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 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.