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

in European Journal of Endocrinology
Authors:
Sinéad M McGlacken-Byrne Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
Genetics and Genomic Medicine Programme, UCL GOS Institute of Child Health, London

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https://orcid.org/0000-0002-4289-0852
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Ashraf Abdelmaksoud International and Private Patient Department, Great Ormond Street Hospital NHS Foundation Trust

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Mohammad Haini Department of Histopathology, Great Ormond Street Hospital for Children, London, UK

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Liina Palm Department of Histopathology, Great Ormond Street Hospital for Children, London, UK

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Michael Ashworth Department of Histopathology, Great Ormond Street Hospital for Children, London, UK

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Juan Li Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

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Wei Wang Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

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Xiumin Wang Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

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Jian Wang Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

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Bridget Callaghan International and Private Patient Department, Great Ormond Street Hospital NHS Foundation Trust

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Veronica A. Kinsler Genetics and Genomic Medicine Programme, UCL GOS Institute of Child Health, London
Department of Dermatology, Great Ormond Street Hospital for Children, London, UK
Mosaicism and Precision Medicine Laboratory, Francis Crick Institute, London, UK

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Francesca Faravelli North East Thames Regional Genetic Service, Great Ormond Street Hospital, London, UK

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Mehul T Dattani Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
Genetics and Genomic Medicine Programme, UCL GOS Institute of Child Health, London

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Correspondence should be addressed to S M McGlacken-Byrne; Email: sinead.mcglacken-byrne@gosh.nhs.uk
DOI:
https://doi.org/10.1530/EJE-22-0287
Volume/Issue:
Volume 187: Issue 6
Page Range:
K55–K61
Article Type:
Case Report
Online Publication Date:
24 Nov 2022
Copyright:
© European Society of Endocrinology 2022
Restricted access

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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.

Significance statement

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.

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Print ISSN:
0804-4643
Online ISSN:
1479-683X

     European Society of Endocrinology

Copyright:
© European Society of Endocrinology 2022
Article Type:
Case Report
Received Date:
04 Apr 2022
Accepted Date:
17 Oct 2022
Print Publication Date:
01 Dec 2022
Online Publication Date:
24 Nov 2022
Sept 2018 onwards Past Year Past 30 Days
Abstract Views 3517 93 76
Full Text Views 56 0 0
PDF Downloads 70 0 0
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