Research Information System
Hormone and Metabolic Research, 2026 (SCI-Expanded, Scopus)
Purpose The purpose of this study was to describe a novel heterozygous missense variant in the nuclear receptor subfamily 3 group C member 1 ligand-binding domain causing primary generalized glucocorticoid resistance and highlight diagnostic pitfalls that can mimic Cushing’s disease. Clinical case A 22-year-old woman was evaluated for suspected Cushing’s disease after elevated cortisol levels and pituitary imaging findings. She underwent three transsphenoidal surgeries, but hypercortisolism and clinical symptoms including hirsutism, acne, menstrual irregularities, and weight gain persisted. The absence of classical Cushing’s stigmata prompted genetic evaluation, which led to the diagnosis of primary generalized glucocorticoid resistance. Methods Whole-exome sequencing was performed in the index case. The identified variant was validated by Sanger sequencing and segregation analysis was carried out in her sister. Results A novel heterozygous, likely pathogenic missense variant (NM_000176.3:c.1940T > C, p.(Leu647Pro)) in the nuclear receptor subfamily 3 group C member 1 gene was detected in two siblings. Conclusions We describe a novel nuclear receptor subfamily 3 group C member 1 variant associated with primary generalized glucocorticoid resistance, expanding the mutational spectrum of glucocorticoid receptor defects. This case underscores the importance of considering primary generalized glucocorticoid resistance in patients with adrenocorticotropic hormone-dependent hypercortisolism lacking typical Cushing’s features to prevent unnecessary invasive procedures and guide appropriate genetic counseling