A novel mutation in the interleukin-1 receptor antagonist associated with intrauterine disease onset

Abstract

Deficiency of the IL-1 receptor antagonist (DIRA) is a recently described rare autoinflammatory disease, caused by loss of function mutations in IL1RN leading to the unopposed activation of the IL-1 pathway. We describe a novel nonsense mutation in the IL1RN gene, associated with early intrauterine onset, death and multiorgan involvement in a prematurely born baby. The protein prediction model indicated that the novel Q119X mutation would result in a nonfunctional protein by impairing the ability of the IL-1Ra to bind and antagonize signaling through the IL-1R. Since the disorder may mimic severe bacterial infections and the treatment with anakinra is life saving, we intend to raise awareness of the syndrome and the possibility of a founder mutation that may lead to the diagnosis of additional cases in Turkey. The clinical suspicion of DIRA is critical to avoid improper management of the patients with antibiotics alone and death from multiorgan failure.

Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies

“…To date, neither increased rate of miscarriage, nor extreme prematurity have been described in patients with CAPS. Prematurity has been reported in the related autoinflammatory disease deficiency of the IL-1R antagonist (25), although the role of other cytokines was not investigated.…”

Autoinflammatory Diseases Predominantly Affecting Bone and Joints

“…40,41 Nearly half of the infants are born preterm (31À36 weeks gestation). 40,41,111,113 A report of intra-uterine demise at 27 weeks' gestation in a suspected case, and reports of infants being small for gestational age in one-third of DIRA patients, suggests that intrauterine onset is possible. 111 All DIRA patients have evidence of systemic inflammation with raised inflammatory markers in the blood 40-…”

“…40,114 All deaths have been from the development of systemic inflammatory response syndrome with multi-organ system failure. 40,111 No deaths have been reported in anakinra-treated infants.…”

“…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.…”

Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist

“…DIRA can cause fetal demise in utero. A postmortem histopathological evaluation of a 27-week fetus (9) showed dense neutrophilic infiltrates, with tissue destruction in the thymus, adrenal gland, and myocardium, and a postmortem bone x-ray suggested osteomyelitis. The consanguineous parents had a second child who was born at 31 weeks gestational age and died at the age of 4 months with skin pustulosis, multifocal osteomyelitis, and increased inflammatory markers.…”