SUMMARY
1. Deficiency of IL-1 Receptor Antagonist (DIRA) is an autosomal recessive autoinflammatory disorder characterized by prominent skin and bone findings.
2. All nine patients reported to date presented at birth or by 2.5 weeks of age. Fetal distress, pustular rash, joint swelling, oral mucosal lesions, and pain with movement were the most common findings at initial presentation.
3. Although all patients had marked elevations of the erythrocyte sedimentation rate and C-reactive protein, no patients had fever. Complete blood counts revealed leukocytosis and elevated platelet counts.
4. The skin findings in DIRA range from discrete crops of pustules to diffuse generalized pustulosis, ichthyosis, or pyoderma gangrenosum. Nail changes were observed in 4 of 9 patients.
5. Bone abnormalities reported in patients include the following:
-Widening of the anterior rib ends (9/9 patients)
-Periosteal elevation along multiple long bones (8 patients)
-Sterile multifocal osteomyelitis (8 patients)
-Heterotopic ossification of the proximal femoral metaphsis (7 patients)
-Widening of the clavicels (2 patients)
-Metaphyseal erosions of the long bones (2 patients)
-Severe epiphyseal ballooning of long bones (1 patient)
6. DIRA is caused by homozygous mutations in the IL1RN gene, which encodes the IL-1 receptor antagonist (this inhibits the pro-inflammatory cytokines IL-1 alpha and IL-1 beta). The mutations result in a truncated protein that is not secreted. As result, there is unopposed stimulation of cells with IL-1 beta.
7. In vitro stimulation (with IL-1 beta) of leukocytes from patients demonstrated a marked elevation of the following chemokines and cytokines: IL-1 alpha, TNF-alpha, IL-8, IL-6, and MIP-1 alpha.
8. The treatment of choice is with recombinant IL-1 receptor antagonist (Anakinra).
9. Two patients died at 2 and 21 months from multiorgan failure secondary to severe inflammation. A third patient died at 9 years of age due to complications of pulmonary hemosiderosis with progressive interstitial fibrosis.
OVERVIEW
Deficiency of IL-1 Receptor Antagonist (DIRA) is an autosomal recessive autoinflammatory disorder which has recently been reported in nine children from six kindreds. DIRA is characterized by prominent skin and bone findings.
All nine patients presented at birth or by 2.5 weeks of age. Fetal distress, pustular rash, joint swelling, oral mucosal lesions, and pain with movement were the most common findings at initial presentation.
Although all patients had marked elevations of the erythrocyte sedimentation rate and C-reactive protein, no patients had fever. Complete blood counts revealed leukocytosis and elevated platelet counts.
The skin findings in DIRA range from discrete crops of pustules to diffuse generalized pustulosis, ichthyosis, or pyoderma gangrenosum. Nail changes were observed in 4 of 9 patients. Skin biopsies may reveal neutophil infiltration into the epidermis and dermis, acanthosis, and hyperkeratosis.
Bone abnormalities reported in patients include the following:
-Widening of the anterior rib ends (9/9 patients)
-Periosteal elevation along multiple long bones (8 patients)
-Sterile multifocal osteomyelitis (8 patients)
-Heterotopic ossification of the proximal femoral metaphsis (7 patients)
-Widening of the clavicels (2 patients)
-Metaphyseal erosions of the long bones (2 patients)
-Severe epiphyseal ballooning of long bones (1 patient)
PATHOGENESIS
DIRA is caused by homozygous mutations in the IL1RN gene, which encodes the IL-1 receptor antagonist (this inhibits the pro-inflammatory cytokines IL-1 alpha and IL-1 beta). The mutations result in a truncated protein that is not secreted. As result, there is unopposed stimulation of cells with IL-1 beta.
DIFFERENTIAL DIAGNOSIS
1. Periodic Fever Syndromes (FMF, TRAPS, Hyper IgD, Mevalonic Aciduria, NOMID)
2. Netherton's Syndrome
3. Omenn Syndrome-like
4. Wiskott-Aldrich syndrome
5. Bacterial osteomyelitis
EVALUATION
The diagnosis should be suspected in infants presenting at birth or soon after birth with pustular rash, ichthyosis, joint swelling, oral mucosal lesions, and pain with movement.
Step 1: Screening Studies
- CBC with Differential
- C reactive protein / Erythrocyte sedimentation rate
-CBC may reveal a leukocytosis and thrombocytosis
-CRP and ESR are markedly elevated
Step 2: Additional Studies
-In vitro cytokine production
-IL-1 receptor antagonist protein levels
-Stimulation of leukocytes with IL-1 beta reveals elevated IL-1 alpha, TNF- alpha, IL-8, and IL-6 secretion.
-Western blotting may reveal markedly decreased IL-1 receptor antagonist protein levels.
Step 3: Genetic Confirmation
-IL1RN gene sequencing
-This is the definitive test for establishing a diagnosis of DIRA. This test is currently available at specialized research centers only.
MANAGEMENT
The treatment of choice is with recombinant IL-1 receptor antagonist (Anakinra). This therapy has resulted in clinical remission for patients including normalization of inflammatory markers and CBC abnormalities, resolution of skin manifestations within days, and resolution of bone abnormalities within weeks.
RESOURCES
Literature Resources
Deficiency of IL-1 receptor antagonist