{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:22:59Z","timestamp":1790752979030,"version":"4.1.0"},"reference-count":89,"publisher":"Georg Thieme Verlag KG","issue":"11","license":[{"start":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T00:00:00Z","timestamp":1663718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Key Laboratory of Science and Technology Department","award":["20190901006JC"],"award-info":[{"award-number":["20190901006JC"]}]},{"name":"Innovation Capability Project of Jilin Provincial Development and Reform Commission","award":["2017C019"],"award-info":[{"award-number":["2017C019"]}]},{"name":"Engineering Technology Research Center for Personalized Precision Diagnosis and Treatment, Science and Technology Department of Jilin Province","award":["20170623005TC"],"award-info":[{"award-number":["20170623005TC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Horm Metab Res"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of\n                    adrenocorticotropin hormone (ACTH)-independent Cushing\u2019s syndrome (CS),\n                    which mainly occurs in children and young adults. Treatment options with proven\n                    clinical efficacy for PPNAD include adrenalectomy (bilateral or unilateral\n                    adrenalectomy) and drug treatment to control hypercortisolemia. Previously, the\n                    main treatment of PPNAD is bilateral adrenal resection and long-term hormone\n                    replacement after surgery. In recent years, cases reports suggest that\n                    unilateral or subtotal adrenal resection can also lead to long-term remission in\n                    some patients without the need for long-term hormone replacement therapy.\n                    Medications for hypercortisolemia, such as Ketoconazole, Metyrapone and Mitotane\n                    et.al, have been reported as a preoperative transition for in some patients with\n                    severe hypercortisolism. In addition, tryptophan hydroxylase inhibitor, COX2\n                    inhibitor Celecoxib, somatostatin and other drugs targeting the possible\n                    pathogenic mechanisms of the disease are under study, which are expected to be\n                    applied to the clinical treatment of PPNAD in the future. In this review, we\n                    summarize the recent progress on treatment of PPNAD, in which options of\n                    surgical methods, research results of drugs acting on possible pathogenic\n                    mechanisms, and the management during gestation are described in order to\n                    provide new ideas for clinical treatment.<\/jats:p>","DOI":"10.1055\/a-1948-6990","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T23:19:50Z","timestamp":1663802390000},"page":"721-730","source":"Crossref","is-referenced-by-count":9,"title":["Treatment of Primary Pigmented Nodular Adrenocortical\n                    Disease"],"prefix":"10.1055","volume":"54","author":[{"given":"Xiaokun","family":"Gang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, The First Hospital of Jilin\n                    University, Changchun, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guixia","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, The First Hospital of Jilin\n                    University, Changchun, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, The First Hospital of Jilin\n                    University, Changchun, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, The First Hospital of Jilin\n                    University, Changchun, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunran","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, The First Hospital of Jilin\n                    University, Changchun, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2022,11,10]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1097\/00000478-198405000-00002","article-title":"Bilateral primary pigmented nodular adrenocortical disease. Rare cause of the\n                    Cushing syndrome","volume":"8","author":"B V Shenoy","year":"1984","journal-title":"Am J Surg Pathol"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"99","DOI":"10.4103\/2230-8210.126586","article-title":"Etiology and clinical profile of patients with Cushing\u2019s syndrome: a\n                    single center experience","volume":"18","author":"A C Ammini","year":"2014","journal-title":"Indian J Endocrinol Metab"},{"key":"ref3","first-page":"7159696","article-title":"Demographic characteristics, etiology, and comorbidities of patients with\n                    Cushing\u2019s syndrome: a 10-year retrospective study at a large general\n                    hospital in China","author":"J Zhou","year":"2019","journal-title":"Int J Endocrinol"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1055\/s-2007-981477","article-title":"Adrenocortical tumors, primary pigmented adrenocortical disease\n                    (PPNAD)\/Carney complex, and other bilateral hyperplasias: the NIH\n                    studies","volume":"39","author":"C A Stratakis","year":"2007","journal-title":"Horm Metab Res"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1097\/00005792-198507000-00007","article-title":"The complex of myxomas, spotty pigmentation, and endocrine overactivity","volume":"64","author":"J A Carney","year":"1985","journal-title":"Medicine"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1750-1172-1-21","article-title":"Carney complex (CNC)","volume":"1","author":"J Bertherat","year":"2006","journal-title":"Orphanet J Rare Dis"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"M85","DOI":"10.1530\/EJE-15-0209","article-title":"Carney complex: an update","volume":"173","author":"R Correa","year":"2015","journal-title":"Eur J Endocrinol"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1515\/jpem-2018-0413","article-title":"Primary pigmented nodular adrenocortical disease (PPNAD): single centre\n                    experience","volume":"32","author":"S S Memon","year":"2019","journal-title":"J Pediatr Endocrinol Metab"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s12020-017-1436-9","article-title":"Efficacy of dexamethasone suppression test during the diagnosis of primary\n                    pigmented nodular adrenocortical disease in Chinese adrenocorticotropic\n                    hormone-independent Cushing syndrome","volume":"59","author":"S Chen","year":"2018","journal-title":"Endocrine"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1097\/PAS.0000000000000748","article-title":"Cushing syndrome in Carney complex: clinical, pathologic, and molecular genetic\n                    findings in the 17 affected Mayo clinic patients","volume":"41","author":"K M Lowe","year":"2017","journal-title":"Am J Surg Pathol"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1210\/jc.2003-032247","article-title":"Cyclical Cushing syndrome presenting in infancy: an early form of primary\n                    pigmented nodular adrenocortical disease, or a new entity?","volume":"89","author":"D F Gunther","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.surg.2008.03.022","article-title":"Operative management of Cushing syndrome secondary to micronodular adrenal\n                    hyperplasia","volume":"143","author":"A C Powell","year":"2008","journal-title":"Surgery"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1007\/s00268-013-2059-9","article-title":"The role of unilateral adrenalectomy in corticotropin-independent bilateral\n                    adrenocortical hyperplasias","volume":"37","author":"Y Xu","year":"2013","journal-title":"World J Surg"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1210\/js.2018-00261","article-title":"Unilateral adrenalectomy could be a valid \u00f6ption for primary nodular\n                    adrenal disease: evidence from twins","volume":"3","author":"A Kyrilli","year":"2019","journal-title":"J Endocr Soc"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1210\/jcem.82.4.3857","article-title":"Primary pigmented nodular adrenocortical disease: reevaluation of a patient with\n                    carney complex 27 years after unilateral adrenalectomy","volume":"82","author":"N J Sarlis","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"ref16","first-page":"300","article-title":"Mitotane and Carney complex: ten years follow-up of a low-dose mitotane regimen\n                    inducing a sustained correction of hypercortisolism","volume":"14","author":"M R Campo","year":"2015","journal-title":"Hormones (Athens, Greece)"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"e87958","DOI":"10.1172\/jci.insight.87958","article-title":"PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in\n                    primary pigmented nodular adrenal disease","volume":"1","author":"Z Bram","year":"2016","journal-title":"JCI Insight"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"E891","DOI":"10.1210\/jc.2013-2657","article-title":"Does somatostatin have a role in the regulation of cortisol secretion in primary\n                    pigmented nodular adrenocortical disease (ppnad)? a clinical and in vitro\n                    investigation","volume":"99","author":"Z Bram","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/nature14034","article-title":"Blocking PGE2-induced tumour repopulation abrogates bladder cancer\n                    chemoresistance","volume":"517","author":"A V Kurtova","year":"2015","journal-title":"Nature"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"4041","DOI":"10.1210\/jcem.86.9.7903","article-title":"Clinical and molecular features of the Carney complex: diagnostic criteria and\n                    recommendations for patient evaluation","volume":"86","author":"C A Stratakis","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1210\/jc.2008-2333","article-title":"Mutations in regulatory subunit type 1A of cyclic adenosine\n                    5\u2019-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis\n                    in 353 patients and 80 different genotypes","volume":"94","author":"J Bertherat","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/S0140-6736(14)61375-1","article-title":"Cushing\u2019s syndrome","volume":"386","author":"A Lacroix","year":"2015","journal-title":"Lancet"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/S0140-6736(00)04172-6","article-title":"Cushing\u2019s syndrome","volume":"357","author":"M Boscaro","year":"2001","journal-title":"Lancet"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"4324","DOI":"10.1210\/jc.2002-020592","article-title":"Mutations of the PRKAR1A gene in Cushing\u2019s syndrome due to sporadic\n                    primary pigmented nodular adrenocortical disease","volume":"87","author":"L Groussin","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1080\/09513590.2018.1493101","article-title":"Primary pigmented nodular adrenocortical disease (PPNAD) as an underlying cause\n                    of symptoms in a patient presenting with hirsutism and secondary amenorrhea:\n                    case report and literature review","volume":"34","author":"E Cyranska-Chyrek","year":"2018","journal-title":"Gynecol Endocrinol"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1172\/JCI118467","article-title":"Carney complex, a familial multiple neoplasia and lentiginosis syndrome.\n                    Analysis of 11 kindreds and linkage to the short arm of chromosome 2","volume":"97","author":"C A Stratakis","year":"1996","journal-title":"J Clin Invest"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ecl.2016.01.006","article-title":"Diagnosis and clinical genetics of Cushing syndrome in pediatrics","volume":"45","author":"C A Stratakis","year":"2016","journal-title":"Endocrinol Metab Clin North Am"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"155","DOI":"10.5114\/pedm.2020.95625","article-title":"Cushing\u2019s syndrome due to primary pigmented nodular adrenal disease in\n                    two brothers with Carney complex","volume":"26","author":"B Attri","year":"2020","journal-title":"Pediatr Endocrinol Diabetes Metab"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s11102-010-0260-5","article-title":"Children with Cushing\u2019s syndrome: primary pigmented nodular\n                    adrenocortical disease should always be suspected","volume":"14","author":"R M da Silva","year":"2011","journal-title":"Pituitary"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.tem.2007.03.005","article-title":"Paediatric Cushing\u2019s syndrome: epidemiology, investigation and\n                    therapeutic advances","volume":"18","author":"H L Storr","year":"2007","journal-title":"Trends Endocrinol Metab"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1210\/jc.2003-031225","article-title":"Activating Gsalpha mutations: analysis of 113 patients with signs of\n                    McCune-Albright syndrome \u2013 a European collaborative study","volume":"89","author":"S Lumbroso","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1210\/jc.2009-2321","article-title":"Cushing syndrome in the McCune-Albright syndrome","volume":"95","author":"R J Brown","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"M45","DOI":"10.1530\/EJE-15-0200","article-title":"Multiple aberrant hormone receptors in Cushing\u2019s syndrome","volume":"173","author":"N El Ghorayeb","year":"2015","journal-title":"Eur J Endocrinol"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1210\/jc.2008-0125","article-title":"The diagnosis of Cushing\u2019s syndrome: an endocrine society clinical\n                    practice guideline","volume":"93","author":"L K Nieman","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1097\/00019616-199201000-00003","article-title":"Primary pigmented nodular adrenocortical disease and its associated\n                    conditions","volume":"2","author":"J A Carney","year":"1992","journal-title":"Endocrinologist"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s13244-012-0208-6","article-title":"The complex of myxomas, spotty skin pigmentation and endocrine overactivity\n                    (Carney complex): imaging findings with clinical and pathological\n                    correlation","volume":"4","author":"N A Courcoutsakis","year":"2013","journal-title":"Insights Imaging"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"4332","DOI":"10.1210\/jc.2015-2174","article-title":"Hormonal, radiological, NP-59 scintigraphy, and pathological correlations in\n                    patients with Cushing\u2019s syndrome due to primary pigmented nodular\n                    adrenocortical disease (PPNAD)","volume":"100","author":"D Vezzosi","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1515\/JPEM.2006.19.S2.561","article-title":"Image diagnosis in McCune-Albright syndrome","volume":"19","author":"C Defilippi","year":"2006","journal-title":"J Pediatr Endocrinol Metab"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"585","DOI":"10.7326\/0003-4819-131-8-199910190-00006","article-title":"Paradoxical response to dexamethasone in the diagnosis of primary pigmented\n                    nodular adrenocortical disease","volume":"131","author":"C A Stratakis","year":"1999","journal-title":"Ann Intern Med"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1210\/clinem\/dgaa002","article-title":"Frequency and incidence of Carney complex manifestations: a prospective\n                    multicenter study with a three-year follow-up","author":"S Espiard","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"101386","DOI":"10.1016\/j.beem.2020.101386","article-title":"Adrenocortical hyperplasia: a multifaceted disease","volume":"34","author":"I Bourdeau","year":"2020","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1507\/endocrj.43.387","article-title":"Serum levels of dehydroepiandrosterone sulfate in patients with asymptomatic\n                    cortisol producing adrenal adenoma: comparison with adrenal Cushing\u2019s\n                    syndrome and 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Paediatr"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1038\/ng1809","article-title":"A genome-wide scan identifies mutations in the gene encoding phosphodiesterase\n                    11A4 (PDE11A) in individuals with adrenocortical hyperplasia","volume":"38","author":"A Horvath","year":"2006","journal-title":"Nat Genet"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/ejhg.2008.85","article-title":"A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia\n                    is expressed widely in human and mouse tissues: a novel PDE8B isoform in human\n                    adrenal cortex","volume":"16","author":"A Horvath","year":"2008","journal-title":"Eur J Hum Genet"},{"key":"ref47","first-page":"5","article-title":"First somatic PRKAR1A defect associated with mosaicism for another PRKAR1A\n                    mutation in a patient with Cushing syndrome","author":"CD C 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