Endocrine Abstracts

Background: Primary adrenal insufficiency (PAI) is a rare, genetically heterogenous condition, characterised by hypocortisolaemia and high plasma ACTH levels in the presence or absence of mineralocorticoid deficiency. PAI can be life-threatening if unrecognised, misdiagnosed or under/untreated. Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive form of PAI characterised by isolated glucocorticoid insufficiency. Mutations in the MC2R/ACTH receptor, MRAP, STAR and CYP11A1 account for >50% of cases of FGD. No previous studies have characterised PAI in the Sudanese paediatric population.

Aims: (1) To describe the clinical presentation of PAI in a small cohort of Sudanese paediatric patients, and (2) to identify monogenic causes of PAI.

Methods: Sanger sequencing was undertaken for variants of candidate genes: MC2R, MRAP, STAR, CYP11A1 and, in one patient with clinical features of autoimmune polyglandular syndrome (APS) type-1, AIRE. Whole exome sequencing (WES) was performed for patients who were mutation negative on candidate gene sequencing.

Results: Fourteen patients from 13 families (7M; 7F, aged 0–7.5 yrs at presentation) with PAI of unknown aetiology were studied. The most frequent presenting clinical features were generalised hyperpigmentation (100%), fatigability (50%) and infection (43%). 29% of the patients experienced recurrent hypoglycaemia. Diagnosis was established biochemically with a low serum cortisol and high plasma ACTH. A genetic diagnosis was obtained in 2/14 patients by candidate gene approach. A homozygous missense mutation in MC2R (c.437G>A, p.R146H) previously reported to cause FGD and a homozygous nonsense mutation in AIRE (c.769C>T, p.R257X) linked to APS type-1. WES in a third patient revealed a novel homozygous nonsense mutation in NNT (c.69T>A, p.C23X). 11/14 PAI patients remain genetically unsolved and have been sent for WES.

Conclusion: Determining the aetiology of PAI can be challenging, owing to phenotypic heterogeneity. A genetic diagnosis can help guide management as well as provide vital prognostic information. Candidate gene approaches are still helpful and here solved 2/14 PAI children. However, with reducing costs, WES may by-pass candidate gene approaches and be the first line to solving the genetic cause of PAI.