Abstract
BACKGROUND/OBJECTIVE: 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. CASE REPORT: 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). DISCUSSION: 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. CONCLUSION: To our knowledge, this is the first reported case of insulinoma in MEN4.