Comment to ‘Glucocorticoid resistance syndrome caused by a novel NR3C1 point mutation’ by Al Argan et al.

Dear Editor,

Al Argan et al. recently reported on this journal [1] a case of a woman with a longstanding history of low body weight, hyperandrogenism and evidence of ACTH-dependent hypercortisolism, consistent with glucocorticoid resistance syndrome (GRS), resulted to be due to a novel pathogenic mutation of the NR3C1 gene encoding the glucocorticoid receptor (GR). They also reviewed the current literature of this extremely rare condition that, according to the Authors, would consist in only 21 reports with 23 index cases published worldwide [1]. Herein we would like to point out, for the sake of completeness, that in 2007, our research group published the case of a 16-yr-old girl presenting with hirsutism and amenorrhea, borderline hypertension in the absence of other stigma of hypercortisolism, despite increased free urinary cortisol, DHEAS and 17OH-progesterone (peak after exogenous ACTH challenge: 4.2 ng/mL), and upregulated circadian periodicity of both ACTH and cortisol, which was not suppressible after administration of low dose (1 mg) of dexamethasone [2]. Genetic testing of our patient revealed a novel mutation affecting the N-terminus of the ligand-binding domain of the GRα gene product, as a result of leucine with valine replacement in the residue 595 (exon 6), which is located in helix 4 that is spatially close to the glucocorticoid hormone binding pocket. According to protein modelling, the Leu595Val substitution would cause change in secondary and tertiary structure of the receptor, destabilizing helix 4 and interfering with agonists binding [2].

Unquestionably, the so far published cases demonstrate that this infrequently reported condition: i) has a considerably variable clinical presentation including hyperandrogenism, altered fertility, hyperaldosteronism with or without hypertension, non-specific symptoms of hypocortisolism such as fatigue, weight loss etc., which can be coupled with other deleterious effects of GC action on differently sensitive target-organs; ii) is a very challenging diagnosis which require a step-by-step complex biochemical and imaging workup, in order to exclude other potential causes of hypothalamic-pituitary-adrenal axis over-activation; iii) has a peculiar genetic background that, influencing steroid hormone sensitivity in different tissues, leads to the heterogeneity of clinical features. On the other hand, an appropriate diagnosis of this under-recognized condition would allow a properly tailored and individualized therapeutic approach and would imply the non-negligible advantages of relatives’ genetic testing. Moreover, an increasing awareness about GRS can also contribute to unravelling the mechanisms underlying altered GC responsiveness in other non-endocrine diseases.

References

• 1   Al Argan  R,  Saskin  A,  Yang  JW,  D’Agostino  MD,  Rivera  J (2018) Glucocorticoid resistance syndrome caused by a novel NR3C1 point mutation. Endocr J 65: 1139–1146.
• 2   Cannavò  S,  Karl  M,  Santarpia  L,  Facchiano  A,  Marabotti  A, et al. (2007) A novel point mutation in the ligand binding domain of the human glucocorticoid receptor (hGR) in a patient with glucocorticoid resistance. Int J Disabil Hum Dev 6: 105–112.