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.
A 32-year-old female patient initially presented at the age of 16 with high fever and severe abdominal pain associated with anorexia, but not diarrhea and vomiting. Over the period of the next 4 years, she had multiple hospital admission with similar presentation, which was always accompanied with raised C-reactive protein (CRP). On few occasions her urine dipstick showed traces of protein, and consequently she was treated for presumed urinary sepsis. However, multiple blood and urinary cultures were negative, other investigations including abdominal ultrasound showed no obvious intraabdominal pathology, and the diagnosis remained inconclusive. At the age of 21, she developed sudden onset polyarthritis, fever, and wide spread erythematous skin rash. The routine investigations at the time showed highly elevated acute phase response with CRP > 200 mg/L and hyperferritinemia. Additional investigations including antinuclear antibody (ANA), rheumatoid factor (RF), and anti-citrullinated peptide antibodies (ACPA) were all negative. Diagnosis of AOSD was at that point established, based on the typical clinical features associated with hyperferritinemia and exclusion other autoimmune rheumatological diagnoses. Her condition improved following initial treatment with oral corticosteroids (prednisolone 40 mg daily), but she remained dependant on prednisolone for the disease control despite attempts to introduce disease-modifying antirheumatic drugs (DMARDs) such as hydroxychloroquine, azathioprine, and methotrexate, which were all largely ineffective. Over the next several years, she continued to suffer from inflammatory polyarthritis affecting predominantly the large joints (hips and knees). Prior to establishing her genetic diagnosis, the patient was eventually treated with tocilizumab to which she made an excellent response. She discontinued long-term corticosteroid treatment and remains well controlled on monotherapy with tocilizumab (IV 8 mg/kg monthly) for the last 2 years.\nSubsequent enquiries into her family history revealed that she has two children, a boy aged 6 and a half and a girl of age 4 years. Both children had history of unexplained inflammatory symptoms. The girl was symptomatic from the age of 8 months, at which point she begun having recurrent episodes of feeling generally unwell, with malaise and high fever up to 40°C. The frequency of these episodes varied between 2 and 4 weeks, and each episode was relatively short-lived, lasting anywhere between 2 and 3 days. On few occasions, the episodes of fever were associated with erythematous macular rash and mouth ulcers. Subsequently, she also developed episodic abdominal pain as well as difficulty walking due to the pain in her knees. All these symptoms would disappear when the fevers resolved and she would fully recover in between these episodes. Since commencing regular colchicine, she has not had any further inflammatory episodes or symptoms. Her brother was well until age 5 when, like his sister he started with monthly episodes of high fever lasting between several hours to several days. On few occasions, these episodes were associated with vomiting, mouth ulcers, and interestingly, salmon-pink skin rash. He was also commenced on colchicine, which in his case has not been as effective, and he is currently awaiting therapeutic trial of tocilizumab. Finally, the father of the index case also appears to have relevant clinical history. He was diagnosed with early onset RA, but the details of symptoms and investigations leading to his diagnosis are lacking since he is looked after by another hospital and he has minimal contact with his daughter with who he has not shared any further details regarding his health.