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Angiofibromas in multiple endocrine neoplasia type 1

  • Author(s): Vashi, Neelam;
  • Hunt, Raegan;
  • Fischer, Max;
  • Meehan, Shane;
  • Pomeranz, Miriam Keltz
  • et al.
Main Content

Angiofibromas in multiple endocrine neoplasia type 1
Neelam Vashi MD, Raegan Hunt MD PhD, Max Fischer MD, Shane Meehan MD, Miriam Keltz Pomeranz MD
Dermatology Online Journal 18 (12): 20

The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is a familial tumor syndrome with autosomal dominant inheritance. Cutaneous tumors in MEN1, which include multiple angiofibromas, collagenomas, and lipomas can easily be overlooked because of their subtle appearance. As markers of this tumor syndrome, recognition of the mucocutaneous manifestations of MEN1 is important in order to facilitate early interdisciplinary care and diagnosis of associated internal disease in both patients and family members.



History

A 30-year-old woman presented to the Dermatology Clinic at Bellevue Hospital Center in March, 2012, for evaluation of papules on her chest and nose. The lesions had been present for approximately eight months and were otherwise asymptomatic.


Figure 1Figure 2

Past medical history included prolactinoma with the development of amenorrhea, parathyroid adenoma with the subsequent development of hypercalcemia and nephrolithiasis, and positive genetic testing for multiple endocrine neoplasia type 1. She took no medications and reported no allergies. She reported no family history of similar findings. The patient had a mutation in the MEN1 gene encoding the protein, Menin.


Physical examination

Small, red papules were present near the left ala nasi. On the right upper chest was a 3-mm, skin-colored-to-white, pedunculated papule.


Laboratory data

Calcium was elevated at 10.9 mg/dL. The parathyroid hormone was 41.1 pg/mL and thyroid stimulating hormone was 0.51 uIU/mL. A basic metabolic panel was normal.


Histopathology


Figure 3Figure 4

The left nasal ala biopsy revealed a dome-shaped lesion composed of a proliferation of blood vessels and fibrosis with plump stellated fibroblasts. The right breast biopsy showed a dome-shaped lesion composed of thick collagen bundles in a haphazard array with preservation of adnexae and the epidermal rete ridge pattern.


Discussion

Multiple endocrine neoplasia type 1 (MEN1) is a rare, familial tumor syndrome with autosomal dominant inheritance. It is caused by an inherited mutation in the tumor suppressor gene, MEN1, which encodes a protein, menin that is important in the regulation of transcription, proliferation, and genome stability [1, 2]. Affected persons develop tumors of the parathyroid glands, the enteropancreatic neuroendocrine system, the anterior pituitary gland, and the skin [3,4]. Angiofibromas, collagenomas, and lipomas are the only cutaneous findings that are regarded as direct manifestations of MEN1 genetic status because all three have been associated with a loss of heterozygosity within the neoplastic cell population [5, 6, 7]. Less common cutaneous lesions also may develop, which include gingival papules, hypopigmented macules, café-au-lait macules, and solitary periungual fibroma [3, 4]. The frequency of cutaneous features of 32 MEN1 patients was observed as: angiofibromas (88%), collagenomas (72%), lipomas (38%), hypopigmented macules (6%), and gingival papules (6%) [4].

The frequency of MEN1 is estimated to be one in 30,000 [8]. The incidence is equal among men and women and there is no racial predilection. Although the age of onset for endocrine tumors is in adolescence, symptoms may not appear for years, which delays the diagnosis. Early detection of cutaneous tumors, which also first develop in the teenage years, is important because these often will develop prior to endocrine tumor-related clinical symptoms [9]. The most common endocrine tumors are parathyroid tumors, which can cause hyperparathyroidism and hypercalcemia. Other tumors include gastrinomas, insulinomas, prolactinomas, and carcinoid tumors [10, 11]. These tumors can cause recurrent nephrolithiasis, hypoglycemia, gastric acid hypersecretion, amenorrhea, acromegaly, and/or mass effect.

MEN1 has overlapping mucocutaneous features of two other genodermatosis, Birt-Hogg-Dubé syndrome and tuberous sclerosis (TS) [5, 12]. All three entities may demonstrate multiple angiofibromas, collagenomas, and mucosal fibromas/papules and, therefore, should be included in the differential diagnosis when persons present with these aforementioned cutaneous findings [12]. Angiofibromas that are associated with MEN1 tend to be smaller in size, less numerous, more commonly located on the upper lip and vermillion border, and have a later age of onset when compared to TS [13].

Recognition of the mucocutaneous manifestations of MEN1 is important in order to facilitate early interdisciplinary care and diagnosis of associated internal disease in both patients and family members. Mutation analysis, which identifies a mutation in about 80 percent of patients with familial MEN1, can be used to confirm the clinical diagnosis and screen asymptomatic family members [10, 14]. Cutaneous lesions may be removed by a variety of surgical methods, which include shave excision, dermabrasion, carbon dioxide laser, and combined pulse-dye laser and fractional resurfacing. Topical sirolimus, which has been shown to be an effective and safe medical alternative to surgery or laser-based therapy in patients with TS-associated facial angiofibromas, may be a novel treatment for them in patients with MEN1 [15, 16].

References

1. Baldauf C, et al. Combination of multiple skin malignancies with multiple endocrine neoplasia type 1: coincidental or pathogenetically related? Dermatology 2009;219:365 [PubMed]

2. Agarwal SK, et al. Menin molecular interactions: insights into normal functions and tumorigenesis. Horm Metab Res 2005;37:369 [PubMed]

3. Darling TN, et al. Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol 1997;133:853 [PubMed]

4. Zeller S, et al. Multiple angiofibromas and collagenomas in a 45-year-old man with recurrent nephrolithiasis, fatigue, and vision loss. J Am Acad Dermatol 2009;61:319 [PubMed]

5. Saggini A, Brandi ML. Skin lesions in hereditary endocrine tumor syndromes. Endocr Pract 2011;17 (Suppl 3):47 [PubMed]

6. Pack S, et al. Cutaneous tumors in patients with multiple endocrine neoplasia type 1 show allelic deletion of the MEN1 gene. J Invest Dermatol 1998;110:438 [PubMed]

7. Böni R, et al. Somatic mutations of the MEN1 tumor suppressor gene detected in sporadic angiofibromas. J Invest Dermatol 1998;111:539 [PubMed]

8. Marx SJ. Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nat Rev Cancer 2005;5:367 [PubMed]

9. Sakurai A, et al. Facial angiofibroma as an initial manifestation in multiple endocrine neoplasia type 1. Intern Med 2008;47:1067 [PubMed]

10. Brandi ML, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658 [PubMed]

11. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab 2010;24:355 [PubMed]

12. Schaffer JV, et al. Multiple facial angiofibromas: a cutaneous manifestation of Birt-Hogg-Dubé syndrome. J Am Acad Dermatol 2005;5:S108 [PubMed]

13. Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol 2004;19:643 [PubMed]

14. Newey PJ, Thakker RV. Role of multiple endocrine neoplasia type 1 mutational analysis in clinical practice. Endocr Pract 2011;17 (Suppl) 3:8 [PubMed]

15. DeKlotz CM, et al. Dramatic improvement of facial angiofibromas in tuberous sclerosis with topical rapamycin: optimizing a treatment protocol. Arch Dermatol 2011;147:1116 [PubMed]

16. Wataya-Kaneda M, et al. A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis complex (TSC): a pilot study of nine Japanese patients with TSC of different disease severity. Br J Dermatol 2011;165:912 [PubMed]

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