ESPE Abstracts (2014) 82 P-D-1-2-3

Transient Generalized Glucocorticoid Hypersensitivity: Clinical Manifestations, Endocrinologic Evaluation, and Transcriptomic Profile: the Potential Role of nf-[kappa]b

Nicolas C Nicolaidesa, Agaristi Lamprokostopouloua, Alexandros Polyzosb, Tomoshige Kinoc, Eleni Katsantonid, Panagiota Triantafylloue, Athanasios Christophoridise, George Katzose, Maria Drakopoulouf, Amalia Sertedakif, George P Chrousosa,f & Evangelia Charmandaria,f


aDivision of Endocrinology and Metabolism, Biomedical Research Foundation of the Academy of Athens, Athens, Attiki, Greece; bInstitute of Molecular Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Atiki, Greece; cUnit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA; dDivision of Hematology, Biomedical Research Foundation of the Academy of Athens, Athens, Attiki, Greece; eFirst Pediatric Department, Aristotle University Medical School, Thessaloniki, Greece; fFirst Department of Pediatrics, Aghia Sophia Children’s Hospital, University of Athens Medical School, Athens, Attiki, Greece


Background: Transient generalized glucocorticoid hypersensitivity 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 molecular mechanisms that underlie its pathophysiology have not been elucidated as yet. Adenovirus 36 has been reported to cause obesity in various animal species.

Objective and Hypotheses: To present the clinical manifestations, endocrinologic evaluation and transcriptomics profile in a rare pediatric case of transient generalized glucocorticoid hypersensitivity.

Patient, methods, and results: A 9-year-old girl presented with an 8-month history of clinical manifestations suggestive of Cushing’s syndrome, including central obesity, moon facies, buffalo hump, purple skin striae, hypertrichosis, and decreased growth velocity. Endocrinologic evaluation revealed undetectable 0800 h ACTH (<1 pg/ml) and cortisol (0.025 μg/dl) concentrations, which remained decreased throughout a 24 h period of study and did not respond to stimulation with ovine CRH (1 μg/kg). The disease gradually resolved spontaneously over the ensuing 3 months. Sequencing of the human glucocorticoid receptor gene revealed no mutations or polymorphisms. Transcriptomic (RNA sequencing) analysis in white blood cells in the disease and post resolution phases identified 903 differentially expressed genes. Of these, 106 genes were up-regulated and 797 were down-regulated in the disease compared with the resolution phase. Bioinformatic analysis on the differentially expressed gene networks revealed nuclear factor-κB as the predominant transcription factor influencing the expression of the majority of these differentially expressed genes, suggesting an active inflammatory reaction. RNA-sequencing showed no enrichment of adenovirus 36 sequence in our patient.

Conclusions: Our findings indicate that a transient post-receptor defect or a virus-encoded molecule may have interfered with glucocorticoid signal transduction leading to transient generalized glucocorticoid hypersensitivity in our patient. The changes in the transcriptome in the active phase of the disease point toward a transient exogenous insult, probably an infectious agent.