Dermatologic Manifestations of Multiple Endocrine Neoplasia Type 1 (MEN1) 

Updated: Sep 14, 2018
Author: Thomas N Darling, MD, PhD; Chief Editor: Dirk M Elston, MD 

Overview

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, 2]

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.[3, 4]

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 dermatological criterion of more than 3 angiofibromas or 1 or more collagenomas was sensitive (75%) and specific (95%) for the diagnosis of MEN1.[5]

Background

 

 

 

Pathophysiology

Patients with MEN1 inherit a mutation in a tumor suppressor gene called MEN1 on chromosome band 11q13.[6, 7] This gene encodes a 610-amino acid protein, menin, 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.[8, 9, 10] A mutant menin has been shown to be defective for the transforming growth factor-beta signaling pathway.[11]

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 that 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.[12, 13, 14]

Epidemiology

Frequency

Worldwide, the frequency of MEN1 is estimated to be 1 case in 30,000 persons.[15]

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, 16, 17]

Age

Endocrine tumors in MEN1

The age of 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 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.[18, 19]

Mortality/Morbidity

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

 

Presentation

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.[3, 5, 18, 20, 21, 22]

A 27-year-old man has telangiectatic, red papules 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.[23] 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.[3, 5, 21, 24, 25]

The shoulder of a 65-year-old man shows multiple f 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 shou 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.[3, 5, 21]

A 39-year-old woman with multiple endocrine neopla 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.

On the attached gingiva of a 27-year-old man with 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.[3]

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.

 

DDx

 

Workup

Laboratory Studies

The observation of multiple facial angiofibromas, collagenomas, and lipomas does not establish the diagnosis of multiple endocrine neoplasia type 1 (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 it identifies a mutation in only about 80% of patients with familial MEN1.[1]  Mutation analysis may be used to confirm the clinical diagnosis, provide a genetic diagnosis in difficult cases, and screen asymptomatic family members.[26]

Also see a clinical guideline summary from the National Academy of Clinical Biochemistry, Intraoperative parathyroid hormone. Laboratory medicine practice guidelines: evidence-based practice for point-of-care testing

Procedures

Skin biopsy may or may not be required in multiple endocrine neoplasia type 1 (MEN1), 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 in multiple endocrine neoplasia type 1 (MEN1) include dermal fibrosis, ectatic blood vessels, and stellate cells in the upper dermis, as shown in the image below.

Light microscopic evaluation of a section of an an 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.

The histologic features of collagenoma include increased amounts of collagen and normal or decreased numbers of elastic fibers, as shown in the image below. The features of the collagenoma may appear normal unless the biopsy sample includes surrounding healthy skin.

Histologic examination of a collagenoma reveals de 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.

The histologic features of lipoma include a circumscribed nodule of uniform adipocytes.

Imaging Studies

Conventional imaging is not useful for all types of MEN1-related tumors. However, researchers have found that 68Ga-DOTATATE PET/CT is useful in the workup of MEN1 because it provides a panoramic view of MEN1-related lesions.[27, 28]

 

Treatment

Medical Care

Clinical practice guidelines have been developed based on a review of peer-review publications for managing MEN1[32] . Related clinical guideline summaries include the following:

  • American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules

  • American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of hypertension

Surgical Care

Patients may desire to have these cutaneous tumors removed because of cosmetic concerns, particularly with the larger facial angiofibromas. A variety of surgical methods have been used to treat angiofibromas in patients with tuberous sclerosis, and these treatments are likely applicable to angiofibromas in patients with multiple endocrine neoplasia type 1 (MEN1). These methods include the following[29, 30] :

  • Shave excision
  • Dermabrasion
  • Carbon dioxide laser
  • Combined pulsed dye laser and fractional resurfacing

Cosmetic improvement of facial angiofibromas in patients with MEN1 has been obtained with shave excision. In some cases, however, lesions treated in this way have slowly reappeared.

Collagenomas and lipomas can be excised, and lipomas can also be treated by liposuction.

Consultations

In view of the wide spectrum of clinical manifestations of MEN1 and the complexities in its management, Endocrine Society guidelines recommend that patients with MEN1 and their families be cared for by a multidisciplinary team comprising relevant specialists with experience in the diagnosis and treatment of endocrine tumors. The guidelines also recommend that the overall care of these patients and their families be coordinated by an endocrinologist with expertise in MEN syndromes.[1]

 

Follow-up

Complications

Endocrine tumors in MEN1

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 in MEN1

Angiofibromas, collagenomas, and lipomas do not typically cause symptoms, and they are mostly of cosmetic concern.

Patient Education

For patient education resources related to multiple endocrine neoplasia type 1 (MEN1), see the Endocrine System Center, as well as Anatomy of the Endocrine System.

 

Questions & Answers

Overview

What multiple endocrine neoplasia type 1 (MEN1)?

What is the pathophysiology of multiple endocrine neoplasia type 1 (MEN1)

What is the prevalence of multiple endocrine neoplasia type 1 (MEN1)?

Which patient groups have the highest prevalence of multiple endocrine neoplasia type 1 (MEN1)?

Which age group has the highest prevalence of multiple endocrine neoplasia type 1 (MEN1) endocrine tumors?

Which age group has the highest prevalence of multiple endocrine neoplasia type 1 (MEN1) cutaneous tumors?

What is the morbidity and mortality associated with multiple endocrine neoplasia type 1 (MEN1)?

Presentation

Which clinical history findings are characteristic of cutaneous tumors in multiple endocrine neoplasia type 1 (MEN1)?

Which physical findings are characteristic of multiple endocrine neoplasia type 1 (MEN1)?

DDX

What are the differential diagnoses for Dermatologic Manifestations of Multiple Endocrine Neoplasia Type 1 (MEN1)?

Workup

What is the role of lab tests in the diagnosis of multiple endocrine neoplasia type 1 (MEN1)?

What is the role of biopsy in the workup of multiple endocrine neoplasia type 1 (MEN1)?

Which histologic findings are characteristic of multiple endocrine neoplasia type 1 (MEN1)?

What is the role of imaging studies in the workup of multiple endocrine neoplasia type 1 (MEN1)?

Treatment

Which organizations have published guidelines on the treatment of multiple endocrine neoplasia type 1 (MEN1)?

What is the role of surgery in the treatment of multiple endocrine neoplasia type 1 (MEN1)?

Which specialist consultations are beneficial to patients with multiple endocrine neoplasia type 1 (MEN1)?

Follow-up

What are the possible complications of multiple endocrine neoplasia type 1 (MEN1) endocrine tumors?

What are the possible complications of multiple endocrine neoplasia type 1 (MEN1) cutaneous tumors?