原发性双侧大结节性肾上腺增生（PBMAH）是库欣综合征的罕见原因。由于胃抑制性多肽受体 (GIPR) 异位表达而患有 PBMAH 和 GIP 依赖​​性库欣综合征的个体通常含有失活的 KDM1A 序列变异体。原发性单侧大结节性肾上腺增生 (PUMAH) 伴有糖皮质激素和雄激素过多的情况从未遇到或研究过。我们调查了一名女性，该女性有巨大的异质性肾上腺肿块和严重的 ACTH 依赖性糖皮质激素和雄激素过多，这是一种通常提示肾上腺皮质癌的生化表现。患者在怀孕期间（妊娠第 22 周）就诊，并报告有 18 个月的月经稀发、多毛症和体重增加病史。我们进行了一项探索性研究，对切除的肾上腺肿块和从患者及其父母收集的白细胞 DNA 进行了详细的组织病理学和遗传学分析。组织病理学显示良性大结节性肾上腺增生。影像学显示对侧肾上腺持续正常。四个代表性结节的全外显子组测序检测到 KDM1A 种系变异、良性 NM_001009999.3:c.136G>A:p.G46S 和可能致病性 NM_001009999.3:exon6:c.865_866del:p.R289Dfs*7。拷贝数变异分析表明，所有结节中染色体 1p36.12 上的 KDM1A 野生型等位基因均存在额外的体细胞丢失。与 52 个单侧散发性腺瘤和 4 个正常肾上腺相比，代表性结节的 RNA 测序显示 KDM1A 表达低/缺失，GIPR 表达增加。 LH 受体 (LHCGR) 表达正常。 Sanger 测序证实父母双方（父亲：p.R289Dfs*7；母亲：p.G46S）均存在杂合 KDM1A 变异，他们没有表现出提示糖皮质激素或雄激素过多的临床特征。我们研究了第一个与严重库欣综合征和伴随雄激素过多相关的 PUMAH ，提示涉及 KDM1A 的致病机制。© 作者 2024。由牛津大学出版社代表欧洲内分泌学会出版。

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and GIP-dependent Cushing's syndrome due to ectopic expression of the gastric inhibitory polypeptide receptor (GIPR) typically harbour inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied.We investigated a woman with a large, heterogeneous adrenal mass and severe ACTH-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhoea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents.Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of four representative nodules detected KDM1A germline variants, benign NM_001009999.3:c.136G>A:p.G46S and likely pathogenic NM_001009999.3:exon6:c.865_866del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA-sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared to 52 unilateral sporadic adenomas and four normal adrenal glands. LH Receptor (LHCGR) expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7; mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess.We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.