ESPE Abstracts (2016) 86 P-P1-7

Transient Generalized Glucocorticoid Hypersensitivity Syndrome

Eleni Magdalini Kyritsia, Nicolas C Nicolaidesa,b, Agaristi Lamprokostopouloub, Athina Xaidaraa, Elizabeth Georgiadoua, Vassiliki Dimitropouloua, Alketa Stefab, Amalia Sertedakia, George P Chrousosa,b & Evangelia Charmandaria,b

aDivision of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, Athens, Greece; bDivision of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

Background: Transient Generalized Glucocorticoid Hypersensitivity (TGGH) is a rare disorder characterized by increased tissue sensitivity to glucocorticoids and compensatory hypoactivation of the hypothalamic–pituitary–adrenal (HPA) axis. The condition itself and the underlying molecular mechanisms have not been fully elucidated.

Objective and hypotheses: To present the clinical manifestations, endocrinologic evaluation and molecular studies in a patient with TGGH.

Method and results: A 14-year old boy presented with a 9-month history of clinical manifestations suggestive of Cushing syndrome. Endocrinologic evaluation revealed low 0800 h plasma ACTH (1 pg/ml), serum cortisol (0.08 μg/dl) and 24 h-urinary free cortisol (UFC) concentrations (2.75 μg/24 h). The oral glucose tolerance test (OGTT) indicated severe insulin resistance and hyperinsulinemia. Moreover, HbA1c levels were elevated (6.1%). Screening for synthetic glucocorticoids in both serum and urine samples was negative. Following stimulation with oCRH (1 μg/kg), ACTH concentrations increased significantly, while the response of cortisol was suboptimal for the degree of post-CRH ACTH elevation. Sequencing of the human glucocorticoid receptor (hGR) gene revealed no mutations or polymorphisms. Serological tests revealed elevated HSV-6 IgG titers (1/320). The dexamethasone-binding assays demonstrated increased affinity of the patient’s hGR receptor for the ligand compared with a control subject matched for sex, age and body mass index (Kd=5.7±2.65 nM vs 14.7±5.3 nM). The clinical manifestations of the disease gradually resolved over the ensuing 5 months. Plasma ACTH, serum cortisol and 24 h-UFC concentrations normalized (ACTH: 35.27 pg/ml, cortisol: 11.02 μg/dl, 24 h-UFC: 55.57 μg/24 h). Following OGTT, serum insulin concentrations remained persistently elevated, however, the HbA1c levels were normal (5.5%). The repeat dexamethasone-binding assays showed that the patient’s hGR receptor had similar affinity for the ligand, compared with the control subject (Kd=17.6±0.0 nM vs Kd=14.7±5.3 nM).

Conclusion: Our results suggest that a transient postreceptor defect may have enhanced glucocorticoid signal transduction, leading to TGGH.