Insulinoma: A Novel Presentation of Multiple Endocrine Neoplasia 4

Multiple endocrine neoplasia 4 (MEN4) is a rare syndrome caused by germline mutations in CKDN1B, and it shares clinical manifestations with MEN1, including primary hyperparathyroidism, pituitary adenomas, and pancreatic neuroendocrine tumors (NETs). The prevalence of MEN4 is <1 per million, whereas prevalence of MEN1 is between 1/10 000 and 1/30 000.

A 51-year-old woman presented with symptomatic hypoglycemia and incidental hypercalcemia. Workup revealed a fasting plasma glucose level of 41 mg/dL (60-99 mg/dL), proinsulin level of 84.3 pmol/L (≤8.0 pmol/L), insulin level of 24 uIU/mL (3-25 uIU/mL), c-peptide level of 5.2 ng/mL (1.1-4.4 ng/mL), and β-hydroxybutyrate level of 0.34 mmol/L (0.02-0.27 mmol/L), consistent with endogenous hyperinsulinism. Computed tomography scan of the abdomen revealed a 1.5 × 1.1 × 1.0 cm pancreatic head nodule. She underwent pancreaticoduodenectomy, and pathology demonstrated a well-differentiated neuroendocrine tumor with no metastases. She became normoglycemic after surgery, and additional workup revealed primary hyperparathyroidism. Germline testing revealed a variant of unknown significance in CDKN1B (p.R93W).

Both MEN1 and MEN4 result from decreased expression of p24 and exhibit similar clinical phenotypes, but there are subtle differences in penetrance and natural history. About 10% of patients with MEN1 have insulinomas, but no insulinomas have been reported in MEN4. primary hyperparathyroidism in MEN4 exhibits a lower risk of recurrence after parathyroidectomy. This case highlights the importance of germline genetic testing when a patient presents with manifestations of MEN1.

To our knowledge, this is the first reported case of insulinoma in MEN4.