Multiple Endocrine Neoplasia Type 1 

  • Author: Thomas N Darling, MD, PhD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Mar 2, 2010
 

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]

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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.

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Epidemiology

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]
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Contributor Information and Disclosures
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, MD, PhD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Terry L Barrett, MD  Clinical Professor of Dermatology and Pathology, University of Texas Southwestern School of Medicine; Director, ProPath Dermatopathology, Dallas, Texas

Terry L Barrett, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Medical Association, American Society of Dermatopathology, College of American Pathologists, and United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Richard P Vinson, MD  Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Lester F Libow, MD  Dermatopathologist, South Texas Dermatopathology Laboratory

Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Texas Medical Association

Disclosure: Nothing to disclose.

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Department of Dermatology, Geisinger Medical Center

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

  1. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. Dec 2001;86(12):5658-71. [Medline].

  2. Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM, Turner M. Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol. Jul 1997;133(7):853-7. [Medline].

  3. Zeller S, Marx SJ, Lungu AO, Cowen EW, Turner ML. Multiple angiofibromas and collagenomas in a 45-year-old man with recurrent nephrolithiasis, fatigue, and vision loss. J Am Acad Dermatol. Aug 2009;61(2):319-22. [Medline].

  4. Asgharian B, Turner ML, Gibril F, Entsuah LK, Serrano J, Jensen RT. Cutaneous tumors in patients with multiple endocrine neoplasm type 1 (MEN1) and gastrinomas: prospective study of frequency and development of criteria with high sensitivity and specificity for MEN1. J Clin Endocrinol Metab. Nov 2004;89(11):5328-36. [Medline].

  5. Agarwal SK, Kennedy PA, Scacheri PC, et al. Menin molecular interactions: insights into normal functions and tumorigenesis. Horm Metab Res. Jun 2005;37(6):369-74. [Medline].

  6. Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. Jan 2008;29(1):22-32. [Medline].

  7. Dreijerink KM, Lips CJ, Timmers HT. Multiple endocrine neoplasia type 1: a chromatin writer's block. J Intern Med. Jul 2009;266(1):53-9. [Medline].

  8. Pack S, Turner ML, Zhuang Z, et al. Cutaneous tumors in patients with multiple endocrine neoplasia type 1 show allelic deletion of the MEN1 gene. J Invest Dermatol. Apr 1998;110(4):438-40. [Medline].

  9. Vortmeyer AO, Boni R, Pack SD, Darling TN, Zhuang Z. Perivascular cells harboring multiple endocrine neoplasia type 1 alterations are neoplastic cells in angiofibromas. Cancer Res. Jan 15 1999;59(2):274-8. [Medline].

  10. Marx SJ. Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nat Rev Cancer. May 2005;5(5):367-75. [Medline].

  11. Sakurai A, Hashizume K, Fukushima Y. Facial angiofibroma as an initial manifestation in multiple endocrine neoplasia type 1. Intern Med. 2008;47(11):1067-8. [Medline].

  12. Witchel SF, Ranganathan S, Kilpatrick M, Carty SE. Reverse referral: from pathology to endocrinology. Endocr Pathol. Spring 2009;20(1):78-83. [Medline].

  13. Hoang-Xuan T, Steger JW. Adult-onset angiofibroma and multiple endocrine neoplasia type I. J Am Acad Dermatol. Nov 1999;41(5 Pt 2):890-2. [Medline].

  14. Vidal A, Iglesias MJ, Fernandez B, Fonseca E, Cordido F. Cutaneous lesions associated to multiple endocrine neoplasia syndrome type 1. J Eur Acad Dermatol Venereol. Jul 2008;22(7):835-8. [Medline].

  15. Sakurai A, Matsumoto K, Ikeo Y, et al. Frequency of facial angiofibromas in Japanese patients with multiple endocrine neoplasia type 1. Endocr J. Oct 2000;47(5):569-73. [Medline].

  16. Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol. Sep 2004;19(9):643-9. [Medline].

  17. Fuleihan Gel-H, Rubeiz N. Dermatologic manifestations of parathyroid-related disorders. Clin Dermatol. Jul-Aug 2006;24(4):281-8. [Medline].

  18. Xia Y, Darling TN. Rapidly growing collagenomas in multiple endocrine neoplasia type I. J Am Acad Dermatol. May 2007;56(5):877-80. [Medline].

  19. Bittencourt RC, Huilgol SC, Seed PT, Calonje E, Markey AC, Barlow RJ. Treatment of angiofibromas with a scanning carbon dioxide laser: a clinicopathologic study with long-term follow-up. J Am Acad Dermatol. Nov 2001;45(5):731-5. [Medline].

 
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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.
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.
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.
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.
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.
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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