Patient 3 (III-1 in Fig. b) is a 12-year-old girl who is the first child of non-consanguineous Japanese parents. At 2 months of age, she presented with 38–39 °C fever accompanied by abdominal pain, diarrhea, ankle arthralgia, oral ulcers, pharyngalgia, and an enlarged tonsil. Febrile attacks were recurrent every 1–2 weeks and resolved within 4 days. She presented with perianal ulcers (at 4 years old), bloody stool, and weight loss (at 5 years old), but colonoscopy did not identify any abnormality. At 9 years of age, she was prescribed with naproxen and methotrexate (MTX) because of left ankle arthritis, but MTX was stopped because of abdominal pain. She was treated with colchicine and mesalazine for abdominal pain, but they were not effective. At 10 years of age, she was suspected of having a periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome and was treated with cimetidine, which contributed to a reduction in the number of febrile attacks. Gastrointestinal and capsule endoscopy revealed multiple ulcers throughout the intestinal tract (Fig. ), and mesalazine was re-administered. Histopathology of ulcer biopsies showed infiltration of lymphocytes and plasma cells. There was no evidence of granuloma, cryptitis, or crypt abscess, and the findings were thought to indicate nonspecific chronic inflammation. At 11 years of age, bilateral non-granulomatous acute anterior uveitis was revealed by ophthalmologic examination and diagnosed as BD. She did not show any neurodevelopmental delay. Currently, she experiences genital ulcers and has been treated with colchicine (400 mg/day), cimetidine (1.0 mg/day), and corticosteroid eye drops. The severity of abdominal pain is milder than before and fever is less frequent.
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.