Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France.
Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
Eur J Endocrinol. 2022 May 24;187(1):123-134. doi: 10.1530/EJE-21-1032.
Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. It can be caused by ARMC5 germline pathogenic variants. In this study, we aimed to identify predictive criteria for ARMC5 variants.
We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5 alteration. Clinical, biological and imaging data were collected retrospectively.
52 patients (14.8%) carried ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-h urinary free cortisol 2.32 vs 1.11-fold ULN, respectively, P < 0.001) and adrenal morphology (maximal adrenal diameter 104 vs 83 mm, respectively, P < 0.001) and were more often surgically or medically treated (67.9 vs 36.8%, respectively, P < 0.001). ARMC5-mutated patients showed a constant, bilateral adrenal involvement and at least a possible autonomous cortisol secretion (defined by a plasma cortisol after 1 mg dexamethasone suppression above 50 nmol/L), while these criteria were not systematic in WT patients (78.3%). The association of these two criteria holds a 100% sensitivity and a 100% negative predictive value for ARMC5 pathogenic variant.
We report the largest series of index patients investigated for ARMC5 and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype in most cases. To minimize negative ARMC5 screening, genotyping should be limited to clear bilateral adrenal involvement and autonomous cortisol secretion, with an optimum sensitivity for routine clinical practice. These findings will also help to better define PBMAH diagnostic criteria.
双侧原发性大结节性肾上腺增生症（PBMAH）是一种异质性疾病，其特征为肾上腺大结节和皮质醇过量程度不同，但目前尚无明确的临床诊断标准。它可能由 ARMC5 种系致病性变异引起。在本研究中，我们旨在确定 ARMC5 变异的预测标准。
我们纳入了来自 12 个欧洲中心的 352 例连续的指数患者，对其进行了 ARMC5 种系改变的测序。回顾性收集了临床、生物学和影像学数据。
52 例（14.8%）患者携带 ARMC5 种系致病性变异，与未突变患者相比，其皮质醇过量（24 小时尿游离皮质醇分别为 ULN 的 2.32 倍和 1.11 倍，均 P<0.001）和肾上腺形态（最大肾上腺直径分别为 104 毫米和 83 毫米，均 P<0.001）更为明显，且更常接受手术或药物治疗（分别为 67.9%和 36.8%，均 P<0.001）。ARMC5 突变患者表现为双侧肾上腺恒定受累，且至少存在潜在的自主皮质醇分泌（定义为 1 毫克地塞米松抑制后血浆皮质醇>50 nmol/L），而这些标准在 WT 患者中并不系统（78.3%）。这两个标准的联合具有 100%的敏感性和 100%的 ARMC5 致病性变异的阴性预测值。
我们报告了最大的 ARMC5 指数患者系列研究，并证实 ARMC5 致病性变异在大多数情况下与更严重的表型相关。为了最大限度地减少 ARMC5 的阴性筛查，基因分型应仅限于明确的双侧肾上腺受累和自主皮质醇分泌，以获得最佳的敏感性，适用于常规临床实践。这些发现还将有助于更好地定义 PBMAH 诊断标准。
