title: NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: study of an international registry and a national cohort in Spain.
abstract: OBJECTIVE
  To study the phenotype characteristics of the largest to date cohort of patients with pediatric granulomatous arthritis (PGA) and documented mutations in the NOD2 gene.
  
  
  METHODS
  We analyzed merged data from 2 prospective cohorts of PGA patients, the International PGA Registry and a Spanish cohort. A systematic review of the medical records of interest was performed to identify phenotype characteristics.
  
  
  RESULTS
  Forty-five patients with PGA (23 sporadic cases and 22 from familial pedigrees) and documented NOD2 mutations were identified and formed the basis of the study. Of these 45 patients, 18 had the R334W-encoding mutation, 18 had R334Q, 4 had E383K, 3 had R587C, 1 had C495Y, and 1 had W490L. The majority of patients manifested the typical triad of dermatitis, uveitis, and arthritis. In contrast, in 13 patients, the following "atypical" manifestations were noted: fever, sialadenitis, lymphadenopathy, erythema nodosum, leukocytoclastic vasculitis, transient neuropathy, granulomatous glomerular and interstitial nephritis, interstitial lung disease, arterial hypertension, hypertrophic cardiomyopathy, pericarditis, pulmonary embolism, hepatic granulomatous infiltration, splenic involvement, and chronic renal failure. In addition, 4 individuals who were asymptomatic carriers of a disease-causing mutation were documented.
  
  
  CONCLUSIONS
  NOD2-associated PGA can be a multisystem disorder with significant visceral involvement. Treating physicians should be aware of the systemic nature of this condition, since some of these manifestations may entail long-term morbidity.
authors.affiliation: Thomas Jefferson University, Philadelphia, Pennsylvania, USA. crose@nemours.org
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Rosé
authors.forename: Juan I
authors.initials: JI
authors.lastname: Aróstegui
authors.forename: Tammy M
authors.initials: TM
authors.lastname: Martin
authors.forename: Graciela
authors.initials: G
authors.lastname: Espada
authors.forename: Lisabeth
authors.initials: L
authors.lastname: Scalzi
authors.forename: Jordi
authors.initials: J
authors.lastname: Yagüe
authors.forename: James T
authors.initials: JT
authors.lastname: Rosenbaum
authors.forename: Consuelo
authors.initials: C
authors.lastname: Modesto
authors.forename: Maria
authors.initials: M
authors.lastname: Cristina Arnal
authors.forename: Rosa
authors.initials: R
authors.lastname: Merino
authors.forename: Julia
authors.initials: J
authors.lastname: García-Consuegra
authors.forename: María Antonia
authors.initials: MA
authors.lastname: Carballo Silva
authors.forename: Carine H
authors.initials: CH
authors.lastname: Wouters
mesh_terms: D000293:Adolescent; D000328:Adult; D001168:Arthritis / Q000453:epidemiology* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003872:Dermatitis / Q000453:epidemiology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D015995:Prevalence; D012042:Registries; D013030:Spain / Q000453:epidemiology; D014605:Uveitis / Q000453:epidemiology / Q000235:genetics; D055815:Young Adult
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein