ACTH-Independent Cushing's Syndrome with Bilateral Micronodular Adrenal Hyperplasia and Ectopic Adrenocortical Adenoma

Estelle Louiset, Françoise Gobet, Rossella Libé, Anelia Horvath, Sylvie Renouf, Juliette Cariou, Anya Rothenbuhler, Jérôme Bertherat, Eric Clauser, Philippe Grise, Constantine A. Stratakis, Jean-Marc Kuhn, and Hervé Lefebvre*

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 982/Equipe Associée 4310, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (E.L., S.R., J.-M.K., H.L.), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23, University of Rouen, 76821 Mont-Saint-Aignan, France; Department of Pathology (F.G.), University Hospital of Rouen, Institute for Biomedical Research, University of Rouen, 76031 Rouen, France; INSERM U567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Assistance Publique-Hôpitaux de Paris, Department of Endocrinology-Metabolism-Cancer (R.L., J.B.), Institut Cochin, Université Paris V-René Descartes, 75014 Paris, France; Section on Endocrinology and Genetics, Program in Developmental Endocrinology and Genetics (A.H., A.R., C.A.S.), National Institute of Child Health & Human Development, Bethesda, Maryland 20892; Oncogenetics Unit (E.C.), Cochin Hospital, 75014 Paris, France; and Departments of Urology (J.C., P.G.) and Endocrinology (J.-M.K., H.L.), University Hospital of Rouen, Institute for Biomedical Research, University of Rouen, 76031 Rouen, France

* To whom correspondence should be addressed. E-mail: herve.lefebvre@chu-rouen.fr.

Context: Bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma are two rare causes of ACTH-independent Cushing's syndrome.

Objective: The aim of the study was to evaluate a 35-yr-old woman with ACTH-independent hypercortisolism associated with both micronodular adrenal hyperplasia and ectopic pararenal adrenocortical adenoma.

Design and Setting: In vivo and in vitro studies were performed in a University Hospital Department and academic research laboratories.

Intervention: Mutations of the PRKAR1A, PDE8B, and PDE11A genes were searched for in leukocytes and adrenocortical tissues. The ability of adrenal and adenoma tissues to synthesize cortisol was investigated by immunohistochemistry, quantitative PCR, and/or cell culture studies.

Main Outcome Measure: Detection of 17{alpha}-hydroxylase and 21-hydroxylase immunoreactivities, quantification of CYP11B1 mRNA in adrenal and adenoma tissues, and measurement of cortisol levels in supernatants by radioimmunological assays were the main outcomes.

Results: Histological examination of the adrenals revealed nonpigmented micronodular cortical hyperplasia associated with relative atrophy of internodular cortex. No genomic and/or somatic adrenal mutations of the PRKAR1A, PDE8B, and PDE11A genes were detected. 17{alpha}-Hydroxylase and 21-hydroxylase immunoreactivities as well as CYP11B1 mRNA were detected in adrenal and adenoma tissues. ACTH and dexamethasone activated cortisol secretion from adenoma cells. The stimulatory action of dexamethasone was mediated by a nongenomic effect involving the protein kinase A pathway.

Conclusion: This case suggests that unknown molecular defects can favor both micronodular adrenal hyperplasia and ectopic adrenocortical adenoma associated with Cushing's syndrome.

From http://jcem.endojournals.org/cgi/content/abstract/jc.2009-0881v1