A 13-month-old boy was referred to the retina clinic for a second opinion. At 4 months of age, his parents reported his right eye was crossing inward. He was evaluated by several pediatric ophthalmologists and retina specialists who noted a retinal fold in the right eye and was subsequently diagnosed with persistent fetal vasculature (PFV).

On our examination under anesthesia, the anterior segment was remarkable for a temporal posterior capsular fibrotic attachment in the right eye. Funduscopic examination showed the radial fold extending from the optic disc to the temporal periphery in the right eye, and inserting toward the ciliary processes and attached to the temporal lens capsule by fibrotic tissue (Figure 1A). The retinal vasculature appeared to be drawn into this fold. Widefield fluorescein angiography (FA) in the right eye revealed retinal vasculature within the radial fold and peripheral avascular retina (Figure 1B). In the left eye, FA revealed peripheral avascular retina and anomalies at the vascular tips (Figure 1C).

Based on these clinical findings, there was a high suspicion for familial exudative vitreoretinopathy (FEVR), and the patient underwent laser to peripheral avascular retina in both eyes. Vitreoretinal surgery is not indicated for these tight retinal folds, therefore surgical intervention was not recommended.

Genetic testing was performed and revealed that the patient had a heterozygous deletion in TSPAN12, which was classified as pathogenic. This mutation was also identified in the patient’s mother, but not the father.

Based on these findings, the patient’s 4-year-old older brother, who was asymptomatic and without genetic testing, was evaluated in the clinic. In-office widefield fundus photography and FA using oral dye showed mild peripheral vascular changes in both eyes (Figure 2) and the patient was subsequently diagnosed with stage 1 FEVR. His eyes were observed, as mild stage 1 without leakage/exudation can be monitored, especially in children who can cooperate with outpatient examinations.

CLINICALLY DISTINGUISHING BETWEEN FEVR AND PFV

FEVR is a hereditary vitreoretinopathy characterized by anomalous retinal vascular development with varying degrees of peripheral nonperfusion. These peripheral retinal abnormalities include avascular peripheral retina, peripheral retinal neovascularization, macular dragging, subretinal exudation, and vitreoretinal traction. FEVR is a bilateral condition, yet often asymmetric in severity.^1,2 FEVR is a lifelong condition where continuous monitoring is required to evaluate for late reactivations, while PFV tends to be more confined to earlier years in life where close monitoring is recommended.

This patient was initially diagnosed with PFV, which is typically a sporadic and unilateral disease. Clinically, PFV is divided into three subcategories: anterior, posterior, or a combination of the two.³ In anterior PFV, remnants of the tunica vasculosa lentis fail to regress, leading to retrolental or lenticular fibrovascular membranes that can obstruct the visual axis. Notably, in this case, there were no anterior segment abnormalities, including early cataract formation or elongated ciliary body processes.

The eye size was also symmetric—eyes affected by PFV are often smaller than the fellow normal eye. In posterior PFV, failed degradation of the hyaloid artery results in a fibrovascular stalk connected to the vitreous and retina. This stalk may pull on surrounding structures causing secondary tractional retinal detachments and retinal dysplasias. However, in this case, the right eye is noted to have a radial fold extending temporally (Figure 1A) without a fibrovascular stalk. These radial folds are classic for FEVR, and atypical for PFV. But do note that elements of PFV can present in eyes with FEVR as well.

DISTINGUISHING FEVR FROM PFV VIA GENETIC TESTING

Although PFV is often a sporadic disease without systemic associations, FEVR is a hereditary disease that has potential systemic implications depending on the genes involved. The classic FEVR genes include FZD4, NDP, TSPAN12, and LRP5, which are all involved in the Wnt-signaling pathway.^4-6 In this case, the patient was found to have a pathologic mutation in TSPAN12.

Advances in genetic testing have identified additional genes implicated in the pathogenesis of FEVR with potential systemic associations. For example, a new syndrome has been described of CTNNB1 mutations associated with developmental delay, microcephaly, and ophthalmic manifestations similar to FEVR.^7,8 Dyskeratosis congenita has also been identified as a potential masquerader of FEVR, and is characterized by reticular skin hyperpigmentation, dystrophic nails, oral leukoplakia, bone marrow failure, and exudative vitreoretinopathy.⁹ These findings highlight the importance of systemic evaluation in all patients diagnosed with FEVR.

WIDEFIELD ANGIOGRAPHY FOR FEVR

Diagnosing a patient with FEVR also has screening implications for family members. More than half of asymptomatic family members of patients with FEVR may have subclinical findings that are only visible on widefield FA.¹⁰ Widefield FA has highlighted the immense variation in the disease process and its anatomic presentation.

Furthermore, widefield FA has underscored the need for lifelong monitoring in patients with FEVR for possible reactivation even after treatment. There can be some overlap in angiographic findings between FEVR and PFV, such as the presence of peripheral avascular retina in the affected, and sometimes to a lesser degree in the fellow eye as well. But in FEVR, the vascular anomalies are much more pronounced, and we should have a lower threshold to treat the avascular retina.

In this case, the patient’s older brother was found to have stage 1 FEVR based on outpatient widefield FA using oral fluorescein. Oral fluorescein administration is a great option for children who cannot tolerate intravenous access but are old enough to cooperate for outpatient imaging.

Although dosing is not standardized, our practice uses 25 mg/kg for children under 20 kg, one bottle (500 mg) for those 21 to 45 kg, and two bottles (1,000 mg) for children heavier than 45 kg.¹¹ We mix fluorescein with 4 to 6 ounces of fruit juice, and images are taken 15 to 20 minutes later for late-frame angiograms (Figure 2).

BOTTOM LINE

PFV and FEVR are two important pediatric vitreoretinopathies that have unique features based on clinical presentation, genetics, and imaging. The distinction between the diseases is critical given the potential systemic associations, screening implications, treatment considerations, and need for lifelong monitoring in patients diagnosed with FEVR. NRP

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