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

• Published in: The journal of clinical endocrinology and metabolism Vol. 94; no. 8; pp. 2930 - 2937
• Main Authors: Hsiao, Hui-Pin, Kirschner, Lawrence S., Bourdeau, Isabelle, Keil, Margaret F., Boikos, Sosipatros A., Verma, Somya, Robinson-White, Audrey J., Nesterova, Maria, Lacroix, André, Stratakis, Constantine A.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.08.2009; Endocrine Society; The Endocrine Society
• Subjects: Adenoma; Adenomatous polyposis coli; Adrenal Cortex - pathology; Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - metabolism; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adrenocorticotropic hormone; Adrenocorticotropic Hormone - physiology; Adult; Aldosterone; Biological and medical sciences; Chromogranins; Corticotropin-Releasing Hormone; Cortisol; Dexamethasone; Dexamethasone - pharmacology; Endocrinopathies; Feeding. Feeding behavior; Female; Fumarase; Fundamental and applied biological sciences. Psychology; Genetic Heterogeneity; Glucocorticoids - metabolism; GTP-Binding Protein alpha Subunits, Gs - genetics; Hormones; Humans; Hyperplasia; Male; Medical sciences; Middle Aged; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Nucleotide sequence; Original; Polyposis; Polyposis coli; Secretion; Tumors; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Immunopathology; Adrenal cortex carcinoma; Obesity; Adrenal cortex diseases; Nutrition; Secretion; Nutrition disorder; Autoimmune disease; Metabolic diseases; Hyperadrenocorticism; Genetic diversity; Malignant tumor; Enzymopathy; Glucocorticoid; Congenital adrenal hyperplasia syndrome; Adrenocorticotropic hormone; Adenohypophyseal hormone; Adrenal gland diseases; Atypical; Endocrinology; Nutritional status; Comparative study; Cancer
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2009-0516

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.