A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: Description of two unrelated cases from Brazil

Adriana A. Jesus, Mazen Osman, Clovis A. Silva, Peter W. Kim, Tuyet Hang Pham, Massimo Gadina, Barbara Yang, Débora R. Bertola, Magda Carneiro-Sampaio, Polly J. Ferguson, Blair R. Renshaw, Ken Schooley, Michael Brown, Asma Al-Dosari, Jamil Al-Alami, John E. Sims, Raphaela Goldbach-Mansky, Hatem El-Shanti

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Objective Monogenic autoinflammatory diseases are disorders of Mendelian inheritance that are characterized by mutations in genes that regulate innate immunity and whose typical features are systemic inflammation without high-titer autoantibodies or antigen-specific T cells. Skin and bone inflammation in the newborn period have been described in 3 of these autoinflammatory disorders: neonatal-onset multisystem inflammatory disease, Majeed syndrome, and deficiency of interleukin-1 (IL-1) receptor antagonist (DIRA) syndrome. This study was undertaken to present the characteristics of the DIRA syndrome in 2 cases from Brazil, and describe a novel mutation in IL1RN. Methods Two unrelated Brazilian patients were evaluated for the clinical signs and symptoms of these 3 disorders, and peripheral blood samples were assessed for mutations in NLRP3, LPIN2, and IL1RN by DNA resequencing analysis. A mutation in IL1RN that encodes a mutant protein was identified, and the expression and function of this mutant protein were compared to those of the wild-type protein. Results Both patients presented with pustular dermatitis resembling generalized pustular psoriasis, recurrent multifocal aseptic osteomyelitis, and elevation in the levels of acute-phase reactants, all of which are features most consistent with the DIRA syndrome. Chronic lung disease was observed in 1 of the patients, and jugular venous thrombosis was observed in the other patient. Both patients showed a partial response to corticosteroid therapy, and 1 patient experienced an initial improvement of dermatitis with the use of acitretin. Both patients were homozygous for a novel 15-bp (in-frame) deletion on the IL1RN gene. The mutated protein expressed in vitro had no affinity with the IL-1 receptor, and stimulation of the patients' cells with recombinant human IL-1α or IL-1β led to oversecretion of proinflammatory cytokines, similar to the findings obtained in previously reported patients. Conclusion The presence of the same homozygous novel mutation in IL1RN in 2 unrelated Brazilian patients suggests that this genetic variant may be a founder mutation that has been introduced in the Brazilian population.

Original languageEnglish
Pages (from-to)4007-4017
Number of pages11
JournalArthritis and Rheumatism
Issue number12
Publication statusPublished - Dec 2011


ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Jesus, A. A., Osman, M., Silva, C. A., Kim, P. W., Pham, T. H., Gadina, M., Yang, B., Bertola, D. R., Carneiro-Sampaio, M., Ferguson, P. J., Renshaw, B. R., Schooley, K., Brown, M., Al-Dosari, A., Al-Alami, J., Sims, J. E., Goldbach-Mansky, R., & El-Shanti, H. (2011). A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: Description of two unrelated cases from Brazil. Arthritis and Rheumatism, 63(12), 4007-4017. https://doi.org/10.1002/art.30588