STING-associated vasculopathy with onset in infancy

STING-associated vasculopathy with onset in infancy (SAVI) is a rare autoinflammatory disease characterized by systemic inflammation, severe skin lesions, and interstitial lung disease. It is caused by gain-of-function mutations in the STING gene (STimulator of INterferon Genes), which plays a crucial role in the innate immune response to cytosolic DNA. The condition is congenital, meaning it is present from birth, and it is part of a broader category of disorders known as interferonopathies, which are associated with an upregulated interferon response.

Symptoms and Signs

The hallmark of SAVI is the development of severe skin lesions shortly after birth, which can range from rashes to more severe ulcerations. These skin manifestations are often accompanied by systemic features such as fever, failure to thrive, and joint swelling. A significant and life-threatening aspect of SAVI is the development of interstitial lung disease, which can lead to respiratory failure. Other symptoms may include vasculopathy, which can affect various organs and lead to further complications.

Genetics

SAVI is caused by mutations in the TMEM173 gene, which encodes the STING protein. These mutations lead to a gain of function, resulting in an overactive STING pathway. This hyperactivity leads to the overproduction of type I interferons, a group of proteins that play a key role in the body's antiviral response. However, in SAVI, this response is dysregulated, leading to chronic inflammation and tissue damage.

Diagnosis

Diagnosis of SAVI is based on clinical presentation, family history, and genetic testing. The presence of characteristic skin lesions, systemic inflammation, and interstitial lung disease in infancy suggests the diagnosis. Genetic testing can confirm the presence of a pathogenic mutation in the TMEM173 gene.

Treatment

There is no cure for SAVI, and treatment focuses on managing symptoms and preventing complications. High-dose corticosteroids and other immunosuppressive medications may be used to control inflammation. Recent advances have also explored the use of Janus kinase (JAK) inhibitors, which can block the signaling pathway downstream of STING and potentially reduce the production of type I interferons. Management of interstitial lung disease is critical and may require supplemental oxygen or mechanical ventilation in severe cases.

Prognosis

The prognosis for individuals with SAVI varies and depends on the severity of the disease manifestations, particularly the extent of lung involvement. Early and aggressive treatment can improve quality of life and may prolong survival, but the disease is chronic and can be life-threatening.

See Also

• Autoinflammatory disease
• Interferonopathies
• Interstitial lung disease
• Innate immune system