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Lookup NU author(s): Professor Timothy Cheetham
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2021 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.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 Design, Setting and Participants: Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research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.
Author(s): Buonocore F, Maharaj A, Qamar Y, Koehler K, Suntharalingham JP, Chan LF, Ferraz-De-Souza B, Hughes CR, Lin L, Prasad R, Allgrove J, Andrews ET, Buchanan CR, Cheetham TD, Crowne EC, Davies JH, Gregory JW, Hindmarsh PC, Hulse T, Krone NP, Shah P, Shaikh MG, Roberts C, Clayton PE, Dattani MT, Thomas NS, Huebner A, Clark AJ, Metherell LA, Achermann JC
Publication type: Article
Publication status: Published
Journal: Journal of the Endocrine Society
Year: 2021
Volume: 5
Issue: 8
Pages: 1-15
Print publication date: 01/08/2021
Online publication date: 11/05/2021
Acceptance date: 03/05/2021
Date deposited: 24/08/2021
ISSN (electronic): 2472-1972
Publisher: Endocrine Society
URL: https://doi.org/10.1210/jendso/bvab086
DOI: 10.1210/jendso/bvab086
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