Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

Overview

Journal BMC Med Genomics

Publisher Biomed Central

Specialty Genetics

Date 2021 Jul 1

PMID 34193132

Citations 4

Authors

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

Soon will be listed here.

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.

Citing Articles

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Al-Hamed M, Qari A, Alrayes L, Alotaibi M, Al Masseri Z, Alotaibi A Mol Genet Genomic Med. 2025; 13(1):e70052.

PMID: 39853971 PMC: 11757666. DOI: 10.1002/mgg3.70052.

Testicular impairment in Primary Adrenal Insufficiency caused by Nicotinamide Nucleotide Transhydrogenase (NNT) deficiency - a case report: implication of oxidative stress and importance of fertility preservation.

Ferreux L, Boumerdassi Y, Dulioust E, Bertagna X, Roucher-Boulez F, Bourdon M Basic Clin Androl. 2023; 33(1):17.

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The etiology and clinical features of non-CAH primary adrenal insufficiency in children.

Liu Z, Liu Y, Gao K, Chen X Front Pediatr. 2022; 10:961268.

PMID: 36061374 PMC: 9437356. DOI: 10.3389/fped.2022.961268.

Heterozygous POR gene mutations in a patient with congenital adrenal hyperplasia.

Gusmano C, Calogero A, Cannarella R Endocrine. 2022; 77(2):401-402.

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Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK.

Buonocore F, Maharaj A, Qamar Y, Koehler K, Suntharalingham J, Chan L J Endocr Soc. 2021; 5(8):bvab086.

PMID: 34258490 PMC: 8266051. DOI: 10.1210/jendso/bvab086.

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