Novel recurrent mutations and genetic diversity in Sudanese children with adrenal insufficiency

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.

Forty-eight patients from 43 families (31 male:17 female) with PAI were included (CAH/triple A excluded). Additional features seen included white matter changes on magnetic resonance imaging, 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.

In 21/43 families, a genetic aetiology consistent with non-autoimmune PAI was discovered, and in 3 families, autoimmune regulator (AIRE) mutations were found, indicating an autoimmune origin. In Sudan, adenosine triphosphate (ATP) binding cassette subfamily D member 1 (ABCD1)/nicotinamide nucleotide transhydrogenase (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 leucodystrophy (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 comorbidities were concomitantly detected.

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 adrenoleucodystrophy and giving plausible gene defects for additional comorbidities such as obesity. Such genetic diagnoses are crucial to design optimal treatment plans and for genetic counselling in affected individuals and their families.