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Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease that is influenced by environmental and genetic factors. Linkage studies and genome-wide association studies have identified genes that contribute to the risk of developing JIA but are limited in their ability to identify disease-risk variants of large effect. Penetrant, heritable risk variants can be detected in high-risk families, but such cases are uncommon due to the low prevalence of JIA. This study utilizes whole-genome sequencing of 23 multiplex families, the largest such cohort to date, to discover variants and genes relevant to JIA pathogenesis. Pathogenic variants in NOD2 associated with Blau syndrome, an ultra-rare Mendelian inflammatory disorder, are the most recurrent variants in the cohort, consistent with previous reports that milder presentations of Blau syndrome are oftentimes misdiagnosed as JIA. For the first time, however, rare variants in ACVR1 and SMAD6, integral components of the Bone Morphogenic Protein (BMP) pathway, are found to be associated with JIA. Identified ACVR1 variants map to critical protein domains. AlphaFold modeling predicts that the ACVR1 interaction with its inhibitor OGT is disrupted by these variants, indicating that the patient-mutated protein has a gain-of-function phenotype. Drosophila melanogaster expressing either a wild-type or patient-mutated version of ACVR1 exhibit embryonic lethality, with the mutant exhibiting 1.4-fold greater lethality than wild-type. The combination of family-based cohorts for gene discovery, AI-based computational tools, and animal model studies for tests of variant function underscores shared disease pathogenesis between JIA and monogenic disorders of immunity and connective tissue.

PURPOSE: Childhood-onset sarcoidosis (COS) is a rare granulomatous autoinflammatory condition characterised by arthritis, dermatitis, and uveitis which includes early-onset forms (sporadic or Blau syndrome) and a later-onset form resembling adult sarcoidosis. Ocular involvement often occurs early and may be a prominent, sight-threatening feature. Despite this, COS is sparsely described in the literature. This case series aims to characterise the ocular manifestations, complications, and outcomes in COS. METHODS: A review of patients diagnosed with COS under a tertiary paediatric uveitis service. Data collected included age at onset, clinical findings, diagnostic methods, treatments, ocular complications, and visual acuity (VA) at presentation and last follow-up. RESULTS: Six patients were identified, all of whom presented with granulomatous uveitis. Four had posterior segment involvement including choroiditis and optic disc swelling. The mean age of ocular disease onset was 7 years. Diagnosis was supported by elevated serum angiotensin converting enzyme (ACE) followed by lymph node biopsy (n = 3), skin biopsy (n = 2), and/or NOD2 mutation (n = 3). All received systemic immunosuppression: methotrexate (n = 6), adalimumab (n = 5), mycophenolate (n = 2), oral corticosteroids (n = 3), and infliximab (n = 1). Complications included uveitic glaucoma (n = 2), cataract (n = 3), and chorioretinal scarring (n = 1). VA improved or remained stable in most, with one case of persistent visual impairment. CONCLUSION: COS-related uveitis demonstrates an aggressive, chronic course with early onset, bilateral involvement, and frequent complications with potential to cause visual loss. Careful ophthalmic screening in children with known or suspected sarcoidosis is critical.

PURPOSE: To describe the long-term ocular and systemic course of a pediatric patient with Blau syndrome carrying aNOD2p.Arg587Cys mutation, and to report the therapeutic response to infliximab after inadequate disease control with adalimumab. METHODS: Single-case report of a girl with genetically confirmed Blau syndrome managed at a tertiary referral center for pediatric uveitis in Japan. Clinical findings, multimodal imaging, treatment course, and long-term outcomes were reviewed from infancy through late childhood. Ocular inflammation was assessed by slit-lamp biomicroscopy, fundus examination, fluorescein angiography, and optical coherence tomography. Systemic therapy comprised methotrexate and tumor necrosis factor-alpha (TNF-α) inhibitors. RESULTS: The patient developed recurrent fever and urticaria-like rash at 7months of age, followed by bilateral granulomatous uveitis with optic disc edema at 9months. Genetic testing at 14months identified a heterozygousNOD2p.Arg587Cys mutation, confirming Blau syndrome. Methotrexate combined with adalimumab achieved only partial control: ocular inflammation recurred despite normalization of C-reactive protein and erythrocyte sedimentation rate, and recurrent hypopyon developed even after dose escalation to the standard pediatric maximum. After switching to infliximab at 4years and 6months of age, sustained remission was maintained for more than four years, with stable visual acuity, stable intraocular pressure, and no further ocular or systemic relapses. CONCLUSION: In this patient, systemic inflammatory markers did not reliably reflect intraocular disease activity, and infliximab achieved durable remission of Blau-associated uveitis refractory to adalimumab. Although limited to a single observation, the long-term outcome supports infliximab as a salvage option in refractory pediatric Blau-associated uveitis and underscores the value of ophthalmologic-rather than serological-monitoring of disease activity.

Blau syndrome is a rare autoinflammatory disorder caused by NOD2 mutations, characterized by granulomatous arthritis, uveitis, and dermatitis. While type I interferon signatures are biomarkers in several autoinflammatory diseases, their role in Blau syndrome remains unclear. We assessed the interferon score in 11 patients with Blau syndrome and correlated it with disease activity. Our results demonstrate that type I interferon signatures were detected in only a minority of patients and showed no significant correlation with clinical disease activity, inflammatory markers, or treatment response. These findings suggest that type I interferon signatures are not useful biomarkers for disease monitoring in Blau syndrome, highlighting the need to identify alternative biomarkers reflecting NOD2-mediated inflammatory pathways.

Blau syndrome, a granulomatous autoinflammatory disease, is a rare condition that is typically characterized by a triad of polyarthritis, uveitis, and dermatitis. It is caused by either an autosomal dominantly inherited or a de novo pathogenic variant in the NOD2 gene. In this report, we present a case of an 11-month-old male with Blau syndrome who presented with calcitriol-mediated hypercalcemia at an early stage. Severe hypercalcemia was controlled by intravenous fluid therapy, diuretics, calcitonin and a short course of corticosteroids. Following resolution of the hypercalcemic episode, the patient gradually developed the full clinical spectrum of Blau syndrome, including symptoms of the classic triad, along with hepatosplenomegaly, lymphadenopathy, and bone marrow involvement. Trio-genome sequencing reported a de novo pathogenic heterozygous variant in the NOD2. Following the genetic testing result, corticosteroids and methotrexate were introduced to control the disease. This is the first reported case of Blau syndrome presenting with hypercalcemia as an initial manifestation, preceding the development of the classic triad of symptoms. This case underscores the importance of considering Blau syndrome in the differential diagnosis of early-onset hypercalcemia of unknown etiology. Molecular genetic testing should be pursued in such cases to facilitate accurate and timely diagnosis, enabling appropriate management.