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

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

来源：Arthritis and Rheumatism, 2011, 63(12): 4007-4017.

DOI：10.1002/art.30588

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-1 alpha or IL-1 alpha 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.

• 出版日期2011-12