Buonocore, F;
Maharaj, A;
Qamar, Y;
Koehler, K;
Suntharalingham, JP;
Chan, LF;
Ferraz-de-Souza, B;
... Achermann, JC; + view all
(2021)
Genetic analysis of pediatric primary adrenal insufficiency of unknown etiology: 25 years’ experience in the UK.
Journal of the Endocrine Society
, 5
(8)
, Article bvab086. 10.1210/jendso/bvab086.
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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 Design, Setting and Participants Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research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 1993-2018. 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 onwards) or next generation sequencing (NGS) (targeted panels, exomes) (2013-2018). Results: A genetic diagnosis was reached in 103/155 (66.5%) individuals. In five children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 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%). 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.
| Type: | Article |
|---|---|
| Title: | Genetic analysis of pediatric primary adrenal insufficiency of unknown etiology: 25 years’ experience in the UK |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1210/jendso/bvab086 |
| Publisher version: | https://doi.org/10.1210/jendso/bvab086 |
| Language: | English |
| Additional information: | © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | adrenal, adrenal insufficiency, Addison disease, genetics, NGS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10128099 |
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