Characterization of a novel variant in the NR3C1 gene: differentiating glucocorticoid resistance from Cushing Syndrome.

Introduction: Primary generalized glucocorticoid resistance syndrome (GGRS) is a rare endocrine disease caused by loss-of-function variants of the NR3C1 gene encoding the Glucocorticoid Receptor. We describe a novel heterozygous missense variant (NM_000176.3, c.1330T>G, p.Phe444Val) within the DNA Binding Domain.

Clinical Case: Elevated urinary-free cortisol levels were detected in a 59-year-old male before bariatric surgery (BMI 39.9 kg/m2). Early-onset hypertension was well controlled. The low dose dexamethasone suppression test was pathologic, but ACTH and midnight salivary cortisol levels were normal. The patient was initially referred to transsphenoidal surgery for a presumed diagnosis of Cushing disease. He presented to our department at the age of 68, when the clinical diagnosis of GGRS was established.

Methods: Functional characterization of the variant was performed ex vivo through transient transfection assays in HEK 293T cells to assess transcriptional activity and nuclear translocation.

Results: The variant showed a lack of transcriptional activity (GRWT: 91.5 [80.5; 101.2] vs. GRF444V: 1.0 [1.0; 1.0]) despite efficient nuclear translocation in response to dexamethasone, suggesting a DNA binding defect of the variant. These results are discussed in the light of previously reported GGRS cases.

Conclusion: We have described a novel heterozygous mutation of the NR3C1 gene associated with primary GGRS. This case highlights the importance of raising awareness of clinical and laboratory features of this rare disorder, to enable early diagnosis and avoid unnecessary and potentially dangerous diagnostic and therapeutic procedures.