Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK.

Angela Huebner,Jenifer P. Suntharalingham ,Katrin Koehler,Jeremy Allgrove,M Guftar Shaikh,Rathi Prasad,Claire Hughes ,Peter Clayton ,Nils Krone ,Pratik Shah,John Welbourn Gregory ,Younus Qamar,Edward Andrews ,Avinaash Maharaj,Mehul Dattani ,Catherine Roberts,Tony Hulse,Adrian J. L. Clark ,Tim Cheetham ,Justin H Davies,Federica Buonocore,Elizabeth Crowne ,Charles Buchanan ,John C. Achermann ,Bruno Ferraz-de-Souza,Li Chan ,Peter C. Hindmarsh ,Louise A. Metherell ,N. Simon Thomas ,Lin Lin

doi:10.1210/jendso/bvab086

Abstract

ContextAlthough 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.ObjectiveWe investigated genetic causes of PAI in children and young people over a 25 year period.Design, Setting and ParticipantsUnpublished 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 MeasurementsGenetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018).ResultsA 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.ConclusionsPAI 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.

Highlights

Establishing a specific diagnosis is important for understanding the natural history of a condition and how it might affect an individual, personalizing therapy, monitoring associated features, counseling about inheritance patterns and fertility, and identifying presymptomatic family members at risk
We report our findings on the genetic analysis of children and young people with primary adrenal insufficiency (PAI) of unknown etiology referred from within the United Kingdom (UK) to 3 major research centers and clinical testing centers for NR0B1 (DAX-1) and provide a combined analysis of our published and unpublished experiences of diagnosing these conditions over 25 years
The total cohort studied consisted of 155 children and young people (102 males, 48 females, five 46,XY girls) with PAI of unknown etiology living in the UK who were referred to our research groups (UCL GOS Institute of Child Health, London, UK; Queen Mary University, London, UK and Technische Universität Dresden, Dresden, Germany) for genetic analysis from several pediatric endocrine centers across the UK and where a genetic diagnosis was made between 1993 and 2018

Summary

Introduction

Establishing a specific diagnosis is important for understanding the natural history of a condition and how it might affect an individual, personalizing therapy (eg, the need for lifelong mineralocorticoid treatment), monitoring associated features (eg, puberty and gonadal function, renal), counseling about inheritance patterns and fertility, and identifying presymptomatic family members at risk. Genetic analysis traditionally required each candidate gene to be sequenced individually. We have used a target-based NGS approach in a cohort study in Turkey of 95 children with PAI of unknown etiology (ie, CAH, autoimmune, metabolic causes excluded). With this approach, a genetic diagnosis was reached in 78/95 (82%) young people, involving just 9 genes [eg, MC2R, NR0B1 (DAX-1), STAR, CYP11A1, MRAP, NNT, ABCD1, NR5A1, AAAS] [9]. We report our findings on the genetic analysis of children and young people with PAI of unknown etiology referred from within the United Kingdom (UK) to 3 major research centers and clinical testing centers for NR0B1 (DAX-1) and provide a combined analysis of our published and unpublished experiences of diagnosing these conditions over 25 years

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