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A Novel Pathogenic Variant in the N-Terminal Domain of the Glucocorticoid Receptor, Causing Glucocorticoid Resistance

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Abstract

Background

Generalized glucocorticoid resistance is characterized by impaired cortisol signaling, resulting from mutations in the NR3C1 gene coding the human glucocorticoid receptor (hGR). Most of the pathogenic hGR variants are identified in the ligand-binding domain (LBD). However, we report a new case associated with a novel NR3C1 pathogenic variant in the N-terminal domain (NTD) of the hGR.

Methods

The index case was an Italian 31-year-old woman with a history of chronic fatigue, anxiety, hirsutism, irregular menstrual cycles, and infertility, but no clinical manifestations suggestive of Cushing’s syndrome. Standard clinical methods were used to assess the patient’s hypothalamic–pituitary–adrenal axis. Molecular analysis of the NR3C1 gene was performed by Sanger sequencing. In addition, we perform an extensive survey of all clinical pathogenic variants modifying the whole sequence of the NR3C1 gene.

Results

Endocrinologic evaluation revealed elevated serum cortisol, plasma adrenocorticotropic hormone, and androstenedione concentration and increased urinary free cortisol excretion. Morning serum cortisol levels remained elevated and were not suppressed during a 2-day, 2-mg dexamethasone suppression test. The identification of the novel p.(Glu123Ter) NR3C1 variant confirmed the diagnosis of glucocorticoid resistance.

Conclusion

Our findings improve the understanding of NR3C1 mutational spectrum in patients affected by glucocorticoid resistance syndrome and contribute to precise diagnosis and genetic counseling.

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Authors and Affiliations

  1. Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Largo S. Vito 1 - 00168, Roma, Italy

    Rosa Maria Paragliola & Andrea Corsello

  2. Unit of Endocrinology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Roma, Italy

    Rosa Maria Paragliola & Andrea Corsello

  3. Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Università Cattolica del Sacro Cuore, Largo S. Vito 1, 00168, Roma, Italy

    Alessandra Costella, Andrea Urbani & Paola Concolino

  4. Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Roma, Italy

    Alessandra Costella, Andrea Urbani & Paola Concolino

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  1. Rosa Maria Paragliola
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Correspondence to Paola Concolino.

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The authors (RMP, AC, AC, AU, and PC) have no conflict of interest to declare.

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Paragliola, R.M., Costella, A., Corsello, A. et al. A Novel Pathogenic Variant in the N-Terminal Domain of the Glucocorticoid Receptor, Causing Glucocorticoid Resistance. Mol Diagn Ther 24, 473–485 (2020). https://doi.org/10.1007/s40291-020-00480-9

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