Glucocorticoid Resistance Syndrome as a Hidden Cause of Nonneoplastic Hypercortisolism

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 <i>NR3C1</i>, 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.