Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Genetic analysis of pediatric primary adrenal insufficiency of unknown etiology: 25 years' experience in the UK

Buonocore, Federica, Maharaj, Avinaash, Qamar, Younus, Koehler, Katrin, Suntharalingham, Jenifer P., Chan, Li F., Ferraz-de-Souza, Bruno, Hughes, Claire R., Lin, Lin, Prasad, Rathi, Allgrove, Jeremy, Andrews, Edward T., Buchanan, Charles R., Cheetham, Tim D., Crowne, Elizabeth C., Davies, Justin H., Gregory, John W., Hindmarsh, Peter C., Hulse, Tony, Krone, Nils P., Shah, Pratik, Shaikh, M. Guftar, Roberts, Catherine, Clayton, Peter E., Dattani, Mehul T., Thomas, N. Simon, Huebner, Angela, Clark, Adrian J., Metherell, Louise A. and Achermann, John C. 2021. Genetic analysis of pediatric primary adrenal insufficiency of unknown etiology: 25 years' experience in the UK. Journal of the Endocrine Society 5 (8) , bvab086. 10.1210/jendso/bvab086

[thumbnail of bvab086.pdf] PDF - Published Version
Available under License Creative Commons Attribution.

Download (941kB)


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 Design, Setting and Participants Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://
Publisher: Oxford University Press
ISSN: 2472-1972
Date of First Compliant Deposit: 15 September 2021
Date of Acceptance: 3 May 2021
Last Modified: 16 Sep 2021 10:45

Citation Data

Cited 4 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item


Downloads per month over past year

View more statistics