Introduction Demographics Clinical features Diagnosis Treatment
Deficiency of the interleukin-1 receptor antagonist (DIRA) (MIM 612852) is a very rare genetic autoinflammatory syndrome that presents in the first days of life. The severe inflammatory reaction resembles an acute severe systemic infection or infection of the bone. If recognised early, treatment with anakinra, a biologic agent, can prevent death from multiorgan failure.
DIRA has been diagnosed in only a very small number of children. It presents at birth or in the first days of life. Cases have been identified from families originating in Puerto Rico, Newfoundland (Canada), The Netherlands and Lebanon.
DIRA is an autosomal recessive genetic disorder, meaning each child of two carrier parents has a 25% chance of suffering from DIRA.
DIRA is due to homozygous point mutations in the gene IL1RN (2q14.2) or a large genomic deletion that affects this gene and others in the IL family on chromosome 2. The same mutation is detected in all patients originating from a given area, suggesting a distinct founder effect in each region. Studies of normal controls from the same areas found carrier rates for the mutation of 0.2% in Newfoundland and 1.3% in Puerto Rica. These mutations, when homozygous, result in the complete absence of functional interleukin-1 receptor antagonist protein. Therefore interleukin-1 has unopposed effects on the receptor. Stimulation of the interleukin-1 receptor is a powerful activator of inflammatory pathways.
The distinctive features of this syndrome are present at birth, or within days of birth, and are due to inflammatory changes in the skin and bone in the absence of fever.
In the first days of life, the common presenting features include:
All affected children develop the pustular rash, in which there may be discrete crops of pustules or a severe generalised pustular eruption that may resemble generalised pustular psoriasis.
Other skin/mucosal changes reported included:
All children develop inflammation in the bones, which cause painful movement and joint swelling. Changes on x-rays are characteristic.
Other features noted in single cases have included:
High fever is not a typical feature.
If untreated, DIRA results in multiorgan failure and death in childhood.
The presenting features of DIRA suggest a severe acute systemic infection (neonatal sepsis) and/or infection of bone (osteomyelitis); however all investigations for infection are negative.
The table below describes the results of investigations.
Useful tests in diagnosis of DIRA? |
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Blood tests |
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X-rays |
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Bone biopsy |
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Cerebral MRI |
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DNA analysis |
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Children with DIRA can be effectively treated with anakinra, a biologic agent that is a recombinant form of interleukin-1 receptor antagonist, the protein these children lack. It had been recently made available to treat rheumatoid arthritis when DIRA was first described and characterised in detail.
Daily subcutaneous administration of anakinra replaces the missing protein with an excellent response, particularly in those children with point mutations. In the initial case series reported, complete and rapid resolution of the symptoms and signs occurred. The skin changes responded within days and the bone x-rays normalised in months. Blood markers of inflammation also returned to normal levels. The response in children with the large genomic deletion was less dramatic as blood markers did not normalise. The dose of anakinra was started at 1 mg/kg/day, and increased by 0.5 mg/kg/day until response achieved. Resolution of symptoms and signs has been reported as longlasting, with rapid deterioration within 36 hours of ceasing the anakinra treatment. Treatment will therefore be lifelong. Local injection site reactions (redness, itch, swelling) are a common adverse effect, but the treatment is otherwise well tolerated. Longterm follow-up is not yet available.
Note: anakinra is not registered or subsidised in New Zealand. In other countries such as the USA and Europe, its registered indication is rheumatoid arthritis.
