Multicenter international cohort study of HA20 reveals novel genetic architecture and phenotypic evolution

ABSTRACT Background Haploinsufficiency of A20 (HA20) is an immune dysregulation disorder caused by loss-of-function TNFAIP3 mutations. This international multicenter study aimed to delineate its clinical spectrum, genetic basis, and natural history. Methods A cross-sectional, retrospective analysis was conducted in HA20 patients with pathogenic or likely pathogenic TNFAIP3 variants. Clinical, laboratory and treatment data were assessed. Clustering analysis was applied to evaluate clinical features and disease phenotypes. Patients were stratified by age (< 16 years vs ≥ 16 years), country of origin (China vs U.S.), and gender. Results A total of 185 patients from 41 clinics across 7 countries were included (median onset 3.3 years). Common clinical features were mucocutaneous involvement (80.5%), recurrent fever (63.3%), gastrointestinal symptoms (58.6%), cytopenias (56.6%), arthritis/arthralgia (46.7%), and recurrent infections (35.5%). Compared with adults and patients from the U.S. cohort, intestinal ulcers were significantly more frequent in children and patients from the Chinese cohort ( P = 0.002 and P < 0.0001, respectively), whereas uveitis was less common in these groups ( P = 0.001 and P < 0.0001, respectively). Hierarchical clustering of clinical disease phenotypes based on Pearson distance identified two major clusters, an autoinflammation-predominant phenotype and an autoimmune-predominant phenotype. The autoinflammation-predominant phenotype was more common in children and patients from the Chinese cohort ( P = 0.033 and P = 0.003, respectively). A total of 89 pathogenic TNFAIP3 mutations were identified, including 46 novel variants. Large deletions were associated with neurologic disease and developmental delay ( P = 0.0054 and P = 0.0245, respectively); however, there were no clear association between disruptions of specific functional A20 domains and onset age or phenotype. Therapeutically, TNF and IL-1 inhibitors were effective in most patients, with thalidomide and JAK inhibitors used in refractory cases; 51.5% had achieved minimal disease activity at the most recent follow-up. Conclusions HA20 is a common dominantly inherited immune dysregulation disorder with phenotypic heterogeneity and potential age-dependent evolution. This large international cohort highlights diagnostic and therapeutic strategies to advance evaluation and management of HA20.