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

Autoinflammatory diseases are a group of disorders characterized by systemic inflammation without high-titer autoantibodies or antigen-specific T cells, and their etiology is thought to be attributable to dysregulation of innate immunity (1,2). A number of the auto-inflammatory diseases are single-gene disorders that are clinically characterized by features of recurrent or persistent systemic inflammation, such as fever and elevation in the levels of acute-phase reactants, and organ-specific manifestations, such as rashes and osteo-articular, serosal, neurologic, and ocular manifestations (1–3). The identification of these monogenic disorders in innate immune pathways has led to a better understanding of the key inflammation pathways, particularly the role of interleukin-1 (IL-1) in a number of these disorders (1). Thus far, studies have identified 3 autoinflammatory disorders that manifest predominantly with skin and bone inflammation in the newborn period, including neonatal-onset multisystem inflammatory disease (NOMID; also called chronic infantile neurologic, cutaneous, articular syndrome) (4–7), Majeed syndrome (8–11), and the recently described deficiency of interleukin-1 receptor antagonist (DIRA) syndrome (12,13). In addition to inflammation of the skin and bone, NOMID also has features of neurologic impairment and papilledema, chronic arthropathy, and persistent fever, and its etiology has been linked to mutations in NLRP3 (previously called CIAS1) (5,6). In Majeed syndrome, the clinical features include microcytic congenital dyserythropoietic anemia, and a causal mutation has been identified in LPIN2 (8). The DIRA syndrome is also characterized by perinatal-onset pustular dermatitis, multifocal aseptic osteomyelitis, periosteitis, leukocytosis, and marked elevation in the levels of acute-phase reactants, and its etiology has been linked to a loss-of-function protein that truncates mutations in IL1RN (12), a gene that encodes the IL-1 receptor antagonist (IL-1Ra), or a major deletion that involves the IL1RN locus (12,13). One of the nonsense mutations of IL1RN (identified in patients from The Netherlands), a frameshift mutation attributable to a 2-bp deletion (in patients from Newfoundland), and a genomic 175-kb deletion (in patients from Puerto Rico) are believed to be founder mutations in their respective populations (12). In the present study, we describe 2 unrelated Brazilian patients whose clinical phenotype was consistent with the DIRA syndrome. Both patients presented with a severe but distinct clinical picture, mainly involving the skin, bones, and lungs, and both were homozygous for the same 15-bp (in-frame) deletion on IL1RN (a mutation not previously described). We hypothesize that this variant is likely to be a possible founder mutation in the Brazilian population. This novel mutation of IL1RN produces a protein that does not bind the IL-1 receptor, and thus lacks functional activity.