The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist

Abstract

Interleukin-1 receptor antagonist (IL-1Ra) deficiency is a rare autoinflammatory disease involving neonatal onset of pustulosis, periostitis, and sterile osteomyelitis. We report the case of a 2-week-old male who presented with a swollen, erythematous left index finger and elevated serum markers of inflammation. He later developed cyclical fevers, diffuse pustular skin lesions, and thrombus formation. After not responding to broad-spectrum antimicrobial therapy and achieving only moderate success with systemic steroid therapy, he was ultimately treated with recombinant IL-1Ra, anakinra, and experienced significant clinical improvement. Sequencing of his IL1RN gene revealed that the patient was compound heterozygous for a known mutation (E77X) associated with IL-1Ra deficiency and a novel mutation in exon 2 of the gene (c.140delC; p.T47TfsX4). His case highlights IL-1Ra deficiency as an autoinflammatory disease that is distinct from neonatal-onset multisystem inflammatory disease but that also responds well to anakinra. Our patient is the first reported compound heterozygote for E77X and the novel mutation in exon 2 of the gene, the latter of which adds to what will surely be a growing database of pathologic mutations in IL1RN.

IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist

“…The importance of members within the IL-1 family functioning as natural "brakes" on the inflammatory properties of other IL-1 family members gained considerable validity with the reports of the deficiency of IL-1 receptor antagonist (DIRA) syndrome (33,34). Recent reports that pustular psoriasis can develop because of a single amino acid mutation in IL-36Ra provide additional evidence supporting this concept.…”

Autoinflammatory Diseases Predominantly Affecting Bone and Joints

“…40,41 Since that time additional mutations have been identified, including Q119X, a compound heterozygote (E77X/T47TfsX4) and a 15-bp in-frame deletion which produces a non-functional protein. 42,111,112 Evidence points to a founder effect in several populations, including the 175-kb Puerto Rican deletion, the E77X Dutch mutation, the 15 base-pair Brazilian deletion, and the Q54X Lebanese mutation. 40À42,113À116 An up-to-date catalog of DIRA mutations can be found online.…”

“…40,114 Fever, hepatosplenomegaly, and failure to thrive occur in many but not all affected infants. 40,42,112,113,115 Venous thrombosis has been reported, typically associated with a central venous line. 41,42,112,114 Respiratory distress can be seen, and one infant developed significant interstitial lung disease 40À42,111,112,115 which was fatal.…”

“…115 Clinically apparent bone inflammation typically follows the onset of pustules, 40,41 but bone inflammation may occur first. 112 Bone involvement may lead to focal swelling or only to discomfort with movement. Plain radiographs typically reveal multifocal osteomyelitis and marked periostitis as early as the first weeks of life, but bone disease may not become apparent until infants are 4À6 months old.…”

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.…”