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Chapter 52: Multiple Endocrine Neoplasia

Rajesh V. Thakker

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INTRODUCTION

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Multiple endocrine neoplasia (MEN) is characterized by a predilection for tumors involving two or more endocrine glands. Four major forms of MEN are recognized and referred to as MEN types 1–4 (MEN 1–4) (Table 52-1). Each type of MEN is inherited as an autosomal dominant syndrome or may occur sporadically; that is, without a family history. However, this distinction between familial and sporadic forms is often difficult because family members with the disease may have died before symptoms developed. In addition to MEN 1–4, at least six other syndromes are associated with multiple endocrine and other organ neoplasias (MEONs) (Table 52-2). These MEONs include the hyperparathyroidism-jaw tumor syndrome, Carney complex, von Hippel-Lindau disease (Chap. 53), neurofibromatosis type 1 (Chap. 48), Cowden’s syndrome, and McCune-Albright syndrome; all of these are inherited as autosomal dominant disorders, except for McCune-Albright syndrome, which is caused by mosaic expression of a postzygotic somatic cell mutation (Table 52-2).

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TABLE 52-1Multiple Endocrine Neoplasia (MEN) Syndromes
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TABLE 52-1 Multiple Endocrine Neoplasia (MEN) Syndromes
Type (Chromosomal Location) Tumors (Estimated Penetrance) Gene and Most Frequently Mutated Codons
MEN 1 (11q13)

Parathyroid adenoma (90%)

Enteropancreatic tumor (30–70%)

 • Gastrinoma (>50%)

 • Insulinoma (10–30%)

 • Nonfunctioning and PPoma (20–55%)

 • Glucagonoma (<3%)

 • VIPoma (<1%)

Pituitary adenoma (15–50%)

 • Prolactinoma (60%)

 • Somatotrophinoma (25%)

 • Corticotropinoma (<5%)

 • Nonfunctioning (<5%)

Associated tumors

 • Adrenal cortical tumor (20–70%)

 • Pheochromocytoma (<1%)

 • Bronchopulmonary NET (2%)

 • Thymic NET (2%)

 • Gastric NET (10%)

 • Lipomas (>33%)

 • Angiofibromas (85%)

 • Collagenomas (70%)

 • Meningiomas (8%)

MEN1

83/84, 4-bp del (≈4%)

119, 3-bp del (≈3%)

209-211, 4-bp del (≈8%)

418, 3-bp del (≈4%)

514-516, del or ins (≈7%)

Intron 4 ss (≈10%)
MEN 2 (10 cen-10q11.2)

 MEN 2A

MTC (90%)

RET
Pheochromocytoma (>50%) 634, e.g., Cys → Arg (~85%)
Parathyroid adenoma (10–25%)
 MTC only MTC (100%) RET 618, missense (>50%)
 MEN 2B (also known as MEN 3) MTC (>90%) RET 918, Met → Thr (>95%)
Pheochromocytoma (>50%)

Associated abnormalities (40–50%)

 • Mucosal neuromas

 • Marfanoid habitus

 • Medullated corneal nerve fibers

 • Megacolon
MEN 4 (12p13)

Parathyroid adenomaa

Pituitary adenomaa

 CDKN1B; no common mutations identified to date
Reproductive organ tumorsa (e.g., testicular cancer, neuroendocrine cervical carcinoma)
?Adrenal + renal tumorsa

aInsufficient numbers reported to provide prevalence information.

Note: Autosomal dominant inheritance of the MEN syndromes has been established.

Abbreviations: del, deletion; ins, insertion; MTC, medullary thyroid cancer; NET, neuroendocrine tumor; PPoma, pancreatic polypeptide–secreting tumor; VIPoma, vasoactive intestinal polypeptide–secreting tumor.

Source: Reproduced from RV Thakker et al: J Clin Endocrinol Metab 97:2990, 2012.

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TABLE 52-2Multiple Endocrine and Other Organ Neoplasia Syndromes (MEONs)
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TABLE 52-2 Multiple Endocrine and Other Organ Neoplasia Syndromes (MEONs)
Diseasea Gene Product Chromosomal ...

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