Work

7016 Glucocorticoid Resistance Syndrome In Two Patients With Diverse Phenotype And Genotype

Year: 2024

Type: article

Abstract: Disclosure: T. Battiola: None. M.F. Couldwell: None. Introduction: Glucocorticoid resistance syndrome (GRS) is a rare genetic disorder characterized by diminished sensitivity of target tissues to cortisol due to impaired glucocorticoid receptor function. Patients lack clinical manifestations of Cushing’s syndrome but may present with mineralocorticoid and/or androgen excess related to ACTH hypersecretion. We report two cases of GRS that highlight its phenotypic and genetic heterogeneity. Case description: Patient A A 66-year-old female presented with anxiety, hypertension, and newly diagnosed diabetes. Her biochemical evaluation demonstrated persistent hypercortisolism, however she had no clinical features of Cushing’s syndrome. Subsequent evaluation showed inappropriately normal ACTH. No abnormal lesions were seen on MRI of the pituitary. Inferior petrosal sinus sampling (IPSS) was not consistent with a pituitary source. Investigation for ectopic ACTH secretion with full body Cu-68 DOTATATE-PET scan was unrevealing. Her clinical picture was consistent with GRS. Genetic testing did not identify a mutation. Patient B A 43-year-old female presented with weight loss, anxiety, and fatigue. She had persistently elevated cortisol levels but no clinical findings of Cushing’s syndrome. Biochemical evaluation revealed inappropriately normal ACTH. There was no pituitary lesion on MRI. IPSS localized ACTH secretion to the pituitary however resected pituitary tissue was negative for ACTH on immunostaining. The patient was found to be heterozygous for NR3C1 c.1322G>C. Discussion: We describe two cases of persistent ACTH-dependent hypercortisolism in the absence of clinical Cushing’s syndrome, leading to a diagnosis of GRS. GRS is diagnostically challenging due to a wide clinical spectrum. When suspected, evaluation should include 24h UFC and dexamethasone suppression testing. ACTH may be inappropriately normal or increased. Genetic testing confirms the diagnosis. The molecular pathogenesis of GRS has been attributed to inactivating mutations in the NR3C1 gene, which encodes the human glucocorticoid receptor (hGR). There have also been reported cases of GRS without a recognizable mutation of hGR, as in Patient A. These cases may be due to mutations in other steps of the glucocorticoid signaling pathway. Treatment of GRS is aimed at suppression of the HPA axis to reduce ACTH-mediated hypercortisolism, mineralocorticoid, and/or androgen excess. Dexamethasone can be titrated to symptoms and biochemical endpoints. Presentation: 6/2/2024

Source: Journal of the Endocrine Society

DOI: 10.1210/jendso/bvae163.198

Authors: Tess Battiola, Marie Francoise Couldwell

Institution: University of Utah

Language: English

Topic: Adrenal Hormones and Disorders

Subfield: Endocrinology, Diabetes and Metabolism

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,418