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.
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.