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

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 Design, Setting and Participants Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research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