The DIRA syndrome is an autosomal-recessive autoinflammatory disorder presenting with systemic inflammation and severe skin and bone inflammation in the neonatal period (12
). Of the 10 previously reported patients with DIRA, 3 had a fatal course, whereby 2 of the patients died in the perinatal period and 1 died at the age of 9 years. DIRA is caused by homozygous mutations in IL1RN
, which encodes the IL-1Ra. All previously reported mutations were deleterious, being either a whole-gene deletion or protein-truncating mutations (frameshift 2-bp deletion or nonsense mutations). The reported mutations led to the absence of the production of a functional IL-1Ra, which is an endogenous antagonist that binds to the IL-1RI. Therefore, it can be concluded that in patients with DIRA, IL-1 signaling cannot be blocked. Treatment with anakinra, a recombinant IL-1Ra, is, in essence, a replacement of the very protein missing in these patients (12
). Treatment with anakinra uniformly leads to a rapid clinical improvement.
Herein we report the first cases of DIRA in South America, in 2 unrelated patients from Brazil, both of whom had the same novel homozygous, in-frame, 15-bp deletion. Since the mutation was absent in 400 control chromosomes, we could not glean insight into the frequency of this mutant allele. Unlike previously described deleterious mutations, the 15-bp deletion is expected to lead to the production of a mutant protein. In silico modeling suggested that secondary structures were altered, and in vitro functional assays confirmed the absence of binding of the mutant protein to the IL-1 receptor. The mutant protein lacks antagonistic activity and is not able to function as an inhibitor of the IL-1 receptor. The stimulation of whole blood cells by IL-1 and LPS led to the overproduction of a number of proinflammatory cytokines in patients compared to healthy controls and heterozygous carriers. Although the mutant protein was detected in both patients, its production was reduced. Similar to previously described patients with deleterious mutations, the 2 patients showed a rapid response to treatment with anakinra.
Both of our patients partially responded to corticosteroid therapy, as indicated by an improvement in the skin, bone, and lung abnormalities. One of the patients also had a marked improvement of her skin lesions after treatment with acitretin, which was previously described to lead to skin improvement in an infant with generalized pustular psoriasis (14
). The response to steroids in our patients was more pronounced than what has been previously reported, and this raised the question as to whether the mutant protein in our patients might have a residual IL-1 blocking activity. In vitro experiments did not provide any evidence of residual IL-1 blocking activity of the mutant protein. The somewhat better response to steroids might be based on in vivo residual function or on differences in genetic background. It appears that this nondeleterious mutation produces a milder syndrome, although the mechanism of the milder presentation remains elusive.
The DIRA syndrome is characterized by a lack of symptoms in obligate and confirmed carriers (12
). In this report, 1 parent from each family had mild inflammatory symptoms. It is quite difficult to interpret these symptoms as part of the phenotype in carriers, but it is prudent to investigate further the medical history of all reported carriers to resolve this issue.
Other monogenic autoinflammatory disorders that can present in the neonatal period include Majeed syndrome, NOMID, and mevalonate kinase deficiency/hyper-IgD syndrome. However, except for the severe presentations observed in patients with NOMID (5
), the other genetically defined autoinflammatory diseases are not life-threatening in the neonatal period (2
). The presenting features of DIRA include low-to-high-grade fevers, rashes, blood neutrophilia, and neutrophilic infiltrates in the skin and bones, and these are often confused with congenital or perinatal infections in the newborn period (16
). Typically, extensive evaluations for infectious causes yield negative results and patients do not respond to treatment with antibiotics. Due to the significant bone involvement, patients with DIRA are often diagnosed as having infectious osteomyelitis, but the negative bone and blood cultures and the unresponsiveness to antibiotics can help to raise the suspicion of an autoinflammatory syndrome.
Although NOMID and the DIRA syndrome share clinical similarities, there are some distinct differences. Patients with NOMID typically present with aseptic meningitis and cochlear inflammation, and mental retardation is quite frequent (17
). Patients with DIRA typically do not have neurologic inflammation. Central nervous system vasculitis has been seen in 1 patient with DIRA, and 1 patient with longstanding, untreated disease had a mild cognitive delay. There was no evidence of inner ear inflammation, hearing loss, or eye inflammation in the previously reported patients (12
) or in the patients in the current study. Another difference in the clinical presentations is the cutaneous eruptions, which, in patients with DIRA, are pustular, involving the epidermis; in contrast, in patients with NOMID, the epidermis is not involved and the rash is urticaria-like with a neutrophilic infiltrate in the dermis (4
). Patients with mevalonate kinase deficiency/hyper-IgD syndrome can also develop manifestations in the newborn period, but patients usually have significant lymphadenopathy, abdominal pain, vomiting, and diarrhea. In addition, a purpuric nonpustular exanthema is present in 80% of the patients (16
). In the severe form of mevalonate kinase deficiency, known as mevalonic aciduria, developmental delay, facial dysmorphism, ataxia, hypotonia, myopathy, and cataracts can be clinical presentations (18
The Majeed syndrome also shares clinical similarities with the DIRA sundrome. Patients present with a neutrophilic dermatosis and chronic recurrent multifocal osteomyelitis. However, congenital dyserythropoietic anemia is found only in Majeed syndrome, but not in DIRA (8
The genetic mutations in NOMID and DIRA are both linked to IL-1. Both diseases respond very well to treatment with IL-1α and IL-1β blocking agents, such as anakinra, and patients with cryopyrin-associated periodic syndromes also respond to therapies directed to IL-1β only. Since IL-1Ra blocks both IL-1α and IL-1β signaling, it remains uncertain whether signaling through IL-1α contributes to the inflammation in patients with DIRA. If there is a specific role for IL-1α, then one might hypothesize that therapies specifically blocking IL-1β may not be sufficient to treat DIRA, but clinical trials to confirm this notion are needed. Patients with Majeed syndrome also present with multifocal osteolytic lesions, but the pathogenic pathways of inflammation linked to LPIN2 mutations, which are the purported genetic cause of Majeed syndrome, have not been resolved. It will be interesting to determine whether the pathogenesis of Majeed syndrome involves the IL-1 pathway, and thus whether patients with this disease respond to IL-1 blockade.
In conclusion, in this report, we have described 2 patients from Brazil with the new autoinflammatory syndrome DIRA. Both patients displayed the same mutation on IL1RN, causing severe cutaneous and bone manifestations. Our findings suggest that the identified novel mutation is a founder mutation that has been introduced in Brazil, which needs to be investigated, since proving a founder effect will facilitate screening for the frequency of this mutation in the Brazilian population and enable genetic screening and prenatal diagnosis and immediate treatment of patients.