Background/Purpose: Haploinsufficiency of A20 (HA20) is a newly discovered autoinflammatory disease caused by mutations in TNFAIP3. A20 is a protein with a crucial role in the negative regulation of inflammation and immunity. This study aimed at describing the clinical phenotypes and disease course of patients with HA20.

Methods: All cases from the initial publication were reviewed (1), additional cases were identified through the group who described the disease. Standardized data collection forms were used to collect demographic, clinical, laboratory, imaging and histologic features, disease course and treatment regimens.

Results: A total of 17 patients (82% female) from 7 families with a genetic diagnosis of HA20 were included. Behçet disease, followed by SLE and JIA were the most frequent diagnoses prior to confirmation of HA20. Clinical phenotypes were heterogeneous between and within families. First symptoms commonly occurred in early childhood, disease onset ranged from the 1^st week of life to 29 years of age. Most common presenting symptoms were recurrent oral and/or genital ulcers in 59% of patients. During disease course, symptoms and disease severity varied highly. Recurrent painful oral, genital and/or gastrointestinal ulcers were the hallmark feature in all patients. Ulcers recurred frequently (monthly to every few months), isolated or in combination with other symptoms such as fever. Singular or multiple ulcers lasted 7-10 days and some healed with scarring. Other symptoms commonly observed during disease course are shown in Table 1. Most patients had a relapsing-remitting disease course, one patient died. Laboratory features included elevated acute phase reactants, especially during relapses, and the fluctuating presence of various autoantibodies such as antinuclear antibodies (4/10 patients tested) and anti-dsDNA (2/5 patients). Lupus anticoagulant was positive in 6/7, anticardiolipin antibodies in 2/5 patients tested. Tissue biopsy of different sites was performed in 9/17 patients (53%) and revealed non-specific chronic inflammation in 6, findings consistent with class V lupus nephritis in 1 and normal results in 2 patients. There was no standardized treatment: 15/17 (88%) patients received various immunosuppressive therapies, seven of them also biologic agents. More recently, therapeutic approaches were based on functional cytokine studies.

Conclusion: Early-onset recurrent oral, genital and/or gastrointestinal ulcers are the hallmark feature of HA20. Other signs and symptoms and disease course varied considerably with an overall high morbidity and mortality. Treatment regimens should be based on disease severity, cytokine inhibitors are often required to control relapses.

(1) Zhou Q et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016;48:67-73

Table 1.