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Haploinsufficiency of A20 (HA20): updates on the genetics, phenotype, pathogenesis and treatment

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Abstract

Background

A20, a protein encoded by the tumor necrosis factor alpha-induced protein 3 gene (TNFAIP3), plays a vital role in the negative regulation of inflammation and immunity. Loss-of-function mutation in TNFAIP3 leads to a new described autoinflammatory disease-haploinsufficiency of A20 (HA20). Since HA20 was first described in 2016, a number of new cases have been described in this literature, however, the disease and its pathogenesis are poorly understood. This review seeks to improve clinical recognition of this disorder, and promote both earlier diagnosis and initiation of targeted therapies to improve patients’ outcomes.

Methods

We reviewed 26 papers about A20 and HA20, and we summarized genetic variants and clinical manifestations of a total of 61 reported patients from 26 families identified to have a genetic diagnosis of germline pathogenic variants in TNFAIP3/A20. Additionally, we discussed the pathogenesis and treatment of HA20.

Results

A total of 24 pathogenic variants of A20 had been reported. There was significant clinical heterogeneity, even among those with the same variants in TNFAIP3. Prior to receiving a molecular diagnosis of HA20, patients had been diagnosed with Behcet’s disease, rheumatoid arthritis, rheumatic fever, juvenile idiopathic arthritis, systemic lupus erythematosus, and even adult-onset Stills’ disease. The patients with HA20 that presented with inflammatory signatures in NF-κB signaling were mostly responsive to treatment.

Conclusions

HA20 is a monogenic autoinflammatory disease with highly variable clinical manifestations. This extensive heterogeneity makes it difficult to set a clinical diagnostic criteria, and genetic sequencing is necessary for a definitive diagnosis of HA20.

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Funding

This study was supported by Basic Public Welfare Research Project of Zhejiang Province (LGF19H100002).

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Authors and Affiliations

  1. Department of Rheumatology Immunology and Allergy, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China

    Mei-Ping Yu, Xi-Sheng Xu & Mei-Ping Lu

  2. MOE Key Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China

    Qing Zhou

  3. Genetics Department, Stanford University, California, USA

    Natalie Deuitch

Authors
  1. Mei-Ping Yu
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  2. Xi-Sheng Xu
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  3. Qing Zhou
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  4. Natalie Deuitch
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Contributions

MPY and XSX are the joint first authors. MPY was involved in data collecting and cleaning, and refreshed data and drafted the manuscript. XSX was involved in data collecting and cleaning, analyzed the data and tabulated the original tables and figures. QZ analyzed the data and contributed to the critical revision of the manuscript for important intellectual content. ND revised the manuscript critically and gave some important intellectual contents. MPL contributed to the critical revision of the manuscript for important intellectual content, proposed the research plan, as well as obtaining funding, and she is the study guarantors. All the authors have read and approved the final manuscript.

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Correspondence to Mei-Ping Lu.

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Yu, MP., Xu, XS., Zhou, Q. et al. Haploinsufficiency of A20 (HA20): updates on the genetics, phenotype, pathogenesis and treatment. World J Pediatr 16, 575–584 (2020). https://doi.org/10.1007/s12519-019-00288-6

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  • DOI: https://doi.org/10.1007/s12519-019-00288-6

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