背景:生殖系CDKN1B变异体使患者易患多发性内分泌瘤4型(MEN4),一种罕见的MEN1样综合征,自2006年发现以来,报告病例<100例。尽管CDKN1B突变经常被建议解释基因阴性MEN1的病例,但MEN4患者的患病率和表型知之甚少。遗传咨询还不清楚。
目的:评估MEN1疑似患者中MEN4的患病率并表征MEN4患者的表型。
方法:回顾性观察性全国性研究。文献叙事回顾与变种类再评价。
方法:我们纳入了2015年至2022年期间法国TENGEN网络实验室鉴定的所有3/4/5类CDKN1B变异的成年患者,通过对MEN1疑似的种系基因检测。在课堂重新评估后,我们比较了4/5类CDKN1B变异的症状患者的表型,即通过基因证实的MEN4诊断,在我们的系列和文献中,66例匹配的MEN1患者来自UMD-MEN1数据库。
结果:从5600名MEN1疑似患者中分析,发现4例CDKN1B变异4/5级患者(0.07%).他们展示了多个十二指肠网,PHPT和肾上腺结节,孤立的PHPT,PHPT和pNET。我们从文献中列出了29例CDKN1B4/5类变异的患者。与匹配的MEN1患者相比,在PHPT诊断时,MEN4患者的NET发生率较低,年龄较大。
结论:MEN4的患病率较低。PHPT和PA代表主要相关病变,NET是罕见的。我们的结果表明,表型比MEN1更温和,更晚。我们的观察将有助于改善MEN4家庭的遗传咨询和管理。
BACKGROUND: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear.
OBJECTIVE: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients.
METHODS: Retrospective observational nationwide
study. Narrative review of literature and variant class reassessment.
METHODS: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database.
RESULTS: From 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis.
CONCLUSIONS: The prevalence of MEN4 is low. PHPT and pituitary adenoma represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families.