Retinopathy of prematurity (ROP) and familial exudative vitreoretinopathy (FEVR) can have very similar clinical presentations. Underlying both diseases is an abnormal development of retinal vessels and, therefore, both have secondary retinal complications, including retinal folds and detachments. ROP is a leading cause of preventable blindness in infants. Risk factors include young gestational age, low birth weight, multiple births, and oxygen concentrations in the neonatal intensive care unit (NICU). On the other hand, FEVR, as its name implies, is familial and therefore has a genetically heterogeneous etiology with mutations in the genes encoding Wnt signaling in the retina. These include the FZD4, LRP5, TSPAN 12, and NDP genes, as well as a plethora of other known and unknown genes.1–5 Phenotypically, both of these diseases are very similar.
The clinical similarities between the two entities were not lost in the early descriptions of fluorescein angiographic findings in FEVR when Canny and Oliver presented them in the 1970s. According to Canny,6 “clinically familial exudative retinopathy may be confused with retrolental fibroplasia [historical name of ROP],” as both conditions eventually develop dragged disks, ectopic maculae, and pseudostrabismus from retinal traction secondary to temporal peripheral fibrovascular lesions. Most importantly, the capillary circulation, as demonstrated by fluorescein angiography, adjacent to the temporal equator in FEVR is remarkably similar to the one seen in retrolental fibroplasia.6 It is important to note that both FEVR and ROP were thought to show abrupt cessation of the capillary network with formation of scalloped border and leakage of fluorescein dye from this border.
Classically, it has always been thought that the only way to distinguish these two entities was by clinical history. FEVR tends to occur in a familial pattern and is seen in infants born at full-term, receiving no oxygen therapy during infancy. On the other hand, ROP, as its name implies, affects infants born prematurely who are placed on supplemental oxygen in the NICU. It was not thought to have any familial or genetic predisposition. In addition, ROP has a defined, more predictable period of activity, whereas FEVR tends to occur later in age and can recur at any time in the future.
Despite the clinical similarities between ROP and FEVR, there has always been an emphasis to categorize both of them as separate diseases. Yet, in our clinical experience in the pediatric retina service at Bascom Palmer, we have encountered infants who have exhibited characteristics of familial exudative vitreoretinopathy, but who were born prematurely. Here, we present the case history and fluorescein angiographic studies of nine children who have behaved like FEVR patients but were also premature in birth, and introduce a new classification: ROPER (ROP vs. FEVR).
Digital wide-field fluorescein angiography has become the standard of care in the diagnosis and management of pediatric vascular diseases such as ROP and FEVR.
The purpose of this study was to examine clinical and angiographic features of children diagnosed with FEVR but who were born prematurely.
Patients and Methods
A retrospective analysis of medical records and a literature review were performed. Chart records of all pediatric patients who underwent examination under anesthesia and laser for FEVR at the Bascom Palmer Eye Institute Pediatric Retina Service under one of the authors (AMB) from Jan. 1, 2006, to June 30, 2013, were reviewed. Approval was obtained from the institutional review board at the University of Miami to retrospectively review the records. Age, sex, race, gestational age at birth, birth weight, laterality of disease, the dates of angiography, exam under anesthesia, and treatments were all recorded.
All patients were examined under general anesthesia with scleral depression. Fundus photography and fluorescein angiography were performed at the discretion of the treating physician (AMB) using a RetCam (Clarity Medical System, Pleasanton, CA) digital imaging system and intravenous injection of AK-Fluor (Acorn, Buffalo Grove, IL) 10% fluorescein solution at a dose of 3.5 mg per pound. The demographic information, along with type of treatment used in each of the children, was documented. The fluorescein angiograms were then retrospectively reviewed by the authors (VJJ, AMB) at a later time.
Nine FEVR patients were identified from the chart review to have been born prematurely (less than 37 weeks gestational age) and were included in the study. In addition, the records of two infants with ROP and their fluorescein angiograms were reviewed for comparison.
Main Outcome Measures
Baseline data, including gestational age and birth weight, were analyzed between the groups. Through angiography, we examined zones of disease, areas of non-perfusion, and features of the vascular/avascular junction in order to identify any salient differences between infant eyes with ROP-only versus the infants of interest in this study with FEVR features who were born prematurely.
Demographic data of the nine infants in this study are summarized in the Table. Gestational age (GA) at birth ranged from 26 weeks to 35 weeks (mean: 30 weeks), and birth weight ranged from 586 grams to 1,615 grams (mean: 1226.2 grams). All of the infants received laser ablative treatment, and two infants received intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA) as an adjuvant treatment. Two children required multiple sessions of laser at the time of study completion as part of their disease management.
Baseline Demographic Data and Treatments Performed
After analyzing the fluorescein angiograms of all nine infants with presumed FEVR and the two infants diagnosed as having classic ROP, our findings are summarized herein. Specific case history and images representative of the characteristic findings of this study are presented, as well,
Overall, in eyes of children with FEVR, regardless of GA, FA clearly shows extreme variability in both retinal and choroidal filling patterns and in the clinical course of the disease despite adequate laser treatment. Yet, some distinct fluorescein patterns emerged between the classic ROP infants and the FEVR children born prematurely, especially in the peripheral retina. As seen in the angiogram of a ROP patient (Figure 1), homogeneous vascularization pattern was observed at the ridge in these two representative untreated patients. Notably, the angiogram was done at 37 weeks GA in both cases. Attention is drawn to the smooth edge of the vascular/avascular transition zone and the lack of vascularization past the ridge. In contrast to the ROP angiograms, several features were unique to FEVR study eyes. These included irregular sprouts of vascularization at the vascular/avascular junction, distinct pruning of vessels, pinpoint areas of hyperfluorescence, and segmental areas of vascular leakage (Figure 2). In addition, vascular loops with tangles beyond the edge of vascularization were also noted in some eyes (Figure 3). Although reports have shown fluorescein angiographic changes after bevacizumab administration, these figures are from patients naïve to any anti-vascular endothelial growth factor (VEGF) agents.7
Classic homogenous vascularization pattern present at the ridge seen in two untreated infants with retinopathy of prematurity (gestational age: 37 weeks).
(A) Angiogram of a child diagnosed with familial exudative vitreoretinopathy but born prematurely showing irregular vascular sprouting beyond transition zone, vascular pruning, and segmental vascular leakage. (B) Highlights of the areas of pinpoint hyperfluorescence seen in the periphery.
Angiograms of a child diagnosed with familial exudative vitreoretinopathy but born prematurely showing vascular loops and further focal areas of leakage beyond the transition zone.
Furthermore, careful examination of the macular angiograms highlighted a finding described before in premature retinas. Eight of the nine patients with FEVR in this study demonstrated either a complete absence or a significantly diminished area of foveal avascular zone (less than one-third the size of the optic nerve diameter) (Figure 3B).
A growing body of evidence is emerging to indicate a small, but clinically significant population of premature infants who demonstrate features more characteristic of FEVR than ROP. Here, we present the clinical and angiographic findings in a cohort of nine infants born prematurely (mean GA: 30 weeks; mean birth weight: < 1,300 grams) seen at the Bascom Palmer Pediatric Retina Service between 2006 and 2013.
FEVR is a hereditary vitreoretinopathy and can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive pattern. Mutations in FZD4, LRP5, TSPAN12, and NDP are known to cause FEVR through their impact on the wingless/integrated (Wnt) receptor signaling pathway, leading to impaired vascular growth.1–5 Recently, several genetic analyses have revealed the presence of FEVR-associated mutations in children with advanced ROP.8–14 In one study, 13% of patients with advanced ROP (stage 4 or 5) were found to carry mutations in FZD4 or LRP5.15 These studies suggest the presence of FEVR mutations may contribute to more aggressive or advanced retinopathy in ROP. One hypothesis proposes that mutations of genes with less severe functional impact lead to advanced ROP, whereas mutations with greater phenotypic consequence lead to FEVR.15 A limitation in many of these reports, however, is the need for functional assays to more definitively assign causality. Underlying genetic susceptibility to ROP and genetic similarities between ROP and FEVR point to a clinical spectrum between ROP and FEVR. In the realm of this paper, we propose that there exists a group of infants with ROPER.
Although genetic studies help better define the overlap between these two conditions, DNA testing is often unavailable during routine evaluation. Separating ROP from FEVR in an infant may, at times, be difficult. Both conditions can present with peripheral avascularity, neovascularization, vitreous hemorrhage, subretinal exudation, vascular dragging, radial retinal folds, and tractional retinal detachments.16–19 In younger children, ROP and FEVR have classically been separated by a history of prematurity and assumptions about onset and disease course. Differentiating children with ROPER from those with classic ROP based solely on ophthalmoscopy presents a challenge.
Fluorescein angiography allows for more accurate evaluation of avascular zones, vascular patterns, vascular leakage, and perfusion dynamics than clinical exam alone. Fluorescein patterns in classic ROP have been well-categorized both on standard and wide-field angiography. Transit time and choroidal filling patterns show significant variability with linear choroidal filling seen in premature infants at birth and a lobular pattern noted at 9 months post-term.7 Features of the vascular/avascular junction in ROP include abnormal branching patterns, such as tangles or circumferential vessels; hyperfluorescent lesions, such as “popcorn” tufts; focal capillary dilatation; neovascularization; and leakage.20,21 Additional anomalies have been identified within the vascularized retina in ROP including areas of hypoperfusion, periarteriolar capillary dropout, and absence of the foveal avascular zone.20 As ROP vascularization involutes following treatment either with laser or bevacizumab, these findings may change and include abnormal branching patterns, telangiectasias, and pigmentary changes.7,22,23
In patients with FEVR, angiography similarly displays delayed transit and delayed or patchy choroidal filling.21 At the vascular/avascular junction, FEVR patients display bulbous vascular terminals, capillary dropout, venous/venous shunting (rather than arterio/venous), and abnormal branching patterns.24 Additionally, our series shows that in FEVR infants, the vascular/avascular junction demonstrates irregular sprouts of vascularization whereas classic ROP patients have a more homogenous vascular advancing front (Figure 1).
Another distinguishing feature of ROPER compared to typical ROP in a premature infant is the clinical course. ROPER presents with unpredictable activation episodes followed by inactive stages similar to FEVR. These infants should not be discharged early from the care of a pediatric ophthalmologist or retina specialist as would be typical for a treated or regressed ROP infant. Recent advances in imaging of infants with wide-field photography and angiography have tremendously increased our understanding of retinal vascular diseases such as ROP, FEVR, and Coats' disease.25 Kashani et al. recently demonstrated the high prevalence of undiagnosed FEVR in asymptomatic family members of FEVR patients, where greater than 50% had evidence of retinal nonperfusion and vascular anomalies consistent with the disease.24 As the authors pointed out, early diagnosis of asymptomatic FEVR is crucial due to its progressive nature and the genetic/familial underpinnings of the condition. In a similar way, the correct diagnosis of ROPER patients is important in distinguishing them from typical ROP, which does not characteristically progress. These infants need to be closely monitored for progression of disease early and often in their life, including serial angiography and treatment with laser, cryotherapy, and anti-VEGF injections.26
- Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet. 1993;5(2):180–183. doi:10.1038/ng1093-180 [CrossRef]
- Robitaille J, MacDonald ML, Kaykas A, et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet. 2002;32(2):326–330. doi:10.1038/ng957 [CrossRef]
- Toomes C, Bottomley HM, Jackson RM, et al. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. 2004;74(4):721–730. doi:10.1086/383202 [CrossRef]
- Poulter JA, Ali M, Gilmour DF, et al. Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy. Am J Hum Genet. 2010;86(2):248–253. doi:10.1016/j.ajhg.2010.01.012 [CrossRef]
- Nikopoulos K, Gilissen C, Hoischen A, et al. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. Am J Hum Genet. 2010;86(2):240–247. doi:10.1016/j.ajhg.2009.12.016 [CrossRef]
- Canny CL, Oliver GL. Fluorescein angiographic findings in familial exudative vitreoretinopathy. Arch Ophthalmol. 1976;94(7):1114–1120. doi:10.1001/archopht.1976.03910040034006 [CrossRef]
- Lepore D, Quinn GE, Molle F, et al. Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings. Ophthalmology. 2014;121(11):2212–2219. doi:10.1016/j.ophtha.2014.05.015 [CrossRef]
- Shastry BS. Genetic susceptibility to advanced retinopathy of prematurity (ROP). J Biomed Sci. 2010;17:69. doi:10.1186/1423-0127-17-69 [CrossRef]
- Shastry BS, Pendergast SD, Hartzer MK, Liu X, Trese MT. Identification of missense mutations in the Norrie disease gene associated with advanced retinopathy of prematurity. Arch Ophthalmol. 1997;115(5):651–655. doi:10.1001/archopht.1997.01100150653015 [CrossRef]
- Hiraoka M, Berinstein DM, Trese MT, Shastry BS. Insertion and deletion mutations in the dinucleotide repeat region of the Norrie disease gene in patients with advanced retinopathy of prematurity. J Hum Genet. 2001;46(4):178–181. doi:10.1007/s100380170085 [CrossRef]
- Talks SJ, Ebenezer N, Hykin P, et al. De novo mutations in the 5′ regulatory region of the Norrie disease gene in retinopathy of prematurity. J Med Genet. 2001;38(12):E46. doi:10.1136/jmg.38.12.e46 [CrossRef]
- Haider MZ, Devarajan LV, Al-Essa M, Kumar H. C597->A polymorphism in the Norrie disease gene is associated with advanced retinopathy of prematurity in the premature Kuwaiti infants. J Biomed Sci. 2002;9(4):365–370.
- Hutcheson KA, Palura PC, Bernstein SL, et al. Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Mol Vis. 2005;11:501–508.
- Hiraoka M, Takahashi H, Orimo H, Hiraoka M, Ogata T, Azuma N. Genetic screening of Wnt signaling factors in advanced retinopathy of prematurity. Mol Vis. 2010;16:2572–2577.
- Kondo H, Kusaka S, Yoshinaga A, Uchio E, Tawara A, Tahira T. Genetic variants of FZD4 and LRP5 genes in patients with advanced retinopathy of prematurity. Mol Vis. 2013;19:476–485.
- No authors listed. An international classification of retinopathy of prematurity. The Committee for the Classification of Retinopathy of Prematurity. Arch Ophthalmol. 1984;102(8):1130–1134. doi:10.1001/archopht.1984.01040030908011 [CrossRef]
- Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol. 1969;68(4):578–594. doi:10.1016/0002-9394(69)91237-9 [CrossRef]
- Miyakubo H, Hashimoto K, Miyakubo S. Retinal vascular pattern in familial exudative vitreoretinopathy. Ophthalmology. 1984;91(12):1524–1530. doi:10.1016/S0161-6420(84)34119-7 [CrossRef]
- Benson WE. Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc. 1995;93:473–521.
- Lepore D, Molle F, Pagliara M, et al. Atlas of fluorescein angiographic findings in eyes undergoing laser for retinopathy of prematurity. Ophthalmology. 2011;118(1):168–175. doi:10.1016/j.ophtha.2010.04.021 [CrossRef]
- Flynn JT, Cassady J, Essner D, et al. Fluorescein angiography in retrolental fibroplasia: experience from 1969–1977. Ophthalmology.1979;86(10):1700–1723. doi:10.1016/S0161-6420(79)35329-5 [CrossRef]
- The Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol. 1984; 102:1130–1134. doi:10.1001/archopht.1984.01040030908011 [CrossRef]
- International Committee for the Classification of Retinopathy of Prematurity. The international classification of retinopathy of prematurity revisited. Arch Ophthalmol. 2005;123(7):991–999. doi:10.1001/archopht.123.7.991 [CrossRef]
- Kashani AH, Brown KT, Chang E, Drenser KA, Capone A, Trese MT. Diversity of retinal vascular anomalies in patients with familial exudative vitreoretinopathy. Ophthalmology. 2014;121(11):2220–2227. doi:10.1016/j.ophtha.2014.05.029 [CrossRef]
- Blair MP, Ulrich JK, Hartnett ME, Shapiro MJ. Peripheral retinal nonperfusion in fellow eyes in Coats disease. Retina. 2013;33(8):1694–1699. doi:10.1097/IAE.0b013e318285cb86 [CrossRef]
- Gologorsky D, Chang JS, Hess D, Berrocal AM. Familial exudative vitreoretinopathy in a premature child. Ophthalmic Surg Lasers Imaging Retina. 2013;44(6):603–605. doi:10.3928/23258160-20131015-04 [CrossRef]
Baseline Demographic Data and Treatments Performed
|Patient #||GA at Birth||BW (gm)||Treatment (both eyes)|
|3||35||1,500||Laser + Avastin|
|6||33||1,350||Laser + Avastin|