Phenotypic spectrum in recessive STING-associated vasculopathy with onset in infancy: Four novel cases and analysis of previously reported cases

Wan, Rensheng; Fänder, Johannes; Zakaraia, Ia; Lee‐Kirsch, Min Ae; Wolf, Christine; Lucas, Nadja; Olfe, Lisa Isabel; Hendrich, Corinna; Jonigk, Danny; Holzinger, Dirk; Steindor, Mathis; Schmidt, Gunnar; Davenport, Claudia; Klemann, Christian; Schwerk, Nicolaus; Griese, Matthias; Schlegelberger, Brigitte; Stehling, Florian; Happle, Christine; Auber, Bernd; Steinemann, Doris; Wetzke, Martin; Hardenberg, Sandra von

doi:10.3389/fimmu.2022.1029423

Cited by 8 publications

(11 citation statements)

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“…Nevertheless, a few studies suggested that some clinical features of SAVI may be related to corresponding mutations. Several authors confirmed that patients with the inherited p.V155M variant have a less severe disease course than those with de novo variants [ 1 , 16 ]. A systematic review demonstrated that, compared to patients with the p.V155M mutation, patients with p.N154S mutations had earlier disease onsets and more severe skin lesions, with no differences in respiratory symptoms [ 2 ].…”

Section: Discussionmentioning

confidence: 98%

“…Previous reports suggested that SAVI remains to be reported as an exclusively autosomal-dominant disease [ 6 ]. However, recent reports have presented that autosomal-recessive inheritance caused by homozygous missense pathogenic variants (such as p.R281W) was found in STING1 [ 16 ]. Thus far, the genotype-phenotype correlations are not definite due to the limited cases.…”

Section: Discussionmentioning

confidence: 99%

“…As for reasoning, Rensheng Wan et al supposed that other factors (environmental factors, ethnic background, etc.) in addition to inheritance patterns that resulted in various genotypes-phenotypes should be considered [ 16 ]. Nevertheless, a few studies suggested that some clinical features of SAVI may be related to corresponding mutations.…”

Section: Discussionmentioning

confidence: 99%

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Case report: JAK1/2 inhibition with baricitinib in the treatment of STING-associated vasculopathy with onset in infancy

Wu,

Zhou,

Zhou

et al. 2023

Pediatr Rheumatol

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Background Gain-of-function mutations in STING1 (also known as TMEM173) which result in constitutive activation of STING, have been reported to cause STING-associated vasculopathy with onset in infancy (SAVI). Although a wider spectrum of associated manifestations and perturbations in disease onset have been observed since its description, the genotype-phenotype correlations are not definite, and there is no established treatment protocol for SAVI. Case presentation Herein, we report a kindred, heterozygous STING mutation (p.V155M) in which the 2-year-old proband suffered from severe interstitial lung disease (ILD) while her father was initially misdiagnosed with connective tissue disease associated with ILD at an adult age. Baricitinib was initiated after the diagnosis of SAVI in the proband combined with steroids, and during the 14-month follow-up, the respiratory symptoms were improved. However, as the improvement of laboratory indicators was limited, especially in autoimmune indices, and the lung CT images remained unaltered, it seems that JAK1/2 inhibition was unsatisfactory in completely controlling the inflammation of the disease in our study. Conclusions Baricitinib was shown to elicit some effect on the ILD but failed to control the inflammation of the disease completely. Further exploration of JAK inhibitors or other therapeutic strategies are needed to more optimally treat this inflammatory disease.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Case report: JAK1/2 inhibition with baricitinib in the treatment of STING-associated vasculopathy with onset in infancy

Wu,

Zhou,

Zhou

et al. 2023

Pediatr Rheumatol

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“…Another puzzling feature that seems to be particularly frequent in genes associated with IEI is the observation that pathogenic variants of the same gene can follow different modes of inheritance. For example, both an autosomal recessive as well as an autosomal dominant inheritance is known to be causative in the genes such as MEFV ( 71 , 72 ), STING1 ( 73 , 74 ) and AICDA ( 75 , 76 ).…”

Section: Current Challengesmentioning

confidence: 99%

Current genetic diagnostics in inborn errors of immunity

von Hardenberg,

Klefenz,

Steinemann

et al. 2024

Front. Pediatr.

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New technologies in genetic diagnostics have revolutionized the understanding and management of rare diseases. This review highlights the significant advances and latest developments in genetic diagnostics in inborn errors of immunity (IEI), which encompass a diverse group of disorders characterized by defects in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and malignancies. Various diagnostic approaches, including targeted gene sequencing panels, whole exome sequencing, whole genome sequencing, RNA sequencing, or proteomics, have enabled the identification of causative genetic variants of rare diseases. These technologies not only facilitated the accurate diagnosis of IEI but also provided valuable insights into the underlying molecular mechanisms. Emerging technologies, currently mainly used in research, such as optical genome mapping, single cell sequencing or the application of artificial intelligence will allow even more insights in the aetiology of hereditary immune defects in the near future. The integration of genetic diagnostics into clinical practice significantly impacts patient care. Genetic testing enables early diagnosis, facilitating timely interventions and personalized treatment strategies. Additionally, establishing a genetic diagnosis is necessary for genetic counselling and prognostic assessments. Identifying specific genetic variants associated with inborn errors of immunity also paved the way for the development of targeted therapies and novel therapeutic approaches. This review emphasizes the challenges related with genetic diagnosis of rare diseases and provides future directions, specifically focusing on IEI. Despite the tremendous progress achieved over the last years, several obstacles remain or have become even more important due to the increasing amount of genetic data produced for each patient. This includes, first and foremost, the interpretation of variants of unknown significance (VUS) in known IEI genes and of variants in genes of unknown significance (GUS). Although genetic diagnostics have significantly contributed to the understanding and management of IEI and other rare diseases, further research, exchange between experts from different clinical disciplines, data integration and the establishment of comprehensive guidelines are crucial to tackle the remaining challenges and maximize the potential of genetic diagnostics in the field of rare diseases, such as IEI.

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“…Studies have reported variant R284S/G and R281Q/W in exon 7 of STING causing SAVI, some patients also suffered from severe interstitial lung disease ( 82 – 84 ). Konno et al.…”

Section: Targeting Cgas-sting Signaling Alleviates Pulmonary Fibrosismentioning

confidence: 99%

The role of cGAS-STING signaling in pulmonary fibrosis and its therapeutic potential

Zhang,

Chen

et al. 2023

Front. Immunol.

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Pulmonary fibrosis is a progressive and ultimately fatal lung disease, exhibiting the excessive production of extracellular matrix and aberrant activation of fibroblast. While Pirfenidone and Nintedanib are FDA-approved drugs that can slow down the progression of pulmonary fibrosis, they are unable to reverse the disease. Therefore, there is an urgent demand to develop more efficient therapeutic approaches for pulmonary fibrosis. The intracellular DNA sensor called cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) plays a crucial role in detecting DNA and generating cGAMP, a second messenger. Subsequently, cGAMP triggers the activation of stimulator of interferon genes (STING), initiating a signaling cascade that leads to the stimulation of type I interferons and other signaling molecules involved in immune responses. Recent studies have highlighted the involvement of aberrant activation of cGAS-STING contributes to fibrotic lung diseases. This review aims to provide a comprehensive summary of the current knowledge regarding the role of cGAS-STING pathway in pulmonary fibrosis. Moreover, we discuss the potential therapeutic implications of targeting the cGAS-STING pathway, including the utilization of inhibitors of cGAS and STING.

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Phenotypic spectrum in recessive STING-associated vasculopathy with onset in infancy: Four novel cases and analysis of previously reported cases

Cited by 8 publications

References 50 publications

Case report: JAK1/2 inhibition with baricitinib in the treatment of STING-associated vasculopathy with onset in infancy

Case report: JAK1/2 inhibition with baricitinib in the treatment of STING-associated vasculopathy with onset in infancy

Current genetic diagnostics in inborn errors of immunity

The role of cGAS-STING signaling in pulmonary fibrosis and its therapeutic potential

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