Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

Abstract

Background: Primary adrenal insufficiency (PAI) is a life-threatening condition, and a definitive aetiological diagnosis is essential for management and prognostication. We conducted this study to investigate the genetic aetiologies of PAI in South China and explore their clinical features.Methods: Seventy children were enrolled. Clinical information was collected, and combined genetic tests were performed according to the children’s manifestations. Statistical analysis was performed among the different groups. In silico or in vitro experiments were applied to determine the pathogenicity of novel variants.Results: Among the 70 children, 84.29% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and a diagnosis of 21-hydroxylase deficiency (21-OHD) was subsequently genetically confirmed in 91.53% of the cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.10% (39/59), 30.51% (18/59), and 3.39% (2/59) of the cases, respectively. Interestingly, 17-hydroxyprogesterone (17-OHP) and testosterone levels in females were significantly higher than those in males among both SW and SV CAH patients. Additionally, 15.71% (11/70) of the patients were diagnosed with PAI, 72.73% (8/11) of whom had positive genetic findings. Among all the cases, two novel variants in CYP21A2, c.833dupT (p.279GfsX17) and c.651+2T>G, were harboured by CAH patients. A microdeletion (Xp21.2-21.3) and five novel variants, including 2 in the NR0B1 gene (p.108S>X, p.L411Vfs*6, c.1231_1234delCTCA, p.L411Vfs*6), 2 in the AAAS gene (c.399+1G>A, p.V103Afs*8, c.250delT, p.W84Gfs*10) and 1 in the NNT gene (p.I758Mfs*10), were detected. The novel variant c.399+1G>A in the AAAS gene was further confirmed to lead to exon 4 deletion in mRNA transcription and produce a truncated ALADIN protein.Conclusions: We found ethnic differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and testosterone levels, which warrants caution in relation to the virilization effect both physically and psychologically. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of paediatric PAI; however, further improvement of genetic testing tools beyond our protocol is still needed to uncover the complete aetiology of PAI in children.