Abstract
Purpose
Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autoinflammatory disease caused by autosomal recessive mutations in IL1RN. DIRA presents clinically with early onset generalized pustulosis, multifocal osteomyelitis, and elevation of acute phase reactants. We evaluated and treated an antibiotic-unresponsive patient with presumed DIRA with recombinant IL-1Ra (anakinra). The patient developed anaphylaxis to anakinra and was subsequently desensitized.
Methods
Genetic analysis of IL1RN was undertaken and treatment with anakinra was initiated.
Results
A 5-month-old Indian girl born to healthy non-consanguineous parents presented at the third week of life with irritability, sterile multifocal osteomyelitis including ribs and clavicles, a mild pustular rash, and elevated acute phase reactants. SNP array of the patient’s genomic DNA revealed a previously unrecognized homozygous deletion of approximately 22.5 Kb. PCR and Sanger sequencing of the borders of the deleted area allowed identification of the breakpoints of the deletion, thus confirming a homozygous 22,216 bp deletion that spans the first four exons of IL1RN. Due to a clinical suspicion of DIRA, anakinra was initiated which resulted in an anaphylactic reaction that triggered desensitization with subsequent marked and sustained clinical and laboratory improvement.
Conclusion
We report a novel DIRA-causing homozygous deletion affecting IL1RN in an Indian patient. The mutation likely is a founder mutation; the design of breakpoint-specific primers will enable genetic screening in Indian patients suspected of DIRA. The patient developed anaphylaxis to anakinra, was desensitized, and is in clinical remission on continued treatment.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
de Jesus AA, Canna SW, Liu Y, Goldbach-Mansky R. Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling. Annu Rev Immunol. 2015;33:823–74.
Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426–37.
Reddy S, Jia S, Geoffrey R, Lorier R, Suchi M, Broeckel U, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009;360(23):2438–44.
Altiok E, Aksoy F, Perk Y, Taylan F, Kim PW, Ilikkan B, et al. A novel mutation in the interleukin-1 receptor antagonist associated with intrauterine disease onset. Clin Immunol. 2012;145(1):77–81.
Brau-Javier CN, Gonzales-Chavez J, Toro JR. Chronic cutaneous pustulosis due to a 175-kb deletion on chromosome 2q13: excellent response to anakinra. Arch Dermatol. 2012;148(3):301–4.
Minkis K, Aksentijevich I, Goldbach-Mansky R, Magro C, Scott R, Davis JG, et al. Interleukin 1 receptor antagonist deficiency presenting as infantile pustulosis mimicking infantile pustular psoriasis. Arch Dermatol. 2012;148(6):747–52.
Jesus AA, Osman M, Silva CA, Kim PW, Pham TH, Gadina M, et al. A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: description of two unrelated cases from Brazil. Arthritis Rheum. 2011;63(12):4007–17.
Stenerson M, Dufendach K, Aksentijevich I, Brady J, Austin J, Reed AM. The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist. Arthritis Rheum. 2011;63(12):4018–22.
Infevers: an online database for autoinflammatory mutations. Copyright. Available at http://fmf.igh.cnrs.fr/ISSAID/infevers/ [.
Ulusoy E, Karaca NE, El-Shanti H, Kilicoglu E, Aksu G, Kutukculer N. Interleukin-1 receptor antagonist deficiency with a novel mutation; late onset and successful treatment with canakinumab: a case report. J Med Case Rep. 2015;9:145.
Gunderson KL, Steemers FJ, Lee G, Mendoza LG, Chee MS. A genome-wide scalable SNP genotyping assay using microarray technology. Nat Genet. 2005;37(5):549–54.
Acknowledgements
We would like to acknowledge Dr. Ivona Aksentijevich for providing the wild type and GAPDH primer sequences and for genetic advice on the multiplex PCR protocol. We would also like to thank Dawn Chapelle, CRNP, and Wendy Goodspeed, RN, for the clinical care of the patient. This research was supported by the Intramural Research Program of the NIH, NIAID, NIAMS, and NHGRI.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The parents provided consent and the patient was enrolled into an IRB-approved NIH natural history protocol (NCT02974595).
Conflicts of Interest
Dr. Leonardo O. Mendonca has received speaker fees from Novartis. All other authors declare that they have no conflicts of interest.
Electronic Supplementary Material
ESM 1
(DOCX 150 kb)
Rights and permissions
About this article
Cite this article
Mendonca, L.O., Malle, L., Donovan, F.X. et al. Deficiency of Interleukin-1 Receptor Antagonist (DIRA): Report of the First Indian Patient and a Novel Deletion Affecting IL1RN . J Clin Immunol 37, 445–451 (2017). https://doi.org/10.1007/s10875-017-0399-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-017-0399-1