D2.353 - Same Disease, Different Clinical Phenotypes: A20 Haploinsufficiency

Introduction:A20 is an intracellular signaling molecule that inhibits NF-κB signaling, NLRP3 activation, and caspase-1. It is encoded by the TNFAIP3 (tumor necrosis factor alpha–induced protein 3) gene. Loss-of-function heterozygous mutations in this gene cause A20 haploinsufficiency, a rare autoinflammatory disease characterized by recurrent fever, oral/genital ulcers, polyarthritis, and autoimmunity. Patients may be followed with diagnoses such as PFAPA, Behcet disease, and SLE before genetic diagnosis.

Case 1:A 19-year-old female had monthly three-day episodes of fever, sore throat, and joint pain since age six and developed Henoch-Schonlein purpura at eight. Due to recurrent oral ulcers, abdominal, joint, and back pain attacks at age 13, she was treated with colchicine for suspected FMF. Recurrent genital ulcers developed at age 15. She responded to steroids and NSAIDs during attacks. She presented to our clinic after a heterozygous TNFAIP3 mutation was detected by WES.

Case 2:A 14-year-old boy was referred to our clinic at age eight for recurrent severe herpes labialis infections, starting at three months old. Immunologic evaluation revealed intermittent neutropenia and low IgG levels. Antiviral and antibacterial prophylaxis was initiated. During follow-up, he developed left ankle pain and morning stiffness and was admitted to rheumatology care. WES analysis identified a heterozygous TNFAIP3 mutation in both the patient and his mother.

Case 3:The mother of Case 2, a 38-year-old female. She reported severe herpes labialis infections during childhood and had been treated for rheumatoid arthritis with NSAIDs and sulfasalazine for ten years. Her father had also been followed for rheumatic disease and reportedly died from disease-related complications.

Conclusion:In A20 haploinsufficiency, clinical manifestations may differ even among family members carrying the same mutation. Treatment is individualized and may include NSAIDs, glucocorticoids, colchicine, biologics, and immunosuppressants. Due to autosomal dominant inheritance, family screening and genetic counseling are required.