(CSEMP053) NOVEL PATHOGENIC GENE VARIANTS IN PATIENTS WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN-1) SYNDROME

Abstract:

Introduction: Multiple endocrine neoplasia type 1 (MEN-1) is a rare autosomal dominate tumour syndrome caused by mutations in the MEN-1 gene.(1) MEN-1 syndrome is characterized by a predisposition to developing tumours, primarily parathyroid adenomas, duodenopancreatic neuroendocrine tumours, and pituitary adenomas.(2) While more than 1200 germline mutations in the MEN-1 gene have been identified, we report two novel gene mutations in MEN-1 that resulted in MEN-1 syndrome.

Case 1: A 61-year-old woman was hospitalized for PTH-dependent hypercalcemia. Workup revealed primary hyperparathyroidism and a parathyroid scan showed a parathyroid adenoma. Hypercalcemia persisted despite a left inferior parathyroidectomy, which necessitated a subsequent subtotal parathyroidectomy which led to normalization of her calcium levels. Shortly thereafter, she had GI symptoms, for which a CT abdomen showed a 1.5x2cm pancreatic mass and endoscopic ultrasound guided aspiration revealed a well differentiated pancreatic neuroendocrine tumour. Biochemical work up was suggestive of a gastrinoma. She had a total pancreatectomy with biopsy suggestive of a gastrinoma and subsequent insulin-dependent diabetes. Pituitary MRI showed a 4mm sellar mass without biochemical evidence of over or underproduction. Genetic testing found a novel MEN1:c.1192delC variant predicted to lead to premature termination of the MEN-1 gene as well as associated with nonsense-mediated decay of the MEN-1 mRNA.

Case 2: A 38-year-old woman with a family history consistent with a clinical diagnosis of MEN-1 syndrome, presented to an outpatient endocrinology clinic with recurrent episodes of nephrolithiasis and PTH-dependent hypercalcemia. Given her family history, a subtotal parathyroidectomy was carried out, which has kept her hypercalcemia and renal stones in remission. She had a pituitary MRI which revealed a sellar mass (largest diameter 18mm) with elevated prolactin suggestive of a prolactinoma. Cabergoline treatment lead to normalization of prolactin and shrinkage of the sellar mass which now measures 8mm, even off treatment. Genetic testing found a novel MEN1:c.784-9G>A variant that is thought to affect RNA splicing of the MEN-1 gene. Nearly a decade after her subtotal parathyroidectomy, she had recurrent nephrolithiasis and is currently being considered for parathyroidectomy for recurrent primary hyperparathyroidism.

Discussion/

Conclusion: The cases above present novel gene mutations associated with MEN-1 syndrome. Further research defining new MEN-1 genetic mutations will provide a larger genetic pool for aiding in the diagnosis of MEN-1 syndrome.

(1)Chandrasekharappa S.C., et al. Positional cloning of the gene for multiple endocrine neoplasia‐type 1. Science. 1997;276:404‐407.
(2)Pieterman C.R.C., Valk G.D. Update on the clinical management of multiple endocrine
neoplasia type 1. Clinical Endocrinology. 2022;97:409–423.