Patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) usually present bilateral benign adrenocortical macronodules at imaging and variable levels of cortisol excess. PBMAH is a rare cause of primary overt Cushing's syndrome but may represent up to one-third of bilateral adrenal incidentalomas with evidence of cortisol excess. The increased steroidogenesis in PBMAH is often regulated by various G protein-coupled receptors (GPCRs) aberrantly expressed in PBMAH tissues; some receptor ligands are ectopically produced in PBMAH tissues, creating aberrant autocrine/paracrine regulation of steroidogenesis. The bilateral nature of PBMAH and familial aggregation led to the identification of germline heterozygous inactivating mutations of the ARMC5 gene, in 20% to 25% of the apparent sporadic cases and more frequently in familial cases; ARMC5 mutations/pathogenic variants can be associated with meningiomas. More recently, combined germline mutations/pathogenic variants and somatic events inactivating the KDM1A gene were specifically identified in patients affected by glucose-dependent insulinotropic peptide (GIP)-dependent PBMAH. Functional studies demonstrated that inactivation of KDM1A leads to GIP-receptor (GIPR) overexpression and over- or downregulation of other GPCRs. Genetic analysis is now available for early detection of family members of index cases with PBMAH carrying identified germline pathogenic variants. Detailed biochemical, imaging, and comorbidity assessment of the nature and severity of PBMAH is essential for its management. Treatment is reserved for patients with overt or mild cortisol/aldosterone or other steroid excesses, taking in account comorbidities. It previously relied on bilateral adrenalectomy; however, recent studies tend to favor unilateral adrenalectomy or, less frequently, medical treatment with cortisol synthesis inhibitors or specific blockers of aberrant GPCR.

中文翻译：

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原发性双侧大结节性肾上腺增生症的临床、病理生理学、遗传学和治疗进展。

原发性双侧肾上腺大结节增生 (PBMAH) 患者通常在影像学上表现为双侧良性肾上腺皮质大结节，并且皮质醇过量水平不同。PBMAH 是原发性明显库欣综合征的罕见原因，但可能代表高达三分之一的双侧肾上腺偶发瘤，并有皮质醇过量的证据。PBMAH 中类固醇生成的增加通常受到 PBMAH 组织中异常表达的各种 G 蛋白偶联受体 (GPCR) 的调节；一些受体配体在 PBMAH 组织中异位产生，造成类固醇生成的异常自分泌/旁分泌调节。PBMAH 的双边性质和家族聚集导致了 ARMC5 基因种系杂合失活突变的鉴定，20% 至 25% 的明显散发病例，且更常见于家族病例；ARMC5 突变/致病变异可能与脑膜瘤有关。最近，在受葡萄糖依赖性促胰岛素肽 (GIP) 依赖性 PBMAH 影响的患者中，专门鉴定了联合种系突变/致病变异和使 KDM1A 基因失活的体细胞事件。功能研究表明，KDM1A 失活会导致 GIP 受体 (GIPR) 过度表达以及其他 GPCR 的过度或下调。遗传分析现在可用于早期检测携带已确定种系致病变异的 PBMAH 指示病例的家庭成员。对 PBMAH 的性质和严重程度进行详细的生化、影像学和合并症评估对于其治疗至关重要。考虑到合并症，治疗仅限于明显或轻度皮质醇/醛固酮或其他类固醇过量的患者。此前，它依赖于双侧肾上腺切除术；然而，最近的研究倾向于单侧肾上腺切除术，或者较少采用皮质醇合成抑制剂或异常 GPCR 的特异性阻断剂进行药物治疗。