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Clinical and Genetic Heterogeneity, Overlap with Other Tumor Syndromes, and Atypical Glucocorticoid Hormone Secretion in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Compared with Other Adrenocortical Tumors

Section on Endocrinology and Genetics (H.-P.H., S.A.B., S.V., A.J.R.-W., M.N., C.A.S.), Program on Developmental Endocrinology and Genetics and Pediatric Endocrinology Interinstitute Training Program (M.F.K., S.V., C.A.S.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Division of Endocrinology, Diabetes, and Metabolism (L.S.K.), Department of Internal Medicine, Ohio State University, Columbus, Ohio 43210; Endocrinology Division (I.B., A.L.), Department of Medicine, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada H2W 1T8; and Department of Pediatrics (H.-P.H.), Kaohsiung Municipal Hsiao-Kang Hospital and Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., D(Med)Sc., Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Clinical Research Center, Room 1-3330, MSC1103, Bethesda, Maryland 20892. E-mail: stratakc{at}mail.nih.gov.

Objective: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is often associated with subclinical cortisol secretion or atypical Cushing’s syndrome (CS). We characterized a large series of patients of AIMAH and compared them with patients with other adrenocortical tumors.

Design and Patients: We recruited 82 subjects with: 1) AIMAH (n = 16); 2) adrenocortical cortisol-producing adenoma with CS (n = 15); 3) aldosterone-producing adenoma (n = 19); and 4) single adenomas with clinically nonsignificant cortisol secretion (n = 32).

Methods: Urinary free cortisol (UFC) and 17-hydroxycorticosteroid (17OHS) were collected at baseline and during dexamethasone testing; aberrant receptor responses was also sought by clinical testing and confirmed molecularly. Peripheral and/or tumor DNA was sequenced for candidate genes.

Results: AIMAH patients had the highest 17OHS excretion, even when UFCs were within or close to the normal range. Aberrant receptor expression was highly prevalent. Histology showed at least two subtypes of AIMAH. For three patients with AIMAH, there was family history of CS; germline mutations were identified in three other patients in the genes for menin (one), fumarate hydratase (one), and adenomatosis polyposis coli (APC) (one); a PDE11A gene variant was found in another. One patient had a GNAS mutation in adrenal nodules only. There were no mutations in any of the tested genes in the patients of the other groups.

Conclusions: AIMAH is a clinically and genetically heterogeneous disorder that can be associated with various genetic defects and aberrant hormone receptors. It is frequently associated with atypical CS and increased 17OHS; UFCs and other measures of adrenocortical activity can be misleadingly normal.