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

Author:

Buonocore Federica1ORCID,Maharaj Avinaash2ORCID,Qamar Younus2ORCID,Koehler Katrin3ORCID,Suntharalingham Jenifer P1ORCID,Chan Li F2ORCID,Ferraz-de-Souza Bruno1ORCID,Hughes Claire R24ORCID,Lin Lin1,Prasad Rathi2ORCID,Allgrove Jeremy4ORCID,Andrews Edward T5ORCID,Buchanan Charles R6ORCID,Cheetham Tim D7ORCID,Crowne Elizabeth C8ORCID,Davies Justin H59ORCID,Gregory John W10ORCID,Hindmarsh Peter C11ORCID,Hulse Tony12ORCID,Krone Nils P13ORCID,Shah Pratik24ORCID,Shaikh M Guftar14ORCID,Roberts Catherine15,Clayton Peter E16ORCID,Dattani Mehul T1ORCID,Thomas N Simon17ORCID,Huebner Angela3ORCID,Clark Adrian J2ORCID,Metherell Louise A2ORCID,Achermann John C1ORCID

Affiliation:

1. Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK

2. Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

3. Children’s Hospital, Universitätsklinikum Dresden, Technische Universität Dresden, Dresden, Germany

4. The Royal London Childrens Hospital, Barts Health NHS Trust, London, UK

5. Department of Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, UK

6. Department of Child Health, King’s College Hospital NHS Foundation Trust, London, UK

7. Newcastle University and Great North Children’s Hospital, Newcastle upon Tyne, UK

8. Bristol Royal Hospital for Children, University Hospitals Bristol, NHS Foundation Trust, Bristol, UK

9. Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK

10. Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, UK

11. Departments of Paediatrics, University College London Hospitals, London, UK

12. Paediatric Endocrinology, Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Trust, London, UK

13. Department of Oncology and Metabolism, University of Sheffield, Sheffield Children’s Hospital, Sheffield, UK

14. Department of Paediatric Endocrinology, Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow, UK

15. Northern Genetics Service, International Centre for Life, Newcastle, UK

16. 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

17. Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK

Abstract

Abstract 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.

Funder

Wellcome Trust

National Institute for Health Research

NIHR Great Ormond Street Hospital Biomedical Research Centre

Barts Charity

Medical Research Council

German Research Foundation

Publisher

The Endocrine Society

Subject

Endocrinology, Diabetes and Metabolism

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