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Conditions

Deficiency of interleukin-1 receptor antagonist

Deficiency of interleukin-1 receptor antagonist is a rare genetic condition causing early-onset, severe systemic autoinflammation.

Overview

Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare autosomal recessive autoinflammatory disease. It is caused by biallelic loss-of-function genetic variants in IL1RN, leading to deficiency of the interleukin-1 receptor antagonist, a negative regulator of the inflammatory system. Deficiency leads to early onset of pustular dermatitis and multifocal sterile bone osteomyelitis, with systemic flares of disease including high fever, and is often fatal without early diagnosis and treatment.

Clinical features

DIRA typically presents shortly after birth, with almost all patients showing symptoms within the first year. The main clinical features are:

  • generalised sterile pustular rash;
  • sterile, multifocal, osteolytic reactions;
  • multifocal osteomyelitis, typically affecting ribs, clavicles and femur;
  • skeletal anomalies, such as widening of ribs with periosteal reaction, gibbus-like spinal changes and cervical vertebral fusion;
  • nail dystrophy and onychomadesis;
  • arthralgia;
  • oral ulcers;
  • elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR);
  • hepatosplenomegaly;
  • interstitial lung disease;
  • anaemia; and
  • thrombocytosis with increased propensity to thrombosis.

Persistent or recurrent high-grade fever may be absent in patients with DIRA, which may distinguish it from other early-onset autoinflammatory conditions. Very rarely, late-onset cases are described presenting with inflammatory arthritis, nail dystrophy and sacroiliitis.

Generally, prognosis is poor, with progressive inflammation leading to infection and respiratory failure.

Genomics

DIRA is caused by biallelic pathogenic variants in the IL1RN gene, located on chromosome 2q14.1. It encodes IL-1 receptor antagonist protein, a key regulator of inflammation, with loss of function leading to unopposed IL-1 signalling and unregulated inflammation with increased production of the pro-inflammatory cytokines IL-36, IL-1, IL-6, IL-8 and TNF-α.

Severe, early-onset features are typically seen in patients with protein-truncating variants, while biallelic missense variants may result in some residual IL-1 receptor antagonist activity.

The most frequently reported pathogenic variants in DIRA are:

  • Puerto Rican large founder deletions (175-kb);
  • Indian founder deletions (22.2-kb); and
  • specific nonsense and frameshift variants.

While massively parallel sequencing (sometimes called next-generation sequencing) panels are usually used to detect pathogenic variants in affected patients, microarray should also be performed to detect large-scale deletions that may encompass IL1RN.

Diagnosis

A diagnosis of DIRA may be made in patients presenting with suggestive clinical features, as listed above, alongside molecular confirmation of biallelic pathogenic variants or large-scale deletions in IL1RN.

Laboratory tests can help support the diagnosis. Results may include the following:

  • radiological features showing osteophytic lesions, widened metaphyses with periosteal reaction;
  • persistently elevated inflammatory markers (CRP, ESR, serum amyloid A);
  • raised platelet count (thrombocytosis);
  • negative blood and skin pustule cultures; and
  • response to trial of IL-1 antagonists is usually rapid and pronounced, and this may support diagnosis while awaiting molecular confirmation.

For information about testing, see ‘Child with a suspected autoinflammatory condition‘.

DIRA may be identified before any symptoms appear; for example, through the Generation Study. Confirmation of the diagnosis will require referral to autoinflammatory or specialist rheumatology services. Please refer to the local pathway for your region for this condition.

Inheritance and genetic counselling

DIRA is inherited in an autosomal recessive pattern. It is extremely rare, with fewer than 50 cases reported in the literature.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate.

  • If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
    • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
    • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
    • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.
  • Note that heterozygous carriers are asymptomatic.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management

DIRA is a very rare, complex condition and is best managed by a multidisciplinary autoinflammatory and/or specialist dermatology service. Treatment is aimed at controlling systemic inflammation and preventing life-threatening complications, such as sepsis and multi-organ failure. If instituted swiftly, patients can have excellent outcomes, with normal growth and life expectancy.

Anti-IL-1 treatments are recommended in the treatment of DIRA, particularly:

  • anakinra: a recombinant IL-1 receptor antagonist; and
  • rilonacept: an IL-1 fusion protein that binds IL-1.

Canakinumab is not recommended, as it does not provide adequate IL-1α inhibition. Treatment is life-long.

DIRA may be identified before any symptoms appear; for example, through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Resources

References:

For patients

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  • Last reviewed: 28/11/2025
  • Next review due: 28/11/2027
  • Authors: Dr Jesmeen Maimaris
  • Reviewers: Dr Eleanor Hay