Interleukin-1 receptor antagonist deficiency

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What is the deficiency of the interleukin-1 receiver antagonist (DIRA)?

Interleukin-1 receptor antagonist (DIRA) deficiency (MIM 612852) is very rare genetic autoinflammatory syndrome that occurs in the first days of life. The severe inflammatory the reaction resembles a acute serious systemic infection or bone infection. If recognized early, treatment with anakinra, a biological agent, can prevent death from multiple organ failure.

Who receives DIRA and why?

DIRA has been diagnosed only in a very small number of children. It occurs at birth or in the first days of life. Cases of families originating from Puerto Rico, Newfoundland (Canada), the Netherlands and Lebanon have been identified.

DIRA is a autosomal recessive genetic disorder, that is, each child of two carrier Parents have a 25% chance of DIRA.

Molecular biology and genetics

DIRA is due to homozygous point mutations at gene IL1RN (2q14.2) or a large genomic deletion that affects this gene and others in the IL family in chromosome 2. the same mutation it is detected in all patients originating from a certain area, suggesting a different founder effect in each region. Normal control studies from the same areas found carrier rates for the 0.2% mutation 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. Interleukin-1 receptor stimulation is a potent activator of inflammatory pathways.

Clinical characteristics of DIRA

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 bones in the absence of fever.

In the first days of life, common presentation features include:

Fetal suffering
Pustular eruption
Oral lesions
Joint inflammation
Painful movement
Enlarged liver and spleen (hepatosplenomegaly)

All affected children develop a pustular rash, in which there may be discreet crops of pustules or a severe generalized pustular eruption It may resemble generalized pustular psoriasis.

Other skin /mucous membrane reported changes included:

Generalized ichthyosis-like changes
Nail changes bites, separation of the nail from the nail bed, such as nail psoriasis
Stomatitis - can blister
Mouth ulcers
Conjunctivitis (eye pain)
Pyoderma gangrenous (one case)

All children develop inflammation in the bones, causing painful movements and swelling of the joints. Changes in radiographs are characteristic.

Other features noted in individual cases have included:

Inflammation of blood vessels in the brain (cerebral vasculitis)
Pulmonary hemosiderosis (iron statement in the lungs) with progressive interstitial fibrosis (scars)
Hypotonia (weak muscle tone)
Not prosper

High fever is not a typical feature.

Left untreated, DIRA results in multiple organ failure and death in childhood.

How is DIRA diagnosed?

The presenting features of DIRA suggest a severe acute systemic infection (neonatal septicemia) and / or bone infection (osteomyelitis); However, all infection investigations are negative.

The following table describes the results of the investigations.

Useful tests in the diagnosis of DIRA?
Blood test	increased erythrocytes sedimentation rate (ESR) increased C-reactive protein (CRP)
Skin biopsy	epidermal neutrophilic pustules pustule training throughout hair follicles epidermal acanthosis (thickening of the skin) hyperkeratosis (climbing) heavy neutrophils infiltrate of dermis clot formationthrombosis) in the blood vessels (a child)
X-rays	balloon-shaped swelling of the ends of the ribs (all children) periosteal elevation along multiple long bones heterotopic ossification around the hip multifocal osteolytic lesions (can result in vertebral crush fracture)
Bone biopsy	purulent osteomyelitis, but not infectious organisms fibrosis sclerosis vasculitis in adjacent fat and connective tissue
Cerebral Magnetic resonance	evidence of vasculitis /vasculopathy (Child)
DNA analysis	point mutations or large genomic deletion involving the IL1RN gene resulting in the absence of a functional interleukin-1 receptor antagonist

DIRA Treatment

Children with DIRA can be effectively treated with anakinra, a biological agent that is a recombinant form of the interleukin-1 receptor antagonist, the protein that these children lack. It had recently been made available to treat rheumatoid. arthritis when DIRA was first described and characterized in detail.

Diary subcutaneous Administration of anakinra replaces the missing protein with an excellent response, particularly in those children with point mutations. In the initial reported case series, complete and rapid resolution of symptoms and signs occurred. The skin changes responded in a few days and the bone radiographs normalized in months. Blood markers of inflammation also returned to normal levels. The response in children with large genomic deletion was less dramatic since blood markers did not normalize. The anakinra dose was started at 1 mg / kg / day, and increased by 0.5 mg / kg / day until the response was achieved. Resolution of symptoms and signs has been reported to be long-lasting, with rapid deterioration within 36 hours after discontinuation of anakinra treatment. Therefore, the treatment will be for life. Local reactions at the injection site (redness, itching, swelling) are a common adverse effect, but treatment is well tolerated. Long-term monitoring is not yet available.

Note: Anakinra is not registered or subsidized in New Zealand. In other countries, such as the US and Europe, its registered indication is rheumatoid arthritis.