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.Conclusion. 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.Pediatric granulomatous arthritis (PGA) encompasses 2 diseases with an identical phenotype, the autosomal-dominant Blau syndrome and early-onset sarcoidosis, a sporadic condition. The finding of identical mutations on exon 4 of the NOD2 gene supports the notion that these diseases are actually the same (1-3). Blau (4) described the syndrome that bears his name as a triad of granulomatous boggy polyarthritis, uveitis, and papuloerythematous rash, whereas Jabs et al (5) described a polyarthritis with uveitis, without rash, but with cranial neuropathy. Early-onset sarcoidosis has been known since the 1970s, and like Blau syndrome, it is characterized by granulomatous boggy synovitis, uveitis, and rash, which is indistinguishable from Blau syndrome, albeit without a familial component (6).

Autoinflammatory Diseases Predominantly Affecting Bone and Joints

“…Inflammatory markers may be elevated or may be normal. 174 Antinuclear antibodies, rheumatoid factor, and angiotensin converting enzyme (ACE) levels are normal or low titer and are not of clinical significance in Blau syndrome. 136,137 Radiologic findings include periarticular soft tissue swelling, carpal crowding, camptodactyly, and joint-space narrowing, as well as unusually narrow or slender diaphysis of the second metacarpal bone 166,172 (Figure 25.3; C. Rose, personal communication).…”

“…135 Atypical presentations (beyond the classic triad) were found in approximately 33% of the 44 CARD15/NOD2 mutation-positive patients from a combined Spanish and international registry. 139,165,174 Non-classic findings include periodic fever, 165 persistent fever, 165 growth failure, 165 sensory neural hearing loss, 137 cranial nerve palsy, 137,165,175 interstitial pneumonitis, 174 hypertension, 165 pericarditis, 165 Takayasu-like arteritis, 139,175À177 leukocytoclastic vasculitis, granulomatous liver disease, 178 interstitial nephritis, thrombosis, 174 organomegaly, adenopathy, 165 and choroiditis. 179 …”

Pediatric hereditary autoinflammatory syndromes

“…AGP (OMIM n o 186580) é o termo aplicado a duas doenças com o mesmo fenótipo clínico: síndrome de Blau, uma condição familiar, e sarcoidose de início precoce, uma condição esporádica 114 . A AGP tem herança autossômica dominante e é causada por mutações no gene NOD2, também conhecido como CARD15, localizado no cromossomo 16 18 .…”

“…O exantema típico da AGP é descrito como de coloração marrom e ictiosiforme e é observado em 88% dos pacientes 116,117 . Achados menos comuns são febre, camptodactilia e neuropatia craniana 114 . A Figura 3 mostra paciente com AGP e exantema ictisioseforme.…”

Síndromes autoinflamatórias hereditárias na faixa etária pediátrica

“…116,117 Less common findings include fever, camptodactyly, and cranial neuropathy. 114 Figure 3 shows a patient with PGA and ichthyosiform rash.…”