Han Hye Jeong, Moalem Jacob, Shih Angela R, Gigliotti Benjamin J
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York.
Department of Surgery, University of Rochester Medical Center, Rochester, New York.
AACE Clin Case Rep. 2024 Dec 3;11(2):93-97. doi: 10.1016/j.aace.2024.11.009. eCollection 2025 Mar-Apr.
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.
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.
背景/目的：多发性内分泌腺瘤4型（MEN4）是一种由CDKN1B基因种系突变引起的罕见综合征，它与MEN1具有共同的临床表现，包括原发性甲状旁腺功能亢进、垂体腺瘤和胰腺神经内分泌肿瘤（NETs）。MEN4的患病率低于百万分之一，而MEN1的患病率在万分之一至三万分之一之间。
一名51岁女性出现症状性低血糖和偶然发现的高钙血症。检查发现空腹血糖水平为41mg/dL（60 - 99mg/dL），胰岛素原水平为84.3pmol/L（≤8.0pmol/L），胰岛素水平为24uIU/mL（3 - 25uIU/mL），C肽水平为5.2ng/mL（1.1 - 4.4ng/mL），β-羟丁酸水平为0.34mmol/L（0.02 - 0.27mmol/L），符合内源性高胰岛素血症。腹部计算机断层扫描显示胰头有一个1.5×1.1×1.0cm的结节。她接受了胰十二指肠切除术，病理显示为高分化神经内分泌肿瘤，无转移。术后她血糖恢复正常，进一步检查发现原发性甲状旁腺功能亢进。种系检测发现CDKN1B基因存在一个意义不明的变异（p.R93W）。
MEN1和MEN4均由p24表达降低引起，表现出相似的临床表型，但在 penetrance 和自然病史方面存在细微差异。约10%的MEN1患者有胰岛素瘤，但MEN4中尚未报道有胰岛素瘤。MEN4中的原发性甲状旁腺功能亢进在甲状旁腺切除术后复发风险较低。该病例突出了患者出现MEN1表现时进行种系基因检测的重要性。
据我们所知，这是首例报道的MEN4合并胰岛素瘤病例。
