Deficiency of the IL-1 Receptor Antagonist (DIRA)
DIRA, deficiency of the IL-1 receptor antagonist, is a monogenic autosomal recessive autoinflammatory disease that presents with systemic inflammation, pustulosis, sterile osteomyelitis, and osteolytic lesions and is caused by loss-of-function mutations in IL1RN, the gene that encodes the IL-1 receptor antagonist (IL-1Ra) (MIM#612852).
Introduction and Background
At a time when whole exome sequencing was not yet available, the diagnosis of sporadic diseases required a candidate gene approach. DIRA was in fact discovered in two patients who had complete responses to empirically administered IL-1 blocking treatments with recombinant IL-1 receptor antagonist, anakinra, which strongly suggested an IL-1-mediated disease, and resulted in a candidate screen of genes in the IL-1/inflammasome pathway that eventually led to finding “the needle in the haystack” (Reddy et al. 2009; Aksentijevich et al. 2009). Historic descriptions of patients with pustulosis and sterile bone lesions point to a pathogenic connection between neutrophilic pustulosis and osteomyelitis. However, the majority of these patients do not have IL1RN mutations, and most are not monogenic. These conditions are referred to as chronic recurrent multifocal osteomyelitis (CRMO), a group of autoinflammatory bone diseases that also include the monogenic disease Majeed syndrome (Stern and Ferguson 2013). Two historical descriptions of patients who likely had DIRA illustrate the poor outcomes of young undiagnosed patients who are not receiving IL-1 blocking therapies (Leung and Lee 1985; Ivker et al. 1993).
DIRA is caused by loss-of-function mutations in IL1RN, which encodes the endogenous interleukin-1 (IL-1) receptor antagonist (IL1Ra). Most of the DIRA-causing mutations are nonsense or frameshift mutations that lead to either no expression of protein or to expression of truncated nonfunctional protein, IL-1Ra. Loss of IL-1Ra results in unopposed IL-1 action leading to escalation of IL-1-driven systemic and organ-specific inflammation involving the skin and bone (Fig. 1).
DIRA presents in early childhood with marked skin and bone involvement and systemic inflammation with elevation of acute-phase reactants. The age of onset is around 2 to 2.5 weeks of life.
Inflammatory bone disease includes osteomyelitis of ribs with rib widening (Fig. 2e), periostitis affecting several long bones, and multifocal osteolytic lesions (Fig. 2d) (Aksentijevich et al. 2009). Sequela of sterile osteomyelitis includes odontoid destruction leading to atlantoaxial joint instability and requiring cervical spine surgery, kyphotic deformities in the form of gibbus formation from vertebral collapse from vertebral osteomyelitis (Fig. 2f), and limb length discrepancy. Osteopenia and osteoporosis are other common findings in untreated patients.
Untreated patients could have a hypercoagulable state manifesting in the form of deep vein thrombosis or thrombosis at the catheter site, CNS vasculitis, or vasculopathy. Carotid arteritis has also been seen in one patient of Puerto Rican descent.
Leukocytosis, thrombocytosis, and elevated acute-phase reactants are present with active disease (Aksentijevich et al. 2009). Anemia can be severe requiring blood transfusions in untreated patients. If available, the absence of IL-1 receptor antagonist by ELISA can aide in making a diagnosis, as endogenous serum IL-1 receptor antagonist levels are undetectable in DIRA (serum needs to be assessed before initiation of treatment with recombinant IL-1 receptor antagonist, anakinra). The severity of escalating inflammation in an infant in critical condition with a clinically suggestive phenotype should prompt empiric treatment with an IL-1 blocking agent rapidly. A rapid response to a therapeutic challenge with the short-acting IL-1 receptor antagonist, anakinra, can be diagnostic.
The diagnosis of DIRA is made based on clinical features as treatment should be started in patients with a suspicion of DIRA even before a genetic diagnosis is made. However, detection of mutations in IL1RN is mandatory for a definitive diagnosis. Specific primers that facilitate the identification of two founder mutations, 175-kb deletion described in two Puerto Rican patients and a the recently described homozygous 22-kb deletion found in an Indian patient, are published and can aid in making a diagnosis (Aksentijevich et al. 2009; Mendonca et al. 2017).
The prognosis of untreated patients with DIRA is historically poor. So far, no adult patients who are homozygous for the disease-causing mutations have been identified. The mortality of untreated DIRA based on published reports is over 25% and occurred at 2, 4, and 21 months and 9.5 years of age. One case of intrauterine demise at 27 weeks of gestational age has also been reported (Aksentijevich et al. 2009; Altiok et al. 2012). In families with an affected child, and in populations where DIRA has been reported, genetic counseling and testing should be recommended. If both patients carry a heterozygous mutation, they have a 25% chance of having an affected child. Prenatal diagnosis can be made through diagnostic techniques like chorionic villous sampling or amniocentesis.
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