Rare causes of pediatric Primary Adrenal Insufficiency: Data of a Large Nationwide Cohort

Primary Adrenal Insufficiency (PAI) is a potentially life-threatening disease characterized by impaired production of steroid hormones due to an adrenal cortex defect. Monogenic disorders are the most common cause of PAI in children. We report the largest well characterized (clinical, biochemical, genetics) nationwide Tunisian subcohort of childhood PAI (74 patients). The genetic diagnostic yield is high, 88%, probably due to the high consanguinity rate. The presence of ancestral background and genetic hotspots in the Tunisian population justifies a candidate gene approach as 77% of our cases have recurrent mutations in AAAS and ABCD1. Nevertheless, thanks to next generation sequencing techniques allowing the study of several genes at a time, the diagnosis yield was improved (11%), sometimes in patients with atypical phenotype. Variations of uncertain significance were identified. Reporting them in the literature will allow cross-referencing of data with other cohorts in the hope of concluding on a diagnosis. Although many questions remain to be elucidated, these genetic discoveries are fundamental because they allow genetic counseling, suitable monitoring with personalized treatment, prevention of complications with pre-symptomatic diagnosis. It also allows a better understanding of the pathophysiological mechanisms involved in the maintenance or development of the adrenal gland.