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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)4007-4017
Number of pages11
JournalArthritis and Rheumatism
Volume63
Issue number12
DOIs
Publication statusPublished - Dec 2011

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Brazil
Mutation
Dermatitis
Mutant Proteins
Interleukin-1
Cryopyrin-Associated Periodic Syndromes
Acitretin
Deficiency of interleukin-1 receptor antagonist
Osteitis
Interleukin-1 Receptors
Acute-Phase Proteins
Osteomyelitis
Psoriasis
Innate Immunity
Venous Thrombosis
Autoantibodies
Lung Diseases
Genes
Signs and Symptoms
Adrenal Cortex Hormones

ASJC Scopus subject areas

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

Cite this

A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome : Description of two unrelated cases from Brazil. / Jesus, Adriana A.; Osman, Mazen; Silva, Clovis A.; Kim, Peter W.; Pham, Tuyet Hang; Gadina, Massimo; Yang, Barbara; Bertola, Débora 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.

In: Arthritis and Rheumatism, Vol. 63, No. 12, 12.2011, p. 4007-4017.

Research output: Contribution to journalArticle

Jesus, AA, Osman, M, Silva, CA, Kim, PW, Pham, TH, Gadina, M, Yang, B, Bertola, DR, Carneiro-Sampaio, M, Ferguson, PJ, Renshaw, BR, Schooley, K, Brown, M, Al-Dosari, A, Al-Alami, J, Sims, JE, 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, vol. 63, no. 12, pp. 4007-4017. https://doi.org/10.1002/art.30588
Jesus, Adriana A. ; Osman, Mazen ; Silva, Clovis A. ; Kim, Peter W. ; Pham, Tuyet Hang ; Gadina, Massimo ; Yang, Barbara ; Bertola, Débora 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. / A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome : Description of two unrelated cases from Brazil. In: Arthritis and Rheumatism. 2011 ; Vol. 63, No. 12. pp. 4007-4017.
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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.",
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T1 - A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome

T2 - Description of two unrelated cases from Brazil

AU - Jesus, Adriana A.

AU - Osman, Mazen

AU - Silva, Clovis A.

AU - Kim, Peter W.

AU - Pham, Tuyet Hang

AU - Gadina, Massimo

AU - Yang, Barbara

AU - Bertola, Débora R.

AU - Carneiro-Sampaio, Magda

AU - Ferguson, Polly J.

AU - Renshaw, Blair R.

AU - Schooley, Ken

AU - Brown, Michael

AU - Al-Dosari, Asma

AU - Al-Alami, Jamil

AU - Sims, John E.

AU - Goldbach-Mansky, Raphaela

AU - El-Shanti, Hatem

PY - 2011/12

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N2 - 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.

AB - 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.

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