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.

• Authors: 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
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 63 Issue 12 Pg. 4007-17 (Dec 2011) ISSN: 1529-0131 [Electronic] United States
• PMID: 22127713 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 by the American College of Rheumatology.

Chemical References

• Carrier Proteins
• IL1RN protein, human
• Interleukin 1 Receptor Antagonist Protein
• LPIN2 protein, human
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Nuclear Proteins

Topics

• Brazil
• Carrier Proteins (genetics)
• Child, Preschool
• Female
• Hereditary Autoinflammatory Diseases (diagnosis, genetics, pathology)
• Homozygote
• Humans
• Interleukin 1 Receptor Antagonist Protein (genetics)
• Mutation (genetics)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nuclear Proteins (genetics)
• Osteomyelitis (diagnosis, genetics, pathology)
• Psoriasis (diagnosis, genetics, pathology)