NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: study of an international registry and a national cohort in Spain.
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.
Rosé
Carlos D
CD
Thomas Jefferson University, Philadelphia, Pennsylvania, USA. crose@nemours.org
Aróstegui
Juan I
JI
Martin
Tammy M
TM
Espada
Graciela
G
Scalzi
Lisabeth
L
Yagüe
Jordi
J
Rosenbaum
James T
JT
Modesto
Consuelo
C
Cristina Arnal
Maria
M
Merino
Rosa
R
García-Consuegra
Julia
J
Carballo Silva
María Antonia
MA
Wouters
Carine H
CH
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
C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein