Molecular diagnostic yield for Blau syndrome in previously diagnosed juvenile idiopathic arthritis with uveitis or cutaneous lesions

Zhenyu Zhong; Lingyu Dai; Jiadong Ding; Yu Gao; Guannan Su; Yunyun Zhu; Yang Deng; Fuzhen Li; Yuan Gao; Peizeng Yang

doi:10.1093/rheumatology/kead596

Molecular diagnostic yield for Blau syndrome in previously diagnosed juvenile idiopathic arthritis with uveitis or cutaneous lesions

Rheumatology (Oxford). 2023 Nov 6:kead596. doi: 10.1093/rheumatology/kead596. Online ahead of print.

Authors

Zhenyu Zhong¹, Lingyu Dai¹, Jiadong Ding², Yu Gao¹, Guannan Su¹, Yunyun Zhu¹, Yang Deng¹, Fuzhen Li², Yuan Gao³, Peizeng Yang¹

Affiliations

¹ The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, and Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China.
² The First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, and Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou, China.
³ Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, and Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China.

PMID: 37941393
DOI: 10.1093/rheumatology/kead596

Abstract

Objective: Diagnostic pitfalls often arise in the community because of potentially misleading similarities between juvenile idiopathic arthritis (JIA) and Blau syndrome, an immune-related disorder caused by NOD2 gene mutations. It remains unclear in which population and to which extent next-generation sequencing techniques can aid in diagnosis.

Methods: We evaluated clinical usefulness of targeted next-generation sequencing in previously diagnosed JIA. Participants were required to have symptoms and signs suspected of Blau syndrome, including at least uveitis or cutaneous lesions in addition to arthritis. Targeted sequencing was conducted on NOD2 gene to detect diagnostic variants classified as pathogenic or likely pathogenic for Blau syndrome. We assessed the molecular diagnostic yield and clinical implications on patient care.

Results: Between May 1, 2008, and June 1, 2021, sequencing data were accrued from 123 previously diagnosed JIA (median age: 5 years; female: 62.6%). Targeted NOD2 sequencing yielded a positive molecular diagnosis of Blau syndrome in 21.1% (95% CI, 14.9%-29.2%), encompassing six heterozygous missense mutations classified as pathogenic variants. Among those receiving a molecular diagnosis, changes in clinical management and treatment were considered as having occurred in 38.5%. Nine predictors were identified to be associated with a higher diagnostic yield, providing clinical clues to suspect the possibility of Blau syndrome.

Conclusion: Among some patients with pediatric-onset arthritis complicated with uveitis or cutaneous lesions, reassessing their diagnosis of JIA may be warranted. Targeted NOD2 sequencing established the molecular diagnosis of Blau syndrome in nearly one fifth of these cases and provided clinically relevant information for patient-care decisions.

Keywords: Blau syndrome; Diagnosis; Juvenile idiopathic arthritis; NOD2; Targeted next-generation sequencing.