into adjacent parenchyma present in both necrotic and non-necrotic tissue. Vessels can exhibit obliterative fibrosis in all the layers of vessel walls, as well as perivascular, adventitial fibrosis with limited intimal thickening. In rare cases, RVCL has been associated with severe disease involving other organs outside the brain and the eye (e.g., osteonecrosis requiring joint replacement, gastrointestinal ischemia leading to bowel resection, or liver failure requiring liver transplantation). Clinical Associations Raynaud's phenomenon Anemia Hypertension Normocytic anemia Normochromic anemia Gastrointestinal bleeding or telangiectasias Elevated alkaline phosphatase Chronic kidney disease Genetics RVCL is caused by mutations in the TREX1 gene. The official name of the TREX1 gene is "three prime repair exonuclease 1". The normal function of the TREX1 gene is to provide instructions for making the 3-prime repair exonuclease 1 enzyme. This enzyme is a DNA exonuclease, which means it trims molecules of DNA by removing DNA building blocks (nucleotides) from the ends of the molecules. In this way, it breaks down unneeded DNA molecules or fragments that may be generated during genetic material in preparation for cell division, DNA repair, cell death, and other processes. Changes (mutations) to the TREX1 gene can result in a range of conditions, one of which is RVCL. The mutant TREX1 protein is produced and mislocalized. Haploinsufficiency of TREX1 does not explain the disease, since the parents of patients with Aicairdi-Goutieres syndrome, a disease characterized by insufficient TREX1 activity, are completely healthy with only one functional TREX1 allele. Different mutations in the TREX1 gene have also been identified in people with disorders involving the immune system. These disorders include a chronic inflammatory disease called Aicardi-Goutieres syndrome, as well as systemic lupus erythematosus (SLE), including a rare form of SLE called chilblain lupus that mainly affects the skin. Those diseases, which are inflammatory, may have a completely distinct mechanism compared with that of RVCL. The TREX1 gene is located on chromosome 3: base pairs 48,465,519 to 48,467,644 Pathogenesis The main pathologic process centers on small blood vessels that prematurely "drop out" and disappear. The retina of the eye and white matter of the brain appear to be among the most sensitive to this pathologic process. Over a five- to ten-year period, this vasculopathy (blood vessel pathology) results in vision loss and destructive brain lesions with neurologic deficits and death. Although brain and eye disease are universally present in patients with RVCL, the disease is truly a