Practice Essentials
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant familial tumor syndrome (also termed Wermer syndrome) characterized by tumors of the parathyroid glands, the enteropancreatic neuroendocrine system, the anterior pituitary gland, and the skin. The most common endocrine tumors are parathyroid tumors that cause hyperparathyroidism and hypercalcemia. Other tumors include gastrinomas, insulinomas, prolactinomas, and carcinoid tumors. [1]
Cutaneous tumors are common in MEN1, but they can be easily overlooked because of their subtle appearance. The cutaneous tumors include multiple angiofibromas (previously considered pathognomonic for tuberous sclerosis), collagenomas, and lipomas. [2, 3] Other dermatologic findings are café au lait macules, confetti-like hypopigmented macules, and multiple gingival papules. [2]
Angiofibromas and collagenomas are markers for this tumor syndrome. In the evaluation of a cohort of patients with Zollinger-Ellison syndrome due to gastrinomas, for example, the dermatologic criterion of more than 3 angiofibromas or 1 or more collagenomas was sensitive (75%) and specific (95%) for the diagnosis of MEN1. [4]
Pathophysiology
MEN1 results from a mutation in a tumor suppressor gene called MEN1 on chromosome band 11q13. [5, 6] This gene encodes menin, a 610-amino acid protein that regulates transcription, proliferation, and genome stability. Menin appears to be located mostly in the nucleus, where it has multiple binding partners, including junD and histone modifiers. [7, 8, 9] A mutant menin has been shown to be defective for the transforming growth factor–beta signaling pathway. [10]
Tumor formation involves inactivating mutations of both alleles of the MEN1 gene. In people without MEN1, two independent somatic mutations must occur within a single cell for tumor formation. In an individual with MEN1, the first mutation is already present in all of the patient's cells, so only a single somatic mutation is required. This accounts for the multiple tumors and the tumors occurring at an earlier age. Second-hit mutations in MEN1 have been documented in angiofibromas, collagenomas, and lipomas in patients with MEN1. [11, 12, 13]
Epidemiology
Frequency
Worldwide, the frequency of MEN1 is estimated to be 1 case in 30,000 persons. [14]
Race- and sex-related demographics
No racial predilection is known for MEN1. Incidence rates of MEN1 are equal for men and women, and the frequencies of most tumors are similar in men and women, except that bronchial carcinoids are more common in women and thymic carcinoids are more common in men. [1, 15, 16]
Age
Onset of endocrine tumors is usually in the teenage years. However, symptoms from these tumors may not appear for several years, and the diagnosis is frequently delayed until the fourth decade of life. Cutaneous tumors may develop prior to the manifestation of overt clinical symptoms resulting from endocrine tumors. The earliest cutaneous tumors appear in the teenage years. Recognition of these cutaneous tumors has led to the diagnosis of MEN1 in patients who are otherwise asymptomatic. [17, 18]
Prognosis
In MEN1, benign endocrine and cutaneous tumors cause morbidity, while malignancies cause most mortality, with 70% of deaths resulting from duodenopancreatic neuroendocrine tumors and thymic carcinoids. Women have lower mortality rates than men, likely due to the higher incidence of thymic tumors. [19]
Hormone hypersecretion by endocrine tumors may result in the following:
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Hypercalcemia and recurrent nephrolithiasis (hyperparathyroidism)
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Zollinger-Ellison syndrome (hypergastrinemia)
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Hypoglycemia (hyperinsulinemia)
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Amenorrhea (hyperprolactinemia)
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Acromegaly (excess growth hormone)
Tumors of the pituitary gland may cause symptoms by mass effects. Pancreatic endocrine tumors, particularly gastrinomas, become malignant in about 50% of patients with MEN1. If not treated, patients may die from peptic ulcer disease, metastatic endocrine pancreatic carcinoma, or foregut carcinoid malignancy.
Angiofibromas, collagenomas, and lipomas do not typically cause symptoms, and they are mostly of cosmetic concern.
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A 27-year-old man has telangiectatic, red papules on the nose, the nasolabial fold, and the upper lip. Histologic examination of one of these lesions confirmed the clinical diagnosis of angiofibroma. In addition to multiple facial angiofibromas, this patient has multiple collagenomas and gingival papules, as well as hyperparathyroidism and a positive family history for multiple endocrine neoplasia type 1.
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The shoulder of a 65-year-old man shows multiple firm, skin-colored to slightly hypopigmented papules. Biopsy results of the largest lesion revealed collagenoma. Endocrinologic features of multiple endocrine neoplasia type 1 in this patient are hyperparathyroidism and Zollinger-Ellison syndrome. Note that the photograph was taken with side lighting to accentuate the lesions.
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A close-up view of a large collagenoma on the shoulder of a 65-year-old man shows multiple firm, skin-colored to slightly hypopigmented papules. Endocrinologic features of multiple endocrine neoplasia type 1 in this patient are hyperparathyroidism and Zollinger-Ellison syndrome.
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A 39-year-old woman with multiple endocrine neoplasia type 1 has a soft nodule on the forehead that is consistent with lipoma. Lipomas in patients with multiple endocrine neoplasia type 1 can be single or multiple, and they are sometimes large.
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On the attached gingiva of a 27-year-old man with multiple endocrine neoplasia type 1, a few small, whitish papules are present. Gingival papules are a rare and subtle finding in multiple endocrine neoplasia type 1. In addition to multiple facial angiofibromas, this patient has multiple collagenomas, hyperparathyroidism, and a positive family history for multiple endocrine neoplasia type 1.
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Light microscopic evaluation of a section of an angiofibroma shows prominent vessels and concentric rings of collagen around vessels and adnexal structures (hematoxylin and eosin, original magnification X100). These findings are indistinguishable from those observed in angiofibromas in patients with tuberous sclerosis.
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Histologic examination of a collagenoma reveals dense, thick collagen in the reticular dermis (hematoxylin and eosin, original magnification X40). An elastic stain showed reduced elastic fibers (not shown). Biopsy samples of collagenomas can be mistaken for healthy skin unless an elliptical excision containing surrounding healthy skin is obtained for comparison. The contrast with healthy skin accentuates the thickened dermis and collagen alterations seen in collagenomas.
