Haploinsufficiency of A20 (HA20) is a rare genetic cause of complex immune dysregulation caused by pathogenic variants in TNFAIP3, encoding A20. A20 is a critical negative regulator of numerous inflammatory pathways. Although initially reported as a monogenic cause of Behcet’s disease, it has become clear that heterozygous loss of A20 results in diverse clinical manifestations. We describe 4 individuals from 2 families with novel variants in TNFAIP3 (c.1069C>T, p.Gln357X and c.2093C>A, p.S698X) and significant variability in age of onset, phenotype, and severity. The 3 affected patients share common features, including oral ulcers, inflammatory skin lesions, leukocytosis, autoantibodies, and elevated interferon scores, but were diagnosed with antibody-negative neuromyelitis optica (NMO) at age 2, giant cell hepatitis with autoimmune cytopenias at age 12, and systemic lupus erythematosus without nephritis at age 35. One individual has not developed disease manifestations at the age of 40, despite an interferon score above healthy control levels. Transaminitis in the 3 patients supports a potential link between HA20 and immune-mediated hepatic injury. Although anti-TNF agents are most frequently used in treatment of HA20, the neuroinflammatory disease of the patient with NMO responded to rituximab as a corticosteroid-sparing agent. She has residual vision loss, spinal cord atrophy with lower extremity weakness, and neurogenic bladder, but she is now 22, and tofacitinib controls her oral ulcers, rashes, and arthritis. Her mother, age 61 and on hydroxychloroquine for her lupus, has a sister who also carries the family variant and has been diagnosed with adult-onset Still’s disease. The patient with hepatitis and cytopenias, the daughter of the unaffected carrier, responded well to 6-mercaptopurine for her liver disease and rituximab for arthritis and rash. However, she subsequently developed fatal pulmonary hypertension age 16, in the absence of parenchymal lung disease. This case series provides important insights into HA20, highlighting its diverse clinical presentations and emphasizing the importance of liver injury as a potential phenotype. The breadth of phenotypes in HA20 combined with incomplete penetrance likely contributes to under recognition of this monogenic cause of complex immune dysregulation, and HA20 could be considered in any family with multiple members affected by inflammatory disease.
