Erythematous nodes, urticarial rash and arthralgias in a large pedigree with
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              <scp>NLRC</scp>
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            ‐related autoinflammatory disease, expansion of the phenotype

Volker‐Touw, Catharina M.L.; Koning, Heleen D. de; Giltay, Jacques C.; Kovel, Carolien G.F. de; Kempen, Tessa S. van; Oberndorff, Karin; Boes, Marianne; Steensel, M.A.M. van; Well, Gijs Th. J. van; Blokx, Willeke A.M.; Schalkwijk, Joost; Simon, Anna; Frenkel, Joost; Gijn, M. E. van

doi:10.1111/bjd.14757

Cited by 68 publications

(63 citation statements)

References 14 publications

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“…In addition, a case series found positive association between IL‐1β+3963 gene polymorphisms with the presence of erythema nodosum in Behcet's disease, implicating the role of IL‐1β in EN 11. A similar correlation was observed by Volker et al, who described the association of erythema nodosum‐like lesions in 13 individuals with NLRC4 mutation induced auto‐inflammatory disorders 14. Although the pathogenesis of EN remains unclear, high levels of circulating innate immunity cytokines, serum neutrophilia, and neutrophils on histology suggest an underlying auto‐inflammatory dysfunction 8…”

Section: Discussionsupporting

confidence: 61%

Erythema nodosum in an adolescent patient with cryopyrin‐associated periodic syndrome

Chan

Campbell

Ming

2018

Clinical Case Reports

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Section: Discussionsupporting

confidence: 61%

Erythema nodosum in an adolescent patient with cryopyrin‐associated periodic syndrome

Chan

Campbell

Ming

2018

Clinical Case Reports

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“…Functional studies of the S445P variant were not conducted, but many individuals displayed highly elevated serum IL-18 concentrations. Unlike FCAS1 patients whose biopsied skin lesions are characteristically neutrophilic (40), skin infiltrates in Dutch patients’ biopsies were lympho-histiocytic as seen in AIFEC (39). …”

Section: Extended Nlrc4 Phenotypesmentioning

confidence: 94%

“…Given the clear phenotypic similarities to the NLRP3-associated familial cold autoinflammatory syndrome (FCAS1), OMIM designated this disease as FCAS4 (#616115; *606831) (29). In 2017, a second large Dutch kindred was reported with prominent skin manifestations (39). A heterozygous S445P NLRC4 variant segregated with disease.…”

Section: Extended Nlrc4 Phenotypesmentioning

confidence: 99%

“…Without a NLRC4-specific therapy, treating physicians have chosen to target downstream inflammatory mediators based upon their patients’ clinical needs. For instance, many patients with FCAS4 were well controlled with only non-steroidal anti-inflammatory drugs or nothing at all (39). Other non-AIFEC patients were treated with recombinant IL-1RA (anakinra) and although skin manifestations were completely responsive, other disease features were not.…”

Section: Treatment Of Nlrc4 Inflammasomopathiesmentioning

confidence: 99%

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NLRC4 inflammasomopathies

Romberg¹,

Vogel

Canna

2017

Current Opinion in Allergy &Amp; Clinical Immunology

114

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Purpose of review The purpose of the review is to highlight developments in autoinflammatory diseases associated with gain-of-function mutations in the gene encoding NLR-family CARD domain-containing protein 4 (NLRC4), the NLRC4-inflammasomopathies. Recent findings Three years since the identification of the first autoinflammation with infantile enterocolitis (AIFEC) patients, there is an improved understanding of how the NLRC4 inflammasome and interleukin 18 (IL-18) contribute to gut inflammation in myeloid and also intestinal epithelial cells. This information has opened new therapeutic avenues to treat AIFEC patients with targeted agents like recombinant IL-18 binding protein and anti-interferon-γ antibodies. Additional phenotypes traditionally associated with NLRP3 mutations like familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID), have now also been associated with gain-of-function NLRC4 mutations. Finally, NLRC4 somatic mosaicism has now been identified in a NOMID and an AIFEC patient, a finding emphasizing nontraditional modes of inheritance in autoinflammatory diseases. Summary The NLRC4 inflammasomopathies comprise a growing autoinflammatory disease category that spans a broad clinical spectrum from cold urticaria to NOMID and the often-fatal disease AIFEC. Rapid case identification with biomarkers like elevated serum IL-18 concentrations and early intervention with targeted immunomodulatory therapies are key strategies to improving outcomes for AIFEC patients.

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“…Response to IL‐1 inhibition and peripheral IL‐18 were not assessed. Subsequently, Volker‐Touw et al described another extended family with a spectrum of autoinflammatory phenotypes, including urticarial and nodular rashes, conjunctivitis, arthritis, IBD, and sensorineural hearing loss (a hallmark symptom of NLRP3‐associated CAPS) that segregated with a missense NLRC4 mutation . Response to IL‐1 inhibition was highly variable in this kindred, and biopsy of the nodular rash demonstrated lymphohistiocytic infiltrate as opposed to the neutrophilic infiltrate of other inflammasomopathy rashes.…”

Section: Nlrc4 and Human Diseasementioning

confidence: 94%

The NLRC4 Inflammasome

Duncan

Canna

2017

Immunological Reviews

263

179

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15 years ago, the fundamental biology of an inflammatory signaling complex eventually dubbed "the inflammasome" began to unravel in chronologic parallel with the discovery that many inflammatory diseases were associated with its hyperactivity. Though the genetic origins of Familial Mediterranean Fever (FMF, caused my mutations in MEFV) were discovered first, it would take nearly two decades before the mechanistic connections to a PYRIN inflammasome were made. In the interim, the intensive study of the NLRP3 inflammasome, and the diseases associated with its hyperactivation, have largely dictated the paradigm of inflammasome composition and function. Despite impressive gains, focusing on NLRP3 left gaps in our understanding of inflammasome biology. Foremost among these gaps were how inflammasomes become activated and the connections between inflammasome structure and function. Fortunately, work in another inflammasome inducer, NLRC4, grew to fill those gaps. The current understanding of the NLRC4 inflammasome is perhaps the most comprehensive illustration of the inflammasome paradigm: trigger (e.g. cytosolic flagellin), sensor (NAIP), nucleator (NLRC4), adaptor (ASC), and effector (CASP1). Detailed work has also identified observations that challenge this paradigm. Simultaneously, the features unique to each inflammasome offer a lesson in contrast, providing perspectives on inflammasome activation, regulation, and function. In this review, we endeavor to highlight recent breakthroughs related to NLRC4 inflammasome structure and activation, important in vivo work in infection and systemic inflammation, and the characterization of a spectrum of human NLRC4-associated autoinflammatory diseases.

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Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC 4 ‐related autoinflammatory disease, expansion of the phenotype

Abstract: Linked Comment: Barzilai and Cohen. Br J Dermatol 2017; 176:18–19.

Cited by 68 publications

References 14 publications

Erythema nodosum in an adolescent patient with cryopyrin‐associated periodic syndrome

Erythema nodosum in an adolescent patient with cryopyrin‐associated periodic syndrome

NLRC4 inflammasomopathies

The NLRC4 Inflammasome

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