Abstract


Introduction:
Coexisting MEN1 and BRCA2 mutations in a single patient is very rare.

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Introduction:
Coexisting MEN1 and BRCA2 mutations in a single patient is very rare.

Clinical case:
A 40-year-old Hispanic woman with no medical history presented to our clinic for evaluation of hypercalcemia. Her family history was only significant for a breast bump in her mother that was never evaluated. Physical examination was only remarkable for multiple skin-colored papules scattered over her chest and abdomen. Labs showed serum calcium 12.1 mg/dL [8.4-10.2], PTH 339.7 pg/mL [15-65], creatinine 0.68 mg/dL, and 25-OH vitamin D 32 ng/mL. DXA revealed low bone density for age. MEN1 was suspected because of the early onset of primary hyperparathyroidism (PHPT) and her skin lesions, thus she was referred to dermatology for biopsy of her skin papules, which returned consistent with a collagenoma. The co-existence of collagenoma and early onset-PHPT was highly suspicious for MEN1, so she underwent a subtotal parathyroidectomy with thymectomy, with pathology showing cellular parathyroid tissue and unremarkable thymic tissue.
Prior to completion of her work-up, she presented with a rapidly growing left breast mass, which was found to be invasive ductal carcinoma of the breast with axillary lymph node metastasis. Her staging CT scans showed a lipoma in her left thigh, but no metastatic disease. She underwent neoadjuvant chemotherapy and radiation therapy. Genetic testing returned positive for BRCA2 c.7976+1G>A mutation. She underwent bilateral mastectomies and bilateral salpingo-oophorectomy. She was subsequently started on tamoxifen.

Genetic testing also showed MEN1 c.432delC mutation. Pituitary studies showed normal prolactin 14 ng/mL and IGF-1 69 ng/mL [49-240] with Z score -1.28. Pituitary MRI was normal. Fasting pancreatic neuroendocrine studies revealed gastrin 64 pg/mL [< 100], PP 364 pg/mL [< 270], VIP 29 pg/mL [< 75], glucagon 57 pg/mL [≤ 80], and chromogranin A 80 ng/mL [0-95], glucose 129 mg/dL [70-99], and insulin 55.4 mcIU/mL [2.6-24.9]. CT abdomen showed 3 hyperenhancing pancreatic nodules, which were too small to be biopsied. Because she is asymptomatic with non-functional, multifocal, and subcentimeter pNETs without liver metastasis, repeat imaging and biochemical studies are planned at this time.

Conclusions:
MEN1 should be considered in a young patient with PHPT and unusual skin lesions despite an absence of family history. MEN1 c.432delC is a novel frameshift mutation leading to a premature stop codon and loss of menin protein function. Menin is a tumor suppressor and a direct coactivator of estrogen receptor in vitro that binds to the same domain as tamoxifen. Limited data suggests MEN1 is associated with decreased menin in breast cancer cells and increased breast cancer risk (1). However, menin-negative breast cancer is associated with a more favorable disease-free survival after tamoxifen (2). These findings may be relevant to MEN1 patients who develop breast cancer.

Reference:
1. Dreijerink KM, Goudet P, Burgess JR, Valk GD, International Breast Cancer in MENSG. Breast-cancer predisposition in multiple endocrine neoplasia type 1. The New England journal of medicine. 2014;371(6):583-584.
2. Imachi H, Murao K, Dobashi H, et al. Menin, a product of the MENI gene, binds to estrogen receptor to enhance its activity in breast cancer cells: possibility of a novel predictive factor for tamoxifen resistance. Breast cancer research and treatment. 2010;122(2):395-407.

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