Background: Primary adrenal insufficiency (PAI) in children is an uncommon condition. Diagnosis is usually challenging especially in resource limited settings where facilities for antibodies and genetic testing are constrained. Many genetic etiologies have been reported in children with PAI due to congenital adrenal hyperplasia (CAH) and Allgrove syndrome are the commonest identified genetic causes to date in Sudan. Studies from Africa are rare and here we describe for the first time the clinical presentation and genetic etiologies of PAI in Sudanese children.
Patients & methods: Thirty-six patients from twenty-nine Sudanese families (22 males and 14 females) with undiagnosed forms of PAI were included in this series. Diagnosis was based on clinical presentation of PAI paired with biochemical finding of low cortisol and high ACTH, +/- a negative response to synacthen stimulation. Candidates with clinical and genetic diagnosis of CAH and Allgrove syndrome were excluded. Gene sequencing (CGS) of commonly causative genes: MC2R, MRAP, CYP11A1 and STAR, was followed by whole exome sequencing (WES) in affected individuals and family members (where available), if they were mutation-negative on CGS. WES results were confirmed by Sanger sequencing.
Results: Hyperpigmentation was the commonest symptom at presentation detected in all patients while adrenal crisis was not uncommon. We were able to identify the genetic etiology in 19/36 patients with a clinical diagnosis of PAI with mutations discovered in NNT (n=5) including a novel, synonymous splice causing variant seen in more than one family (T731=), MC2R (n=1), AIRE (n=4) including a 5 exon deletion, in two families, ABCD1 (n=4), NROBI (n=1), CYP11A1 (n=1), CYP11B1-CYP11B2 fusion (n=3), of which NNT mutations are the commonest in our patients.
Conclusion: CGS of “commonly causative” genes was of limited use in this cohort with NNT, ABCD1 and AIRE variants more common in this population. In addition, the study highlighted the importance of considering “silent” mutations in rare disease. Determining the etiology of adrenal insufficiency can be challenging, due to poor phenotype-genotype correlation and WES is invaluable in this. PAI in Sudan has heterogeneous etiology and gaining a genetic diagnosis is priceless to the patient and family, helping to guide the management and provide vital information on the prognosis.
15 Sep 2022 - 17 Sep 2022