{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T19:07:13Z","timestamp":1788030433096,"version":"build-2784847793"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T00:00:00Z","timestamp":1669248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Genetic alterations within the cAMP\/protein kinase A (PKA) pathway result in a spectrum of adrenocortical disorders. Implicated genes include GNAS, PDE8B, PDE11A, PRKAR1A\/B, and PRKACA. To date, pathogenic somatic PRKACA variants and germline PRKACA copy number gain have been associated with the development of cortisol-secreting adrenocortical adenomas and bilateral adrenal hyperplasia, respectively. While perturbations within the PRKAR1A gene are known to cause Carney complex, PKRACA mutations are rarely associated with an extra-adrenal phenotype. We describe a mosaic PRKACA duplication in an infant who presented with a Carney-like complex at the age of 3 months with bilateral non-pigmented micronodular adrenal hyperplasia, severe early-onset Cushing's syndrome, and distinct acral soft tissue overgrowth due to cutaneous mucinosis. This represents a novel manifestation of PRKACA disruption and broadens its extra-adrenal phenotype. It suggests that the Cushing's syndrome phenotypes arising from somatic and germline PRKACA abnormalities likely exist on a spectrum. We emphasise the importance of ascertaining a genetic diagnosis for PRKACA-mediated disease.<\/jats:p>\n               <jats:sec>\n                  <jats:title>Significance statement<\/jats:title>\n                  <jats:p>We describe a mosaic PRKACA duplication in a young infant who presented with a Carney-like complex: bilateral non-pigmented micronodular adrenal hyperplasia, severe early-onset Cushing's syndrome, and distinct acral soft tissue overgrowth due to cutaneous mucinosis. This represents a novel manifestation of PRKACA disruption and broadens the extra-adrenal phenotype of PRKACA-associated Cushing's syndrome. Our data suggest that Cushing's syndrome phenotypes arising from somatic and germline PRKACA abnormalities can exist on a spectrum. We emphasise the value of ascertaining a genetic diagnosis for PRKACA-mediated adrenal and extra-adrenal disease to guide individualised and targeted care.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1530\/eje-22-0287","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T17:18:26Z","timestamp":1666027106000},"page":"K55-K61","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-7","source":"Crossref","is-referenced-by-count":4,"title":["Mosaic <i>PRKACA<\/i> duplication causing a novel and distinct phenotype of early-onset Cushing's syndrome and acral cutaneous mucinosis"],"prefix":"10.1093","volume":"187","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4289-0852","authenticated-orcid":false,"given":"Sin\u00e9ad M","family":"McGlacken-Byrne","sequence":"first","affiliation":[{"name":"Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children , London, UK"},{"name":"Genetics and Genomic Medicine Programme, UCL GOS Institute of Child Health , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashraf","family":"Abdelmaksoud","sequence":"additional","affiliation":[{"name":"International and Private Patient Department, Great Ormond Street Hospital NHS Foundation Trust , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Haini","sequence":"additional","affiliation":[{"name":"Department of Histopathology, Great Ormond Street Hospital for Children , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liina","family":"Palm","sequence":"additional","affiliation":[{"name":"Department of Histopathology, Great Ormond Street Hospital for Children , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ashworth","sequence":"additional","affiliation":[{"name":"Department of Histopathology, Great Ormond Street Hospital for Children , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Ruijin Hospital, Shanghai Jiaotong University School of Medicine , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine , Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget","family":"Callaghan","sequence":"additional","affiliation":[{"name":"International and Private Patient Department, Great Ormond Street Hospital NHS Foundation Trust , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica A","family":"Kinsler","sequence":"additional","affiliation":[{"name":"Genetics and Genomic Medicine Programme, UCL GOS Institute of Child Health , London, UK"},{"name":"Department of Dermatology, Great Ormond Street Hospital for Children , London, UK"},{"name":"Mosaicism and Precision Medicine Laboratory, Francis Crick Institute , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Faravelli","sequence":"additional","affiliation":[{"name":"North East Thames Regional Genetic Service, Great Ormond Street Hospital , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehul T","family":"Dattani","sequence":"additional","affiliation":[{"name":"Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children , London, UK"},{"name":"Genetics and Genomic Medicine Programme, UCL GOS Institute of Child Health , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"2023012409101177700_bib1","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/jemt.10337","article-title":"Mechanism of action of ACTH: beyond cAMP","volume":"61","author":"Gallo-Payet","year":"2003","journal-title":"Microscopy Research and Technique"},{"key":"2023012409101177700_bib2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1677\/jme.0.0290163","article-title":"cAMP-dependent transcription of steroidogenic genes in the human adrenal cortex requires a dual-specificity phosphatase in 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