Blau syndrome is a rare autoimmune disease with autosomal dominant inheritance, typically involving the skin, joints and eyes. It is considered to be the early-onset form of sarcoidosis. Our patient is currently a 23-year-old young man who first developed skin symptoms in infancy, followed by inflammation of the small and large joints at the age of one and a half years. He also developed uveitis, iridocyclitis and glaucoma in early childhood. Despite intensive anti-inflammatory and various biological therapies, the arthritis progressed, and over time, severe contractures developed, confining him to wheelchair. Over time, the complexity and progression of his ophthalmological problems led to almost complete loss of vision, and required several surgical interventions. Unusually for Blau syndrome, our patient developed extensive central nervous system involvement one and a half years ago, which regressed on corticosteroids. The proband’s two-year-old sister also showed early symptoms of Blau syndrome in addition to Down syndrome. Next-generation sequencing using an immune gene panel identified the heterozygous pathogenic variant of the NOD2 gene c.1000C>T, p.(Arg334Trp) in the little sister, which has been previously reported in association with Blau syndrome. The presence of this variant was also detected in our proband by Sanger sequencing, but the carrier status was excluded in both asymptomatic parents and the asymptomatic middle child. In addition to presenting the clinical and genetic features of this rare disease, this paper highlights two unusual phenomena of Blau syndrome in our patient: involvement of the central nervous system, and suspected germline mosaicism in one of the parents. Orv Hetil. 2025; 166(16): 623–630. A Blau-szindróma ritka, autoszomális domináns öröklődésű autoimmun betegség, tipikusan a bőr, az ízületek és a szem érintettségével, melyet a sarcoidosis gyermekkori megjelenésű formájának tartanak. Betegünk egy jelenleg 23 éves fiatalember, akinél csecsemőkorban észleltek először bőrtüneteket, majd másfél évesen a kis- és nagyízületek gyulladása jelentkezett. Kisgyermekkorban uveitis, iridocyclitis és glaucoma is kialakult. Az intenzív gyulladásgátló és különböző biológiai terápiák ellenére az ízületi gyulladás progrediált, és idővel súlyos contracturák alakultak ki, melyek miatt az önálló járás már nem lehetséges. A szemészeti problémák komplexitása és progressziója a beteg látásának csaknem teljes elvesztéséhez vezetett, és számos sebészeti beavatkozás vált szükségessé. A Blau-szindrómában szokatlan módon, betegünknél másfél évvel ezelőtt a központi idegrendszer kiterjedt érintettségét észleltük, mely kortikoszteroidra azonban regrediált. A proband kétéves kistestvérénél szintén észlelték a Blau-szindróma korai tüneteit Down-kór mellett. A génpanelvizsgálat újgenerációs szekvenálással a kistestvérnél azonosította heterozigóta formában a NOD2 gén c.1000C>T, p.(Arg334Trp) patogén variánsát, melyet korábban már leírtak Blau-szindrómával összefüggésben. E variáns jelenlétét a probandban is kimutattuk Sanger-szekvenálással, a hordozóságot azonban kizártuk mindkét tünetmentes szülő és a középső testvér esetében. E ritka betegség tipikus klinikai és genetikai jellegzetességeinek ismertetése mellett, tanulmányunk két szokatlan jelenséget is feltár: a központi idegrendszer érintettségét és a feltételezhető mozaikosságot valamelyik szülő ivarsejtjeiben. Orv Hetil. 2025; 166(16): 623–630.

Over the past decade, S-acylation has emerged as a crucial regulator of several innate immune signaling pathways, with new insights continually being gained. S-acylation, a reversible post-translational modification, involves the attachment of fatty acyl chains to cysteine residues, influencing protein localization, function, and stability. In this mini-review, we examine the accumulating evidence of the role of S-acylation in regulating nucleotide oligomerization domain (NOD)-like receptors. NOD-like receptor subfamily P3 (NLRP3), a key player in inflammasome formation, undergoes S-acylation at specific cysteine residues, which are essential for its localization to the trans-Golgi network and other organelles. Various zinc finger Asp-His-His-Cys motif-containing (zDHHC) enzymes mediate this modification, with zDHHC5 being particularly important for activation and the ability of NLRP3 to interact with never in mitosis gene A (NIMA)-related protein kinase 7 (NEK7), promoting inflammasome assembly, caspase-1 activation, and pyroptosis. Alternatively, S-acylation by zDHHC12 targets NLRP3 for chaperone-mediated autophagy, preventing excessive inflammation. NOD2, another NLR, requires S-acylation for membrane localization and effective signaling via the NF-κB and mitogen-activated protein kinase pathways in response to peptidoglycan components. Dysregulation of S-acylation in NOD2 is associated with Crohn's Disease (hypo-acylated) and Blau syndrome/early-onset sarcoidosis (hyper-acylated). Soluble NOD2 lacking S-acylation is ubiquitinated and eliminated by the autophagic pathway. This review highlights the significance of understanding the S-acylation cycle and its regulatory mechanisms in developing potential therapeutic interventions for related inflammatory diseases. We also discuss unresolved questions regarding the S-acylation of NOD2 and NLRP3, as well as the regulation of S-acylation in general.

Blau syndrome (BS) is a rare autoinflammatory disease caused by gain of function variants in NOD2. Uveitis is one of the triad features with arthritis and dermatitis. Management of uveitis is challenging, and uncontrolled uveitis may lead to blindness. We aim to evaluate the evidence regarding effectiveness of systemic treatments, including conventional Disease Modifying anti-Rheumatic drugs(cDMARDs) and biologic DMARDs(bDMARDs), for the management of uveitis in BS. A systematic literature review and meta-analysis was performed according to PRISMA guidelines. Papers were selected if they reported patients with BS and uveitis who received systemic treatment. Papers were selected if reporting efficacy according to Standardization of Uveitis Nomenclature (SUN) criteria. We identified 1205 papers with 11 selected for systematic review and meta-analysis. Among the 11 selected papers, we identified 88 treatments. Among these, 53 were cDMARDs (36 methotrexate, 7 azathioprine, 5 mycophenolate, 3 thalidomide, 1 tacrolimus and 1 cyclosporine) and 35 bDMARDs (23 adalimumab, 6 infliximab, 4 etanercept, 1 golimumab and 1 canakinumab). The proportion of children showing improvement of uveitis was 20 % (95 % CI 2-46) and 22 % (95 % CI3-47) for cDMARDs and bDMARDs respectively (χ20.23, p = 0.631). No differences were observed among the administered drugs (χ27.21, p = 0.706). The data show that there is not enough evidence to establish a preferred treatment for managing uveitis in BS. Considering the rarity, the potential severity and refractoriness to current treatments of the disease, there is a critical need for better understanding of pathophysiology and expert driven treatment guidelines for of BS-uveitis.

Granulomatous tubulointerstitial nephritis (GTIN) attributed to early onset sarcoidosis is an ultrarare finding in an allograft kidney biopsy. We present the case of a young man with allograft dysfunction who had GTIN upon biopsy. We performed a thorough case review based on recovered records from early childhood and reassessed genetic testing results. We revised his underlying diagnosis from cryopyrin-associated periodic syndrome to early-onset sarcoidosis with wild-type NOD2 and established a rationale to use the interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ). This suppressed his inflammatory disease and stabilised kidney function. We performed a literature review related to the emerging role of IL-6 pathway blockade in kidney transplantation. We identified 18 reports with 417 unique patients treated with TCZ for indications including HLA-desensitisation, transplant immunosuppression induction, treatment of chronic antibody-mediated rejection, and treatment of subclinical rejection. Both TCZ and the direct IL-6 inhibitor clazakizumab are being studied in ongoing randomised control trials.

The aim of this study was to describe the clinical and molecular genetic findings in seven individuals from three unrelated families with Blau syndrome. A complex ophthalmic and general health examination including diagnostic imaging was performed. The NOD2 mutational hot spot located in exon 4 was Sanger sequenced in all three probands. Two individuals also underwent autoinflammatory disorder gene panel screening, and in one subject, exome sequencing was performed. Blau syndrome presenting as uveitis, skin rush or arthritis was diagnosed in four cases from three families. In two individuals from one family, only camptodactyly was noted, while another member had camptodactyly in combination with non-active uveitis and angioid streaks. One proband developed two attacks of meningoencephalitis attributed to presumed neurosarcoidosis, which is a rare finding in Blau syndrome. The probands from families 1 and 2 carried pathogenic variants in NOD2 (NM_022162.3): c.1001G>A p.(Arg334Gln) and c.1000C>T p.(Arg334Trp), respectively. In family 3, two variants of unknown significance in a heterozygous state were found: c.1412G>T p.(Arg471Leu) in NOD2 and c.928C>T p.(Arg310*) in NLRC4 (NM_001199139.1). In conclusion, Blau syndrome is a phenotypically highly variable, and there is a need to raise awareness about all clinical manifestations, including neurosarcoidosis. Variants of unknown significance pose a significant challenge regarding their contribution to etiopathogenesis of autoinflammatory diseases.