Pediatric Multiple Endocrine Neoplasia

Updated: Oct 11, 2017
  • Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Robert P Hoffman, MD  more...
  • Print
Overview

Background

First reported in 1963 by Wermer, multiple endocrine neoplasia (MEN) syndromes, found in pediatric and adult patients, consist of rare, autosomal dominant mutations in genes that regulate cell growth. [1] Current classification recognizes type 1 and type 2 MEN, with the latter being divided into the subcategories type 2A MEN (Sipple syndrome) and type 2B MEN. (See Etiology.)

Menin protein, produced by the MENIN gene, is a tumor suppressor. Loss of this protein allows tumors to arise. Alternatively, Ret protein, produced by the RET gene, a proto-oncogene, can be constitutively activated, causing abnormal cell proliferation. (See Pathophysiology, Etiology, and Workup.) [2, 3]

Type 1 MEN

Type 1 MEN is defined by hyperfunctioning tumors in the following:

  • All 4 parathyroid glands
  • Pancreatic islets - Eg, gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor (VIPoma), pancreatic polypeptide–producing tumor (PPoma)
  • Anterior pituitary - Eg, prolactinoma, somatotropinoma, corticotropinoma, nonfunctioning tumors

Other associated tumors include lipomas, angiofibromas, and those located in the adrenal gland cortex (rarely, in the adrenal medulla).

Type 2A MEN

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). (See Pathophysiology, Presentation, Workup, and Treatment.

Type 2B MEN

Type 2B MEN is defined by MTC and pheochromocytoma. Associated abnormalities include mucosal neuromas, medullated corneal nerve fibers, and marfanoid habitus. (See Pathophysiology, Presentation, Workup, and Treatment.)

Familial MTC

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

Epidemiology

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

The male-to-female ratio for MEN is 2:1. 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. However, all MEN syndromes are rare in children.

Patient education

For patient education information, see 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.

Next:

Pathophysiology

Type 1 MEN

Hyperparathyroidism is the most common manifestation of type 1 MEN (80% of presentations); it 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) can 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 also be associated with type 1 MEN. [4] Lipomas and angiofibromas may often lead to the diagnosis of type 1 MEN before the endocrine manifestations.

Type 2A MEN (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.

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.

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 2A MEN are unknown. Although various RET mutations can cause type 2A MEN, those mutations within exon 16 are most often reported in association with hyperparathyroidism.

Type 2B MEN

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.

 

Content.

Previous
Next:

Etiology

Type 1 MEN

The MENIN gene responsible for type 1 MEN has been localized to chromosome band 11q13; it produces a nuclear protein called menin, a tumor suppressor. The MENIN gene is ubiquitously expressed and is localized to the nucleus of cells; there is increasing evidence that menin may act in DNA repair or synthesis.

Patients with type 1 MEN possess a germline mutation in the MENIN gene and develop tumors when inactivation of the wild-type allele occurs, resulting in unsuppressed growth. Mutations are distributed over the entire coding region without showing any significant hot spot region. [5]

In type 1 MEN, neuroendocrine tumors can derive from various tissues, including the so-called APUD cells, as well as from pluripotent stem cells of these respective tissue (eg, pituitary tissue). [6] Most tumors arise in the pituitary gland and pancreatic islet cells. There is a lower incidence of parathyroid involvement in type 1 MEN compared with tumor rates in other tissues. However, patients with type 1 MEN–associated hyperparathyroidism tend to be younger than patients with sporadic primary hyperparathyroidism.

Type 2 MEN

The genetic mutation in type 2 MEN occurs in a proto-oncogene called RET, located on band 10q11.2. 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. 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. The presence or absence of RET expression in parathyroid tissue is unknown.

There are typical genetic signatures for most cases of type 2 MEN. In type 2A MEN, 95% of RET mutations occur in exons 10, 11, and 14. Of patients with type 2B MEN, 95% have a point mutation in exon 16 (M918T). A second point mutation at codon 883 has been found in 2-3% of type 2B MEN cases. Interestingly, risk stratification strategies, targeting the age of development of medullary thyroid cancer, have been developed. These are based on the genomic signature of the RET mutation. Consensus guidelines for children with the highest risk mutations (eg, c.918,c.883) recommend total thyroidectomy and central lymph node dissection as early as 6 months after birth. [7] Mechanisms of tumorigenesis that have been elucidated show allelic imbalance between mutant and wild type RET alleles.

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

So-called inactivating mutations due to deletions of RET are associated with congenital neurologic defects, such as aganglionic colon (ie, Hirschsprung disease). [8] Of interest, these mutations also occur on exons 10 and 11 (associated with type 2A MEN).

Previous
Next:

Prognosis

Type 1 MEN

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 MEN

The prognosis depends on the stage of medullary thyroid cancer and is generally good after prophylactic thyroidectomy.

Type 2B MEN

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. MTC may appear within the first year of life.

Morbidity and mortality

Death related to MEN can be caused by the following:

  • 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
  • Arrhythmias from cardiac myxomas

Zollinger-Ellison syndrome (ZES) is the major cause of morbidity and mortality in type 1 MEN. Mortality in type 2B MEN is mainly due to the aggressive nature of MTCs.

In a report on 103 patients with type 1 MEN, Doherty et al found that 46% of these individuals died from causes related to their endocrine tumors after a median of 47 years. [9]

Previous