title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Servicio de Inmunología, Hospital Clínic, Barcelona, Spain. jiaroste@clinic.ub.es
authors.forename: Juan I
authors.initials: JI
authors.lastname: Aróstegui
authors.forename: Cristina
authors.initials: C
authors.lastname: Arnal
authors.forename: Rosa
authors.initials: R
authors.lastname: Merino
authors.forename: Consuelo
authors.initials: C
authors.lastname: Modesto
authors.forename: María
authors.initials: M
authors.lastname: Antonia Carballo
authors.forename: Purificación
authors.initials: P
authors.lastname: Moreno
authors.forename: Julia
authors.initials: J
authors.lastname: García-Consuegra
authors.forename: Antonio
authors.initials: A
authors.lastname: Naranjo
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ramos
authors.forename: Pilar
authors.initials: P
authors.lastname: de Paz
authors.forename: Josefa
authors.initials: J
authors.lastname: Rius
authors.forename: Susana
authors.initials: S
authors.lastname: Plaza
authors.forename: Jordi
authors.initials: J
authors.lastname: Yagüe
mesh_terms: D000293:Adolescent; D000328:Adult; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006099:Granuloma / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010375:Pedigree; D012008:Recurrence; D013030:Spain; D013577:Syndrome; D014605:Uveitis / Q000188:drug therapy / Q000235:genetics*
chemical_list: D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein