in one third of patients, normalization of IGF-1 levels can be expected in as many as two thirds.
• Pregnancy may ensue with treatment that includes cabergoline or bromocriptine in patients with prolactinoma.

Further Outpatient Care

• In MTC, measure serum calcitonin levels every 6-12 months after surgery. Elevated serum levels in the neck region indicate recurrence that possibly requires further surgery. However, micrometastases often cannot be visualized by using current imaging techniques.
• The resection of one endocrine tumor does not exclude a second tumor, even after an interval of several years. Patients need lifelong surveillance, as do their offspring.
• Pheochromocytomas are monitored with blood pressure and plasma free metanephrines as well as 24-hour urinary catecholamines, including fractionated metanephrine measurements, to exclude recurrence.

In/Out Patient Meds

• Patients with type 1 multiple endocrine neoplasia (MEN) and ZES need lifelong acid inhibition with PPIs.
• Chemotherapy with streptozocin and dacarbazine may reduce the size of nonoperable neuroendocrine tumors.

Deterrence/Prevention

• Because early therapy substantially improves the patient's prognosis, screening is of paramount importance in all forms of multiple endocrine neoplasia (MEN).
• Risk factors include known MEN, a positive family history of MEN, ZES, ganglioneuromas, cutaneous neuromas, a marfanoid somatic phenotype, parathyroid hyperplasia, multicentric medullary carcinoma of the thyroid, and multicentric or bilateral pheochromocytomas.
• Screening tests include the following measurements based on the type of MEN:
• • Type 1 multiple endocrine neoplasia - Serum calcium and intact PTH, prolactin, plasma chromogranin A, fasting gastrin, fasting glucose and insulin, and free IGF-I determinations
  • Type 2A multiple endocrine neoplasia - RET germline mutation testing and determinations of plasma calcitonin, plasma free metanephrines and 24-hour urinary catecholamines (including fractionated metanephrines), and serum calcium levels
  • Type 2B multiple endocrine neoplasia - RET germline mutation testing and determinations of serum calcitonin, plasma free metanephrines, and 24-hour urinary catecholamines including fractionated metanephrines
• If test results are in the reference range on 3 occasions and if the patient is older than 35 years, he or she can be declared a noncarrier. Offspring of noncarriers do not require testing. Mutation analysis of the MENIN gene enables the identification of people carrying a germline mutation.

Prognosis

• Type 1 multiple endocrine neoplasia
• • The prognosis is generally good in the presence of discrete parathyroid and pancreatic islet disease or pituitary adenoma.
  • Pancreatic islet cell carcinoma and carcinoids are slowly progressive.
  • Patients with gastrinoma in type 1 MEN may have a prognosis better than that of patients with the sporadic form of the disease.
• Type 2A multiple endocrine neoplasia: The prognosis depends on the stage of medullary thyroid cancer and is generally good after prophylactic thyroidectomy.
• Type 2B multiple endocrine neoplasia
• • The prognosis for patients with type 2B MEN is worse than for patients with type 2A MEN because tumors, such as MTCs, are relatively aggressive, resulting in a 10-year survival rate of 50%.
  • Therefore, individuals with an RET germline mutation in exon 16 should undergo early prophylactic thyroidectomy and screening for pheochromocytomas.

Patient Education

• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Anatomy of the Endocrine System.
• Families can locate an endocrinologist and access helpful information through the Hormone Foundation and the Endocrine and Metabolic Diseases Information Service, which is a service of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• In patients with type 1 multiple endocrine neoplasia (MEN) with ZES who have hypercalcemia, perform parathyroidectomy before abdominal tumoral resection. Lowering serum calcium levels to the reference range may also normalize elevated gastric acid secretion.
• Pheochromocytomas in patients with type 2 MEN may be bilateral. Explore both adrenal glands during surgery.
• Patients with a pheochromocytoma and MTC should receive appropriate preparation with alpha-blocker therapy. Then, the pheochromocytoma should be removed first to avoid life-threatening complications (eg, hypertensive crisis, arrhythmias) caused by the adrenal tumor. Laparoscopic adrenalectomy has now become a routine procedure.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Wermer P. Endocrine adenomatosis and peptic ulcer in a large kindred. Inherited multiple tumors and mosaic pleiotropism in man. Am J Med. Aug 1963;35:205-12. [Medline].
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3. Doherty GM, Olson JA, Frisella MM, Lairmore TC, Wells SA Jr, Norton JA. Lethality of multiple endocrine neoplasia type I. World J Surg. Jun 1998;22(6):581-6; discussion 586-7. [Medline].
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6. Agarwal SK, Lee Burns A, Sukhodolets KE, Kennedy PA, Obungu VH, Hickman AB, et al. Molecular pathology of the MEN1 gene. Ann N Y Acad Sci. Apr 2004;1014:189-98. [Medline].
7. Anlauf M, Schlenger R, Perren A, Bauersfeld J, Koch CA, Dralle H, et al. Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. Am J Surg Pathol. May 2006;30(5):560-74. [Medline].
8. Bahlo M, Schott M, Kaminsky E, Cupisti K. [Multiple endocrine neoplasia 2a: late manifestation of a newly-discovered mutation]. Dtsch Med Wochenschr. Mar 2008;133(10):464-6. [Medline].
9. Berna MJ, Annibale B, Marignani M, Luong TV, Corleto V, Pace A, et al. A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: identification of risk factors. J Clin Endocrinol Metab. May 2008;93(5):1582-91. [Medline].
10. Brauer VF, Scholz GH, Neumann S, Lohmann T, Paschke R, Koch CA. RET germline mutation in codon 791 in a family representing 3 generations from age 5 to age 70 years: should thyroidectomy be performed?. Endocr Pract. Jan-Feb 2004;10(1):5-9. [Medline].
11. Byard RW, Thorner PS, Chan HS, Griffiths AM, Cutz E. Pathological features of multiple endocrine neoplasia type IIb in childhood. Pediatr Pathol. 1990;10(4):581-92. [Medline].
12. Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore). Jul 1985;64(4):270-83. [Medline].
13. Ciccarelli A, Daly AF, Beckers A. The epidemiology of prolactinomas. Pituitary. 2005;8(1):3-6. [Medline].
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Article Last Updated: Jun 12, 2008