Blau syndrome (BS) is a rare autoinflammatory disease first described by Edward Blau in 1985 1). In the same year, a similar disease entity was reported by Douglas Jabs.
It is caused by a gain-of-function mutation in the NOD2/CARD15 gene (chromosome 16, 16q12.1–13) and follows an autosomal dominant inheritance pattern 1). Sporadic cases (de novo mutations) are also called early-onset sarcoidosis (EOS). Currently, familial Blau syndrome and sporadic EOS are treated as the same disease 1).
It is characterized by the triad of granulomatous dermatitis, polyarthritis, and bilateral uveitis, with onset before age 10. The prevalence is estimated at less than 1 per million, making it an extremely rare disease, with at least 200 reported cases worldwide 1). There is no sex predilection, and cases have been reported in all races.
Both are two phenotypes—familial and sporadic—of the same disease sharing NOD2 gene mutations 1). Cases with a family history are called Blau syndrome, while sporadic cases are called EOS (or Jabs syndrome), but they are now treated uniformly.
The triad symptoms often appear at different times and may not all be present simultaneously.
Ocular involvement is almost always bilateral 2). A detailed multinational study found that 97% of uveitis cases were bilateral, with panuveitis in 51%, anterior uveitis in 29%, and mixed type in 20% 2).
Anterior Segment Findings
Mutton-fat keratic precipitates (KPs): A characteristic finding indicating granulomatous inflammation.
Busacca nodules: Granulomatous nodules on the anterior surface of the iris.
Band keratopathy: Appears as a result of chronic inflammation.
Nummular corneal opacities: Opacities in the corneal stroma.
Posterior synechiae, anterior chamber cells, flare: Indicators of inflammatory activity.
Posterior Segment Findings
Multifocal chorioretinitis: Multiple lesions in the choroid and retina.
Peripapillary nodules: Granulomatous lesions around the optic disc.
Vitreous opacities: Findings of posterior inflammation.
Retinal vascular sheathing: Reflects perivasculitis.
Optic disc edema/pallor: Seen in severe cases.
Recurrent inflammation leads to cataract (55%), elevated intraocular pressure (36%), band keratopathy (23%), optic atrophy (14%), macular edema (14%), and retinal detachment (9%)3). In a 3-year follow-up study, an average of 28% of patients had visual acuity of 20/50 or worse, and 11% declined to 20/200 or worse2).
Recurrent inflammation leads to cataract in 55% and elevated intraocular pressure in 36% of cases3). Some cases progress to optic atrophy or retinal detachment, and ocular lesions pose the greatest threat to quality of life. Early introduction of biologic agents is considered important for protecting vision.
The NOD2 protein is an intracellular pattern recognition receptor of the innate immune system, mainly expressed in antigen-presenting cells such as monocytes, macrophages, and intestinal Paneth cells 1). Normally, it responds to bacterial muramyl dipeptide (MDP) to activate NF-κB and induce transcription of inflammatory genes.
In Blau syndrome, gain-of-function mutations in the NACHT domain of NOD2 cause excessive activation of NF-κB even in the absence of bacterial triggers, leading to systemic granulomatous inflammation 2). The most common mutations are missense mutations at codon 334 (R334W, R334Q), accounting for more than half of confirmed mutations 2).
Zeng et al. (2023) summarized vasculitis associated with NOD2 mutations over the past 40 years, revealing 18 reported cases 1). The majority were medium-to-large vessel vasculitis (aortitis, Takayasu arteritis-like).
Suspect this disease when a child under 5 years old presents with the triad of uveitis, arthritis, and dermatitis. However, diagnosis can be difficult because the triad often appears with a time lag rather than simultaneously. It is easily misdiagnosed as juvenile idiopathic arthritis (JIA). Key distinguishing points: only 10–20% of JIA patients have uveitis, and JIA-associated uveitis is almost always anterior uveitis 1).
| Test | Purpose | Findings |
|---|---|---|
| Skin or synovial biopsy | Confirmatory diagnosis aid | Non-caseating granuloma |
| NOD2 genetic testing (NGS) | Definitive diagnosis | Identification of gain-of-function mutation |
| Ophthalmic examination (OCT, slit lamp) | Evaluation of ocular lesions | KP, iris nodules, choroidal lesions |
Definitive diagnosis is made by demonstrating non-caseating granulomas (skin biopsy is recommended due to low invasiveness) and genetic testing for NOD2 mutations. If a novel mutation is found, confirmation of increased NF-κB activity is recommended 2).
Tests required for differential diagnosis include CBC, ESR, CRP, serum ACE, ANA, ANCA, rheumatoid factor, HLA typing, and tuberculin reaction.
Juvenile idiopathic arthritis, sarcoidosis (juvenile and adult types), rheumatoid arthritis, systemic lupus erythematosus, vasculitis, tuberculosis, Lyme disease, syphilis, Behçet’s disease.
The frequency of juvenile idiopathic arthritis-associated uveitis is 10–20%, and most cases involve only anterior uveitis 1). In Blau syndrome, bilateral panuveitis (including posterior and intermediate lesions) is common (51%), and skin rash (scaly erythematous papules) and camptodactyly are also important clues for differentiation. NOD2 genetic testing is useful for confirmation.
There are no official guidelines for the treatment of Blau syndrome. Multidisciplinary comprehensive management is required, with collaboration among ophthalmology, rheumatology, dermatology, and pediatrics.
Acute exacerbation phase
Disease-modifying and maintenance therapy
Anti-TNF therapy
Adalimumab and infliximab: effective for both joint and eye symptoms.
In a Japanese cohort study, among 26 patients treated with anti-TNF therapy, only 1 case of blindness occurred (before initiation of biologic agents) 1).
Alternative biologic agents
IL-1 inhibitors (anakinra, canakinumab): used in cases resistant to anti-TNF therapy.
IL-6 inhibitors (tocilizumab): same as above.
JAK inhibitors (tofacitinib, baricitinib): cases of efficacy in patients resistant to TNF inhibitors and tocilizumab have been reported 4).
Zhang et al. (2021) reported that tofacitinib (1.7–2.5 mg/day) was administered to 3 pediatric patients with Blau syndrome who were resistant to steroids, methotrexate, and biologic agents, achieving clinical remission of polyarthritis and improvement in inflammatory markers (ESR, CRP, cytokines) in all cases 4). No adverse effects were observed.
Topical treatments for uveitis include steroid eye drops and mydriatic agents. Surgery may be necessary for complications such as cataracts and glaucoma.
The NOD2 protein is a multi-domain protein consisting of 1040 amino acids, composed of three domains: CARD (caspase recruitment domain), NACHT (nucleotide-binding domain), and LRR (leucine-rich repeat) 1).
Normally, when NOD2 binds to muramyl dipeptide (MDP), it activates NF-κB via RIP kinase (RICK) and the IKK complex, producing inflammatory cytokines such as IL-1β, IL-6, and TNF-α. In Blau syndrome, gain-of-function mutations in the NACHT domain constitutively activate this pathway 1,2).
In contrast to Crohn’s disease-associated mutations (loss-of-function mutations in the LRR region), Blau syndrome mutations are gain-of-function mutations concentrated in the NACHT domain 1). This difference leads to distinct inflammatory patterns between the two diseases.
Furthermore, recent studies suggest that overactivated Th17 cells due to dysfunctional NOD2 are involved in the onset of uveitis 2). The JAK-STAT pathway also contributes to pathogenesis through the production of IFN-γ and IL-6, making it a therapeutic target for JAK inhibitors 4).
Regarding vasculitis (aortitis, Takayasu arteritis-like), 18 cases have been reported over the past 40 years, the majority being medium to large vessel arteritis 1). Vasculitis often progresses asymptomatically and is easily overlooked clinically.
Constitutive activation of the JAK-STAT pathway has been shown to be involved in the pathogenesis of Blau syndrome/sarcoidosis, and JAK inhibitors (tofacitinib, baricitinib) are attracting attention 4).
In a study of 7 patients from 3 families by Brichova et al. (2024), a severe case was reported in which remission was maintained from age 12 after introduction of baricitinib 3). The study showed that the phenotype of Blau syndrome is highly variable, ranging from mild cases with only camptodactyly to severe cases with neurosarcoidosis.
With the spread of autoinflammatory disease gene panel testing using next-generation sequencing (NGS), diagnosis of undiagnosed and mild cases is progressing 3). Interpretation of variants of uncertain significance (VUS) remains a future challenge, and combination with functional analysis is considered important.
Neurosarcoidosis associated with Blau syndrome has rarely been reported in the past, but recent case reports have revealed its diverse phenotypes (meningoencephalitis, white matter lesions, hydrocephalus) 3).
