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New variant in the IL1RN-gene (DIRA) associated with late-onset, CRMO-like presentation
Jasmin B Kuemmerle-Deschner1, Tatjana Welzel1,2, Konstanze Hoertnagel3
1Autoinflammation Reference Center Tuebingen (arcT), Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany.
Objective:
To report a chronic recurrent multifocal osteomyelitis (CRMO)-like clinical phenotype with multisystem inflammation associated with a novel gene variant in the spectrum of IL-1-mediated diseases.
Methods:
A 3-year-old boy presented with recurrent episodes of fever, serositis, pancreatitis and high inflammatory markers with onset at age 13 months. At age 3 years, he started limping. Imaging revealed multifocal pelvic bone inflammation suggestive of CRMO. Autoinflammation panel testing was non-contributory. Whole exome sequencing (WES) and advanced IL-1 pathway analysis was conducted.
Results:
WES identified a novel homozygous interleukin receptor 1 (IL1RN) variant (c.62C>G; p. Ser21*) (NM_173842.2). Functional analysis of IL1RN mRNA and IL-1 receptor antagonist (IL-1RA) protein confirmed the diagnosis of a deficiency of the IL-1 receptor antagonist (DIRA). Treatment with the nonselective IL-1 inhibitor anakinra resulting in rapid remission; switch to the selective IL-1β antagonist canakinumab led to a flare within 6 weeks. Re-start of anakinra recaptured remission, last documented at the recent 19-month follow-up.
Conclusion:
This is the first report of a novel late-onset DIRA confirmed by advanced diagnostic testing. In patients with systemic inflammation and CRMO-like bone lesions, IL1RN testing should be considered; even in the absence of skin manifestations. Non-selective IL-1 inhibition is an effective therapy.
Insights
A novel genetic variant caused a rare Deficiency of Interleukin-1 Receptor Antagonist (DIRA) in a child with CRMO-like symptoms. Non-selective IL-1 inhibition with anakinra effectively treated this multisystem inflammatory disease.
Area of Science:
- Genetics
- Immunology
- Pediatrics
Background:
- Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory bone disease.
- Interleukin-1 (IL-1) mediated inflammatory diseases encompass a spectrum of conditions.
- Novel genetic variants can present with complex autoinflammatory phenotypes.
Observation:
- A 3-year-old boy exhibited recurrent fevers, serositis, pancreatitis, and elevated inflammatory markers since 13 months of age.
- Later onset of limping and pelvic bone inflammation suggestive of CRMO was observed.
- Standard autoinflammation panel testing was unrevealing.
Findings:
- Whole exome sequencing identified a novel homozygous variant in the Interleukin-1 Receptor Antagonist (IL1RN) gene.
- This variant confirmed a diagnosis of Deficiency of the Interleukin-1 Receptor Antagonist (DIRA).
- Treatment with anakinra (nonselective IL-1 inhibitor) induced rapid remission, while canakinumab (selective IL-1β antagonist) led to a flare.
Implications:
- This case represents the first report of late-onset DIRA diagnosed via advanced genetic testing.
- IL1RN gene testing should be considered in patients with systemic inflammation and CRMO-like bone lesions, even without skin findings.
- Nonselective IL-1 inhibition demonstrates efficacy in managing this rare autoinflammatory condition.
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