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Multiple Endocrine Neoplasia Type 1
Article Last Updated: Oct 2, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 9  
Author: Thomas N Darling, MD, PhD, Director of Dermatologic Research, Associate Professor of Dermatology, Department of Dermatology, Uniformed Services University of the Health Sciences
Thomas N Darling is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology
Editors: Terry L Barrett, MD, Director, Associate Professor, Department of Dermatology, Division of Dermatopathology and Oral Pathology, Johns Hopkins University School of Medicine; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Lester F Libow, MD, Dermatopathologist, South Texas Dermatopathology Laboratory; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
Wermer syndrome, multiple endocrine adenomatosis, MEN1, endocrine tumors, cutaneous tumors, angiofibromas, collagenomas, lipomas
Background
Multiple endocrine neoplasia type 1 (MEN1) is a familial tumor syndrome in which persons develop 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.
Cutaneous tumors are common, 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. Recognizing these benign tumors is important because they can serve as markers for this tumor syndrome. In the evaluation of a cohort of patients with Zollinger-Ellison syndrome due to gastrinomas, for example, the dermatological criterion of more than 3 angiofibromas or 1 or more collagenomas was sensitive (75%) and specific (95%) for the diagnosis of MEN1.
Pathophysiology
Patients with MEN1 inherit a mutation in a tumor suppressor gene called MEN1 on band 11q13. This gene encodes a protein, menin, whose functions are unclear. Menin appears to be located mostly in the nucleus, where it has multiple binding partners, including junD. For a tumor to form, both alleles of the gene must be mutated, inactivating the normal gene product. In people without MEN1, 2 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 that only a single somatic mutation is required. This accounts for the multiple tumors and the tumors occurring at an earlier age.
Frequency
International
The frequency of MEN1 is estimated to be 1 case in 30,000 persons.
Mortality/Morbidity
Benign endocrine and cutaneous tumors cause morbidity, and malignancies cause most mortality (see Complications).
Race
No racial predilection is known.
Sex
The incidence is equal for men and women.
Age
- Endocrine tumors: The age of onset of endocrine tumors is usually in the teenaged 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: Cutaneous tumors may develop prior to the manifestation of overt clinical symptoms resulting from endocrine tumors. The earliest cutaneous tumors appear in the teenaged years. The recognition of these cutaneous tumors has been used in the presymptomatic diagnosis of patients with MEN1.
History
Cutaneous tumors are of long duration and generally grow slowly or not at all. This permanence helps differentiate these lesions from inflammatory skin lesions.
- Ask patients with the cutaneous abnormalities seen in MEN1 about symptoms of hormone hypersecretion.
- Ask patients if any family members have similar skin lesions or endocrine tumors.
- Ask if any family members have tuberous sclerosis.
Physical
- Angiofibromas are telangiectatic, skin-colored, pink or light-brown papules that are 1-4 mm in diameter. Approximately 2-50 lesions may be present. They are mostly located on the central part of the face. In separate studies, angiofibromas were reported in 5%, 8%, 43%, 64%, and 88% of patients with MEN1.
- Angiofibromas in patients with MEN1 tend to be smaller in size and less numerous than angiofibromas in patients with tuberous sclerosis. In addition, angiofibromas in MEN1 are common on the upper lip and vermillion border of the lip, whereas angiofibromas in tuberous sclerosis tend to spare the upper lip.
- The age at onset of angiofibromas is later in MEN1 than in tuberous sclerosis; typically, they occur in the second decade and later in life in MEN1 compared with the first decade of life in tuberous sclerosis.
- Patients with MEN1 do not exhibit several findings described in tuberous sclerosis, including the forehead plaque, multiple periungual fibromas, and pitting of the teeth.
- Collagenomas are skin-colored to slightly hypopigmented, firm, round to oval papules that are 0.2-2 cm in diameter. Multiple smaller lesions and/or a few larger lesions may be observed. They are mostly located on the upper part of the trunk and on the neck. They have been reported in 63-72% of patients with MEN1, with 83-91% of patients with collagenomas having multiple lesions.
- Lipomas are soft, compressible, subcutaneous nodules that are generally 0.5-5 cm in diameter. They are solitary or multiple, and they occur on the trunk, the extremities, and the scalp. Lipomas have been reported in 3-34% of patients with MEN1.
- Additional skin findings include café au lait macules; hypopigmented macules, including confettilike hypopigmented macules; gingival papules; and solitary periungual fibroma.
- Solitary hypopigmented macules or café au lait macules are common in the general population and should not be used as markers for MEN1.
- Multiple hypopigmented macules or confettilike hypopigmented macules are more commonly observed in persons with tuberous sclerosis but have been observed in patients with MEN1.
- Similarly, gingival papules are typically associated with tuberous sclerosis and Cowden syndrome, but they have also been observed in 2 patients with MEN1.
- Café au lait macules numbering 3 or less have been seen in patients with MEN1. Six or more café au lait macules indicates neurofibromatosis.
Causes
See Pathophysiology.
Birt-Hogg-Dube Syndrome
Connective Tissue Nevus
Cowden Disease (Multiple Hamartoma Syndrome)
Fibrous Papule of the Face
Nevi, Melanocytic
Syringoma
Trichilemmoma
Trichoepithelioma
Trichofolliculoma
Tuberous Sclerosis
Other Problems to be Considered
Familial cutaneous collagenoma
Familial multiple lipomas
Multiple familial trichoepithelioma
Lab Studies
- The observation of multiple facial angiofibromas, collagenomas, and lipomas does not establish the diagnosis of MEN1. These cutaneous findings indicate the need for further testing for MEN1 (and/or tuberous sclerosis, depending on the overall clinical picture), including both blood studies to examine for evidence of hormone hypersecretion and imaging studies to look for the presence of tumors. DNA testing is available but identifies a mutation in only about 80% of patients with familial MEN1.
Procedures
- Skin biopsy may or may not be required, depending on the clinical appearance, the physician's experience, and whether the skin findings are being used to help establish the diagnosis of MEN1.
Histologic Findings
The histologic features of angiofibroma include dermal fibrosis, ectatic blood vessels, and stellate cells in the upper dermis.
The histologic features of collagenoma include increased amounts of collagen and normal or decreased numbers of elastic fibers. The features of the collagenoma may appear normal unless the biopsy sample includes surrounding healthy skin.
The histologic features of lipoma include a circumscribed nodule of uniform adipocytes.
Surgical Care
- Patients may desire to have these cutaneous tumors removed because of cosmetic concerns, particularly with the larger facial angiofibromas. A variety of methods have been used to treat angiofibromas in patients with tuberous sclerosis, and these methods are likely applicable to angiofibromas in patients with MEN1. These methods include shave excision, dermabrasion, and carbon dioxide laser. Cosmetic improvement of facial angiofibromas in patients with MEN1 has been obtained with shave excision. In some cases, lesions treated in this way have slowly reappeared.
- Collagenomas and lipomas can be excised, and lipomas can also be treated by liposuction.
Consultations
- Consult an endocrinologist.
Complications
- Endocrine tumors
- Tumors may hypersecrete hormone, causing hypercalcemia and recurrent nephrolithiasis (hyperparathyroidism), Zollinger-Ellison syndrome (hypergastrinemia), hypoglycemia (hyperinsulinemia), amenorrhea (hyperprolactinemia), or 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. Untreated, patients may die from peptic ulcer disease, metastatic endocrine pancreatic carcinoma, or foregut carcinoid malignancy.
- Cutaneous tumors: Angiofibromas, collagenomas, and lipomas do not typically cause symptoms, and they are mostly of cosmetic concern.
Patient Education
| Media file 1:
A 27-year-old man has telangiectatic, red papules on the nose, the nasolabial fold, and the upper lip. Histologic examination of 1 of these lesions confirmed the clinical diagnosis of angiofibroma. In addition to multiple facial angiofibromas, this patient has multiple collagenomas and gingival papules (see Image 5), as well as hyperparathyroidism and a positive family history for multiple endocrine neoplasia type 1. |
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| Media file 2:
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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| Media file 3:
A closer view of the largest collagenoma in Image 2. |
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| Media file 4:
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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| Media file 5:
On the attached gingiva of the patient in Image 1, a few small, whitish papules are present. Gingival papules are a rare and subtle finding in multiple endocrine neoplasia type 1. |
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| Media file 6:
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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| Media file 7:
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. |
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Multiple Endocrine Neoplasia Type 1 excerpt Article Last Updated: Oct 2, 2006
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