Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), formerly known as cerebroretinal vasculopathy (CRV), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), or hereditary vascular retinopathy (HVR), is a rare progressive small vessel disease caused by heterozygous frameshift mutations in the TREX1 gene on chromosome 3p21. These mutations result in C-terminal truncation of the TREX1 protein, leading to dysfunction of the major mammalian 3'-to-5' DNA exonuclease and subsequent vascular endothelial damage affecting multiple organ systems. The disease primarily affects the eyes, brain, kidneys, and liver. Retinal vasculopathy is typically the earliest manifestation, presenting with progressive vision loss due to retinal capillary obliteration, microaneurysms, and telangiectasias. Cerebral involvement includes white matter lesions (leukoencephalopathy) that can mimic tumors or inflammatory conditions, leading to cognitive decline, psychiatric symptoms, migraines, seizures, and stroke-like episodes. Systemic features may include Raynaud phenomenon, renal dysfunction (proteinuria, elevated creatinine), hepatic nodular regenerative hyperplasia, anemia, and bone pain. Symptoms typically begin in the third to fifth decade of life and progress over 5 to 15 years. There is currently no cure or disease-modifying treatment for RVCL-S. Management is supportive and symptomatic, focusing on monitoring and treating complications such as vision loss, neurological deterioration, and renal impairment. Anti-VEGF injections may be used for retinal complications. Clinical trials investigating potential therapies are ongoing. Genetic counseling is recommended for affected families given the autosomal dominant inheritance pattern, with each child of an affected individual having a 50% chance of inheriting the pathogenic variant.

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