Clinical characteristics: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a small-vessel disease that affects highly vascularized tissues including the retina, brain, liver, and kidneys. Age of onset is often between 35 and 50 years. The most common presenting finding is decreased visual acuity and/or visual field defects. Neurologic manifestations may include hemiparesis, facial weakness, aphasia, and hemianopsia. Migraines and seizures are less frequently described. Renal manifestations may include mild-to-moderate increase in serum creatinine and mild proteinuria; progression to end-stage renal disease (ESRD) is uncommon. Hepatic manifestations frequently include mildly elevated levels of alkaline phosphatase and gamma-glutamyltransferase (GGT). Less common findings include psychiatric disorders, hypertension, mild-to-moderate anemia, and Raynaud phenomenon.

Diagnosis/testing: The diagnosis of RVCL-S is established in a proband with suggestive findings and a heterozygous pathogenic variant in TREX1 identified by molecular genetic testing.

Management: Treatment of manifestations: Retinal vasculopathy may be treated with laser therapy, which may also prevent and slow the progression of visual impairment; macular edema may respond to bevacizumab; ESRD may require renal replacement therapy (including renal transplantation); corticosteroid therapy may be considered for those with cerebral vasogenic edema; standard treatment for glaucoma, hypertension, migraine headaches, seizure disorders, hypothyroidism, anemia, Raynaud phenomenon, and psychiatric disorders.

Surveillance: Ophthalmologic evaluation, blood pressure assessment, renal function tests (serum creatinine, BUN, and urinalysis to include creatinine and protein content), liver function tests (AST, ALT, alkaline phosphatase, GGT, serum albumin), TSH and free T4, and complete blood count annually starting in the fourth decade or as appropriate based on symptoms; annual assessment of cognition and psychiatric manifestations.

Agents/circumstances to avoid: Intravenous tissue-type plasminogen activator therapy for acute ischemic stroke is not warranted, as there is no proof that neurologic manifestations are caused by occluded large blood vessels and the risk of complications is assumed to be higher in affected individuals.

Evaluation of relatives at risk: It is appropriate to evaluate the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the TREX1 pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Genetic counseling: RVCL-S is inherited in an autosomal dominant manner. Most individuals diagnosed with RVCL-S have an affected parent. However, disease onset and severity vary considerably even within the same family. The offspring of an individual with RVCL-S are at a 50% risk of inheriting the TREX1 pathogenic variant. If the pathogenic variant in the family is known, prenatal testing for pregnancies at increased risk for RVCL-S and preimplantation genetic testing are possible; however, such testing for adult-onset disorders is uncommon.