eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Multiple Endocrine Neoplasia

Author: Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Diabetes, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis and St Jude Children's Research Hospital; Lieutenant Colonel (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Coauthor(s): Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine; Christian A Koch, MD, PhD, FACP, FACE, Professor and Director, Division of Endocrinology, University of Mississippi Medical Center; George P Chrousos, MD, FAAP, MACP, MACE, Professor and Chair, Department of Pediatrics, Athens University Medical School
Contributor Information and Disclosures

Updated: Jun 12, 2008

Introduction

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

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).

More on Multiple Endocrine Neoplasia

Overview: Multiple Endocrine Neoplasia
Differential Diagnoses & Workup: Multiple Endocrine Neoplasia
Treatment & Medication: Multiple Endocrine Neoplasia
Follow-up: Multiple Endocrine Neoplasia
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

multiple endocrine neoplasia, MEN syndrome, MEN 1, MEN 2A, MEN 2B, Wermer syndrome, Wermer's syndrome, Sipple syndrome, Sipple's syndrome, multiple endocrine adenopathy, MEA, pluriglandular syndrome, Carney complex, vasoactive intestinal peptide tumor, VIPoma, pancreatic polypeptide–producing tumor, PPoma, medullary thyroid carcinoma, MTC, gastrinoma, insulinoma, glucagonoma, prolactinoma, somatotropinoma, corticotropinoma, nonfunctioning tumors, lipomas, angiofibromas, pheochromocytoma, hyperparathyroidism, parathyroid gland hyperplasia, thyroid cancer, mucosal neuroma, medullated corneal nerve fibers, marfanoid habitus, peptic ulcer disease, coronary heart disease, hypercalcemia, stroke, heart failure, Zollinger-Ellison syndrome, ZES, Hirschsprung disease

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Contributor Information and Disclosures

Author

Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Diabetes, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis and St Jude Children's Research Hospital; Lieutenant Colonel (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society
Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching

Coauthor(s)

Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Klaus Radebold, MD, PhD is a member of the following medical societies: American Gastroenterological Association and New York Academy of Sciences
Disclosure: Nothing to disclose.

Christian A Koch, MD, PhD, FACP, FACE, Professor and Director, Division of Endocrinology, University of Mississippi Medical Center
Christian A Koch, MD, PhD, FACP, FACE is a member of the following medical societies: American Academy of Neurology, American Association of Clinical Endocrinologists, American College of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Society for Clinical Pharmacology and Therapeutics, American Society for Dermatologic Surgery, Endocrine Society, and German Diabetes Society
Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, Professor and Chair, Department of Pediatrics, Athens University Medical School
George P Chrousos, MD, FAAP, MACP, MACE is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Arlan L Rosenbloom, MD, Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology
Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Lynne Lipton Levitsky, MD, Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor, Department of Pediatrics, Harvard University Medical School
Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfiser, Inc. Honoraria Consulting

 
 
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