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Mosaic PRKACA duplication causing a novel and distinct phenotype of early-onset Cushing’s syndrome and acral cutaneous mucinosis

McGlacken-Byrne, SM; Abdelmaksoud, A; Haini, M; Palm, L; Ashworth, M; Li, J; Wang, W; ... Dattani, MT; + view all (2022) Mosaic PRKACA duplication causing a novel and distinct phenotype of early-onset Cushing’s syndrome and acral cutaneous mucinosis. European Journal of Endocrinology , 187 (6) K55-K61. 10.1530/EJE-22-0287. Green open access

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Abstract

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.

Type: Article
Title: Mosaic PRKACA duplication causing a novel and distinct phenotype of early-onset Cushing’s syndrome and acral cutaneous mucinosis
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1530/EJE-22-0287
Publisher version: https://doi.org/10.1530/EJE-22-0287
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, PROTEIN-KINASE-A, CATALYTIC SUBUNIT, REGULATORY SUBUNIT, SOMATIC MUTATIONS, VARIANTS, GERMLINE, ACTIVATION, MECHANISMS, PATHWAY, DISEASE
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10173540
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