{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T09:18:43Z","timestamp":1787995123738,"version":"build-2784847793"},"reference-count":17,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Familial Cancer"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Rare pathogenic variants affecting components of the evolutionary conserved cAMP\/protein kinase A (PKA) signalling pathway are implicated in a spectrum of adrenocortical disorders. Germline inactivating\n                    <jats:italic>PRKAR1A<\/jats:italic>\n                    variants leading to constitutive PKA activation, underlie primary pigmented nodular adrenocortical disease (PPNAD) in Carney complex. More recently, several patients with PPNAD and other types of bilateral nodular adrenal disease (BNAD) have been diagnosed with rearrangements in chromosome 19 at band p13.12, resulting in copy number gains of the entire\n                    <jats:italic>PRKACA<\/jats:italic>\n                    gene. Here, we report the identification of a 19p13.12 rearrangement, resulting in a duplication of the\n                    <jats:italic>PRKACA<\/jats:italic>\n                    gene, in a 32-year-old female from whom the genetic aetiology remained unknown for 20 years. Furthermore, we provide an updated overview of patients with\n                    <jats:italic>PRKACA<\/jats:italic>\n                    germline copy number gains that have previously been reported in the literature.\n                  <\/jats:p>","DOI":"10.1007\/s10689-026-00594-9","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T08:59:34Z","timestamp":1787993974000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The identification of a PRKACA duplication at 19p13.12 in a female with PPNAD and thyroid carcinoma after a 20-year diagnostic journey"],"prefix":"10.1007","volume":"25","author":[{"given":"Marjoleine F.","family":"Broekema","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Violon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Vaduva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maartje","family":"Vogel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"de Leeuw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenne","family":"Komdeur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"issue":"3","key":"594_CR1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1113\/jphysiol.2014.282871","volume":"593","author":"H Raff","year":"2015","unstructured":"Raff H, Carroll T (2015) Cushing\u2019s syndrome: from physiological principles to diagnosis and clinical care. J Physiol 593(3):493\u2013506. https:\/\/doi.org\/10.1113\/jphysiol.2014.282871","journal-title":"J Physiol"},{"issue":"1","key":"594_CR2","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1007\/s12022-022-09710-8","volume":"33","author":"O Mete","year":"2022","unstructured":"Mete O, Erickson LA, Juhlin CC et al (2022) Overview of the 2022 WHO Classification of Adrenal Cortical Tumors. Endocr Pathol 33(1):155\u2013196. https:\/\/doi.org\/10.1007\/s12022-022-09710-8","journal-title":"Endocr Pathol"},{"key":"594_CR3","unstructured":"Stratakis CA (2001) Genetics of adrenocortical tumors: Carney complex. (0003-4266 (Print))"},{"issue":"1","key":"594_CR4","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/79238","volume":"26","author":"LS Kirschner","year":"2000","unstructured":"Kirschner LS, Carney JA, Pack SD et al (2000) Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 26(1):89\u201392. https:\/\/doi.org\/10.1038\/79238","journal-title":"Nat Genet"},{"issue":"5","key":"594_CR5","doi-asserted-by":"publisher","first-page":"R31","DOI":"10.1172\/JCI10841","volume":"106","author":"M Casey","year":"2000","unstructured":"Casey M, Vaughan CJ, He J et al (2000) Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex. J Clin Invest 106(5):R31\u2013R38. https:\/\/doi.org\/10.1172\/JCI10841","journal-title":"J Clin Invest"},{"issue":"6","key":"594_CR6","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1086\/344579","volume":"71","author":"L Groussin","year":"2002","unstructured":"Groussin L, Kirschner LS, Vincent-Dejean C et al (2002) Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am J Hum Genet 71(6):1433\u20131442. https:\/\/doi.org\/10.1086\/344579","journal-title":"Am J Hum Genet"},{"issue":"6","key":"594_CR7","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1530\/EJE-14-1154","volume":"172","author":"MB Lodish","year":"2015","unstructured":"Lodish MB, Yuan B, Levy I et al (2015) Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations. Eur J Endocrinol 172(6):803\u2013811. https:\/\/doi.org\/10.1530\/EJE-14-1154","journal-title":"Eur J Endocrinol"},{"issue":"1","key":"594_CR8","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.humpath.2014.09.005","volume":"46","author":"JA Carney","year":"2015","unstructured":"Carney JA, Lyssikatos C, Lodish MB, Stratakis CA (2015) Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes. Hum Pathol 46(1):40\u201349. https:\/\/doi.org\/10.1016\/j.humpath.2014.09.005","journal-title":"Hum Pathol"},{"issue":"11","key":"594_CR9","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1056\/NEJMoa1310359","volume":"370","author":"F Beuschlein","year":"2014","unstructured":"Beuschlein F, Fassnacht M, Assie G et al (2014) Constitutive activation of PKA catalytic subunit in adrenal Cushing\u2019s syndrome. N Engl J Med 370(11):1019\u20131028. https:\/\/doi.org\/10.1056\/NEJMoa1310359","journal-title":"N Engl J Med"},{"issue":"6","key":"594_CR10","doi-asserted-by":"publisher","first-page":"K55","DOI":"10.1530\/EJE-22-0287","volume":"187","author":"SM McGlacken-Byrne","year":"2022","unstructured":"McGlacken-Byrne SM, Abdelmaksoud A, Haini M et al (2022) Mosaic PRKACA duplication causing a novel and distinct phenotype of early-onset Cushing\u2019s syndrome and acral cutaneous mucinosis. Eur J Endocrinol 187(6):K55\u2013K61. https:\/\/doi.org\/10.1530\/EJE-22-0287","journal-title":"Eur J Endocrinol"},{"key":"594_CR11","doi-asserted-by":"publisher","first-page":"e220491","DOI":"10.20945\/2359-4292-2022-0491","volume":"68","author":"WR Yang","year":"2023","unstructured":"Yang WR, Liang XH, Qin YF et al (2023) Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review. Arch Endocrinol Metab 68:e220491. https:\/\/doi.org\/10.20945\/2359-4292-2022-0491","journal-title":"Arch Endocrinol Metab"},{"key":"594_CR12","doi-asserted-by":"publisher","unstructured":"Ravi Kumar P, Dash B, Dash DK, Patro D, Majhi JK, Dhal BS. A Rare Case of PRKACA Duplication\u2013Associated Childhood-Onset Primary Pigmented Nodular Adrenocortical Disease, JCEM Case Reports 3(3), luaf035. https:\/\/doi.org\/10.1210\/jcemcr\/luaf035","DOI":"10.1210\/jcemcr\/luaf035"},{"issue":"6","key":"594_CR13","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1093\/ejendo\/lvaf255","volume":"193","author":"P Vaduva","year":"2025","unstructured":"Vaduva P, Violon F, Chansavang A et al (2025) PRKACA constitutional duplication: a specific cause of primary pigmented nodular adrenocortical disease. Eur J Endocrinol 193(6):733\u2013744. https:\/\/doi.org\/10.1093\/ejendo\/lvaf255","journal-title":"Eur J Endocrinol"},{"issue":"43","key":"594_CR14","first-page":"2390","volume":"150","author":"G Bocca","year":"2006","unstructured":"Bocca G, van Mil EG, Voorhoeve PG, Wijnaendts LC, Delemarre-van de Waal HA (2006) [A girl with Cushing\u2019s syndrome due to primary pigmented nodular adrenocortical disease]. Ned Tijdschr Geneeskd 150(43):2390\u20132393","journal-title":"Ned Tijdschr Geneeskd"},{"issue":"2","key":"594_CR15","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/s41436-019-0686-8","volume":"22","author":"ER Riggs","year":"2020","unstructured":"Riggs ER, Andersen EF, Cherry AM et al (2020) Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 22(2):245\u2013257. https:\/\/doi.org\/10.1038\/s41436-019-0686-8","journal-title":"Genet Med"},{"issue":"6","key":"594_CR16","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1038\/gim.2016.163","volume":"19","author":"R Pfundt","year":"2017","unstructured":"Pfundt R, Del Rosario M, Vissers L et al (2017) Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders. Genet Med 19(6):667\u2013675. https:\/\/doi.org\/10.1038\/gim.2016.163","journal-title":"Genet Med"},{"issue":"1","key":"594_CR17","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s13073-024-01301-y","volume":"16","author":"G Schobers","year":"2024","unstructured":"Schobers G, Derks R, den Ouden A et al (2024) Genome sequencing as a generic diagnostic strategy for rare disease. Genome Med 16(1):32. https:\/\/doi.org\/10.1186\/s13073-024-01301-y","journal-title":"Genome Med"}],"container-title":["Familial Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-026-00594-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10689-026-00594-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-026-00594-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T08:59:35Z","timestamp":1787993975000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10689-026-00594-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,29]]},"references-count":17,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["594"],"URL":"https:\/\/doi.org\/10.1007\/s10689-026-00594-9","relation":{},"ISSN":["1573-7292"],"issn-type":[{"value":"1573-7292","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,29]]},"assertion":[{"value":"24 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Conflict of interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Consent obtained directly from patient(s) or guardian(s).","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval was not sought for present case series because all procedures were part of standard clinical care and no additional investigations were undertaken.","order":3,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"83"}}