The index patient is a 12-year-old male, who was born healthy at term to consanguineous parents of Pakistani origin. At 1 year of age, he developed mild, self-limiting oral aphthous ulcers. Neutropenia was first noted on an incidental blood test when he was 3 years old. From the age of 7 years, he suffered progressive, deep oral ulceration severe enough to result in complete dysphagia and several hospital admissions. He also developed transient perianal ulceration associated with episodic diarrhea and intermittent abdominal pain. Other pertinent features included a swinging pyrexia (39°C), oligoarthritis (knees) associated with a joint effusion on at least one occasion, and cervical lymphadenopathy. At the age of 11, he developed a rash on his right shin. The rash was diagnosed as erythema nodosum. He had no eye symptoms, or any other organ involvement. The only notable infections were paronychial nail infections and a conjunctival infection due to herpes simplex virus. The patient had two other siblings, and only the younger brother who initially was asymptomatic, later developed similar but less severe clinical features. There was no other significant family history of inflammatory disorders. The index patient responded well to prednisolone, but he remained dependent on high doses of the steroid. The trial of colchicine was ineffective, but he subsequently responded fully to adalimumab.
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.