Journal of Pediatric Ophthalmology and Strabismus

Short Subjects 

Novel Frizzled-4 Mutation Is Associated With Familial Exudative Vitreoretinopathy Mimicking Persistent Fetal Vasculature

Patrick C. Staropoli, MD; Nicolas A. Yannuzzi, MD; Nimesh A. Patel, MD; Catherin I. Negron, BA, MBA; Supalert Prakhunhungsit, MD; Audina M. Berrocal, MD

Abstract

This is a report of a 13-month-old boy who presented with a large unilateral fibrovascular stalk and bilateral peripheral retinal avascularity. Although consistent with both persistent fetal vasculature and familial exudative vitreoretinopathy, genetic testing disclosed a novel pathogenic mutation in the frizzled class receptor 4 gene (FZD4, c.427_428delCT). [J Pediatr Ophthalmol Strabismus. 2020;57:e4–e7.]

Abstract

This is a report of a 13-month-old boy who presented with a large unilateral fibrovascular stalk and bilateral peripheral retinal avascularity. Although consistent with both persistent fetal vasculature and familial exudative vitreoretinopathy, genetic testing disclosed a novel pathogenic mutation in the frizzled class receptor 4 gene (FZD4, c.427_428delCT). [J Pediatr Ophthalmol Strabismus. 2020;57:e4–e7.]

Introduction

Familial exudative vitreoretinopathy (FEVR) is a rare hereditary disorder defined by failure of peripheral retinal vascularization. Described by Criswick and Schepens in 1969,1 this asymmetric, bilateral disease can range from asymptomatic vascular anomalies to retinal detachment. Diagnosis is made through fundus examination, fluorescein angiography, and genetic testing. Treatment relies on laser photocoagulation of avascular zones and vitrectomy surgery in the case of late stage retinal detachment. Mutations in the FZD4, LRP5, and TSPAN12 genes are identified in 50% of cases.2 Patients with early onset FEVR can have retinal folds extending from disc to lens, mimicking persistent fetal vasculature (PFV), a usually unilateral, idiopathic congenital malformation in which the hyaloid artery fails to regress.3 We present the case of a novel FZD4 mutation in association with a fibrovascular stalk mimicking PFV.

Case Report

A 13-month-old boy, born at 41 weeks from an uncomplicated pregnancy, was referred to the retina clinic after developing nystagmus at 6 months of age. There was no ocular history in the family. At presentation, the patient could fix and follow in both eyes. He had no skin markings or rashes. Examination under anesthesia and fluorescein angiography of the right eye revealed a macular scar, epiretinal membrane, and incomplete peripheral vascularization with inferior leakage (Figures 1A–1B). Examination of the left eye disclosed a leaking fibrovascular stalk extending from the disc to the posterior capsule of the lens with incorporation of temporal retina and incomplete peripheral vascularization (Figures 1C–1F). Both eyes had straightening of vessels. Similar findings were also seen on ultrasound and optical coherence tomography (Figure 2). A-scan showed an axial length of 21.4 mm in the right eye and 20.8 mm in the left eye. Corneal diameter was 11 mm in both eyes.

(A) Fundus photograph of the right eye with macular scar and (B) fluorescein angiography showing peripheral avascularity and leakage most prominent inferiorly. (C) Fundus photograph of the left eye showing a fibrovascular stalk with incorporation of temporal retina extending from disc to (D) posterior lens capsule. (E) Fluorescein angiography demonstrating peripheral avascularity and (F) late leakage.

Figure 1.

(A) Fundus photograph of the right eye with macular scar and (B) fluorescein angiography showing peripheral avascularity and leakage most prominent inferiorly. (C) Fundus photograph of the left eye showing a fibrovascular stalk with incorporation of temporal retina extending from disc to (D) posterior lens capsule. (E) Fluorescein angiography demonstrating peripheral avascularity and (F) late leakage.

B-scan ultrasound of (A) the right eye showing epiretinal membrane and retinal thickening and (B) the left eye showing the fibrovascular stalk. (C) Optical coherence tomography of the right macula with retinal thickening, epiretinal membrane, and subfoveal inner segment/outer segment drop out.

Figure 2.

B-scan ultrasound of (A) the right eye showing epiretinal membrane and retinal thickening and (B) the left eye showing the fibrovascular stalk. (C) Optical coherence tomography of the right macula with retinal thickening, epiretinal membrane, and subfoveal inner segment/outer segment drop out.

Laser indirect ophthalmoscopy with argon (500 mW) was performed to avascular areas in both eyes. Repeat examination under anesthesia 6 months later showed improvement in leakage in the right eye and stable leakage in the left eye (Figure 3). Additional laser treatment was applied in the right eye and sub-Tenon's triamcinolone acetonide was injected in both eyes. Genetic testing, specifically the MVL Vision Panel (v2) consisting of 581 genes associated with inherited retinal dystrophies, was sent to Molecular Vision Laboratory (Hillsboro, OR). Results showed a novel frameshift mutation c.427_428delCT in the FZD4 gene. The mother was found to have the same mutation (LabGenetics, Madrid, Spain).

Repeat fluorescein angiography 6 months later showing (A) improvement of leakage in the right eye after photocoagulation and (B) stable leakage in the left eye.

Figure 3.

Repeat fluorescein angiography 6 months later showing (A) improvement of leakage in the right eye after photocoagulation and (B) stable leakage in the left eye.

Discussion

Many studies have reported on FZD4 mutations in association with FEVR.4–6FZD4, LRP5, TSPAN12, and NDP are components of the wingless (Wnt) pathway in the retina responsible for normal angiogenesis. The most well-studied pathway involves FZD4, a gene encoding a seven-transmembrane protein of 537 amino acids, acting as a coreceptor with LRP5 for the Norrin and Wnt ligands. Binding of this complex activates the Dishevelled (Dsh) protein, which dephosporylates β-Catenin, an intracellular signal transducer. β-Catenin subsequently translocates into the nucleus, where it serves as a transcription factor promoting expression of vascular endothelial growth factor, c-myc, and CCND1, leading to angiogenesis. FZD4 mutations can inactivate this cascade and impair normal peripheral retinal vascularization.7 Inheritance of FEVR-associated mutations can be autosomal dominant, recessive, X-linked, or even sporadic. Some have proposed that homozygosity results in a more severe disease course.8 However, no definitive phenotype–genotype correlation has been established.

The variant in this case is a novel frameshift mutation c.427_428delCT located at 11q14.2, position 86663370. At the protein level, this corresponds to p.Leu143TyrfsX22 (L143YfsX22). This variant was not found in an extensive online database of FZD4 variants.9 It is considered pathogenic by American College of Medical Genetics guidelines, which compare actual and expected rates of variants. For example, the FZD4 gene has a significantly higher rate of pathogenic frameshift variants (42.35%) than the expected rate (10.0%).10 The FZD4 protein also has a higher rate of pathogenic variants (100%) than expected (66.7%).11 Therefore, a new mutation in FZD4 associated with a disease process is likely to be pathogenic. In addition, it is considered pathogenic and novel by the National Center for Biotechnology Information (NCBI) Clin-Var database because the deletion causes a frameshift (changing a Leucine to a Tyrosine at codon 143) that leads to a premature stop codon at position 22 of the new reading frame. This results in loss of function of the FZD4 receptor due to either protein truncation or nonsense-mediated mRNA decay. Faulty signaling along the Wnt pathway subsequently causes failed peripheral retinal vascularization.7 The NCBI database also notes that this variant has not been reported in the literature.12

In addition to a novel genotype, this patient also presented with an unexpected phenotype. FEVR manifesting with PFV-like features only occurs in approximately 6% of cases, typically those with very early onset.13 Robitaille et al.4 described 3 children with features of bilateral PFV found to have avascular peripheral retina and mutations in the FZD4 gene (M493_W494del and I114T). Kartchner and Hartnett14 also reported a unilateral PFV-like stalk in association with an FZD4 mutation. Kondo et al.8 described a 5-month-old infant with a large falciform retinal fold and homozygous FZD4 mutation with asymptomatic, heterozygous parents. It is inconclusive at this time whether FZD4 mutations have a higher risk of a FEVR-PFV phenotype, or if they lead to earlier presentation.

In fact, much remains to be elucidated about this disease: how much of a reduction in FZD4 activity is required to trigger FEVR, can gene therapy reverse or prevent retinal changes, and why do FZD4 mutations only manifest in the retina when it is widely expressed throughout the body? Although this case does not answer these questions, it does highlight the importance of a thorough bilateral examination because FEVR can be highly asymmetric and mimic other vitreoretinal diseases. Fortunately, the correct diagnosis was identified early, and laser photocoagulation has slowed progression. We have discovered a novel pathogenic mutation in the FZD4 gene associated with a rare presentation of FEVR mimicking PFV.

References

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Authors

From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida (PCS, NAY, NAP, CIN, SP, AMB); and the Department of Ophthalmology, Siriraj Hospital, Mahidol University, Bangkok, Thailand (SP).

Supported in part by the Heed Foundation.

The authors have no financial or proprietary interest in the materials presented herein.

Correspondence: Audina M. Berrocal, MD, Bascom Palmer Eye Institute, 900 NW 17th Avenue, Miami, FL 33136. E-mail: aberrocal@med.miami.edu

Received: September 17, 2019
Accepted: October 18, 2019
Posted Online: January 24, 2020

10.3928/01913913-20191230-01

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