Endocrine Abstracts

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary autosomal dominant tumor syndrome caused by inactivating mutations of the tumor suppressor gene MEN1 which encodes the protein menin. It is characterized by the occurrence of tumors involving two or more endocrine glands, primarily parathyroid, entero-pancreatic, and anterior pituitary, as well as non-endocrine neoplasms. Glucagonomas occur in fewer than 3% of patients with MEN1, causing hyperglycemia, skin rash (necrolytic migratory erythema), weight loss, anemia, and stomatitis.

Case report: In March 2019 a 35-year-old Pakistani woman underwent surgical removal of 2 overactive parathyroid glands causing primary hyperparathyroidism diagnosed after a pelvic fracture and the identification of brown tumors. After surgery, she was lost at follow-up. In August 2020, she was admitted to Emergency Department for fever, weight loss, and new-onset diabetes mellitus causing polyuria and polydipsia without ketoacidosis. Glucagon was at the upper limits of normal (252 pg/ml) and abdominal MRI revealed a neuroendocrine tumor (10 mm in the pancreatic tail) and left adrenal adenoma, confirmed by a 68Ga-DOTATOC-PET, that showed 4 areas of abnormal uptake in the pancreatic tail, body, and head, and in left adrenal gland. Duodenocephalopancreatectomy and left adrenalectomy were performed; histological examination revealed the presence of multiple well-differentiated G1 neuroendocrine tumors (Ki67<3%) with intensive positive IIC for glucagon, and adrenal adenoma. The post-surgical period was complicated by cava vein thrombosis, typical of glucagonoma, and endocarditis. The study of other endocrine glands showed the persistence of primary hyperparathyroidism due to hyperplasia of the remnant parathyroid glands confirmed by Sesta-MIBI-scintigraphy; pituitary function and MRI were normal. Dermatological investigation showed cutaneous collagenomas. Genetic testing identified a novel missense MEN1 heterozygous pathogenetic variant c.703T>C-p.(Cys235Arg) in exon 4. The patient was monitored by MRI, 68Ga-DOTATOC-PET, and FDG-PET and no significant abnormal uptakes have been identified until now, however, she developed skin lesions suspected for necrolytic migratory erythema and she is in a close follow-up. Genetic inheritance is under investigation.

Conclusion: The clinical behavior of MEN1 depends on histological features of the tumors, the type, and degree of hormone hypersecretion and the risk of tumor recurrence. Some authors described a potential genotype-phenotype correlation, but this link remains debated. Current clinical guidelines recommend that index case and their relatives should be included in a screening program to reduce morbidity and mortality. Our case of a new pathogenetic mutation associated with glucagonoma underlines the need for a closer follow-up and surveillance with an interdisciplinary approach.