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Extended report
A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease
  1. Florence A Aeschlimann1,
  2. Ezgi D Batu2,
  3. Scott W Canna3,
  4. Ellen Go4,
  5. Ahmet Gül5,
  6. Patrycja Hoffmann6,
  7. Helen L Leavis7,
  8. Seza Ozen2,
  9. Daniella M Schwartz8,
  10. Deborah L Stone6,
  11. Annet van Royen-Kerkof9,
  12. Daniel L Kastner6,
  13. Ivona Aksentijevich6,
  14. Ronald M Laxer1,10
  1. 1 Division of Rheumatology, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
  2. 2 Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey
  3. 3 Department of Pediatric Rheumatology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA
  4. 4 Division of Pediatric Rheumatology, Riley Hospital for Children, Indiana University, Indianapolis, Indiana, USA
  5. 5 Department of Internal Medicine, Istanbul University, Istanbul, Turkey
  6. 6 Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA
  7. 7 Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
  8. 8 Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
  9. 9 Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
  10. 10 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Ronald M Laxer, Division of Rheumatology, The Hospital for Sick Children, Department of Paediatrics University of Toronto, Toronto, Ontario, Canada; ronald.laxer{at}


Objectives The association between mutations in TNFAIP3, encoding the NF-kB regulatory protein A20, and a new autoinflammatory disease has recently been recognised. This study aims at describing the clinical phenotypes and disease course of patients with A20 haploinsufficiency (HA20).

Methods Data for all cases from the initial publication, and additional cases identified through collaborations since, were collected using standardised data collection forms.

Results A total of 16 patients (13 female) from seven families with a genetic diagnosis of HA20 were included. The disease commonly manifested in early childhood (range: first week of life to 29 years of age). The main clinical symptoms were recurrent oral, genital and/or gastrointestinal ulcers (16/16), musculoskeletal (9/16) and gastrointestinal complaints (9/16), cutaneous lesions (8/16), episodic fever (7/16), and recurrent infections (7/16). Clinical phenotypes varied considerably, even within families. Relapsing-remitting disease course was most common, and one patient died. Laboratory abnormalities included elevated acute-phase reactants and fluctuating presence of various autoantibodies such as antinuclear antibodies (4/10 patients tested) and anti-dsDNA (2/5). Tissue biopsy of different sites revealed non-specific chronic inflammation (6/12 patients tested), findings consistent with class V lupus nephritis in one patient, and pustules and normal results in two patients each. All patients were treated: 4/16 received colchicine and 12/16 various immunosuppressive agents. Cytokine inhibitors effectively suppressed systemic inflammation in 7/9 patients.

Conclusions Early-onset recurrent oral, genital and/or gastrointestinal ulcers are the hallmark feature of HA20. Frequency and intensity of other clinical manifestations varied highly. Treatment regimens should be based on disease severity, and cytokine inhibitors are often required to control relapses.

  • autoinflammatory disease
  • pediatric rheumatology
  • ulcers

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  • Handling editor Josef S Smolen

  • Contributors FAA and RML: coordination of the study, data collection and analysis, manuscript preparation. EDB, SWC, EG, AG, PH, HLL, SO, DMS, DLS, AvR-K, IA and DLK: data collection and analysis, revision of the manuscript for important intellectual content. All authors approved the final version to be published.

  • Funding FAA was supported by grants from the Rhyner-Bangerter Foundation, Starr-Foundation, Swiss League against Rheumatism, Foundation W!, Alberta Children’s Hospital Research Institute Foundation and SickKids Foundation.

  • Competing interests None declared.

  • Ethics approval The study was approved by the Institutional Research Ethics Board (REB 1000053697).

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

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