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  • Genetic and phenotypic spectrum of non-21-hydroxylase-deficiency primary adrenal insufficiency in childhood: data from 111 Chinese patients

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Diagnostics
Original research
Genetic and phenotypic spectrum of non-21-hydroxylase-deficiency primary adrenal insufficiency in childhood: data from 111 Chinese patients
  1. Ying Duan1,
  2. Wanqi Zheng1,
  3. Yu Xia1,
  4. Huiwen Zhang1,
  5. Lili Liang1,
  6. Ruifang Wang1,
  7. Yi Yang1,
  8. Kaichuang Zhang1,
  9. Deyun Lu1,
  10. Yuning Sun1,
  11. Lianshu Han1,
  12. Yongguo Yu2,
  13. Xuefan Gu1,
  14. Yu Sun2,
  15. Bing Xiao2,
  16. Wenjuan Qiu1
  1. 1 Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Yangpu, Shanghai, China
  2. 2 Department of Pediatric Endocrinology and Genetic Metabolism, Clinical Genetics Center, Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Yangpu, Shanghai, China
  1. Correspondence to Dr Wenjuan Qiu, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Yangpu, Shanghai, 200082, China; qiuwenjuan{at}xinhuamed.com.cn; Dr Bing Xiao; xiaobing{at}xinhuamed.com.cn; Dr Yu Sun; sunyu{at}xinhuamed.com.cn

Abstract

Background Primary adrenal insufficiency (PAI) is a rare but life-threatening condition. Differential diagnosis of numerous causes of PAI requires a thorough understanding of the condition.

Methods To describe the genetic composition and presentations of PAI. The following data were collected retrospectively from 111 patients with non-21OHD with defined genetic diagnoses: demographic information, onset age, clinical manifestations, laboratory findings and genetic results. Patients were divided into four groups based on the underlying pathogenesis: (1) impaired steroidogenesis, (2) adrenal hypoplasia, (3) resistance to adrenocorticotropic hormone (ACTH) and (4) adrenal destruction. The age of onset was compared within the groups.

Results Mutations in the following genes were identified: NR0B1 (n=39), STAR (n=33), CYP11B1 (n=12), ABCD1 (n=8), CYP17A1 (n=5), HSD3B2 (n=4), POR (n=4), MRAP (n=2), MC2R (n=1), CYP11A1 (n=1), LIPA (n=1) and SAMD9 (n=1). Frequent clinical manifestations included hyperpigmentation (73.0%), dehydration (49.5%), vomiting (37.8%) and abnormal external genitalia (23.4%). Patients with adrenal hypoplasia typically presented manifestations earlier than those with adrenal destruction but later than those with impaired steroidogenesis (both p<0.01). The elevated ACTH (92.6%) and decreased cortisol (73.5%) were the most common laboratory findings. We generated a differential diagnosis flowchart for PAI using the following clinical features: 17-hydroxyprogesterone, very-long-chain fatty acid, external genitalia, hypertension and skeletal malformation. This flowchart identified 84.8% of patients with PAI before next-generation DNA sequencing.

Conclusions STAR and NR0B1 were the most frequently mutated genes in patients with non-21OHD PAI. Age of onset and clinical characteristics were dependent on aetiology. Combining clinical features and molecular tests facilitates accurate diagnosis.

  • Paediatrics
  • Gene Frequency
  • Adrenal Gland Diseases
  • Diagnosis
  • Phenotype

Data availability statement

Data are available upon reasonable request. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

https://doi.org/10.1136/jmg-2022-108952

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    Data availability statement

    Data are available upon reasonable request. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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    Footnotes

    • YD, WZ and YX are joint first authors.

    • Correction notice This article has been corrected since it was published online. Co-first authorship details and statement have been added. Secondly, funding information has been amended.

    • Contributors YD, Yu Sun, BX and WQ conceived the study. YD, WZ, YX, RW, YY, KZ, DL and Yuning Sun collected the patients’ data. HZ, LL, LH, YG Yu, XG and WQ evaluated the clinical features. Yu S and BX performed molecular analysis. YD, WZ, YX, Yu Sun, BX and WQ wrote the manuscript. WQ, as the guarantor, accepts full responsibility for the conduct of the study, had access to the data, and controlled the decision to publish. All authors read and approved the final manuscript.

    • Funding This work was financially supported by the National Key R&D Program of China (2022YFC2703400); the Clinical Research Center For Primary Adrenal Insufficiency, Pediatric College, Shanghai Jiao Tong University School of Medicine (ELYZX202106); National Natural Science Foundation of China (81873724); Shanghai Healthcare Commission Project (202340103) and Natural Science Foundation of Shanghai (20ZR1472700, 22ZR1451400, 19ZR1442100).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.