IL1RN and sterile multifocal osteomyelitis with periostitis and pustulosis

Deficiency of the interleukin-1 receptor antagonist (DIRA) is an autosomal recessive autoinflammatory syndrome caused by biallelic loss-of-function variants in IL1RN. Patients present in the neonatal period or later infancy with multifocal sterile osteomyelitis, periostitis, and pustular dermatosis, often accompanied by systemic inflammation and complications such as sepsis and respiratory insufficiency. Early genetic diagnosis is critical for targeted therapy with recombinant IL-1Ra (anakinra) or related biologics, which rapidly reverse inflammation and prevent morbidity and mortality (PMID:22431714).

Genetic evidence includes at least 11 unrelated probands with homozygous or compound heterozygous IL1RN variants across seven studies (22431714, 26100510, 28503715, 31467740, 37575641, 32819369, 21792839). Segregation analysis in two affected siblings confirmed autosomal recessive inheritance and perfect co-segregation of pathogenic alleles (PMID:38646532). The variant spectrum is dominated by frameshift, nonsense, and genomic deletions, exemplified by c.76C>T (p.Arg26Ter), which abolishes IL-1Ra function and receptor binding. Founder mutations have been described in Puerto Rican (175 kb deletion) and Brazilian (15 bp in-frame deletion) populations.

Phenotypic variability includes neonatal pustulosis, late-onset arthritis, joint swelling, onychomycosis, and respiratory distress. Periostitis (HP:0040165), arthritis (HP:0001369), joint swelling (HP:0001386), sepsis (HP:0100806), and respiratory insufficiency (HP:0002093) are frequent manifestations that warrant prompt consideration of DIRA in differential diagnosis.

Functional studies demonstrate that mutant IL-1Ra proteins lack receptor affinity, leading to unchecked IL-1 signaling and oversecretion of proinflammatory cytokines in patient cells. In vitro assays confirmed loss of antagonistic activity, and recombinant IL-1Ra restores normal signaling thresholds (PMID:22127713).

Therapeutic evidence shows life-saving responses to anakinra, with rapid clearance of skin lesions and resolution of systemic inflammation. Alternative biologics, including canakinumab and adalimumab, have been used successfully in individual cases, underscoring the tractability of IL-1 axis inhibition for disease control (PMID:26100510; PMID:31467740).

Integration of genetic, experimental, and therapeutic data supports a definitive causal relationship between IL1RN LoF and sterile multifocal osteomyelitis with periostitis and pustulosis. Genetic testing for IL1RN variants should be standard in infants and children with unexplained pustulosis and bone inflammation. Key take-home: early recognition and IL-1 receptor antagonist therapy are essential to reduce the high morbidity and mortality of DIRA.

References

• Archives of dermatology • 2012 • Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis. PMID:22431714
• Journal of medical case reports • 2015 • Interleukin-1 receptor antagonist deficiency with a novel mutation; late onset and successful treatment with canakinumab: a case report. PMID:26100510
• Journal of clinical immunology • 2017 • Deficiency of Interleukin-1 Receptor Antagonist (DIRA): Report of the First Indian Patient and a Novel Deletion Affecting IL1RN. PMID:28503715
• Case reports in immunology • 2019 • Deficiency of Interleukin-1 Receptor Antagonist: A Case with Late Onset Severe Inflammatory Arthritis, Nail Psoriasis with Onychomycosis and Well Responsive to Adalimumab Therapy. PMID:31467740
• Journal of pediatric genetics • 2023 • Deficiency of Interleukin-1 Receptor Antagonist: New Genetic Autoinflammatory Disease as a Diagnostic Challenge for Pediatricians. PMID:37575641
• Pediatric rheumatology online journal • 2020 • A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of Interleukin-1 receptor antagonist (DIRA). PMID:32819369
• Arthritis and rheumatism • 2011 • The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist. PMID:21792839
• Frontiers in immunology • 2024 • Case report: Novel compound heterozygous IL1RN mutations as the likely cause of a lethal form of deficiency of interleukin-1 receptor antagonist. PMID:38646532
• Arthritis and rheumatism • 2011 • A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: description of two unrelated cases from Brazil. PMID:22127713

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