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Published on: September 15, 2017
Genetic aetiology of primary adrenal insufficiency in Chinese children
Zhuo Chang1, Wei Lu1, Zhuhui Zhao1
1Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, 399 Wan Yuan Road, Shanghai, 201102, People's Republic of China.
Insights
Genetic testing identified the causes of primary adrenal insufficiency (PAI) in South China children, revealing novel variants in key genes like CYP21A2 and AAAS. This expands the understanding of PAI
Area of Science:
- Pediatric Endocrinology
- Human Genetics
- Molecular Biology
Background:
- Primary adrenal insufficiency (PAI) is a critical condition requiring precise etiological diagnosis for effective management.
- Investigating the genetic basis of PAI is crucial for understanding its diverse clinical presentations and prognoses.
Purpose of the Study:
- To elucidate the genetic causes of PAI in a South China pediatric cohort.
- To correlate genetic findings with clinical manifestations and hormone levels.
- To identify novel genetic variants associated with PAI.
Main Methods:
- Cross-sectional study involving 70 children with PAI.
- Comprehensive clinical data collection and combined genetic testing based on phenotype.
- In silico and in vitro analyses to ascertain variant pathogenicity.
Main Results:
- Congenital adrenal hyperplasia (CAH), primarily 21-hydroxylase deficiency (21-OHD), accounted for 84.3% of cases.
- Identified novel variants in CYP21A2, NR0B1, AAAS, and NNT genes, expanding the known genetic spectrum of PAI.
- Demonstrated significant differences in hormone levels (17-OHP, testosterone) between CAH subtypes and sexes.
Conclusions:
- Genetic testing is essential for diagnosing PAI in children, with CAH/21-OHD being the most common cause in South China.
- Novel variants in genes including AAAS (e.g., c.399+1G>A causing exon skipping) contribute to PAI.
- Further advancements in genetic testing are needed for comprehensive etiological diagnosis of pediatric PAI.
Background:
Primary adrenal insufficiency (PAI) is life-threatening, 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 in this cross-sectional study. 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, 84.3% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and 21-hydroxylase deficiency (21-OHD) was genetically confirmed in 91.5% of these cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.1% (39/59), 30.5% (18/59), and 3.4% (2/59) of the cases, respectively. The 17-hydroxyprogesterone (17-OHP) and testosterone (TES) levels were significantly higher in children with SW than with SV. The 17-OHP and cortisol levels in female SW patients were significantly higher than those in males. The 17-OHP, cortisol, dehydroepiandrosterone (DHEAS) and TES levels in female SW patients were significantly higher than those in female SV patients. Additionally, 72.7% (8/11) of uncharacterized PAI patients had positive genetic findings. Among all the patients, two novel variants in the CYP21A2 gene (c.833dupT and c.651 + 2T > G) were found. A microdeletion (Xp21.2-21.3) and five novel variants, including 2 in the NR0B1 gene (c.323-324CG > GA and c.1231_1234delCTCA), 2 in the AAAS gene (c.399 + 1G > A and c.250delT) and 1 in the NNT gene (c.2274delT), were detected. The novel variant c.399 + 1G > A in the AAAS gene was further confirmed to lead to exon 4 skipping during mRNA transcription and produce a truncated ALADIN protein.
Conclusions:
We found ethnicity-based differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and TES levels, which warrants caution in relation to the effects of virilization. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of PAI, however, further improvement of genetic testing tools beyond our protocol are still needed to uncover the complete aetiology of PAI in children.
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