ESPE Abstracts (2022) 95 RFC5.5

ESPE2022 Rapid Free Communications Adrenals and HPA Axis (6 abstracts)

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

Sinead M McGlacken-Byrne 1,2 , Ashraf Abdelmaksoud 3 , Mohammad Haini 4 , Liina Palm 4 , Michael Ashworth 4 , Juan Li 5 , Wei Wang 6 , Xiumin Wang 5 , Jian Wang 7 , Bridget Callaghan 3 , Veronica A Kinsler 8,9,2 , Francesca Faravelli 10 & Mehul T Dattani 1,2

1Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom; 2Genetics and Genomic Medicine Programme, UCL GOS Institute of Child Health, London, United Kingdom; 3International and Private Patient Department, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom; 4Department of Histopathology, Great Ormond Street Hospital for Children, London, United Kingdom; 5Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China; 6Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; 7Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China; 8Department of Dermatology, Great Ormond Street Hospital for Children, London, United Kingdom; 9Mosaicism and Precision Medicine Laboratory, Francis Crick Institute, London, United Kingdom; 10North East Thames Regional Genetic Service, Great Ormond Street Hospital, London, United Kingdom

Introduction: Genetic alterations within the cAMP/PKA pathway, including the genes GNAS, PDE11A, PDE8, PRKAR1A/B, and PRKACA, result in a spectrum of adrenocortical disorders. To date, 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 variants within the PRKAR1A gene are known to cause Carney complex, PKRACA variants are rarely associated with an extra-adrenal phenotype.

Methods: Clinical, biochemical, and radiological data were collected from hospital patient records. Histopathological examination of relevant patient tissue was performed. Genetic testing including trio exome sequencing and comparative genomic hybridisation (aCGH) analysis was conducted.

Case: We describe a mosaic PRKACA duplication in an infant who presented with a Carney-like complex at the age of three months. He developed severe early-onset Cushing syndrome requiring bilateral adrenalectomy. Histopathology of the resected adrenal tissue showed bilateral non-pigmented micronodular cortical hyperplasia. He also had multiple non-tender, non-pigmented, firm lumps on his hands and feet at presentation. This distinct acral soft tissue overgrowth was demonstrated to be cutaneous mucinosis on histopathological examination. aCGH analysis of DNA extracted from the skin biopsy demonstrated a duplication on the short arm of chromosome 19, spanning a 900kB region inclusive of the PRKACA gene, which was absent from blood. This confirmed that the clinical features were due to a post-zygotic mosaic duplication of PRKACA. Post-adrenalectomy, the Cushing syndrome features resolved and there was an improvement in the appearance of his skin lesions, suggesting that circulating cortisol may have contributed to the underlying dermatopathological process.

Discussion: We elucidate a novel manifestation of PRKACA disruption and broaden its extra-adrenal phenotype. To date, only germline PRKACA duplication has been associated with Cushing syndrome secondary to adrenal hyperplasia. This case suggests that the Cushing syndrome phenotypes arising from somatic and germline PRKACA abnormalities likely exist on a spectrum. Furthermore, the skin features described have not been associated previously with either germline or somatic PRKACA mutations. A confirmed mosaic PRKACA duplication linked the patient’s adrenal disease to his extra-adrenal features. We emphasise the importance of ascertaining a genetic diagnosis for PRKACA-mediated disease.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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