Division of Endocrinology, Department of Medicine and Research Center, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec H2X 0A9, Canada.
Eur J Endocrinol. 2023 Mar 2;188(3):R56-R72. doi: 10.1093/ejendo/lvad026.
Thirty years ago, we identified that cortisol secretion in some patients with unilateral adenoma or primary bilateral macronodular adrenal hyperplasia (PBMAH) was stimulated by food intake; this was secondary to the abnormal adrenocortical responsiveness to physiological post-prandial increase in glucose-dependent insulinotropic peptide (GIP). This resulted from the ectopic expression of non-mutated GIP receptor in the pathological adrenal tissues of those patients. Although ectopic GIP receptor (GIPR) was confirmed in a relatively limited number of cases to date, its elucidation leads to the identification of a wide diversity of aberrant G-protein-coupled receptors regulating steroidogenesis and cell proliferation in a high proportion of patients with PBMAH or cortisol-secreting adenomas. In addition, ectopic GIPR was identified in other endocrine tumors including somatotroph pituitary tumors with paradoxical growth hormone response to oral glucose, medullary thyroid carcinomas, and other neuroendocrine tumors. The first molecular pathogenic mechanism responsible for ectopic GIPR expression was elucidated in unilateral GIP-dependent adenomas in which somatic duplication and rearrangements in chromosome region 19q13.32 containing the GIPR locus lead to increased expression of GIPR which was enhanced by the activity of a glucocorticoid response element. Recently, germline lysine demythylase 1A (KDMIA) mutations combined with somatic chromosome 1p deletions were found to be specifically responsible for ectopic GIPR in sporadic or familial GIP-dependent PBMAH and can be associated with adrenal myelolipoma, monoclonal gammopathy of unknown significance (MGUS), or multiple myeloma. Screening for ectopic GIPR should be conducted in all patients with PBMAH; genetic studies to identify KDM1A mutations should be offered to such patients in order to detect affected members and provide early detection of PBMAH and other potential associated neoplasias. The elucidation of GIP-dependent Cushing's syndrome (CS) illustrates that careful bedside phenotyping of rare conditions can lead to identification of genetically determined diseases requiring personalized approaches to investigation and therapy.
三十年前，我们发现一些单侧腺瘤或原发性双侧大结节性肾上腺增生症（PBMAH）患者的皮质醇分泌受到食物摄入的刺激；这是由于异常的肾上腺对生理餐后葡萄糖依赖性胰岛素释放肽（GIP）增加的反应。这是由于这些患者的病理性肾上腺组织中存在非突变的 GIP 受体的异位表达。尽管迄今为止，异位 GIP 受体（GIPR）仅在相对有限的病例中得到证实，但它的阐明导致了广泛的异常 G 蛋白偶联受体的鉴定，这些受体调节 PBMAH 或分泌皮质醇的腺瘤患者中类固醇生成和细胞增殖。此外，异位 GIPR 还存在于其他内分泌肿瘤中，包括伴有口服葡萄糖时生长激素反应反常的垂体生长激素瘤、甲状腺髓样癌和其他神经内分泌肿瘤。第一个负责异位 GIPR 表达的分子发病机制在单侧依赖 GIP 的腺瘤中得到了阐明，其中染色体 19q13.32 区域内包含 GIPR 基因座的体细胞重复和重排导致 GIPR 表达增加，糖皮质激素反应元件的活性增强了这种表达。最近，发现种系赖氨酸去甲基酶 1A（KDM1A）突变与体细胞 1p 缺失相结合，特异性负责散发或家族性依赖 GIP 的 PBMAH 中的异位 GIPR，并且可能与肾上腺髓样脂肪瘤、意义未明的单克隆丙种球蛋白血症（MGUS）或多发性骨髓瘤相关。应在所有 PBMAH 患者中进行异位 GIPR 的筛查；应向此类患者提供 KDM1A 突变的遗传研究，以发现受影响的成员，并早期发现 PBMAH 和其他潜在相关肿瘤。依赖 GIP 的库欣综合征（CS）的阐明表明，对罕见疾病的仔细床边表型分析可以导致确定需要个性化方法进行调查和治疗的遗传疾病。
