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Chang Z, Lu W, Zhao Z, et al. Genetic aetiology of primary adrenal insufficiency in Chinese children. BMC Med Genomics. 2021;14(1):172doi: 10.1186/s12920-021-01021-x.
Chang, Z., Lu, W., Zhao, Z., Xi, L., Li, X., Ye, R., Ni, J., Pei, Z., Zhang, M., Cheng, R., Zheng, Z., Sun, C., Wu, J., & Luo, F. (2021). Genetic aetiology of primary adrenal insufficiency in Chinese children. BMC medical genomics, 14(1), 172. https://doi.org/10.1186/s12920-021-01021-x
Chang, Zhuo, et al. "Genetic aetiology of primary adrenal insufficiency in Chinese children." BMC medical genomics vol. 14,1 (2021): 172. doi: https://doi.org/10.1186/s12920-021-01021-x
Chang Z, Lu W, Zhao Z, Xi L, Li X, Ye R, Ni J, Pei Z, Zhang M, Cheng R, Zheng Z, Sun C, Wu J, Luo F. Genetic aetiology of primary adrenal insufficiency in Chinese children. BMC Med Genomics. 2021 Jun 30;14(1):172. doi: 10.1186/s12920-021-01021-x. PMID: 34193132; PMCID: PMC8243448.
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BMC Med Genomics. 2021 Jun 30;14(1):172. doi: 10.1186/s12920-021-01021-x.

Genetic aetiology of primary adrenal insufficiency in Chinese children.

BMC medical genomics

Zhuo Chang, Wei Lu, Zhuhui Zhao, Li Xi, Xiaojing Li, Rong Ye, Jinwen Ni, Zhou Pei, Miaoying Zhang, Ruoqian Cheng, Zhangqian Zheng, Chengjun Sun, Jing Wu, Feihong Luo

Affiliations

  1. Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, 399 Wan Yuan Road, Shanghai, 201102, People's Republic of China.
  2. Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, 399 Wan Yuan Road, Shanghai, 201102, People's Republic of China. [email protected].

PMID: 34193132 PMCID: PMC8243448 DOI: 10.1186/s12920-021-01021-x

Abstract

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.

Keywords: Congenital adrenal hyperplasia; Genetic diagnosis; Primary adrenal insufficiency; Triple A syndrome; Whole-exome sequencing; X-linked adrenoleukodystrophy

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