NOD2 gene–associated pediatric granulomatous arthritis: Clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin‐1 blockade in a Spanish cohort

Abstract

Objective. Blau syndrome and early-onset sarcoidosis are NOD2 gene-associated chronic autoinflammatory diseases characterized by skin rash, arthritis, and/or eye involvement, with noncaseating granulomata as their pathologic hallmark. This study was undertaken to describe the expanded clinical phenotype, treatment outcomes, and NOD2 gene mutation analysis in a Spanish cohort with pediatric granulomatous arthritis, a chronic disease resembling Blau syndrome/ early-onset sarcoidosis.Methods. Clinical, laboratory, and treatment data on the 12 patients in the cohort were obtained through direct interviews. NOD2 gene analysis was performed in a central laboratory, by bidirectional sequencing. Cytokine levels were measured using the human Flex-Set cytokine bead array.Results. The classic Blau syndrome/early-onset sarcoidosis triad of skin rash, arthritis, and recurrent uveitis was identified in 5 patients (41.7%), whereas 7 patients (58.3%) presented with fewer than 3 of the classic features. Novel atypical manifestations such as persistent fever and myocardiopathy were also observed. NOD2 analysis revealed 1 heterozygous mutation in each patient, and familial studies confirmed its full penetrance. Of the 12 cases, 58.3% were sporadic, due to de novo mutations. Four different missense mutations on exon 4 were detected. Two of them (R334W and R334Q) were recurrent mutations and were found in 77.8% of the Spanish families, whereas the other 2 (C495Y and R587C) were novel. In the patient who received anakinra treatment, all clinical inflammatory symptoms improved and plasma cytokine levels normalized.Conclusion. These findings indicate that the expanding clinical heterogeneity of the disease (that is, the presentation of incomplete forms of the classic triad and atypical manifestations) and the high prevalence of sporadic cases should alert clinicians to the possible genetic basis of the condition and support the inclusion of DNA analysis as a diagnostic test. The positive response to anakinra observed in 1 patient suggests a new potential therapeutic approach that merits further investigation, and suggests that the pathogenesis of pediatric granulomatous arthritis may involve interleukin-1-mediated events.

SomaticNLRP3mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes

“…It is interesting to note that most patients (4/7; 57.1%) were misdiagnosed as having juvenile idiopathic arthritis when the disease started, a similar misdiagnosis previously reported in different inherited autoinflammatory diseases. [20][21][22][23] Despite the evidence shown here, the actual frequency of somatic NLRP3 mosaicism is unknown and probably underestimated. In our study a potential bias in the selection of patients could exist because they were selected on the basis of the presence of an urticaria-like skin rash associated with other symptoms.…”

Ex vivo and in vitro production of pro-inflammatory cytokines in Blau syndrome

“…The autoinflammatory nature of BS is related with its associated mutations. The gain of function hypothesis of BS mutations may suggest a spontaneous release of more cytokines, such as IL-1β (15). Moreover, several studies published in the literature have stated the importance of pro-inflammatory cytokines in driving the inflammation in different autoinflammatory conditions.…”

Pediatric hereditary autoinflammatory syndromes

“…Até o momento, foram descritas 15 mutações relacionadas à doença, localizadas principalmente no domínio NOD 18 . Interessantemente, mutações no domínio leucin rich repeats (LRR) da NOD2 estão relacionadas à doença de Crohn 18,117 . A NOD2 é considerada um sensor citoplasmático para componentes patogênicos, de forma semelhante aos toll-like receptors, e o estímulo da NOD2 pode resultar na ativação das vias do nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) e mitogen-activated protein kinase (MAPK), determinando a produção de citocinas envolvidas na resposta imune inata, como IL1-beta e defensinas 42 .…”