Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

A novel MEN1 genetic variant identified in a young male with asymptomatic glucagonoma and recurrent hyperparathyroidism (#573)

Tomasz J Block 1 2 , Anthony Russell 1 , John Burgess 3 4 , Roderick Clifton-Bligh 5 6 , Hui Tay 7 , Annabelle M Warren 1
  1. Department of Endocrinology and Diabetes, Alfred Health, Melbourne, VIC, Australia
  2. Department of Diabetes, Monash University, Melbourne, VIC, Australia
  3. Department of Endocrinology and Diabetes, Royal Hobart Hospital, Hobart, TAS, Australia
  4. School of Medicine, University of Tasmania, Hobart, TAS, Australia
  5. Department of Endocrinology, Royal North Shore Hospital , Sydney, NSW, Australia
  6. Cancer Genetics Laboratory, Kolling Institute, Sydney, NSW, Australia
  7. Department of Anatomical Pathology, Alfred Health, Melbourne, VIC, Australia

Case Summary:

A 26-year-old obese male presented with recurrent primary hyperparathyroidism despite 3-gland parathyroidectomy. He had no other significant medical history, nor any family history of endocrinopathies. Biochemical screening for potential Multiple Endocrine Neoplasia Type 1 (MEN1) revealed a normal pituitary panel but raised fasting serum glucose 6.4 mmol/L, insulin 64 mIU/L (N 3-25), C-peptide 1.75 pmol/L (N 0.3-1.3), and HbA1c 6.4% (N 4-6). A hyperparathyroidism gene panel identified a variant of uncertain significance in the MEN1 gene at c.919G>C, p.(Ala307Pro). Further screening revealed that glucagon was markedly elevated at >522 pg/ml (N <208), without clinical signs or symptoms of glucagon excess. Subsequent imaging showed multiple Gallium-68 DOTATE avid but 18-FDG negative foci throughout the pancreas, largest 16 mm in pancreatic head, without evidence of metastases (Figure 1). Endoscopic biopsy confirmed a well-differentiated Grade 1 neuroendocrine tumour without atypia, Ki67 <2%, immunostaining positive for glucagon. The surgical team and patient have opted for surveillance of the lesions. Cascade testing of family members for this MEN1 variant is underway.

Discussion:

Glucagonomas are extremely rare neuroendocrine tumours (NETs). The annual incidence is ~0.2 cases per million(1), of which ~20% are associated with MEN1(2). This patient’s single-nucleotide heterozygous missense variant has not been previously reported. MEN1 missense variants are thought to either destabilise menin protein structure or impair its protein-protein interactions leading to deleterious effects, so this may be a novel pathogenic variant(3).

Differentiating a functional glucagonoma from other pancreatic NETs is challenging as immunohistological staining for glucagon is neither specific nor sensitive in distinguishing between benign, malignant, or secretory lesions(4). The diagnosis of glucagonoma is often delayed by several years resulting in significant morbidity and metastatic disease(1). Identification of an early asymptomatic glucagonoma in a complex surgical location presents a dilemma regarding optimal surgical timing given the high morbidity associated with pancreaticoduodenectomy.66b6ef6722e17-Figure+1+Short+Abstract+resised.png

  1. Song X, Zheng S, Yang G, Xiong G, Cao Z, Feng M, et al. Glucagonoma and the glucagonoma syndrome. Oncol Lett. 2018;15(3):2749-55.
  2. Lévy-Bohbot N, Merle C, Goudet P, Delemer B, Calender A, Jolly D, et al. Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroenterol Clin Biol. 2004;28(11):1075-81.
  3. Murai MJ, Chruszcz M, Reddy G, Grembecka J, Cierpicki T. Crystal structure of menin reveals binding site for mixed lineage leukemia (MLL) protein. J Biol Chem. 2011;286(36):31742-8.
  4. Lam KY, Lo CY. Pancreatic endocrine tumour: a 22-year clinico-pathological experience with morphological, immunohistochemical observation and a review of the literature. Eur J Surg Oncol. 1997;23(1):36-42.