Yamamoto Naoki, Kido Nozomi, Sugawara Kenji, Bando Hironori, Yamamoto Masaaki, Urai Shin, Tsujimoto Yasutaka, Ohmachi Yuka, Motomura Yuma, Oi-Yo Yuka, Sasaki Yuriko, Suzuki Masaki, Takahashi Michiko, Iguchi Genzo, Ogawa Wataru, Fukuoka Hidenori
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Hospital, Kobe, Hyogo 650-0017, Japan.
J Endocr Soc. 2025 May 20;9(7):bvaf097. doi: 10.1210/jendso/bvaf097. eCollection 2025 Jul.
Cases of hypercortisolemia without physical signs of Cushing's syndrome (CS), suggestive of nonneoplastic hypercortisolism (NNH), often remain partially unexplained. We present a unique case that was initially misdiagnosed as ACTH-dependent CS due to abnormal laboratory findings, despite the absence of Cushingoid features. Molecular and functional analyses ultimately led to a diagnosis of glucocorticoid resistance syndrome (GRS). A 54-year-old female patient underwent endocrinological evaluation for an adrenal incidentaloma associated with hypokalemia, which revealed hypercortisolemia. Subsequent endocrinological testing was consistent with ACTH-dependent CS; however, no Cushingoid features were observed on physical examination, suggesting NNH. As no apparent cause of NNH was identified, we hypothesized a functional disorder of the glucocorticoid receptor (GR) and performed a genetic analysis of , which encodes GR. This revealed a novel germline heterozygous variant, p.L670P, located in the ligand-binding domain of the GR. Structural analyses revealed that Leu670 forms a hydrophobic core near the ligand-binding pocket. The p.L670P variant disrupted the secondary structure, suggesting a potential compromise in the structural stability of the ligand-binding site. In vitro experiments showed that this GR variant failed to suppress the transcriptional activity of the proopiomelanocortin promoter following dexamethasone administration. These findings confirmed that the patient had a loss-of-function variant in GR, leading to a diagnosis of GRS and ruling out ACTH-dependent CS. This case highlights that GRS may underline cases of NNH without a clear etiology, and genetic testing for GR can aid in its diagnosis.
无库欣综合征（CS）体征的高皮质醇血症病例，提示为非肿瘤性高皮质醇血症（NNH），其病因往往部分不明。我们报告一例独特病例，该患者最初因实验室检查结果异常被误诊为促肾上腺皮质激素（ACTH）依赖性CS，尽管并无库欣样特征。分子和功能分析最终确诊为糖皮质激素抵抗综合征（GRS）。一名54岁女性患者因肾上腺意外瘤合并低钾血症接受内分泌评估，检查发现存在高皮质醇血症。随后的内分泌检查结果与ACTH依赖性CS相符；然而，体格检查未发现库欣样特征，提示为NNH。由于未发现NNH的明显病因，我们推测为糖皮质激素受体（GR）功能障碍，并对编码GR的 进行了基因分析。结果发现一个新的种系杂合变异体p.L670P，位于GR的配体结合域。结构分析显示，亮氨酸670在配体结合口袋附近形成一个疏水核心。p.L670P变异体破坏了二级结构，提示配体结合位点的结构稳定性可能受损。体外实验表明，给予地塞米松后，该GR变异体无法抑制阿黑皮素原启动子的转录活性。这些发现证实该患者的GR存在功能丧失变异，从而确诊为GRS，排除了ACTH依赖性CS。该病例突出表明，GRS可能是病因不明的NNH病例的潜在原因，对GR进行基因检测有助于其诊断。
