Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Novel Founder Mutation in IL1RN Accounts for Deficiency of the IL-1 Receptor (DIRA) in Brazil.

Jesus4,  Adriana Almeida, Silva4,  Clovis Artur Almeida, Kim2,  Peter W., Pham2,  Tuyet H., Bertola4,  Débora Romeo, Carneiro-Sampaio4,  Magda, Yang2,  Barbara

Amgen Inc, Thousand Oaks, CA
NIAMS/NIH, Bethesda, MD
Shafallah Medical Genetics Center, Doha, Qatar
Universidade de São Paulo, Sao Paulo, Brazil


To describe the clinical, immunological and genetic phenotype of 2 unrelated patients from Brazil presenting with pustular skin disease, osteolytic bone lesions and systemic inflammation and incoplete responses to multiple DMARDs.

Patients and Evaluation:

Two Brazilian patients with perinatal onset skin pustulosis and osteolytic bone lesions and systemic inflammation, consistent with the clinical diagnosis of DIRA were evaluated and genetic analysis of the IL1RN gene locus was performed. Multi-disciplinary clinical evaluation including a total body MRI, and immunological and laboratory characterization of the structure and function of the mutated gene and encoded protein were performed to characterize the inflammatory phenotype of these patients.


Both patients had classical pustular skin lesions with a neutrophilic infiltrate in the dermis and epidermis. One patient presented with clinically concerning spine lesions, she has non-fusion of the os odontoid with the body of the dens (C2) and an incomplete posterior arch of C1 leading to an over 7 mm atlantoaxial subluxation between head flexion and extension. Post-inflammatory fusion of several lower cervical and thoracic spine lesions led to the formation of a gibbus. Genetic analysis of IL1RN (isoform 1) showed a homozygous inframe 15 base pair deletion (c.213–228delAGATGTGGTACCCAT; p.72–77del DVVPI) in both girls leading to 5 amino acid deletion. Expression levels of messenger RNA were reduced on RT PCR and the mutated protein was expressed at low levels compared to healthy controls and heterozygous parents. Modeling of the mutated protein predicted a severe defect in the secondary structre and functional analysis confirmed no binding of the protein to the IL-1 receptor. Both patients had an immediate response to treatment with the rcombinant Il-1 receptor antagonist, anakinra, with complete resolution of skin lesions and normalization of systemic and organ specific inflammation. The patient's parents were carriers for the mutation but clinically asymptomatic.


A novel founder mutation in IL1RN accounts for 2 cases of DIRA from 2 unrelated Brazilian families. The clinical signs and symptoms in these patients are similar to those previously reported. In contrast to the previously reported cases of DIRA, in whom the mutated protein is not secreted, patients with the Brazilian mutation express low levels of the mutated protein. The severity of the 5 AA deletion was predicted based on modeling data and the response to the recombinat IL-1 receptor antagonist, anakinra, was immediate with complete resolution of inflammatory disease manifestations.

Determination of the frequency of the mutation in Brazil and establishing neonatal screening in areas with a high prevalence of the disease may be indicated.

To cite this abstract, please use the following information:
Jesus, Adriana Almeida, Silva, Clovis Artur Almeida, Kim, Peter W., Pham, Tuyet H., Bertola, Débora Romeo, Carneiro-Sampaio, Magda, et al; Novel Founder Mutation in IL1RN Accounts for Deficiency of the IL-1 Receptor (DIRA) in Brazil. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :260
DOI: 10.1002/art.28029

Abstract Supplement

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