Deficiency of the interleukin-1–receptor antagonist

Rare autoinflammatory genetic disorder

Deficiency of the interleukin-1–receptor antagonist
Synonyms	Interleukin-1 receptor antagonist deficiency (DIRA)
Pronounce
Field	Immunology, Medical genetics, Pediatrics
Symptoms	Joint swelling, pustular skin lesions, respiratory distress, bone inflammation
Complications	Chronic inflammation, joint damage, growth impairment
Onset	Neonatal (at or shortly after birth)
Duration	Lifelong
Types
Causes	Mutations in the IL1RN gene
Risks	Family history, consanguinity
Diagnosis	Genetic testing, radiological findings, clinical evaluation
Differential diagnosis	Infantile pustular psoriasis, Majeed syndrome, chronic recurrent multifocal osteomyelitis
Prevention	None
Treatment	Colchicine, anakinra, corticosteroids, biologic therapy
Medication	Interleukin-1 inhibitors (e.g., anakinra)
Prognosis	Improved with early treatment; can be life-threatening if untreated
Frequency	Extremely rare
Deaths	Rare with treatment; higher risk without therapy

Interleukin-1Alpha

Colchicine

Deficiency of the interleukin-1–receptor antagonist (DIRA) is a rare autosomal recessive autoinflammatory disease caused by mutations in the IL1RN gene. This gene encodes the interleukin-1 receptor antagonist (IL-1Ra), a protein that normally inhibits the activity of pro-inflammatory cytokines, especially interleukin-1α and interleukin-1β.

In DIRA, loss of IL-1Ra leads to unchecked inflammation from birth, resulting in widespread inflammatory symptoms involving the skin, joints, bones, and lungs.

Signs and symptoms

Fused cervical vertebrae may be seen in DIRA

DIRA typically manifests in the neonatal period or early infancy with signs of severe systemic inflammation. The characteristic features include:

• Joint swelling
• Hepatomegaly (enlarged liver)
• Osteomyelitis (inflammation of bone)
• Fused cervical vertebrae
• Respiratory distress
• Stomatitis and mouth ulcers
• Pustulosis or pustular psoriasis-like rash
• Periostitis (inflammation of bone covering)
• Cerebral vasculitis (inflammation of brain blood vessels)
• Splenomegaly (enlarged spleen)
• Bone pain or joint pain
• Pulmonary abnormalities on imaging

These features often appear within the first days or weeks of life. Affected infants can present with fever, irritability, and failure to thrive.

Cause

DIRA is caused by biallelic mutations in the IL1RN gene, located on chromosome 2. This gene encodes the interleukin-1 receptor antagonist (IL-1Ra), which functions to competitively inhibit the effects of pro-inflammatory cytokines IL-1α and IL-1β.

In individuals with DIRA, the defective IL-1Ra protein is either absent or nonfunctional, resulting in persistent activation of the IL-1 receptor and continuous inflammation.

DIRA follows an autosomal recessive inheritance pattern, meaning both copies of the IL1RN gene must be mutated for the disease to manifest. Carriers (with one mutated gene) are typically asymptomatic.

Diagnosis

Diagnosis of DIRA involves a combination of:

• **Clinical features** — including pustular rash, bone inflammation, and systemic symptoms in neonates
• **Imaging** — X-rays or MRI may reveal multifocal osteomyelitis, periostitis, and spinal abnormalities
• **Genetic testing** — confirms biallelic mutations in the IL1RN gene
• **Laboratory findings** — elevated inflammatory markers such as CRP and ESR, but sterile cultures

Differential diagnosis

DIRA can mimic several other inflammatory and infectious conditions:

• Neonatal sepsis
• Majeed syndrome
• Chronic recurrent multifocal osteomyelitis (CRMO)
• Infantile pustular psoriasis
• Hyper IgD syndrome
• Autoimmune diseases in infancy

Treatment

Early diagnosis and prompt initiation of anti-inflammatory treatment are essential for improving outcomes.

Medications

• Anakinra – a recombinant IL-1 receptor antagonist, is the primary treatment and dramatically reduces symptoms
• Colchicine – may be used for additional inflammatory control
• Corticosteroids – may help control inflammation in acute phases
• Biologics – other IL-1 inhibitors like canakinumab and rilonacept may also be considered

Supportive care

• Management of bone pain and joint inflammation
• Treatment of secondary infections if present
• Monitoring growth and development

Prognosis

With timely and appropriate treatment, most patients show significant improvement in symptoms and reduced systemic inflammation. Without treatment, the disease can be fatal due to uncontrolled inflammation and multi-organ involvement.

Epidemiology

DIRA is extremely rare, with fewer than 20 documented cases worldwide. It has been reported in populations with high consanguinity, including Pakistani, Lebanese, and Dutch communities.

See also

• Autoinflammatory disease
• Interleukin 1
• Anakinra
• Osteomyelitis
• Genetic testing