Familial Exudative Vitreoretinopathy (FEVR) is a vitreoretinal disease first reported by Criswick and Schepens in 1969. The essence is peripheral retinal avascularity and abnormal vascularization due to incomplete retinal vascular development, leading to secondary lesions such as retinal exudates, neovascularization, vitreous hemorrhage, and retinal detachment. The fundus appearance resembles that of retinopathy of prematurity.
It is a hereditary disease, and four main causative genes are known: FZD4, LRP5, TSPAN12, and NDP. The inheritance pattern is most often autosomal dominant, but autosomal recessive and X-linked recessive cases also occur. Heredity is often unclear, and half of the cases are sporadic.
The incidence in newborns is 0.11%, and the average age of onset is 6 years 1). The most common inheritance pattern is autosomal dominant (AD), but autosomal recessive (AR) and X-linked recessive (XLR) have also been reported 1). More than 11 causative genes have been identified, but known mutations explain only about 50% of cases 1).
Clinical presentation is asymmetric both between patients and within the same family, ranging from asymptomatic mild cases to severe visual impairment 1). Visual acuity is good unless retinal detachment occurs, but once severe, it tends to become refractory. Early diagnosis and preventive treatment determine the prognosis.
Despite the name “familial,” half of the cases are sporadic, and a clear family history is often absent. Due to incomplete penetrance, there may be asymptomatic mutation carriers within a family, and phenotypes can vary widely. Genetic testing can increase diagnostic certainty if a mutation is identified, but the absence of a detected mutation does not rule out FEVR.
Many patients are asymptomatic and may be discovered during school vision screenings or through family history. Many cases have only mild peripheral retinal abnormalities and are asymptomatic. The trigger for discovery varies by age.
The clinical findings of FEVR are classified into stages 1 to 5. Age-related changes in clinical presentation are characteristic. In infancy, proliferative changes and tractional retinal detachment manifest as leukocoria or falciform retinal folds; in childhood, exudative plaques from neovascularization and vitreous hemorrhage may occur.
The fundus appearance resembles that of retinopathy of prematurity (ROP), but unlike ROP, FEVR can reactivate even after postnatal quiescence. This is particularly frequent up to 2–3 years of age, and importantly, reactivation can occur even after age 10.
Mild (Stages 1–2)
Peripheral avascular zone: A V-shaped avascular area forms in the temporal periphery. This is the most basic finding.
Vascular straightening and traction: Blood vessels become straightened near the border of the avascular zone and are dragged toward the macula.
Brushing: On fluorescein angiography, brush-like dilatation of retinal vessels at the edge of the avascular zone is characteristic.
Macular dragging: Lateral displacement of the macula due to traction.
Severe (Stages 3–5)
Retinal fold: Formation of retinal folds with proliferative changes. Observed in approximately 28% of cases 5).
Neovascularization and exudation: Formation of new blood vessels and lipid exudation from the ischemic retina.
Partial/total retinal detachment: Exudative or tractional retinal detachment. Observed in 21–64% of cases 5).
Leukocoria: The most severe finding observed in stage 5 (total detachment).
The details of the stage classification are shown below.
| Stage | Findings | Main treatment strategy |
|---|---|---|
| 1 | Avascular zone only | Observation |
| 2 | Neovascularization and exudation | Laser/anti-VEGF |
| 3 | Peripheral retinal detachment | Vitrectomy/buckling |
| 4 | Extramacular retinal detachment | Vitrectomy |
| 5 | Total retinal detachment | Vitrectomy |
Detailed fundus findings include avascular areas, multiple branching and straightening of retinal vessels, and excessive arteriovenous crossings in the periphery. In the posterior pole, optic disc hypoplasia, macular traction, and multiple vascular branching are observed. Temporal macular dragging is also a characteristic of this disease, and retinal tears may form in avascular areas, leading to retinal detachment.
Optical coherence tomography (OCT) may reveal macular hypoplasia, epiretinal membrane, and proliferation of glial tissue around the optic disc.
Most cases of FEVR are bilateral, but unilateral cases have also been reported. Boal et al. (2021) reported a case of unilateral FEVR, demonstrating that it can present with clinically asymmetric phenotypes 5). Severity can vary greatly even within families, and highly asymmetric clinical presentation is a characteristic of this disease.
The four major genes responsible for FEVR are FZD4, LRP5, TSPAN12, and NDP, all of which are involved in the Wnt signaling pathway and are essential for normal retinal vascular development. The inheritance pattern is often autosomal dominant, but autosomal recessive and X-linked recessive cases also exist.
AD/AR (Autosomal)
FZD4: Encodes the Frizzled-4 receptor. Plays a central role in the Norrin/β-catenin pathway 1).
LRP5: Wnt co-receptor. Involved in capillary maturation 3). Can be inherited in both autosomal dominant and recessive patterns.
TSPAN12: Found in 5.6–8.0% of FEVR patients 1). 38% of mutations are concentrated in extracellular loop 2 (ECL-2) 1).
ZNF408 and KIF11: Other causative genes.
XLR (X-linked recessive)
NDP: Encodes the Norrin protein. Causative gene for X-linked recessive FEVR.
Association with Norrie disease: NDP mutations are also associated with Norrie disease (blindness, hearing loss, intellectual disability), forming a disease spectrum.
Multiple mutations can lead to more severe disease. Cases with double mutations in LRP5 and TSPAN12 have been reported to show significantly more severe phenotypes than those with single mutations 3).
Novel deletion mutations in TSPAN12 have been identified in FEVR patients, suggesting that exon deletions may constitute a portion of all TSPAN12 mutations 1).
Yes, it can be diagnosed. Only about 50% of cases can be explained by known mutations, and the remaining cases are thought to be caused by unidentified genetic mutations 1). If typical clinical findings (peripheral avascular area, V-shaped FA findings, family history) are present, a clinical diagnosis is possible even without detecting a mutation.
Wide-field fluorescein angiography (wide-field FA) is the most important test for diagnosing FEVR. Retinal vascular abnormalities may be unclear on ophthalmoscopy but are visualized on FA, making it useful. FA is also necessary to determine the presence of neovascularization.
Whole genome sequencing (WGS) is useful for detecting copy number variations (CNVs) and is superior for detecting exon deletions that may be missed by conventional targeted sequencing 1).
| Test | Main information | Features |
|---|---|---|
| Wide-field FA | Avascular area, leakage | Mainstay of diagnosis, all ages |
| OCT | Retinal layer structure, traction | Non-invasive, repeatable |
| OCTA | Capillary density, FAZ | No FA contrast needed |
FEVR must be differentiated from the following diseases. Particularly important are diseases presenting with retinal vascular dysplasia, diseases causing sickle retinal folds, and rhegmatogenous retinal detachment in young individuals.
Even if asymptomatic, it is important to perform fundus examination of family members to confirm the presence or absence of disease. The usefulness of a newborn screening program using RetCam III has been reported4).
Yes. FEVR has a high rate of incomplete penetrance, and lesions may be present even in asymptomatic family members. Screening from infancy is recommended for individuals with a family history. The usefulness of a newborn screening program using RetCam III has been reported4).
Treatment for FEVR is selected stepwise according to the stage. Early diagnosis and preventive treatment such as laser photocoagulation are crucial for prognosis.
In children, correction of refractive errors and amblyopia training may be necessary. Moderate myopia and astigmatism are common, and appropriate spectacle correction and amblyopia training during the visual development period are important. In cases of anisometropia, occlusion of the healthy eye may be considered.
If retinal neovascularization or retinal tears are present, laser photocoagulation is performed around the avascular areas or tears. Photocoagulation of non-perfused areas is the standard treatment 4, 6), aiming to regress neovascularization and suppress exudation. It is particularly effective for early-stage lesions (stages 1–2).
Anti-VEGF agents such as bevacizumab and ranibizumab are used 3, 4). They are effective against neovascularization and exudation, but caution is needed because monotherapy may worsen tractional changes 3). They are often used in combination with laser photocoagulation.
Vitrectomy is performed for proliferative changes (proliferative membranes, tractional detachment) 3). It is indicated for stage 3 or higher cases. Early intervention is recommended because retinal detachment can become refractory if severe.
Scleral buckling is chosen for retinal detachment with peripheral tears. Even if the lesion is controlled with buckling or laser, there is a risk of retinal detachment later due to tractional changes as the eye grows. Long-term follow-up throughout the growth period is essential.
Yes. In FEVR, progression of ischemia has been reported even in adulthood. Cases with double mutations in LRP5 and TSPAN12 have shown disease progression after age 19 3), so lifelong regular ophthalmic management is recommended even after treatment.
The essence of FEVR is retinal vascular maldevelopment due to genetic abnormalities. All causative gene products are involved in the Wnt signaling pathway and are essential for normal retinal vascular development.
The core of FEVR pathology is dysfunction of the Norrin/β-catenin pathway 1).
Normally, Norrin protein (encoded by NDP) binds to the FZD4 receptor and activates Wnt/β-catenin signaling via LRP5 co-receptor and TSPAN12. This signaling is essential for retinal vascular formation and maturation 1).
When this signaling is impaired, capillary formation in the peripheral retina becomes incomplete, leading to avascular areas. Avascular areas cause ischemia, elevating VEGF and resulting in neovascularization, exudation, and traction.
In FEVR-like lesions due to FADD (Fas-associated protein with death domain) deficiency, downregulation of apoptosis via the TNFα–FAS–FADD–caspase pathway is thought to lead to abnormal survival of retinal vascular endothelial cells, ischemia, and neovascularization 7).
Meer et al. (2022) reported FEVR-like retinal vascular abnormalities in patients with FADD deficiency 7). This example indicates the existence of a FEVR-like phenotype independent of the Norrin/FZD4 pathway, suggesting diversity in pathology.
SZN-413, a specific agonist of the FZD4 receptor, has shown restoration of retinal vascular development in preclinical studies 4). By directly activating the Norrin/FZD4 pathway, it is expected to correct the common pathology downstream of genetic mutations.
In the case report of FZD4 mutation by Yang et al. (2025), the rationale for therapeutic approaches aiming to enhance FZD4 signaling is also discussed4).
EMC1 has been identified as a novel regulator of the Wnt pathway4). EMC1 may be involved in the stability of the FZD4 protein and could represent a new therapeutic target.
WGS is more sensitive than conventional methods for genetic diagnosis of FEVR and can detect copy number variations such as exon deletions1). It plays an important role in identifying novel TSPAN12 deletion mutations and exploring unresolved genetic mutations1).
The usefulness of a newborn and infant screening program using RetCam III has been reported4), and early detection and treatment are expected to improve prognosis.
