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.
The patient was a 29-year-old female who had suffered from recurrent oral ulcers, abdominal pain and diarrhea since the age of 15 years. Recurrent ascending colonic ulcers and anastomotic ulcers along with intestinal obstruction were observed prior to and for 8 years after right hemicolectomy surgery (), accompanied by vasculitis in extremities (). Laboratory data showed elevated C-reactive protein (19.6 mg/L; normal range (NR) <5 mg/L) and erythrocyte sedimentation rate (25 mm/h; NR<20 mm/h), along with a low titer of the antinuclear antibody (1:100). Serum IgG and IgM were within the normal range but IgA levels were low (IgG 19.3–25.8g/L, IgM 0.73–0.92 g/L, IgA <0.07g/L). The patient responded to a glucocorticoid and thalidomide in 3 months with reduced frequency of diarrhea and less severe abdominal pain. The patient's IgA increased but did not reach normal levels after treatment. Subsequent inquiries into the patient's family history revealed that her father suffered from recurrent oral ulcers when he was young, and her brother had suffered from recurrent fever, oral ulcers and erythema nodosum-like lesions in the skin since he was 4 years old. The level of serum immunoglobulins in the father and brother were in the normal ranges. Because of the mild and non-specific symptoms, they accepted treatment of only antimicrobial mouthwash and dental ulcer paste instead of immunomodulators.