How I Treat: Haploinsufficiency of A20

Haploinsufficiency of A20 (HA20) is a primary immune regulation disease caused by heterozygous loss-of-function variants in TNFAIP3, resulting in unchecked inflammatory signaling. HA20 is a highly heterogeneous disorder with overlapping features of autoinflammation, autoimmunity, immunodeficiency, atopy, and lymphoproliferation. Most patients develop symptoms in early childhood mimicking Behcet's disease, inflammatory bowel disease, periodic fevers with aphthous stomatitis, pharyngitis, and adenopathy (PFAPA), systemic lupus erythematosus (SLE), autoimmune hepatitis, vasculitis, and other conditions. This phenotypic variability contributes to diagnostic delays. Diagnosis requires identification of a pathogenic TNFAIP3 variant or deletion encompassing TNFAIP3: most are null, but missense variant interpretation remains challenging. After diagnosis, we use comprehensive clinical laboratory studies, imaging, and multidisciplinary evaluations to screen for complications. Treatment is guided by clinical phenotype and biomarkers. Colchicine and PDE4 inhibitors may control mild disease, whereas IL-1, TNF, and JAK inhibitors are often necessary for moderate-severe cases. Acute withdrawal of immunosuppression can precipitate disease flares. Genetic counseling and evaluation of at-risk family members are essential.