6776 A case of non-neoplastic hypercortisolism leading to the diagnosis of glucocorticoid resistance syndrome due to a novel NR3C1 variant
Authors: Yamamoto Naoki , Kido Nozomi , Bando Hironori , Yamamoto Masaaki , Urai Shin , Tsujimoto Yasutaka , Ohmachi Yuka , Motomoura Yuma , Oi-Yo Yuka , Sasaki Yuriko , Suzuki Masaki , Takahashi Michiko , Iguchi Genzo , Ogawa Wataru , Fukuoka Hidenori 
Published: October 2024

Abstract
Disclosure: N. Yamamoto: None. N. Kido: None. H. Bando: None. M. Yamamoto: None. S. Urai: None. Y. Tsujimoto: None. Y. Ohmachi: None. Y. Motomoura: None. Y. Oi-Yo: None. Y. Sasaki: None. M. Suzuki: None. M. Takahashi: None. G. Iguchi: None. W. Ogawa: None. H. Fukuoka: None.
Introduction: Non-neoplastic hypercortisolism is often difficult to distinguish from Cushing syndrome (CS) because of overlapping clinical and biochemical features. Glucocorticoid resistance syndrome (GRS), caused by variants in NR3C1 which encodes the glucocorticoid receptor (GR), can be its rare cause. Patients with GRS are usually detected by clinical signs such as adrenal hyperplasia or hirsutism. We present a unique case in which non-neoplastic hypercortisolism led to the diagnosis of GRS. Clinical Case: A 54-year-old woman with type 1 diabetes underwent endocrinologic testing due to transient hypokalemia and a left adrenal incidentaloma. As a result, her serum cortisol levels were found to be high at 26.5 μg/dL, without suppression of plasma adrenocorticotropic hormone (ACTH) levels (27.0 pg/mL), suggesting ACTH-dependent CS. Physical examination revealed no features suggestive of CS, including moon face, central obesity, easy bruising, or hirsutism. However, serum cortisol levels after an overnight 1 mg-dexamethasone suppression test showed as high as 8.3 μg/dL with no suppression of midnight serum cortisol levels (8.7 μg/dL). In addition, urinary free cortisol levels were 91.2 μg/day (reference range: 5.5-66.7 μg/day), suggesting autonomous excessive cortisol secretion. Based on the discrepancy between physical and endocrinological findings, non-neoplastic hypercortisolism was suspected, while there was no common cause such as alcohol abuse, psychiatric disorder, or chronic kidney disease. Then, GRS was considered, and genetic testing for NR3C1 was performed. Genetic and functional analysis: Genetic testing revealed novel heterozygous missense variant in the exon 7 of NR3C1 (c.2009T&gt;C, p.L670P). Moreover, in silico analysis predicted that this variant would be damaging to GR function. For functional analysis, we constructed a GR expression plasmid with wild type (GR WT) and this variant (GR L670P). The respective plasmids were transfected into HEK293T and Pomc promoter activity after dexamethasone treatment was assessed by luciferase reporter assay. In cells expressing GR WT, Pomc promoter activity was suppressed by dexamethasone, whereas no significant change was detected in cells expressing GR L670P, suggesting that this variant causes loss of GR function. Then, GRS due to a novel NR3C1 variant was diagnosed, and CS was successfully ruled out. Learning lessons: GRS may be hidden in cases of non-neoplastic hypercortisolism. In the present case, the absence of physical symptoms suggestive of CS despite hypercortisolemia, and the lack of an obvious cause of non-neoplastic hypercortisolism led to the suspicion of GRS. Identification of NR3C1 variants may rule out CS and avoid unnecessary invasive testing and treatment in such cases.
Presentation: 6/2/2024