BASICS

DESCRIPTION

• Familial exudative vitreoretinopathy (FEVR) is a rare, inherited disorder in which one of several known gene mutations results in abnormal development of the retinal vasculature, characterized by a peripheral avascular zone.

• Secondary neovascularization (NV) may develop in response to retinal ischemia and may progress to fibrosis, retinal folds, macular ectopia, and ultimately, tractional retinal detachment (TRD). Cataract, neovascular glaucoma, and band keratopathy may occur in advanced stages.

• Phenotypic variability exists within families and even between eyes of the same patient; most are asymptomatic, while some suffer partial or even complete loss of vision.

• The clinical course can vary as well, from a nonprogressive or only slowly progressive course over a lifetime to a rapidly progressive course with total retinal detachment at a young age.

• Originally thought to stabilize in early adult life, FEVR is now recognized to have the potential of progressing even after years of stability.

• FEVR is usually bilateral, but may be markedly asymmetric.

EPIDEMIOLOGY

Incidence

Unknown (many are asymptomatic).

Prevalence

Unknown, yet likely underestimated given that molecular testing has suggested up to 90% of affected individuals may be asymptomatic (1).

RISK FACTORS

Family history of FEVR.

Genetics

• Autosomal dominance is the most common mode of inheritance, with autosomal recessive and X-linked recessive cases also being reported.

• Penetrance estimated to be 90–100% when using indirect ophthalmoscopy and fluorescein angiography to evaluate.

• Highly variable phenotypic expressivity ranging from asymptomatic disease to complete blindness in infancy.

• Thus far, 4 loci have been mapped, with genes from 3 of these loci identified:

– The EVR1 locus localizes to chromosome 11q13-q23; the EVR1 gene is FZD4.

– The EVR2 locus is the X-linked recessive locus and localizes to chromosome Xp11.4; the EVR2 gene is NDP, the same mutated gene in Norrie disease (X-linked recessive disorder characterized by congenital blindness as well as sensorineural deafness and mental deficiencies in 30% of patients).

– The EVR3 locus localizes to chromosome 11p12-p13; the specific gene at this locus has not yet been identified.

– The EVR4 locus localizes to a region within the original EVR1 locus, near FZD4; the EVR4 gene is LRP5.

– A recent study suggests at least a 4th locus for autosomal dominant FEVR, indicating FEVR to be even more heterogeneous than formerly realized (2).

• Proteins encoded by the 3 known FEVR genes are part of a signaling complex in the Norrin-β-catenin pathway, which is pivotal to retinal vasogenesis.

– Recently, Junge et al. (3) identified TSPAN12, (another component of this signaling complex) and Poulter et al. (4) showed TSPAN12 mutations lead to autosomal dominant FEVR.

GENERAL PREVENTION

None.

PATHOPHYSIOLOGY

• Gene mutations lead to defective protein products within a signaling complex that activates the Norrin-β-catenin pathway, which is vital to proper development of retinal vasculature.

• Defects in this pathway lead to incomplete retinal vascularization, leaving a peripheral avascular zone, which is thought to be the primary event in all affected patients.

• Complications secondary to the resulting peripheral retinal ischemia may ultimately result in variable degrees of vision loss.

• 20% of FEVR cases experience partial or total blindness (2).

ETIOLOGY

One of several gene mutations results in incomplete development of the retinal vasculature. Subsequently, peripheral ischemia leads to multiple complications and visual morbidity.

COMMONLY ASSOCIATED CONDITIONS

Patients with FEVR due to mutations in LRP5 have been shown to have reduced bone mass, a finding not yet reported in other forms of FEVR (1).

DIAGNOSIS

HISTORY

• A complete family history as well as history of any prematurity and/or oxygen therapy should be ascertained.

• Earlier studies suggested roughly ½ of affected individuals are asymptomatic. Recent molecular testing suggests this figure could be as high as 90% (1).

• Diagnosis of asymptomatic patients is typically made when family members of suspected or known cases are examined.

• Most infants present with failure to fix/follow, pendular nystagmus, heterotropia, or rarely, leukocoria from large retinal detachment (RD) or significant lipid exudation.

• Most children/adults present with a decrease in vision caused by RD, retinal folds, or macular ectopia.

• Some may present with pseudoexotropia (positive angle kappa due to ectopic macula).

PHYSICAL EXAM

• Visual acuity ranges from 20/20 to <20/200.

• Complete dilated fundus examination including scleral depression

• Avascular zone in the peripheral retina is present in all patients and may be the lone manifestation. It is usually confined to the temporal periphery, but may extend 360°

– Visualization of avascular zone enhanced with green filter during ophthalmoscopy

• Other funduscopic findings may include the following:

– Brushlike appearance of retinal vessels near the avascular zone

– Extensive branching of retinal vasculature

– Dilated vessels with temporally bent course

– Neovascularization

– Vitreous hemorrhage

– Subretinal exudation

– Fibrotic reaction manifest as vitreoretinal opacities

– Retinal traction leading to retinal folds, macular ectopia (optic disc and retina dragged temporally), or TRD

DIAGNOSTIC TESTS & INTERPRETATION

Imaging

• Fluorescein angiography (FA) with peripheral sweeps, or ultrawide field FA

• Key angiographic features include the following (5)[B]:

– Abrupt capillary closure (avascular zone)

– Dragging of perimacular capillaries and vessels temporally toward periphery

– Dilation of perimacular capillaries with mild leakage

– Abnormal tortuous and stretched vessels

– Peripheral AV shunts with leakage

Pathological Findings

Cases to date have shown total retinal detachment with prominent fibrovascular membranes. In addition, some cases have shown intraretinal and subretinal cells/exudates, and focal retinal inflammation (6).

DIFFERENTIAL DIAGNOSIS

• The condition that most closely resembles FEVR is retinopathy of prematurity (ROP).

– Positive family history and lack of history of prematurity help distinguish FEVR from ROP.

• Other conditions that may mimic FEVR: Persistent fetal vasculature, X-linked retinoschisis, Norrie disease, incontinentia pigmenti, Coats’ disease, pars planitis, and Toxocara infection (7).

TREATMENT

ADDITIONAL TREATMENT

Additional Therapies

• Anti-VEGF therapy:

– 1 case series (8)[C] of 4 patients with increasing exudates despite standard therapy were given a single injection of pegaptanib sodium. After 11 months, all patients had evidence of decreased exudation. However, traction continued to progress, possibly even accelerated by the anti-VEGF agent.

– More data needed to assess role/long term complications of VEGF inhibitors in FEVR

SURGERY/OTHER PROCEDURES

• The following recommendations are based on a retrospective case series by Pendergast and Trese (9)[C]:

– Eyes with presence of avascular zone only should be observed.

– Eyes with early stages of neovascularization or exudate without retinal detachment should receive laser ablation or cryotherapy if there is significant exudation and retinal elevation.

– Eyes with mild TRD not involving the fovea may respond well to scleral buckling alone, while more advanced detachments require pars plana vitrectomy as well.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Children require regular monitoring for early detection of neovascularization, exudate, and TRD.

• Asymptomatic patients whose only manifestation is the peripheral avascular region may require annual follow-up only.

• Those with neovascularization or exudate should undergo treatment and close observation.

• Those with retinal traction should be followed at intervals based on stability of clinical findings.

Patient Monitoring

See Follow-Up Recommendations section.

PATIENT EDUCATION

• Genetic counseling appropriate to the mode of inheritance should be offered.

• Family members should be educated on the chronic, progressive course and variable nature of the disease and should undergo screening examination.

PROGNOSIS

• Benson (7) reported a poor visual prognosis with onset of symptoms prior to age 3; older patients were thought to have a better prognosis due to more asymmetric involvement.

• Even those considered stable for years have the potential to progress.

• Patients with early exudation in which the abnormal vessels respond to laser or cryotherapy appear to have the best prognosis.

COMPLICATIONS

Neovascularization, hemorrhage, exudation, AV malformations, falciform folds and macular ectopia, retinal tears and TRD, blindness.

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