BACKGROUND: Studies of Primary Adrenal Insufficiency (PAI) in African children are rare but in Sudan, congenital adrenal hyperplasia (CAH) and Triple A syndrome are the most common genetic causes. Differential diagnosis is challenging, especially in resource-limited settings, where presentation can mimic common childhood diseases and facilities for biochemical and genetic testing may be restricted. PATIENTS & METHODS: Forty-eight (48) patients from 43 families (31M:17F) with PAI were included (CAH/Triple A excluded). Additional features seen included white matter changes on MRI, auto-immune features and/or obesity. Sanger and whole exome sequencing (WES) were employed for diagnosis, confirmation and segregation with in vitro assays to investigate potential splice defects. RESULTS: In 21/43 families a genetic aetiology consistent with non-autoimmune PAI was discovered, and in 3 families AIRE mutations were found, indicating an autoimmune origin. In Sudan, ABCD1/NNT/AIRE mutations were commonest, including recurrent NNT splice and AIRE deletion mutations. In 2 families we identified ARSA mutations fitting a diagnosis of Metachromatic Leukodystrophy (MLD), in which adrenal insufficiency has not previously been described. In the remaining 17 families, no causative gene mutations were found. Putative causal variants for co-morbidities were concomitantly detected. CONCLUSION: In this population WES revealed itself as a useful frontline tool for the differential diagnosis of individuals presenting with adrenal insufficiency, including discrimination between MLD and adrenoleukodystrophy, and giving plausible gene defects for additional co-morbidities such as obesity. Such genetic diagnoses are crucial to design optimal treatment plans and for genetic counselling in affected individuals and their families.