Familial Exudative Vitreoretinopathy (FEVR)

Etiology

As the name suggests, FEVR is acquired via familial inheritance. FEVR has been linked to the genes NDP, FZD4, LRP5, and TSPAN12 through knockout mouse models. These genes encode components of the Wnt signaling pathway, which is essential for retinal vascular formation.[1] Additionally, the transcription factor ZNF408 has also been associated with the disease. Together, these 5 genes may account for up to 50% of FEVR cases.[3] Inheritance patterns identified so far include autosomal dominant (FZD4, TSPAN12, ZNF408, LRP5, and KIF11), autosomal recessive (FZD4, TSPAN12, and LRP5), and X-linked recessive (NDP).[4] 

Epidemiology

Numerous genetic risk factors for FEVR have been identified. However, due to variable inheritance patterns and differences in gene expression, individuals within the same family may present with significantly different stages of the disease. As a result, epidemiological data may underrepresent the true incidence and prevalence of the condition, including the range of genotype–phenotype combinations and associated demographics.[4]

A large multicenter, cross-sectional study conducted in China documented the incidence of various ocular abnormalities detected through digital funduscopic examination of newborns within 42 days of birth. A total of 199,851 newborns were examined, and 18,198 (9.11%) were found to have ocular abnormalities, with no gender difference in prevalence. FEVR was diagnosed in 217 newborns, accounting for 1.19% of all ocular abnormalities and indicating an incidence of 0.11% in the general population. Although the study is limited by demographic constraints and the absence of confirmatory testing with wide-field fluorescein angiography, the findings suggest that the incidence of FEVR may be higher than previously recognized.[7] 

A recent systematic review and meta-analysis of 3257 patients from 32 studies analyzed the frequency of multiple FEVR-associated genes in relation to gender, age, and severity. The findings showed that LRP5 and FZD4 were the most common gene mutations implicated in FEVR, accounting for 13.6% and 11.5% of cases. Mutations in the NDP, TSPAN12, ZNF408, and KIF11 genes were less common, representing 4.6%, 6.7%, 1.6%, and 5.7% of cases, respectively. The gender distribution for NDP mutations was almost exclusively male, consistent with its X-linked recessive inheritance pattern. No significant gender differences were observed for patients with TSPAN12, FZD4, or LRP5 mutations.

The average age of onset for FEVR associated with the gene mutations NDP, LRP5, TSPAN12, and FZD4 was 3.0, 5.0, 5.3, and 7.4 years, respectively. Disease severity linked to these mutations was also analyzed in the study, with presentations classified as either mild or severe using a 5-stage classification system—stages 1 and 2 represent "mild" disease (typically asymptomatic) and stages 3 to 5 indicate "severe" disease involving some degree of retinal detachment. All genetic variants were predominantly associated with severe disease. Notably, mutations in NDP and LRP5 were most strongly associated with stage 4 and stage 5 disease, respectively. TSPAN12 was associated with the least severe form of the disease among all subtypes.[8] Further epidemiological studies and genotype-phenotype correlations may help guide treatment recommendations and monitoring parameters.

Pathophysiology

In the developing eye, 2 processes drive the formation of the vascular retina—vasculogenesis and angiogenesis. Vasculogenesis refers to the de novo formation of new blood vessels from endothelial precursors. The hyaloid vasculature, which is a transient embryonic vascular plexus, supplies nutrients to the eye from 4 to 6 weeks of gestation and is primarily driven by vasculogenesis. Angiogenesis, on the other hand, involves the formation of new blood vessels from preexisting vasculature and is responsible for the development of capillaries in the deeper and peripheral retina.

Signaling pathways, particularly Wnt/β-catenin signaling, are crucial in angiogenesis and have been the focus of extensive research in understanding FEVR. Of the 6 alleles commonly associated with FEVR (NDP, FZD4, LRP5, TSPAN12, ZNF408, and KIF11), 4 of them (NDP, FZD4, LRP5, and TSPAN12) are involved in the Wnt/β-catenin signaling pathway. The ultimate effect of this pathway is the prevention of cytoplasmic β-catenin phosphorylation and degradation. The accumulation of this signaling molecule causes its translocation to the nucleus, where it binds to lymphoid enhancer factor/T-cell factor (LEF/TCF) to promote the transcription of Wnt target genes. The absence of expression of these genes leads to angiogenesis errors, a leaky endothelium, and the failure of endothelial cell apoptosis during the regression of hyaloid vasculature.[1][5] 

Therapies aimed at activating the Wnt signaling pathway independently of Frizzled receptors and LRP may represent a novel treatment approach. A 2016 study using LRP5 knockout mouse models demonstrated statistically significant recovery of retinal vascularization and regression of hyaloid vasculature when treated with lithium, a receptor-independent activator of the Wnt signaling pathway.[9] The normal progression of the disease begins with peripheral retina avascularity. Hypoxia at the junction of the vascular and avascular regions of the retina promotes neovascularization and fibrovascular changes. These changes lead to posterior pole traction and, eventually, retinal detachment, which may be either tractional or rhegmatogenous. Subretinal exudation is also commonly observed.[4]

History and Physical

Patients with FEVR can present with a variety of symptoms depending on the stage of the disease. In the early stages, patients are often asymptomatic but may show evidence of peripheral retinal avascularity on a dilated eye examination. Patients may experience decreased visual acuity due to neovascularization, subretinal exudation, or retinal detachment in more severe stages. In cases of total retinal detachment or extensive exudate, a child may present with leukocoria (a white pupil). 

An eye with decreased vision may present with strabismus (misalignment of the eyes). These features are also seen in ROP, but a thorough history can help differentiate between the 2 conditions. Additional family history can aid in establishing the diagnosis, although family members may be asymptomatic. A dilated funduscopic examination of family members may reveal asymptomatic disease. Notably, while FEVR is familial, prior studies have shown that a positive family history is present in only 10% to 50% of cases.[4]

Evaluation

Patients with FEVR are evaluated with a dilated funduscopic examination, often followed by ancillary ophthalmic tests such as fluorescein angiography, fundus photography, and optical coherence tomography (OCT). Areas of peripheral retinal ischemia may initially be detected during the dilated examination and then confirmed with fluorescein angiography. In young children who are unable to cooperate with the examination, an eye examination under anesthesia may be required to confirm the diagnosis (see Images. Familial Exudative Vitreoretinopathy—Preoperative Fundus Photograph and Familial Exudative Vitreoretinopathy—Postoperative Fundus Photograph).

Classically, the avascular retina occurs in the temporal periphery but may extend to involve all retinal quadrants, depending on the severity of the disease.[10] Additional angiographic findings may include arterial tortuosity, fluorescein leakage, and peripheral neovascularization.[11] OCT allows visualization of common FEVR complications, such as cystoid macular edema, intraretinal exudation, and vitreomacular distortion and traction (see Image. Macular Edema in Familial Exudative Vitreoretinopathy). As with many retinal pathologies, OCT findings often correlate with the presenting symptoms. However, a dilated peripheral examination, fluorescein angiography, and patient history are essential in making an accurate diagnosis.

Treatment / Management

The management of FEVR includes various procedural and surgical interventions, largely guided by the clinical stage of the disease. In mild, asymptomatic cases, observation with close follow-up is a reasonable approach. For symptomatic patients, primary treatment options include laser photocoagulation, anti-vascular endothelial growth factor (VEGF) injections, pars plana vitrectomy, and scleral buckling. In patients with stage 2 disease, laser photocoagulation is typically applied to areas of avascular retina.[12] Anti-VEGF has also been used with varying degrees of success.[13][14][15](B3)

In more advanced stages (ie, stages 3–5), pars plana vitrectomy is commonly required, with or without scleral buckling.[16][17] The primary goal of surgical intervention is to relieve traction on the retina and reduce underlying angiogenic activity. This may involve various surgical techniques, including membrane peeling, retinal tamponades, silicone oil or intraocular gas use, and focal or panretinal photocoagulation.[4] 

In addition, it is important to remember that FEVR is both a familial and lifelong condition. Screening asymptomatic family members can often help elucidate the underlying inheritance pattern. Additionally, while many patients present with complications in early childhood, adults who were previously asymptomatic may later develop complications that require treatment as well.[1]

Differential Diagnosis

A differential diagnosis for patients with examination findings suggestive of FEVR includes ROP, Coats disease, Norrie disease, persistent fetal vasculature, and retinoblastoma.[18] Unlike ROP, patients with FEVR are typically born full term with normal birth weight and no history of supplemental oxygen use.[19] Although Coats disease shares many clinical similarities with FEVR, it is usually unilateral and lacks the genetic associations seen in FEVR.[20][21] 

Norrie disease can be caused by mutations in similar genes; however, it progresses much more rapidly than FEVR. Many patients experience severe vision loss at birth or shortly thereafter and often exhibit cognitive and behavioral deficits that are not typically associated with FEVR.[22][23] Persistent fetal vasculature may cause retinal dragging but is distinguished by a fibrovascular stalk extending from the optic nerve to the lens—an anatomical feature not seen in FEVR.[24] Retinoblastoma is a metastatic cancer that can initially mimic other ocular conditions but presents with distinct features in later stages as the tumor enlarges.[25]

Staging

FEVR is classified into 5 stages, with the most recent staging system proposed by Kashani et al.[6]

Prognosis

The prognosis of FEVR depends on the clinical stage at presentation, with later stages being more likely to result in permanent vision loss. The disease can progress without proper evaluation and treatment, potentially leading to total retinal detachment in some cases. Early intervention with laser photocoagulation may help prevent progression. Surgical cases generally have a more guarded prognosis.[4] In a case series, 30% of eyes with FEVR developed retinal detachments. However, the reattachment rate after surgery was 12 out of 14 eyes, and half of the eyes achieved a best corrected visual acuity of 5/60 or better after 2 years.[26]

Complications

Complications of FEVR include neovascularization, subretinal exudates, peripheral retinal avascularity, retinal folds, epiretinal membranes, dragged macula, and retinal detachments.[1] These complications can result in irreversible vision loss. If left untreated during early childhood, they may also lead to amblyopia (abnormal visual development). Please see StatPearls' companion resource, "Amblyopia," for more information.

Poor vision can also lead to strabismus, a condition where the normal alignment of the eyes is disrupted, affecting physical appearance. In rare cases, eyes with complications from FEVR may need to be removed due to abnormal physical appearance and chronic pain associated with the complications of the disease.[27]