ESPE Abstracts (2021) 94 P2-19

1Genetics & Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; 2Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; 3Children’s Hospital, Universitätsklinikum Dresden, Technische Universität Dresden, Dresden, Germany; 4The Royal London Childrens Hospital, Barts Health NHS Trust, London, United Kingdom; 5Department of Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; 6Department of Child Health, King’s College Hospital NHS Foundation Trust, London, United Kingdom; 7Newcastle University and Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom; 8Bristol Royal Hospital for Children, University Hospitals Bristol, NHS Foundation Trust, Bristol, United Kingdom; 9Faculty of Medicine, University of Southampton, Southampton, United Kingdom; 10Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, United Kingdom; 11Department of Paediatrics, University College London Hospitals, London, United Kingdom; 12Paediatric Endocrinology, Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Trust, London, United Kingdom; 13Academic Unit of Child Health, Department of Oncology and Metabolism, University of Sheffield, Sheffield Children’s Hospital, Sheffield, United Kingdom; 14Department of Paediatric Endocrinology, Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom; 15Northern Genetics Service, International Centre for Life, Newcastle, United Kingdom; 16Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, University of Manchester, and the Royal Manchester Children’s Hospital, Manchester University Hospital NHS Foundation Trust, Manchester, United Kingdom; 17Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, United Kingdom

Introduction: Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that requires appropriate diagnosis and treatment. The most common cause of PAI is congenital adrenal hyperplasia (CAH), but other well-established aetiologies include metabolic and autoimmune disorders, and physical damage. Mutations in more than 30 genes have now been associated with PAI, with considerable biochemical and phenotypic overlap. It is therefore important to adopt a comprehensive genetic analysis to help reach a diagnosis. Here, we report the molecular basis underlying PAI in children and young people over a 25 year-period, combining published and unpublished data from our research centres.

Methods: The main cohort consisted of 155 children with PAI of unknown aetiology from the UK studied at three research centres from 1993 until 2018. Children with CAH, metabolic and autoimmune causes of PAI were excluded. Genetic analysis was performed using Sanger sequencing and a candidate gene approach (1993 onwards) or next generation sequencing (NGS), using both targeted panels and whole exome sequencing (WES) (2013-2018). An additional sub-group of 51 patients were included where a genetic diagnosis of X-linked adrenal hypoplasia congenita (AHC) due to pathogenic variants in NR0B1 (DAX-1) had been established through clinical genetic testing services.

Results: Using these approaches, a genetic diagnosis was identified in 103/155 (66.5%) individuals. Pathogenic variants were identified in 11 different genes: MC2R (ACTH 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/SF-1 (0.6%). The adrenal insufficiency resolved in five children where no genetic cause was found. Taken together with the research cohort, X-linked AHC represented the largest group where a diagnosis was made (NR0B1, research n = 12; clinical n = 51). An excess of boys was observed, even when individuals with X-linked AHC were excluded from analysis. This difference in sex ratio was even more marked in the “undiagnosed” group of patients.

Conclusions: PAI in children and young people often has a genetic basis. Although age at presentation, treatment, ancestral background and birthweight can provide diagnostic clues, genetic testing was required to establish the definitive cause. NGS approaches improve the diagnostic yield when many potential candidate genes are involved. Defining the specific aetiology can have important implications for affected individuals and their families for the management of this lifelong condition, such as for monitoring associated features, counselling about recurrence risk in families, and sometimes for predicting disease course and modifying treatment.

Volume 94

59th Annual ESPE (ESPE 2021 Online)

22 Sep 2021 - 26 Sep 2021

European Society for Paediatric Endocrinology 

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