A Family With A20 Haploinsufficiency Presenting With Novel Clinical Manifestations and Challenges for Treatment

Supplemental digital content is available in the text. Background Tumor necrosis factor α–induced protein 3 gene (TNFAIP3, also called A20) haploinsufficiency (HA20) leads to autoinflammation and autoimmunity. We have recently shown that a p.(Lys91*) mutation in A20 disrupts nuclear factor κB signaling, impairs protein-protein interactions of A20, and leads to inflammasome activation. Methods We now describe the clinical presentations and drug responses in a family with HA20 p.(Lys91*) mutation, consistent with our previously reported diverse immunological and functional findings. Results We report for the first time that inflammasome-mediated autoinflammatory lung reaction caused by HA20 can be treated with interleukin 1 antagonist anakinra. We also describe severe anemia related to HA20 successfully treated with mycophenolate. In addition, HA20 p.(Lys91*) was found to associate with autoimmune thyroid disease, juvenile idiopathic arthritis, psoriasis, liver disease, and immunodeficiency presenting with specific antibody deficiency and genital papillomatosis. Conclusions We conclude that HA20 may lead to combination of inflammation, immunodeficiency, and autoimmunity. The condition may present with variable and unpredictable symptoms with atypical treatment responses.

[1]  T. Jacques,et al.  Janus kinase 1/2 inhibition for the treatment of autoinflammation associated with heterozygous TNFAIP3 mutation , 2019, The Journal of allergy and clinical immunology.

[2]  M. McDermott,et al.  Faculty Opinions recommendation of Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. , 2019, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[3]  J. Kolls,et al.  Updates on T helper type 17 immunity in respiratory disease , 2018, Immunology.

[4]  M. Varjosalo,et al.  Haploinsufficiency of A20 impairs protein–protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation , 2018, RMD Open.

[5]  I. Touitou,et al.  Autosomic dominant familial Behçet disease and haploinsufficiency A20: A review of the literature. , 2018, Autoimmunity reviews.

[6]  I. Touitou,et al.  ‘A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease’ , 2018, Annals of the rheumatic diseases.

[7]  M. Kool,et al.  A20/Tumor Necrosis Factor α-Induced Protein 3 in Immune Cells Controls Development of Autoinflammation and Autoimmunity: Lessons from Mouse Models , 2018, Front. Immunol..

[8]  D. Kastner,et al.  A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease , 2018, Annals of the rheumatic diseases.

[9]  Feng Li,et al.  The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis , 2017, Nature Medicine.

[10]  J. Kere,et al.  Unexpectedly High Prevalence of Common Variable Immunodeficiency in Finland , 2017, Front. Immunol..

[11]  M. Schmidt-Supprian,et al.  A20 Restrains Thymic Regulatory T Cell Development , 2017, The Journal of Immunology.

[12]  Qing Zhou,et al.  NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases , 2017, Front. Immunol..

[13]  M. McDermott,et al.  Lessons from characterization and treatment of the autoinflammatory syndromes , 2017, Current opinion in rheumatology.

[14]  J. Kere,et al.  Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3. , 2015, Blood.

[15]  M. Varjosalo,et al.  Haploinsufficiency of A20 impairs protein–protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation , 2018, RMD Open.