Haploinsufficiency of A20 (HA20): updates on the genetics, phenotype, pathogenesis and treatment
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REVIEW ARTICLE
Haploinsufficiency of A20 (HA20): updates on the genetics, phenotype, pathogenesis and treatment Mei‑Ping Yu1 · Xi‑Sheng Xu1 · Qing Zhou2 · Natalie Deuitch3 · Mei‑Ping Lu1 Received: 4 February 2019 / Accepted: 4 July 2019 © Children’s Hospital, Zhejiang University School of Medicine 2019
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. Keywords Autoinflammatory disease · HA20 · NF-κB signaling · TNFAIP3 · Treatment
Introduction TNFAIP3 encodes the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, also known as A20), an important negative regulator of nuclear factor kappa B (NF-κB) signaling pathway [1]. Loss-of-function mutations in TNFAIP3 result in insufficient suppression of NF-κB activity, as * Mei‑Ping Lu [email protected] 1
Department of Rheumatology Immunology and Allergy, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
2
MOE Key Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China
3
Genetics Department, Stanford University, California, USA
well as enhancement of nucleotide-binding domain-like receptor protein (NLRP3) inflammasome activation, both of which may lead to an overproduction of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-18 and TNF-α. Dysregulation of innate i
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