Background Deficiency of the IL-1 receptor antagonist (DIRA) is an autosomal-recessive disorder caused by mutations of the IL-1 receptor antagonist (IL-1Ra) presenting with systemic inflammation, periostitis, osteolytic lesions, and a pustular rash. Mutations in the IL-1 pathway may also cause chronic recurrent multifocal osteomyelits (CRMO) with the leading symptom of sterile osteomyelits.

Methods We report here a 2 year-old German girl with unremarkable family history. She was admitted to the pediatric rheumatology service due to refusal to walk, mild diarrhea, high fever and swollen right foot and left hand. Laboratory tests showed highly elevated inflammatory parameters (ESR 85 mm/h, CRP 14 mg/dl) but normal results for LDH, liver enzymes and uric acid. Whole body MRI revealed osteitis and periostitis in arms and legs. Bone biopsy showed fibrosis of the bone marrow and inflammation of the subcortical bone with signs of chronic osteomyelitis. The patient tested negative for DIRA-associated mutations in the IL-1RN gene, however she was found to carry an unreported intronic variant of unknown clinical significance in the IL-1R1 gene. This variant resides at the position c.840-6bp upstream to the exon 9 splice-acceptor site and could potentially interfere with transcript splicing. Further testing of other family members showed that this variant has been inherited through the unaffected mother and the grandmother. Initial therapy consisted of high-dose steroids with no significant improvement however in face of the novel genetic variant, an autoinflammatory disease was suspected and the patient was treated with anakinra. Inflammatory parameters normalized promptly and bone lesions decreased on MRI. After nine months, the patient was readmitted due to bad general condition, high inflammatory markers, severe oral mucosal lesions and mild pustular lesions of the perioral skin but this time without bone involvment. Endoscopy of the GI-tract showed nonspecific inflammation of the whole intestine but without granulomas. Immunosuppressive therapy (short-time steroids, azathioprine) and iv-immunoglobulines were reintroduced while anakinra was discontinued. Subsequently MRI showed typical signs of CRMO with no further systemic inflammation. Levels of IL-1 receptor antagonist, different cytokines and chemokines were analyzed prior to anakinra treatment and after withdrawal of anakinra-therapy.

Results In summary, this child presents with inconsistant features of both CRMO and DIRA. In addition to the polymorphism of the IL1-R1 gene, which was also found in the female first-degree relatives, a so far uncharacterized IL-1β mediated disorder was suspected and treated empirically.

Conclusions Further insight into the course of this disease and study of the novel IL1-R1 polymorphism are needed to provide an accurate diagnosis and effective treatment.

1. Aksentijevich I et al, An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist, N Engl J Med 2009; 360:2426-2437

Disclosure of Interest None Declared