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

Abstract

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.

DNAX-activating Protein 10 (DAP10) Membrane Adaptor Associates with Receptor for Advanced Glycation End Products (RAGE) and Modulates the RAGE-triggered Signaling Pathway in Human Keratinocytes

“…Mutation in IL-1Ra and deletion in IL-36Ra have been observed in patients with pustular psoriasis (61)(62)(63)(64). A functional defect in the antagonists caused a failure in the control of inflammatory signals from the IL-1 receptor family.…”

Autoinflammatory Diseases Predominantly Affecting Bone and Joints

“…40,41 Affected individuals either do not produce, or produce defective, IL-1 receptor antagonist (IL-1Ra). 40,42 This results in unopposed signaling through the IL-1 receptor with resulting chronic inflammation. 40 Genetics DIRA was recognized as a distinct clinical entity in 2009, when two groups simultaneously reported the syndrome associated with deleterious mutations in IL-1RN, the gene that encodes the IL-1Ra.…”

“…Dysregulation of the IL-1 pathway is etiologic in DIRA, and Majeed syndrome improves with IL-1 blockade, implicating this cytokine in the pathogenesis of CRMO. 40,42,43 Peripheral blood mononuclear cells from one woman with SAPHO hyper-produced IL-1β when she was treated with LPS or LPS plus benzoyl-ATP, an agonist of the P2X7 receptor known to trigger the inflammasome. 44 There are a few reports of CRMO or SAPHO patients improving on IL-1 blocking agents.…”

Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist

“…Their case histories have been published (3,4,18,33,34). None of the patients enrolled were on disease-modifying antirheumatic drugs, including methotrexate or oral steroids, at the time of enrollment.…”