New variant in the IL1RN-gene (DIRA) associated with late-onset, CRMO-like presentation

Abstract

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.

The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist

“…In patients with presumed DIRA, a diagnostic workup includes assessing peripheral neutrophilia and elevated inflammatory markers, determining bone involvement (ie, X-ray or bone MRI) and genetic testing 2 120. The differential diagnosis for DIRA includes chronic recurrent multifocal osteomyelitis (CRMO),121 122 synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO)123 syndrome and pustular psoriasis 124. Genetic testing for monogenic defects with overlapping clinical features should include LPIN2, FGR, FBLIM1 for CRMO,125 126 CARD14 for CARD14-mediated psoriasis (CAMPS),127 128 IL36RN for deficiency of IL-36 receptor antagonist,127 128 AP1S3 128 for other pustular psoriasis and MEFV for pyrin-associated autoinflammation with neutrophilic dermatosis 129…”

“…The FDA recently approved both anakinra and rilonacept for treatment of DIRA 53 55. Blocking IL-1α may be necessary to completely block bone inflammation, as observed in a patient who developed osteitis during treatment with canakinumab, which only blocks IL-1β 121. While anakinra has been used initially in all patients with DIRA to achieve disease control, rilonacept can be used to maintain remission 120.…”

Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features

“…One is Majeed syndrome which is the focus of this review. The other is the deficiency of the interleukin-1 receptor antagonist (DIRA) in which , sterile multifocal osteomyelitis/osteitis and skin pustulosis are the dominant phenotypes [34,35,[67][68][69][70][71][72][73][74][75][76][77][78]. Patients with DIRA present in infancy with systemic inflammation, severe multifocal osteomyelitis and pustulosis of the skin.…”

“…Patients with DIRA present in infancy with systemic inflammation, severe multifocal osteomyelitis and pustulosis of the skin. It is caused by either deficiency or loss of function mutations in the gene that encodes the IL-1 receptor antagonist leading to unfettered IL-1 signaling and results in a systemic inflammatory disorder that if left untreated is often fatal [34,35,[67][68][69][70][71][72][73][74][75][76][77][78]. While a direct connection to IL-1 signaling is evident in DIRA, that connection had been less clear in the Majeed syndrome which is caused by pathogenic variants in LPIN2, in which the encoded protein plays a central role in lipid metabolism.…”

Chronic Nonbacterial Osteomyelitis in Children

“…Recently, Kuemmerle-Deschner et al reported the case of an atypical DIRA presentation, CNO-like with a later clinical onset at 1 year of age. This reported case increases the spectrum of DIRA presentation and highlights the importance of considering serum IL-1Ra dosage in patients with early-onset CNO-like bone lesions and biologic inflammation, even without skin manifestations [ 59 ].…”