Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome

• Published in: The New England journal of medicine Vol. 370; no. 11; pp. 1019 - 1028
• Main Authors: Beuschlein, Felix, Fassnacht, Martin, Assié, Guillaume, Calebiro, Davide, Stratakis, Constantine A, Osswald, Andrea, Ronchi, Cristina L, Wieland, Thomas, Sbiera, Silviu, Faucz, Fabio R, Schaak, Katrin, Schmittfull, Anett, Schwarzmayr, Thomas, Barreau, Olivia, Vezzosi, Delphine, Rizk-Rabin, Marthe, Zabel, Ulrike, Szarek, Eva, Salpea, Paraskevi, Forlino, Antonella, Vetro, Annalisa, Zuffardi, Orsetta, Kisker, Caroline, Diener, Susanne, Meitinger, Thomas, Lohse, Martin J, Reincke, Martin, Bertherat, Jérome, Strom, Tim M, Allolio, Bruno
• Format: Journal Article
• Language: English
• Published: Waltham, MA Massachusetts Medical Society 13.03.2014
• Subjects: Adenoma; Adenoma - complications; Adenoma - enzymology; Adenoma - genetics; Adrenal cortex; Adrenal Gland Neoplasms; Adrenal Gland Neoplasms - complications; Adrenal Gland Neoplasms - enzymology; Adrenal Gland Neoplasms - genetics; Adrenal glands; Adrenal Hyperplasia, Congenital; Adrenal Hyperplasia, Congenital - genetics; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adrenocorticotropic hormone; Adult; Biochemistry, Molecular Biology; Biological and medical sciences; Catalytic Domain; Chromosome 19; Cortisol; Cushing Syndrome; Cushing Syndrome - enzymology; Cushing Syndrome - etiology; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Dependent Protein Kinases - chemistry; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Endocrinopathies; Exome; General aspects; Genes; Germ-Line Mutation; Humans; Hydrocortisone; Hydrocortisone - biosynthesis; Hyperplasia; Kinases; Life Sciences; Medical sciences; Middle Aged; Mutation; Nervous system diseases; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Pituitary; Protein Conformation; Protein kinase A; Sequence Analysis, DNA; Tumors; Endocrinopathy; Medicine; Adrenal cortex diseases; Adrenal glands; Adrenal gland diseases; Cushing syndrome; Hyperadrenocorticism; Subunit
• ISSN: 0028-4793; 1533-4406; 1533-4406
• DOI: 10.1056/NEJMoa1310359

Corticotropin-independent Cushing's syndrome occurs with adrenocortical tumors or hyperplasia. The authors report that germline duplications of PRKACA lead to bilateral adrenal hyperplasia, whereas somatic mutations lead to unilateral cortisol-producing adrenal adenomas. Endogenous hypercortisolism, referred to as Cushing's syndrome, is associated with substantial morbidity and mortality. 1 When Cushing's syndrome is severe, patients have catabolic symptoms such as muscle weakness, skin fragility, osteoporosis, and severe metabolic sequelae. 2 Hypersecretion of cortisol can be driven by an excess of pituitary or ectopic corticotropin or can be due to adrenocortical tumors or hyperplasias with corticotropin-independent cortisol production. Adrenal adenomas are common, with a prevalence of at least 3% among persons older than 50 years of age. 3 Whereas only a subset of these tumors is associated with overt Cushing's syndrome, some degree of cortisol excess is present, . . .