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.

Suggestive Findings

RVCL-S should be suspected in individuals with the following findings [Stam et al 2016, Pelzer et al 2019].

Major features

• Vascular retinopathy typically manifesting as decreased visual acuity and/or visual field defects
• Focal and/or global brain dysfunction and brain MRI abnormalities
  • Focal neurologic signs can include but are not limited to hemiparesis, facial weakness, aphasia, and hemianopsia.
  • Global brain dysfunction may manifest as progressive cognitive impairment.
  • Brain MRI abnormalities are restricted to the white matter (see Clinical Characteristics, Neurologic Features).
• Family history of middle-age onset of disease manifestations consistent with an autosomal dominant inheritance pattern
  Note: Absence of a known family history of similarly affected individuals does not preclude the diagnosis.

Supportive features

• Calcifications on brain CT scan, typically not present in healthy controls
• Nonspecific MRI white matter lesions that occur more frequently than expected given the age of the individual
• Microvascular liver disease, manifested by modest elevations of alkaline phosphatase and gamma-glutamyltransferase
• Microvascular kidney disease, typically manifested by a mild-to-moderate increase in serum creatinine or by proteinuria

Likely associated features

• Anemia consistent with blood loss and/or chronic disease (typically normocytic and normochromic)
• Microscopic gastrointestinal bleeding
• Hypertension
• Migraine with or without aura
• Raynaud phenomenon (typically mild)
• Subclinical hypothyroidism

Establishing the Diagnosis

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 (see Table 1).

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis of TREX1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis of TREX1.
• A multigene panel that includes TREX1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  Note: At the Leiden University Medical Center, a panel of genes is used to screen for pathogenic variants that cause cerebral angiopathies and adult-onset leukoencephalopathies. New pathogenic variants that cause these disorders continue to be discovered; click here for more information.

Clinical Description

Clinical information about RVCL-S is summarized from the following reports of individuals with molecularly confirmed RVCL-S: Storimans et al [1991], Terwindt et al [1998], Cohn et al [2005], Richards et al [2007], Winkler et al [2008], Mateen et al [2010], Gruver et al [2011], Schuh et al [2014], Dhamija et al [2015], DiFrancesco et al [2015], Stam et al [2016], Vodopivec et al [2016], Carra-Dalliere et al [2017], Hardy et al [2017], and Pelzer et al [2019]. The numerators and denominators in this section are derived from the study by Stam et al [2016], which included 11 affected families and is the largest study to date on RVCL-S.

RVCL-S is a small-vessel disease that systemically affects various highly vascularized organs. Affected individuals develop retinal vasculopathy and neurologic symptoms, in addition to other systemic manifestations including impaired liver and renal function.

Clinical presentation is variable; onset is often between ages 35 and 50 years, with a mean age at clinical diagnosis of 42.9 years (SD ±8.3, range 25-61 years). Life expectancy is decreased; the average age of death is 53.1 years (SD ±9.6, range 32-72). Cause of death is frequently pneumonia or sepsis in the setting of general debilitation. For clinical course see Figure 1.

Figure 1.

Clinical course of RVCL-S Adapted from Pelzer et al [2019]

Genotype-Phenotype Correlations

To date, all pathogenic variants have been frameshift variants in the region of TREX1 encoding the carboxyl terminus of TREX1 (see Molecular Genetics).

To date no genotype-phenotype correlations have been observed.

Penetrance

Penetrance of RVCL-S is age dependent; however, it is thought that all individuals with a heterozygous pathogenic TREX1 variant will develop features of this condition if they live long enough.

Nomenclature

Previous descriptions of families with cerebroretinal vasculopathy (CRV); hereditary vascular retinopathy (HRV); hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS); hereditary systemic angiopathy (HSA); and retinal vasculopathy with cerebral leukodystrophy (RVCL) represent early reports of RVCL-S.

Prevalence

Currently, fewer than 25 families with RVCL-S are known. However, RVCL-S is most likely underdiagnosed because physicians are generally unfamiliar with the disorder. For example, in the Netherlands alone three unrelated families have been identified because of increased awareness of this condition. The widespread availability of exome and genome sequencing techniques likely also contribute to increased recognition of RVCL-S.

Focal and/or Global Brain Dysfunction / MRI Brain Abnormalities

Focal and/or global brain dysfunction and MRI brain abnormalities (intracerebral mass lesions and white matter abnormalities) seen in RVCL-S can be similar to intracranial neoplasm, multiple sclerosis, multi-infarct dementia, and central nervous system vasculitis. In these disorders other organs are usually not affected. Moreover, these conditions do not typically follow an autosomal dominant inheritance pattern.

• In sarcoidosis and systemic lupus erythematosus (SLE) (see Table 3) there can be focal and/or global brain dysfunction as well as involvement of multiple organs, as is seen in RVCL-S.
• With sarcoidosis, however, there is frequent involvement of the lungs and skin. No lesions in the lungs have been described in individuals with RVCL-S and skin lesions are not frequently reported [Hardy et al 2017].

Vascular Retinopathy

Vascular retinopathy can occur as a long-term complication of diabetes mellitus and hypertension:

• As the vascular retinopathy in RVCL-S is usually observed at a relatively young age (retinopathy has been found in the third decade of life) it is unlikely to be a complication of hypertension or diabetes mellitus, even in those with RVCL-S who have co-occurrence of hypertension or diabetes.
• Vascular retinopathy can also be caused by systemic lupus erythematosus, sarcoidosis, and ophthalmologic infections (which are outside of the scope of this GeneReview).
• In Susac syndrome, vascular retinopathy and encephalopathy are part of the symptomatology, as is hearing loss, but hearing loss is very rare in RVCL-S. The pattern of white matter lesions seen on MRI may also help to distinguish the two conditions.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

It is crucial that unnecessary diagnostic tests not be undertaken. Biopsies of the brain, kidney, or liver are not required in individuals with RVCL-S and do not appear to provide additional prognostic or treatment information.

Treatment of Manifestations

Table 5 summarizes treatment for the manifestations of an individual diagnosed with RVCL-S.

Surveillance

There are currently no consensus guidelines for monitoring individuals with RVCL-S. However, close monitoring is recommended. The frequency of monitoring depends on the manifestations and rate of disease progression (see Table 6).

Agents/Circumstances to Avoid

Although there is no evidence, the authors would advise against intravenous tissue-type plasminogen activator (IV tPA) for acute ischemic stroke. There is to date no proof that the neurologic manifestations are caused by occluded large blood vessels (RVCL-S is a small vessel disease), and the risk of complications of such treatment (e.g., a secondary hemorrhage) 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 that could benefit eyesight and prevent secondary damage due to hypertension. Furthermore, clarification of the genetic status of at-risk relatives could prevent unnecessary diagnostic tests (e.g., liver/kidney/brain biopsies).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Currently, a pilot study for treating RVCL-S with aclarubicin has been started. For details, see ClinicalTrials NCT02723448.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with RVCL-S have an affected parent. However, there is large variability within families in disease onset and severity.
• Some individuals diagnosed with RVCL-S have the disorder as the result of a de novo TREX1 pathogenic variant [DiFrancesco et al 2015]. Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the pathogenic variant occurred de novo, the proportion of RVCL-S caused by a de novo pathogenic variant is unknown.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the TREX1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
• The family history of some individuals diagnosed with RVCL-S may appear to be negative because of failure to recognize the disorder in family members (RVLC-S can be misdiagnosed as multiple sclerosis, multi-infarct / frontal lobe dementia, or other organ dysfunction), early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to be heterozygous for the TREX1 pathogenic variant, the risk to the sibs is 50%.
• If the proband has a known TREX1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• The absence of clinical manifestations in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance or late onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with RVCL-S has a 50% chance of inheriting the TREX1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TREX1 pathogenic variant, his or her family members may be at risk.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the TREX1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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Author Notes

Leiden University Medical Center web pages (in Dutch)

RVCL-S patient information
RVCL research

The Leiden University Medical Center has expertise in the diagnosis and treatment of RVCL-S and other cerebral hereditary angiopathies (CHA). As part of a consortium we were involved in finding the locus and gene – TREX1 – responsible for RVCL-S. We aim to study RVCL-S disease pathology through our collaboration with world-renowned scientists and our integrated clinical, radiologic, molecular, and biological approach with this unique patient group and our transgenic mouse model, and aim to include new exciting research opportunities such as brain-on-chip development.

Revision History

• 19 September 2019 (ma) Review posted live
• 15 November 2017 (gt) Original submission