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

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 Design, Setting and Participants Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research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

Pediatric Adrenal Insufficiency: Challenges and Solutions

“…12 Steroidogenesis may also be impaired by steroidogenic acute regulatory (StAR) protein deficiency, which is involved in cholesterol transport into mitochondria, or P450 cytochrome side-chain cleavage (P450scc) deficiency, that converts cholesterol into pregnenolone. 12,13 Of these conditions, 21OHD and 11BOHD only affect adrenal steroidogenesis, whereas the other deficits also impact gonadal steroid production. In classic CAH, enzyme activity can be absent (saltwasting form) or low (1-2% enzyme activity, simple virilizing form).…”

“…In lysosomal acid lipase A deficiency, 24 AI is due to calcification of the adrenal gland as a result of the accumulation of esterified lipids; in infantile form, that is Wolman disease, hepatosplenomegaly with hepatic fibrosis and malabsorption lead to death in the first year of life, if not treated with enzyme replacement therapy such as sebelipase alfa. 25 Adrenal development may be impaired in X-linked congenital adrenal hypoplasia (AHC), 13,26 a disorder caused by defective nuclear receptor DAX-1, presenting with salt-losing AI in infancy in approximately half of the cases, but also later in childhood or adolescence with two other key features such as hypogonadotropic hypogonadism and impaired spermatogenesis. Two syndromes combine adrenal hypoplasia with intrauterine growth restriction (IUGR): in IMAGe syndrome, 27 caused by CDKN1C gain-of-function mutations, IUGR and AI present with metaphyseal dysplasia and genitourinary anomalies; MIRAGE syndrome 28 is instead characterized by myelodysplasia, infections, genital abnormalities, and enteropathy, as a result of gain-of-function mutations in SAMD9, with elevated mortality rates.…”

“…In some other conditions, AI is due to ACTH resistance. Familial Glucocorticoid Deficiency type 1 (FGD1) 13,29 and type 2 (FGD2) 30 derive from defective ACTH receptor (MC2R) or its accessory protein MRAP, and both present with early glucocorticoid insufficiency (hypoglycemia, prolonged jaundice) and pronounced hyperpigmentation; there is usually an excellent response to cortisol replacement therapy, even though ACTH levels remain elevated.…”

“…In Allgrove or Triple-A Syndrome, 13,31 defective Aladin protein (an acronym for alacrimia-achalasiaadrenal insufficiency) leads to primary ACTH-resistant adrenal insufficiency with achalasia and absent lacrimation, often combined with neurological dysfunction, either peripheral, central, or autonomic. It is an autosome recessive condition, phenotypically characterized by microcephaly, short stature, and skin hyperpigmentation.…”

Molecular Diagnosis of Steroid 21-Hydroxylase Deficiency: A Practical Approach

“…Since CAH due to 21-OHD accounts for 95% of all CAH cases, CYP21A2 should be the first gene to investigate in males and virilized girls with adrenal insufficiency. The remaining genes causing CAH ( 1 , 2 , 12 , 40 ) as well as other involved in adrenal insufficiency ( 41 ) should be investigated using high-throughput approaches (massive sequencing gene panels) ( 40 – 42 ). On regard CYP11B1 , it is important to highlight its high homology with CYP11B2 and the consequent existence of hybrid genes ( 43 – 45 ).…”