Patient 3 was a 24-year-old woman. She had suffered from athetoid cerebral palsy due to cardiopulmonary arrest of unknown cause on postnatal day 1. She had developed epilepsy at the age of 4 years and type 1 diabetes with positive anti-glutamic acid decarboxylase antibody at the age of 12 years. At the age of 24 years, she had a fever, facial erythema, and proteinuria. She was diagnosed with systemic lupus erythematosus (SLE) with the following findings: positive antinuclear antibodies, anti-dsDNA antibodies, anti-Sm antibodies, anti-cardiolipin antibodies, hypocomplementemia, and positive direct Coombs test. She had a heterozygous c.2126A>G (p.Gln709Arg) variant of TNFAIP3. Her father had the same variant but lacked any symptoms.\nThe variant Glu192Lys was identified among 55 patients suspected of having autoinflammatory diseases analyzed at Gifu University Hospital from October 2017 to September 2020. The patients with variants Ile310Thr and Gln709Arg were recruited by personal communication with the collaborators (Nagasaki University and Tokyo Medical and Dental University).\nWritten informed consent to participate in this study was obtained from each of the patients or their parents. This study was conducted in accordance with the Declaration of Helsinki and approved by the ethics boards of Gifu University and Tokyo Medical and Dental University.
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.