title: Adrenal pathophysiology: lessons from the Carney complex.
abstract: The Carney complex (CNC) is a dominantly inherited syndrome responsible mainly for spotty skin pigmentation (lentiginosis), endocrine overactivity, and cardiac myxomas. Adrenocorticotropic hormone independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) is a main characteristic of CNC. PPNAD is a very rare cause of Cushing's syndrome due to a primary bilateral adrenal defect that can be also observed in some patients without other CNC manifestations nor familial history. One of the putative CNC genes, located on 17q22-24, has been identified as the regulatory subunit R1A of protein kinase A (PRKAR1A). Heterozygous inactivating mutations of PRKAR1A have been reported initially in about 45% of the CNC index cases and could be found in about 80% of the CNC families presenting mainly with Cushing's syndrome. PRKAR1A is a key component of the cyclic AMP signaling pathway that has been implicated in endocrine tumorigenesis and could, at least partly, function as a tumor suppressor gene. Interestingly, patients with isolated PPNAD and no familial history of CNC can also present a germline de novo mutation of PRKAR1A. Somatic mutations of PRKAR1A have been found in PPNAD as a mechanism of inactivation of the wild-type allele, in a patient already presenting a germline mutation, and in a subset of sporadic secreting adrenocortical adenomas with clinical, hormonal, and pathological features quite similar to PPNAD. This review will summarize the recent findings on CNC from the perspective of the pathophysiology of adrenal Cushing's syndrome and PPNAD.
authors.affiliation: INSERM U 567, CNRS UMR 8104, Université René-Descartes Paris V, Institut Cochin, Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Laure
authors.initials: L
authors.lastname: Cazabat
authors.forename: Fernande
authors.initials: F
authors.lastname: René-Corail
authors.forename: Eric
authors.initials: E
authors.lastname: Jullian
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
mesh_terms: D000303:Adrenal Cortex Diseases / Q000235:genetics / Q000503:physiopathology*; D000311:Adrenal Glands / Q000503:physiopathology*; D000328:Adult; D002675:Child, Preschool; D000242:Cyclic AMP / Q000502:physiology; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases; D006801:Humans; D009377:Multiple Endocrine Neoplasia / Q000235:genetics / Q000503:physiopathology*; D047748:Pituitary ACTH Hypersecretion / Q000209:etiology / Q000503:physiopathology; D011506:Proteins / Q000235:genetics; D015398:Signal Transduction
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D011506:Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases