乳児発症 STING 関連血管炎

STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by mutations in TMEM173 gene encoding STING (stimulator of interferon genes). It typically presents in infancy and is mainly characterized by interstitial lung disease, skin rash, and systemic inflammation. This report presents the case of adult-onset SAVI:A 28-year-old male patient was admitted with recurrent episode of cough, expectoration, chest tightness with shortness of breath and erythematous rashes on the extremities, chest, and back.His CT revealed bilateral diffuse fine reticular opacities and irregular reticular shadows, with focal areas of honeycombing. Further inquiry into the family history revealed that the patient's mother had been diagnosed with interstitial lung disease (ILD).Thus, a genetic etiology should be highly suspected.Later, whole-exome sequencing identified a heterozygous mutation in the STING1 gene: c.842G>A (p.R281Q), establishing the diagnosis of SAVI. The patient was subsequently referred to a tertiary care hospital for specialized management. During one year of follow-up, the patient underwent lung transplantation in August 2025 and had since received long-term immunosuppressive therapy for rejection prophylaxis. Cough and expectoration improved markedly, although exertional dyspnea persisted; the cutaneous rash had resolved completely.

We report the case of an 18-year-old previously healthy female who developed acute liver and kidney injuries with cytopenia and hyperinflammatory markers following cytomegalovirus (CMV) infection. Despite not meeting the hemophagocytic lymphohistiocytosis (HLH)-2004 or H-score criteria, her clinical and biochemical profiles suggested an HLH-like syndrome. Whole-exome sequencing revealed a heterozygous dominant stimulator of interferon genes (STING1) (c.841C>T; p. Arg281Trp) mutation. Although the patient lacked classic STING-associated vasculopathy with onset in infancy (SAVI)-associated skin or lung manifestations, immunological profiling revealed an inverted cluster of differentiation (CD)4/CD8 ratio and absolute CD4+ lymphopenia, supporting a state of underlying immune dysregulation that likely predisposed the patient to severe CMV infection. The patient showed partial clinical and biochemical improvements following antiviral and corticosteroid therapy, supporting our hypothesis of a genetically primed infection-triggered hyper-inflammatory response. This case broadens the STING1 disease spectrum and emphasizes the importance of genomic evaluation of unexplained hyperinflammation, even in apparently immunocompetent hosts. Conclusion: This case highlights a novel STING1 (p. Arg281Trp) gain-of-function mutation with a previously unreported autosomal dominant inheritance pattern identified in both the patient and her asymptomatic father, suggesting incomplete penetrance and variable expression rather than a fully penetrant autosomal dominant pattern. The patient's presentation was atypical compared with classical SAVI, manifesting as a CMV-triggered HLH-like syndrome with acute renal and liver cell injury in an adolescent with no prior evidence of immune deficiency or family history of genetic disease. Notably, this presentation lacked the characteristic cutaneous and pulmonary involvement. This case highlights a distinct phenotypic spectrum and expands our understanding of STING1-related interferonopathies.

Identification of the genetic mutations underlying the ultrarare monogenic conditions STING-associated vasculopathy with onset in infancy (SAVI) and coatomer protein complex subunit alpha (COPA) syndrome revealed a role for the stimulator of interferon genes (STING) immune pathway in the pathogenesis of interstitial lung disease (ILD) in these conditions. STING-focused therapeutics could be a potential avenue for the treatment of SAVI and COPA syndrome in the future, yet the relevance of STING to more common types of ILD is not clear. Here, we provide an overview of SAVI and COPA syndrome, the nature of ILD in these conditions, and current evidence regarding STING activity in their pathogenesis. We discuss data from studies of a variety of other ILDs and model systems and explore the potential role for STING in more common forms of ILD.

Breakthroughs in rare genetic disease research elucidate the relationships among cytosolic DNA sensing, genome instability, and autoimmune disease phenotypes. Cytosolic self-DNA is a potent trigger of innate immunity, activating the DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING). This pathway is negatively regulated by the DNA-degrading enzyme three-prime repair exonuclease 1 (TREX1); loss-of-function TREX1 variants lead to accumulation of cytosolic DNA, resulting in STING-mediated autoinflammation. Similarly, STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy, another disease characterized by multi-organ damage, disability, and premature death. The TREX1-cGAS-STING pathway has also been implicated in regulation of genome stability. Indeed, DNA damage lies at the heart of a separate TREX1-mediated disease, known as retinal vasculopathy with cerebral leukoencephalopathy, where the aberrant nuclear activity of mislocalized TREX1 damages genomic DNA, resulting in multi-organ degeneration syndrome with features of autoimmunity. Thus, monogenic autoimmune diseases and DNA damage syndromes sometimes overlap clinically, and the study of these diseases has created pathways for developing first-in-class small molecule therapeutics.

Stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) is a monogenic autoinflammatory disorder caused by gain-of-function mutations in TMEM173, leading to constitutive STING activation and persistent type I interferon signaling. Affected children develop early-onset cutaneous vasculopathy, systemic inflammation, and progressive interstitial lung disease, often refractory to standard immunosuppressive treatments. Janus kinase (JAK) inhibitors offer partial transient control, with risk of irreversible organ damage. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) could cure SAVI by replacing the mutant immune system, but experience is very limited. We report a 6-year-old boy with SAVI carrying the TMEM173 p.N154S mutation who failed multiple JAK inhibitors, including ruxolitinib, tofacitinib, and baricitinib and developed worsening lung fibrosis and cutaneous ulcers. He underwent allo-HSCT from a fully HLA-matched sibling after myeloablative conditioning. Engraftment was rapid. By 12 months post hematopoietic stem cell transplantation (HSCT), vasculitic skin lesions had healed, lung disease was stable, and inflammatory markers normalized, and cellular and humoral immunity reconstituted, including recovery of CD8+ central memory T cells and IgG and IgA. No graft-versus-host disease or major infections were observed. A transient autoimmune hemolytic anemia resolved with corticosteroids. This first successful SAVI allo-HSCT suggests curative potential via a durable immune reconstitution approach in selected patients with severe, treatment-refractory SAVI.