Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study

Vitellius, Géraldine; Trabado, Séverine; Hoeffel, Christine; Bouligand, Jérôme; Bennet, A.; Castinetti, Frédéric; Decoudier, B.; Guiochon‐Mantel, Anne; Lombès, Marc; Delemer, Brigitte; Amiot-Chapoutot, F.; Ancelle, Deborah; Bertoin, F.; Brue, Thierry; Caron, Philippe; Borson‐Chazot, Françoise; Christin-Maître, Sophie; Chabre, Olivier; Dessailloud, Rachel; Estour, Bruno; Grulet, H.; Illouz, Frédéric; Jeandidier, N.; Kerlan, V.; Klein, M.L.; Penfornis, A.; Pierre, P.; Tabarin, Antoine; Touraine, Philippe; Vantyghem, Marie-Christine; Young, Jacques

doi:10.1530/eje-17-1071

Cited by 35 publications

(45 citation statements)

References 47 publications

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“…Five novel heterozygous NR3C1 mutations that cause impaired GR signaling were identified, which represents a relatively high prevalence of 5% in the analyzed cohort. These findings suggest that the overall prevalence of NR3C1 mutations may have been previously underestimated and advise to perform GR mutation screening in patients with adrenal incidentalomas (Vitellius et al 2016(Vitellius et al , 2018. Although most of the identified NR3C1 mutations mapped at the GR-LBD, other (p.R477S, p.R477C, p.R477H and p.Y478C) were located at the C-terminal end of the second zinc finger, implicated in the dimerization of the receptor.…”

Section: Nr3c1/gr Mutations Linked To Either Glucocorticoid Resistancmentioning

confidence: 92%

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Jiménez-Panizo

Pérez

Rojas

et al. 2019

Endocrine-Related Cancer

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Nuclear receptors are transcription factors that play critical roles in development, homeostasis and metabolism in all multicellular organisms. An important family of nuclear receptors comprises those members that respond to steroid hormones, and which is subdivided in turn into estrogen receptor (ER) isoforms α and β (NR3A1 and A2, respectively), and a second subfamily of so-called oxosteroid receptors. The latter includes the androgen receptor (AR/NR3C4), the glucocorticoid receptor (GR/NR3C1), the mineralocorticoid receptor (MR/NR3C2) and the progesterone receptor (PR/NR3C3). Here we review recent advances in our understanding of the structure-and-function relationship of steroid nuclear receptors and discuss their implications for the etiology of human diseases. We focus in particular on the role played by AR dysregulation in both prostate cancer (PCa) and androgen insensitivity syndromes (AIS), but also discuss conditions linked to mutations of the GR gene as well as those in a non-steroidal receptor, the thyroid hormone receptor (TR). Finally, we explore how these recent results might be exploited for the development of novel and selective therapeutic strategies.

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Section: Nr3c1/gr Mutations Linked To Either Glucocorticoid Resistancmentioning

confidence: 92%

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Jiménez-Panizo

Pérez

Rojas

et al. 2019

Endocrine-Related Cancer

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“…A recent study revealed an incidence of 5% of mild glucocorticoid resistance (heterozygous NR3C1 mutations) in patients with adrenal incidentalomas, particularly if bilateral characterized by elevated UFC, incomplete suppression of cortisol and ACTH after overninght 1-mg dexamethasone test. This was associated with hypertension and/or biological hypercortisolism without clinical Cushing's signs (84)…”

Section: Note Added In Proofmentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Differential diagnosis, investigation and therapy of bilateral adrenal incidentalomas

Bourdeau

Ghorayeb

Gagnon

et al. 2018

European Journal of Endocrinology

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The investigation and management of unilateral adrenal incidentalomas have been extensively considered in the last decades. While bilateral adrenal incidentalomas represent about 15% of adrenal incidentalomas (AIs), they have been less frequently discussed. The differential diagnosis of bilateral incidentalomas includes metastasis, primary bilateral macronodular adrenal hyperplasia and bilateral cortical adenomas. Less frequent etiologies are bilateral pheochromocytomas, congenital adrenal hyperplasia (CAH), Cushing's disease or ectopic ACTH secretion with secondary bilateral adrenal hyperplasia, primary malignancies, myelolipomas, infections or hemorrhage. The investigation of bilateral incidentalomas includes the same hormonal evaluation to exclude excess hormone secretion as recommended in unilateral AI, but diagnosis of CAH and adrenal insufficiency should also be excluded. This review is focused on the differential diagnosis, investigation and treatment of bilateral AIs.

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“…Although an explanation of this observation is largely speculative it provides some ground that HPA dysregulation, in the direction of HPA axis hyperactivity, may be potentially involved in adrenocortical hyperplasia. A potentially relevant recent study suggests a role for mutations of the NR3C1 gene, encoding for the glucocorticoid receptor (GR), in adrenocortical hyperplasia (Vitellius et al 2018). Heterozygous lossof-function NR3C1 mutations were identified in 5% of patients with bilateral adrenal incidentalomas associated with hypertension and/or cortisol excess without clinical CS.…”

Section: Pathophysiologymentioning

confidence: 99%

“…ACTH levels may not be fully suppressed in PBMAH, especially in patients with mild cortisol hypersecretion. Additional reasons include ectopic ACTH production by the adrenal glands or in patients with GR loss-of-function mutations (Vitellius et al 2018). The use of dexamethasone-CRH test may lead to the erroneous diagnosis of ACTH-dependent CS, since a number of patients may have positive responses .…”

Section: Endocrine Evaluationmentioning

confidence: 99%

Diagnosis and management of primary bilateral macronodular adrenal hyperplasia

Vassiliadi

Tsagarakis

2019

Endocrine-Related Cancer

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Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogeneous entity. The incidental identification of an increasing number of cases has shifted its clinical expression from the rarely encountered severe forms, regarding both cortisol excess and adrenal enlargement, to mild forms of asymptomatic or oligosymptomatic cases with less impressive imaging phenotypes. Activation of cAMP/PKA pathway, either due to alterations of the different downstream signaling pathways or through aberrantly expressed G-protein-coupled receptors, relates to both cortisol secretion and adrenal growth. Germline ARMC5 mutations are a frequent genetic defect. The diagnostic approach consists of both imaging and hormonal characterization. Imaging characterization should be done separately for each lesion. Endocrine evaluation in cases with clinically overt Cushing’s syndrome (CS) is similar to that applied for all forms of CS. In incidentally detected PBMAH, hormonal evaluation includes testing for primary aldosteronism, pheochromocytoma and evaluation for autonomous cortisol secretion, using the 1 mg overnight dexamethasone suppression test. Midnight cortisol or 24-h urinary free cortisol may aid in establishing the degree of cortisol excess. In patients with hypercortisolism, ACTH levels should be measured in order to establish ACTH independency. At variance with other forms of CS, PBMAH may be characterized by a distinct pattern of inefficient steroidogenesis. The appropriate management of PBMAH remains controversial. Bilateral adrenalectomy results in lifetime steroid dependency and is better reserved only for patients with severe CS. Unilateral adrenalectomy might be considered in selected patients. In cases where the regulation of cortisol secretion is mediated by aberrant receptors there is some potential for medical therapy.

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Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study

Abstract: The 5% prevalence of heterozygous mutations discovered in our series is higher than initially thought and encourages GR mutation screening in patients with adrenal incidentalomas to unambiguously differentiate from Cushing's states and to optimize personalized follow-up.

Cited by 35 publications

References 47 publications

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

MANAGEMENT OF ENDOCRINE DISEASE: Differential diagnosis, investigation and therapy of bilateral adrenal incidentalomas

Diagnosis and management of primary bilateral macronodular adrenal hyperplasia

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