Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK.

Autor:	Buonocore F; Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK., Maharaj A; Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK., Qamar Y; Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK., Koehler K; Children's Hospital, Universitätsklinikum Dresden, Technische Universität Dresden, Dresden, Germany., Suntharalingham JP; Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK., Chan LF; Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK., Ferraz-de-Souza B; Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK., Hughes CR; Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK.; The Royal London Childrens Hospital, Barts Health NHS Trust, London, UK., Lin L; Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK., Prasad R; Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK., Allgrove J; The Royal London Childrens Hospital, Barts Health NHS Trust, London, UK., Andrews ET; Department of Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, UK., Buchanan CR; Department of Child Health, King's College Hospital NHS Foundation Trust, London, UK., Cheetham TD; Newcastle University and Great North Children's Hospital, Newcastle upon Tyne, UK., Crowne EC; Bristol Royal Hospital for Children, University Hospitals Bristol, NHS Foundation Trust, Bristol, UK., Davies JH; Department of Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.; Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK., Gregory JW; Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, UK., Hindmarsh PC; Departments of Paediatrics, University College London Hospitals, London, UK., Hulse T; Paediatric Endocrinology, Evelina London Children's Hospital, Guy's and St Thomas' NHS Trust, London, UK., Krone NP; Department of Oncology and Metabolism, University of Sheffield, Sheffield Children's Hospital, Sheffield, UK., Shah P; Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK.; The Royal London Childrens Hospital, Barts Health NHS Trust, London, UK., Shaikh MG; Department of Paediatric Endocrinology, Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow, UK., Roberts C; Northern Genetics Service, International Centre for Life, Newcastle, UK., Clayton PE; Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, University of Manchester, and the Royal Manchester Children's Hospital, Manchester University Hospital NHS Foundation Trust, Manchester, UK., Dattani MT; Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK., Thomas NS; Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK., Huebner A; Children's Hospital, Universitätsklinikum Dresden, Technische Universität Dresden, Dresden, Germany., Clark AJ; Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK., Metherell LA; Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK., Achermann JC; Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
Jazyk:	angličtina
Zdroj:	Journal of the Endocrine Society [J Endocr Soc] 2021 May 11; Vol. 5 (8), pp. bvab086. Date of Electronic Publication: 2021 May 11 (Print Publication: 2021).
DOI:	10.1210/jendso/bvab086
Abstrakt:	Context: Although primary adrenal insufficiency (PAI) in children and young people is often due to congenital adrenal hyperplasia (CAH) or autoimmunity, other genetic causes occur. The relative prevalence of these conditions is poorly understood. Objective: We investigated genetic causes of PAI in children and young people over a 25 year period. Design Setting and Participants: Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research centers between 1993 and 2018. We pre-excluded those with CAH, autoimmune, or metabolic causes. We obtained additional data from NR0B1 (DAX-1) clinical testing centers. Intervention and Outcome Measurements: Genetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018). Results: A genetic diagnosis was reached in 103/155 (66.5%) individuals. In 5 children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 genes: MC2R (adrenocorticotropin receptor; 30/155, 19.4%), NR0B1 (DAX-1; 7.7%), CYP11A1 (7.7%), AAAS (7.1%), NNT (6.5%), MRAP (4.5%), TXNRD2 (4.5%), STAR (3.9%), SAMD9 (3.2%), CDKN1C (1.3%), and NR5A1 /steroidogenic factor-1 (SF-1; 0.6%). Additionally, 51 boys had NR0B1 variants identified through clinical testing. Although age at presentation, treatment, ancestral background, and birthweight can provide diagnostic clues, genetic testing was often needed to define the cause. Conclusions: PAI in children and young people often has a genetic basis. Establishing the specific etiology can influence management of this lifelong condition. NGS approaches improve the diagnostic yield when many potential candidate genes are involved. (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)
Databáze:	MEDLINE
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