Patient 1 was a 4-year-old boy. At 11 months old, he had been hospitalized for cervical lymphadenitis and then suffered from repeated tonsillitis, cervical lymphadenitis, and bronchitis with elevated serum C-reactive protein (CRP). He was initially suspected of having an immunodeficiency disease but had no abnormalities in neutrophil function, lymphocyte fraction, or immunoglobulin levels. During the fever episodes, no significant pathogens were detected and his fever often improved without antibiotics. Because a single dose of prednisolone (PSL) was effective for the fever, he was diagnosed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome based on Thomas’s criteria []. At the age of 4 years and 2 months, fever with pharyngeal redness persisted for 9 days, with PSL not being effective for it. The patient also had temporary nonbacterial coxitis. He had a heterozygous c.574G>A (p.Glu192Lys) variant of TNFAIP3. After undergoing tonsillectomy, the frequency of the fever episodes decreased. His father also suffered from recurrent stomatitis, folliculitis, and hemorrhoids and possessed the same variant of TNFAIP3.
Patient 2 was a 20-year-old woman. From around the age of 12, she had occasionally suffered from severe abdominal pain of unknown cause. Around 13 years of age, she had suffered from a recurrent fever that persisted for 3–7 days and abdominal pain with a high level of serum CRP approximately every 2 months. Serum inflammatory reactants were negative during the intermittent episodes of fever. Lower gastrointestinal endoscopy showed erosion in Peyer’s patch of the ileum. Histopathologically, this lesion showed ulcers and granulation tissue with inflammatory cell infiltration. This case was initially considered to possibly involve familial Mediterranean fever (FMF) related to the heterozygous c.329T>C (p.Leu110Pro; rs11466018) and c.442G>C (p.Glu148Gln; rs3743930) variants of MEFV. However, colchicine given for diagnostic and therapeutic purposes failed to reduce the fever attacks, while NSAIDs and PSL were also ineffective for the fever and abdominal pain. When infliximab treatment was started with methotrexate as secondary prevention, the episodes of fever and abdominal pain completely disappeared. Finally, the heterozygous c.929T>C (p.Ile310Thr; rs530310566) variant of TNFAIP3 was identified in this patient. Her mother had the same variant but lacked any symptoms.