Background: Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that requires accurate diagnosis and urgent treatment. Congenital adrenal hyperplasia is the most common cause of PAI in children. Non-CAH causes of PAI are relatively rare. Although several molecular causes have been found, it is emerging that considerable overlap in the clinical and biochemical features of these conditions exists.
Objective and hypotheses: We investigated the clinical and molecular characteristics of a national cohort of 96 children (45 females, aged between 018 years, eight familial) with non-CAH PAI of unknown aetiology recruited from 22 paediatric endocrinology clinics in Turkey.
Method: A structured questionnaire was used to evaluate clinical, biochemical and imaging data. A custom Haloplex panel-based next generation sequencing approach was used to study all known PAI-associated genes. Patients with clinical or biochemical findings suggestive of CAH, adrenoleukodystrophy, autoimmune adrenal insufficiency or known syndromic causes of PAI (e.g., Triple A syndrome) were excluded.
Results: A molecular genetic diagnosis was obtained in 78 (81%) patients. The range of genetic aetiologies found in this cohort was:MC2R (n=25), NR0B1 (n=12), StAR (n=11), CYP11A1 (n=9), MRAP (n=9), NNT (n=7), ABCD1 (n=2), NR5A1 (1), AAAS (n=1), HSD3B2 (n=1).Of note, recurrent mutations in several genes were detected, such as c.560delT and p.C251W mutations in MC2R, the p.R451W mutation in CYP11A1, MRAP c.IVS3ds+1delG, and StAR p.S13P. The incidence of childhood non-CAH PAI was approximately five in 1.000.000, with geographical enrichment of certain mutations due to founder effects. Several novel clinical and molecular insights emerged.
Conclusion: This is the largest cohort study of PAI in children to date. Establishing a specific diagnosis of PAI is extremely valuable for counselling family members and for identifying presymptomatic children.Knowing the genetic aetiology can also help modify treatments, such as the need for long-term mineralocorticoid replacement, and can predict potential co-morbidities, such as impaired puberty or fertility and neurological dysfunction.
Funding information: J.C.A. is a Wellcome Trust Senior Research Fellow in Clinical Science (098513) and T.G is a European Community, Marie-Curie research fellow (PIEF-GA-2012-328959). This study is also supported with Turkish Pediatric Endocrinology Research Grant.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology