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Multiple Endocrine Neoplasia Type 1

Author: Thomas N Darling, MD, PhD, Director of Dermatologic Research, Associate Professor of Dermatology, Department of Dermatology, Uniformed Services University of the Health Sciences
Contributor Information and Disclosures

Updated: Mar 2, 2010

Introduction

Background

Multiple endocrine neoplasia type 1 (MEN1) is a familial tumor syndrome (also termed Wermer 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.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 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 MEN1.⁴

Pathophysiology

Patients with multiple endocrine neoplasia type 1 (MEN1) inherit a mutation in a tumor suppressor gene called MEN1 on band 11q13. This gene encodes a protein, menin, whose functions are still being elucidated. Menin appears to be located mostly in the nucleus, where it has multiple binding partners, including junD and members of histone methyltransferase complexes.^5,6,7 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.^8,9 This accounts for the multiple tumors and the tumors occurring at an earlier age.

Frequency

International

The frequency of multiple endocrine neoplasia type 1 (MEN1) is estimated to be 1 case in 30,000 persons.¹⁰

Mortality/Morbidity

Benign endocrine and cutaneous tumors cause morbidity, and malignancies cause most mortality (see Complications) in multiple endocrine neoplasia type 1 (MEN1).

Race

No racial predilection is known for multiple endocrine neoplasia type 1 (MEN1).

Sex

The incidence of multiple endocrine neoplasia type 1 (MEN1) is equal for men and women.

Age

• Endocrine tumors in multiple endocrine neoplasia type 1 (MEN1): 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 in MEN1: 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.^11,12

Clinical

History

Cutaneous tumors in multiple endocrine neoplasia type 1 (MEN1) 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

• In multiple endocrine neoplasia type 1 (MEN1), angiofibromas are telangiectatic, skin-colored, pink or light-brown papules that are 1-4 mm in diameter, as shown in the image below. 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%, 22%, 43%, 64%, and 88% of patients with MEN1.^{2,4,11,13,14,15}
  • 
    

    

    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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    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.

  • 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.¹⁶
  • 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, as shown in the images below. 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 0-72% of patients with MEN1, with 83-91% of patients with collagenomas having multiple lesions.^2,4,14,17,18
  • 
    

    

    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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    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.

  • 
    

    

    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 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.

• Lipomas are soft, compressible, subcutaneous nodules that are generally 0.5-5 cm in diameter, as shown in the image below. 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.^2,4,14
  • 
    

    

    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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    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.

• Additional skin findings include café au lait macules; hypopigmented macules, including confettilike hypopigmented macules; gingival papules (see image below); and solitary periungual fibroma.
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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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    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.

  • 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 MEN1.²
  • 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.

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