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Familial Exudative Vitreoretinopathy

Home / Pediatric Ophthalmology and Strabismus / Disorders of the Retina and Vitreous

Title: Familial Exudative Vitreoretinopathy
Author (s): Jeffrey Z. Kartchner, BS; Mary E. Hartnett, MD
Photographer: Unknown
Date: 07/20/2016
Keywords/Main Subjects: Familial exudative vitreoretinopathy, exudative retinal detachment, persistent fetal vasculature, retinopathy, leukocoria
Secondary CORE Category:  Retina and Vitreous / Diseases of the Vitreous and Vitreoretinal Interface
Diagnosis: Familial Exudative Vitreoretinopathy
Format: Case presentation

History of Present Illness: A 4-month old boy born at full term after an uncomplicated pregnancy presented with exophoria and microphthalmia of the left eye, and also with right eye preference. He was seen by an outside pediatric ophthalmologist and diagnosed with leukocoria and probable persistent fetal vasculature (PFV) and referred to our retina service for surgery.

Past medical history was unremarkable. Family history was positive for mother with strabismus and maternal uncle with congenital cataract of unknown etiology.

Initial Examination: The patient’s visual acuity was “fix & follow” in both eyes. He had a mild afferent pupillary defect in the left eye, but none present in the right eye. His corneal diameter on the left side was 10mm, compared to 11mm on the right. External exam was otherwise normal bilaterally. Fundus exam of the right eye was normal, but no view was achieved on the left eye because of a dense retrolental membrane. A B-Scan ultrasound was performed, which showed a total retinal detachment with an open funnel. The decision was made to proceed with examination under anesthesia (EUA) with plans to perform a lensectomy and vitrectomy in the left eye for presumed PFV.

Clinical Course: The patient underwent EUA and was found to have an area of peripheral avascular retina in the right eye. Fluorescein angiography of this eye later showed peripheral avascular retina and leakage of the vessels at the junction of vascular and avascular retina consistent with stage 2A FEVR (Figure 1). The patient underwent lensectomy and vitrectomy in the left eye which revealed a retrolental membrane and a complete retinal detachment with a nasal exudative retinal fold, consistent with Stage 5 FEVR (Figure 2).

Figure 1: Fluorescein angiography (FA) of the right eye. There is an area of peripheral avascular retina with neovascular tufts along the border.

Figure 1: Fluorescein angiography (FA) of the right eye. There is an area of peripheral avascular retina with neovascular tufts along the border.

Figure 2: Fundus photography of the right eye following initial lensectomy-vitrecomy, demonstrating the nasal fold from the surgeon’s view and a circumferential subretinal band surrounding the optic nerve.

Figure 2: Fundus photography of the right eye following initial lensectomy-vitrecomy, demonstrating the nasal fold from the surgeon’s view and a circumferential subretinal band surrounding the optic nerve.

The patient underwent scatter photocoagulation of the avascular retina in the right eye (Figure 3). The patient subsequently underwent several additional EUAs and surgeries to drain subretinal fluid or release traction. Genetic studies revealed a heterozygous mutation of the FZD4 gene via the EyeGene research study.

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Figure 3: FA of the right eye. Scatter photocoagulation has been performed to include the avascular retina and neovascularization in its entirety.

Current Exam: At age 21-months the patient’s visual acuity in the right eye is 20/32 by Allen acuity cards and light reactive in the left eye. There is a 3+ afferent pupillary defect in the left eye. Disease in the right eye has been stable after scatter photocoagulation. The left eye shows reattachment of the retinal detachment with resolving subretinal exudates and the persistent subretinal band and nasal fold (Figure 4). Current management includes regular monitoring and maximizing his visual outcome with consideration of the aphakic correction of the left eye.

Figure 4: Fundus photography of the left eye. Intra-retinal cholesterol crystals remain after some resolution of exudates. A sub-retinal band with persistent exudates is observed extending anteriorly.

Figure 4: Fundus photography of the left eye. Intra-retinal cholesterol crystals remain after some resolution of exudates. A sub-retinal band with persistent exudates is observed extending anteriorly.

Discussion:
FEVR is a genetically inherited disease with multiple modes of inheritance, including autosomal dominant, autosomal recessive, and X-linked. Expressivity is variable, such that it is common for patients to present with widely different phenotypes, even between eyes in the same individual. Up to 58% of relatives of patients diagnosed with FEVR have asymptomatic clinical findings1. Mutations in FZD4, LRP5, NDP and TSPAN12, members of the Wnt signaling pathway, are implicated in about 50% of cases. Newly discovered mutations in ZNF408 have also been shown to lead to disease2.
Genetic mutations lead to incomplete vascularization of the peripheral retina in full-term infants that may progress to neovascularization. The disease appears similar to acute retinopathy of prematurity (ROP). Exudative retinal detachment, retinal folds, macula ectopia, fibrous bands, and tractional retinal detachments also occur with FEVR progression. Studies have been performed evaluating the location of retinal folds in children with FEVR3,4. It was shown that patients with retinal folds extending from the posterior pole to the lens present in such a way that the diagnosis of FEVR can be difficult to distinguish from PFV, as was the case in the current patient presentation. It is, therefore, imperative to perform EUA with careful examination of the contralateral eye for any signs of FEVR.
Management of FEVR includes early screening in suspected cases, with prompt laser photocoagulation therapy or cryotherapy to any avascular retina and neovascularization. Retinal detachments are managed surgically, with frequent follow-up for monitoring of repeat detachments. Recent studies have been performed evaluating the efficacy of anti-VEGF agents in the treatment of FEVR. While initial results can be promising, the long-term therapy in these patients did not provide sustained positive outcomes5. Limitations to research regarding FEVR include the small patient population and wide variability of expressivity between patients.

References:
1. Trese MD et al. High prevalence of peripheral retinal vascular anomalies in family members of patients with familial exudative vitreoretinopathy. Ophthalmology. 2014;121(1):262-8.
2. Collin RW, Nikopoulos K, Dona M, Gilissen C, Hoischen A, Boonstra FN et al. ZNF408 is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature. Proc Natl Acad Sci USA. 2013; 110: 9856–9861.
3. Robitaille JM et al. Phenotypic Overlap of Familial Exudative Vitreoretinopathy (FEVR) with Persistent Fetal Vasculature (PFV) Caused by FZD4 Mutations in two Distinct Pedigrees. Ophthalmic Genet. 2009;30(1):23-30
4. Trese MD et al. Clinical Presentation of Familial Exudative Vitreoretinopathy. Ophthalmology. 2011;118(4):2070–2075.
5. Henry CR. Long-term follow-up of intravitreal bevacizumab for the treatment of pediatric retinal and choroidal diseases. J AAPOS. 2015 Dec;19(6):541-8.
Faculty Approval by: Mary E. Hartnett, MD

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Identifier: Moran_CORE_21639

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