Deficiency of Interleukin-1 Receptor Antagonist (DIRA): Report of the First Indian Patient and a Novel Deletion Affecting IL1RN

Mendonca, LO; Malle, Louise; Donavan, FX; Chandrasekharappa, SC; Montealegre, GA; Chapelle, Dawn; Suri, Deepti; Goldbach‐Mansky, Raphaela; Jesus, AA de

doi:10.1186/1546-0096-13-s1-p143

Cited by 6 publications

(13 citation statements)

References 10 publications

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“…Of note, since canakinumab blocks specifically the serum free IL1β, it is possible that the accumulation of IL1α may lead to independently activate the natural receptor. Indeed, the introduction of recombinant IL-1Ra allowed a complete control of disease activity, as reported on Table 1 [9][10][11].…”

Section: Discussionmentioning

confidence: 99%

A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of Interleukin-1 receptor antagonist (DIRA)

et al. 2020

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Background: Deficiency of the natural antagonist of interleukin-1 was first described in 2009 and so far 20 patients has been reported. In Brazil just two cases have been reported both carrying the same homozygous 15 bp deletion. Blocking interleukin-1 has changed rate survival for DIRA patients. The use of anakinra and rilonacept has been reported safe and efficient, whereas the selective blockade of interleukin-1 beta, using the monoclonal antibody canakinumab has been reported in a single case only. Case presentation: Here we report a case of a 7 years old Brazilian boy that presented with recurrent episodes of systemic inflammation with severe disabling osteomyelitis with mild pustular skin rash. A Next Generation Sequencing gene panel allowed to detect two pathogenic mutations in the IL1RN gene, described in compound heterozygosity. Corticosteroids was effective in controlling inflammation and anti-IL1 beta blocker triggered disease flare. Complete clinical control could be achieved using IL-1 receptor antagonist. Conclusions: DIRA is a severe, life threatening autoinflammatory condition with low numbers of patients described all over the world. The mutation p.Asp72_Ile76del in IL1RN is presented in all Brazilian DIRA patients already described and p.Q45* (rs1019766125) is a new mutation affecting the IL1RN gene. Following the pathogenesis of DIRA, blocking both subunits of interleukin one as well as antagonizing the receptor using anakinra or rilonacept seems to be effective. There is just one report using canakinumab for the treatment of DIRA and this is the first report of disease flare using this drug.

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Section: Discussionmentioning

confidence: 99%

A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of Interleukin-1 receptor antagonist (DIRA)

et al. 2020

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“…DIRA was described first in 2009 in two articles by Aksentijevich et al and Reddy et al [18,19]. To date, there are around 20 cases reported [19][20][21][22][23][24][25][26]. Almost all the DIRA cases were symptomatic within the newborn period [22,27].…”

Section: Definitionmentioning

confidence: 99%

“…To date, there are around 20 cases reported [19][20][21][22][23][24][25][26]. Almost all the DIRA cases were symptomatic within the newborn period [22,27].…”

Section: Definitionmentioning

confidence: 99%

Rare Monogenic Causes of Periodic Fevers

Gulmus

Berard

Demirkaya

2019

Periodic and Non-Periodic Fevers

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“…One is Majeed syndrome which is the focus of this review. The other is the deficiency of the interleukin-1 receptor antagonist (DIRA) in which , sterile multifocal osteomyelitis/osteitis and skin pustulosis are the dominant phenotypes [34,35,[67][68][69][70][71][72][73][74][75][76][77][78]. Patients with DIRA present in infancy with systemic inflammation, severe multifocal osteomyelitis and pustulosis of the skin.…”

Section: Autoinflammatory Bone Disease Syndromesmentioning

confidence: 99%

“…Patients with DIRA present in infancy with systemic inflammation, severe multifocal osteomyelitis and pustulosis of the skin. It is caused by either deficiency or loss of function mutations in the gene that encodes the IL-1 receptor antagonist leading to unfettered IL-1 signaling and results in a systemic inflammatory disorder that if left untreated is often fatal [34,35,[67][68][69][70][71][72][73][74][75][76][77][78]. While a direct connection to IL-1 signaling is evident in DIRA, that connection had been less clear in the Majeed syndrome which is caused by pathogenic variants in LPIN2, in which the encoded protein plays a central role in lipid metabolism.…”

Section: Autoinflammatory Bone Disease Syndromesmentioning

confidence: 99%

Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features

Ferguson

El‐Shanti

2021

Biomolecules

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Majeed syndrome is a multi-system inflammatory disorder affecting humans that presents with chronic multifocal osteomyelitis, congenital dyserythropoietic anemia, with or without a neutrophilic dermatosis. The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid phosphatase LIPIN2. It is exceedingly rare. There are only 24 individuals from 10 families with genetically confirmed Majeed syndrome reported in the literature. The early descriptions of Majeed syndrome reported severely affected children with recurrent fevers, severe multifocal osteomyelitis, failure to thrive, and marked elevations of blood inflammatory markers. As more affected families have been identified, it has become clear that there is significant phenotypic variability. Data supports that disruption of the phosphatidic acid phosphatase activity in LIPIN2 results in immune dysregulation due to aberrant activation of the NLRP3 inflammasome and overproduction of proinflammatory cytokines including IL-1β, however, these findings did not explain the bone phenotype. Recent studies demonstrate that LPIN2 deficiency drives pro-inflammatory M2-macrophages and enhances osteoclastogenesis which suggest a critical role of lipin-2 in controlling homeostasis at the growth plate in an inflammasome-independent manner. While there are no approved medications for Majeed syndrome, pharmacologic blockade of the interleukin-1 pathway has been associated with rapid clinical improvement.

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Deficiency of Interleukin-1 Receptor Antagonist (DIRA): Report of the First Indian Patient and a Novel Deletion Affecting IL1RN

Cited by 6 publications

References 10 publications

A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of Interleukin-1 receptor antagonist (DIRA)

A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of Interleukin-1 receptor antagonist (DIRA)

Rare Monogenic Causes of Periodic Fevers

Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features

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