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STING-associated vasculopathy with onset in infancy

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Description

STING-associated vasculopathy with onset in infancy (SAVI) is a disorder involving abnormal inflammation throughout the body, especially in the skin, blood vessels, and lungs. Inflammation normally occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and help with tissue repair. Excessive inflammation damages the body's own cells and tissues. Disorders such as SAVI that result from abnormally increased inflammation are known as autoinflammatory diseases.

The signs and symptoms of SAVI begin in the first few months of life, and most are related to problems with blood vessels (vasculopathy) and damage to the tissues that rely on these vessels for their blood supply. Affected infants develop areas of severely damaged skin (lesions), particularly on the face, ears, nose, fingers, and toes. These lesions begin as rashes and can progress to become wounds (ulcers) and dead tissue (necrosis). The skin problems, which worsen in cold weather, can lead to complications such as scarred ears, a hole in the tissue that separates the two nostrils (nasal septum perforation), or fingers or toes that require amputation. Individuals with SAVI also have a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin. Affected individuals may also experience episodes of Raynaud phenomenon, in which the fingers and toes turn white or blue in response to cold temperature or other stresses. This effect occurs because of problems with the small vessels that carry blood to the extremities.

In addition to problems affecting the skin, people with SAVI have recurrent low-grade fevers and swollen lymph nodes. They may also develop widespread lung damage (interstitial lung disease) that can lead to the formation of scar tissue in the lungs (pulmonary fibrosis) and difficulty breathing; these respiratory complications can become life-threatening. Rarely, muscle inflammation (myositis) and joint stiffness also occur.

Frequency

The prevalence of this condition is unknown. Only a few affected individuals have been described in the medical literature.

Causes

SAVI is caused by mutations in the STING1 gene. This gene provides instructions for making a protein called STING, which is involved in immune system function. STING helps produce beta-interferon, a member of a class of proteins called cytokines that promote inflammation.

The STING1 gene mutations that cause SAVI are described as "gain-of-function" mutations because they enhance the activity of the STING protein, leading to overproduction of beta-interferon. Abnormally high beta-interferon levels cause excessive inflammation that results in tissue damage, leading to the signs and symptoms of SAVI.

Inheritance

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, this condition likely results from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

Other Names for This Condition

  • SAVI
  • STING-associated vasculopathy, infantile onset

Additional Information & Resources

Genetic and Rare Diseases Information Center

Research Studies from ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE. STING is a direct innate immune sensor of cyclic di-GMP. Nature. 2011 Sep 25;478(7370):515-8. doi: 10.1038/nature10429. Citation on PubMed or Free article on PubMed Central
  • Chen H, Sun H, You F, Sun W, Zhou X, Chen L, Yang J, Wang Y, Tang H, Guan Y, Xia W, Gu J, Ishikawa H, Gutman D, Barber G, Qin Z, Jiang Z. Activation of STAT6 by STING is critical for antiviral innate immunity. Cell. 2011 Oct 14;147(2):436-46. doi: 10.1016/j.cell.2011.09.022. Citation on PubMed
  • Chiliveru S, Rahbek SH, Jensen SK, Jørgensen SE, Nissen SK, Christiansen SH, Mogensen TH, Jakobsen MR, Iversen L, Johansen C, Paludan SR. Inflammatory cytokines break down intrinsic immunological tolerance of human primary keratinocytes to cytosolic DNA. J Immunol. 2014 Mar 1;192(5):2395-404. doi: 10.4049/jimmunol.1302120. Epub 2014 Jan 31. Citation on PubMed
  • Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008 Oct 2;455(7213):674-8. doi: 10.1038/nature07317. Epub 2008 Aug 24. Erratum in: Nature. 2008 Nov 13;456(7219):274. Citation on PubMed or Free article on PubMed Central
  • Ishikawa H, Barber GN. The STING pathway and regulation of innate immune signaling in response to DNA pathogens. Cell Mol Life Sci. 2011 Apr;68(7):1157-65. doi: 10.1007/s00018-010-0605-2. Epub 2010 Dec 15. Review. Citation on PubMed or Free article on PubMed Central
  • Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009 Oct 8;461(7265):788-92. doi: 10.1038/nature08476. Epub 2009 Sep 23. Citation on PubMed or Free article on PubMed Central
  • Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GAM, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CR, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014 Aug 7;371(6):507-518. doi: 10.1056/NEJMoa1312625. Epub 2014 Jul 16. Citation on PubMed or Free article on PubMed Central
  • Paludan SR, Bowie AG. Immune sensing of DNA. Immunity. 2013 May 23;38(5):870-80. doi: 10.1016/j.immuni.2013.05.004. Review. Citation on PubMed or Free article on PubMed Central
  • Xiao TS, Fitzgerald KA. The cGAS-STING pathway for DNA sensing. Mol Cell. 2013 Jul 25;51(2):135-9. doi: 10.1016/j.molcel.2013.07.004. Review. Citation on PubMed or Free article on PubMed Central
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