Diagnostic and Therapeutic
Challenges
Youning Zhang, Dr. Amir H. Kashani, and Dr. G. Baker Hubbard
T his case is submitted by Youning Zhang and Dr.
Amir H. Kashani of the University of Southern
California Eye Institute, Keck School of Medicine of
University of Southern California, Los Angeles,
California; commented by G. Baker Hubbard, Emory
Eye Center, Emory University School of Medicine,
Atlanta, Georgia.
Case Report
We present a case of a 33-year-old female with subtle decrease in
vision in the left eye since the age of 17 and further decline in
vision in the last 3 years. On presentation, she reported worsening
floaters in her left eye in the last 3 months. She was born at
a gestational age of 26 weeks with a questionable diagnosis of
retinopathy of prematurity (ROP); however, she was never treated
for ROP. She reported no history of trauma, laser treatment or
amblyopia, although her right eye had always been dominant.
Ocular medications included artificial tears. Medical history was
significant for hyperlipidemia. Family history was not significant.
On examination, visual acuity was 20/20 in the right eye and 20/50
in the left eye. Intraocular pressure was within normal limits. Visual
field by confrontation was full in both eyes. Fundus examination of
the left eye showed numerous pigmented cells in the vitreous,
vitreous condensation over the macula with traction on the macula,
disk and temporal periphery, dragged and straightened vessels, retinal
striae, large fibrovascular plaque in temporal periphery with hemor-
rhages and some hard exudates, as well as shallow peripheral
tractional detachment around the neovascular plaque. Fluorescein
angiography of the left eye showed a large fibrovascular plaque with
surrounding areas of nonperfusion (Figure 1). Optical coherence
tomography of the left eye demonstrated epiretinal membrane and
vitreomacular traction (Figure 2). Fundus examination of the right eye
was unremarkable; however, fluorescein angiography demonstrated
temporal vascular shunting and circumferential vessels with associ-
ated areas of diffuse retinal staining, and focal areas of avascular
retina in the temporal periphery.
Patient was seen 1 month later and reported further decrease in vision
in the left eye. Patient was treated with targeted panretinal photocoag-
ulation to the areas of nonperfusion and was stable at 1 month follow-up
(Figure 3). She was unable to return for further follow-up despite exten-
sive discussion of the need for further care including possible surgery
for the traction detachment if it progressed after laser treatment.
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
Edited by H. Richard McDonald
This case is presented for discussion regarding diagnosis and
management.
Dr. G. Baker Hubbard, III (Atlanta, Georgia):
Drs. Y. Zhang and A. H. Kashani present an
interesting case of a 33-year-old woman with worsen-
ing vision in the left eye. She was born at a gestational
age of 26 weeks but was never treated for ROP. Her
right eye has always been dominant but she was never
treated for amblyopia. There is no known family
history of retinal disease.
Examination revealed normal acuity on the right
and 20/50 vision on the left with temporal dragging
of retinal vessels and a large fibrovascular plaque
over the peripheral retina temporally in the left eye.
In addition, the temporal periphery had shallow
traction retinal detachment with associated yellow
exudates and hemorrhages. Fluorescein angiography
showed staining and leakage of the large fibrovascu-
lar plaque in the temporal periphery of the left eye.
There were zones of nonperfusion and diffuse retinal
staining in the temporal periphery of both eyes.
Optical coherence tomography of the left eye showed
epiretinal membrane with vitreomacular traction.
Based on these findings, the diagnosis of familial
exudative vitreoretinopathy was made (familial exu-
dative vitreoretinopathy [FEVR]).
A diagnosis of FEVR in this case is supported by
many of the clinical findings. The age at presentation,
temporal dragging, peripheral fibrovascular plaque
temporally, vitreoretinal traction, avascular zones,
yellow exudates, and bilaterality with asymmetric
manifestations between the two eyes are all classic
features of FEVR. The etiology of FEVR is related to
genetically mediated abnormalities in retinal vascular
development. Inheritance is generally autosomal dom-
inant, but autosomal recessive and X-linked recessive
inheritance have also been described. Mutations in five
2 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2016  VOLUME 0  NUMBER 0

Fig. 1. Color fundus photo-

graphs and fluorescein angiogra-
phy. A. Color fundus photograph
of the right eye demonstrating
mild macular and vascular drag-
ging. B. Color fundus photograph
of the left eye demonstrating
dragging of the macula, disk, and
overlying vitreous condensation.
In the periphery, there is a large
white plaque consistent with ne-
ovascular membrane and exudate
is visible. C. Late-phase fluores-
cein angiography of the right eye
demonstrating late staining of the
temporal periphery and peripheral
areas of avascular retina with
vascular loops and venous anas-
tomoses. D. Late phase fluores-
cein angiography of the left eye
demonstrating prominent area of
peripheral temporal nonperfusion.
There is also a prominent area of
hyperfluorescence that is consis-
tent with neovascular plaque seen
in color images, as well as a hy-
perfluorescent disk consistent
with traction at the disk.

genes have been identified that cause FEVR; NDP, a variant of the Wnt signaling pathway termed
FZD4, LRP5, TSPAN12, and ZNF408, and the genet- Norrin/Frizzled-4 signaling. Avascular retina in the
ics of FEVR has been the subject of an excellent recent periphery results during fetal development from these
review.1 Four of the genes identified play a role in mutations with subsequent ischemia, fibrovascular

Fig. 2. Color fundus photo-

graphs and optical coherence
tomography. A. Color fundus
photograph of higher magnifica-
tion of the right eye demonstrat-
ing mild macular and vascular
dragging. B. Color fundus pho-
tograph of higher magnification
of the left eye demonstrating mild
dragging of the macula, disk, and
overlying vitreous condensation.
In the periphery, there is a large
white plaque consistent with ne-
ovascular membrane and exudate.
White lines in panel A and B
show the location of the OCT
scans in the following panels. C.
Macular OCT of the right eye
demonstrating relatively normal
foveal contour and no gross
pathology. D. Macular OCT of
the left eye demonstrating prom-
inent epiretinal membrane with
overlying vitreous condensation
and vitreomacular traction. OCT,
optical coherence tomography.

Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
 DIAGNOSTIC AND THERAPEUTIC CHALLENGES
Fig. 3. Color fundus photograph of the left eye after sectoral laser
treatment. In the periphery, there is a large white plaque consistent with
neovascular membrane and exudate. Laser ablation was applied dif-
fusely in the area of nonperfusion in the temporal retina.
proliferation, traction, and exudation. The clinical
manifestations of FEVR can be nearly identical to
ROP, and ROP is the main entity in the differential
for this case. There are several important distinctions
between the clinical features of FEVR and ROP. One
is that FEVR generally is found in patients with no
history of prematurity. A second is that FEVR presents
in older children and adults, whereas ROP is almost
always diagnosed in the neonatal period. A third
important distinction is that FEVR can have episodes
of exudation and progressive traction separated by
long periods of inactivity.2,3 The ROP, however, has
an acute phase during infancy with exudation and then
the exudative process ends permanently. How these
distinctions between FEVR and ROP relate to the cur-
rent case make it particularly intriguing.
Our patient has features consistent with FEVR but
she also has a history of significant prematurity. The
age of her presentation is at 33 years, and she has
signs of active exudation with the presence of yellow
deposits, blood, and progressive traction. This of
course would be very unusual for ROP. She also has
a history of subtle long-standing decreased vision
first identified at age 17. This suggests a course with
periods of activity separated by long periods of
quiescence and is supportive of FEVR as her
diagnosis. However, she was born at 26 weeks
gestation during an era when ROP screening was
not routine in every neonatal intensive care unit. She
almost certainly had ROP as an infant that may have
never been diagnosed. Could she have both FEVR
and ROP?
We know that FEVR has a broad range in the
severity of its phenotype. This is true both among
individuals in the same family and also between the
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
3
two eyes of the same individual. For instance, children
who are diagnosed with FEVR will commonly have an
asymptomatic parent whose phenotype is so mild it
escapes attention for years. Between two eyes of the
same individual, there can be substantial asymmetry as
is seen in the current case. It is quite possible that
a patient with a FEVR mutation who might have
otherwise been destined to have a mild phenotype may
instead have more severe disease related to their
history of having been born prematurely. The interac-
tion between FEVR mutations and prematurity has
been reported previously, and this interaction has been
used to explain cases of severe ROP in infants with
only mild prematurity.4–6 This genotype–phenotype
interaction reported in cases of severe ROP may also
be at work in adults with FEVR who, like the current
case, probably have worse disease because of their
history of prematurity.
As for management, additional considerations
would include genetic testing, possible anti–
vascular endothelial growth factor (VEGF) injec-
tion, additional laser to more thoroughly ablate
avascular retina, and vitrectomy to relieve vitre-
omacular traction. The diagnosis of FEVR could be
confirmed in this case by genetic testing but a nega-
tive test would not exclude the possibility of FEVR
because known mutations only account for approxi-
mately 50% of FEVR cases.1 Negative genetic testing
in cases of FEVR is common, and these cases are
presumed to be due to mutations that have yet to be
discovered. Anti-VEGF injections may be useful in
some cases of FEVR as levels of VEGF are thought
to be elevated in this disorder because of extensive
vascular nonperfusion.7,8 The authors performed
scatter laser photocoagulation in areas of vascular
nonperfusion but denser treatment may be needed to
obtain long-term stability. Vitrectomy for the vitre-
omacular traction may result in better long-term
macular function. Vitrectomy would be best per-
formed after the exudative process is controlled with
anti-VEGF and/or complete laser. I have seen
“crunch” phenomena after laser or anti-VEGF for
FEVR so a staged ablation of the avascular retina is
reasonable. In addition, when anti-VEGF is used,
preparations to go to the operating room soon may be
prudent because of the risk of progressive traction.
In summary, we have a 33-year-old woman with
a history of significant prematurity who also has
classic features of FEVR. An interaction between
a genetic FEVR mutation and the history of pre-
maturity in this case is hypothesized to account for
a more severe phenotype. Genetic testing may confirm
the diagnosis, and additional treatment with laser, anti-
VEGF, or vitrectomy may be beneficial.
4 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2016  VOLUME 0  NUMBER 0
Editor’s Report:
Y. Zhang and Dr. A. H. Kashani present a woman
with decreasing vision. Dr. G. B. Hubbard, III, has
consulted on this case.
Dr. G. B. Hubbard believes that familial exudative
vitreoretinopathy (FEVR) is the diagnosis for this
patient, supported by a number of classic findings. He
reviews the genetics of FEVR, identifying NDP, FZ04,
LRP5, TSPAN12, and ZNF408 as mutated genes
causing FEVR. All these genes are related to retinal
vascular development. Four of these genes play a role
in a variant of the Wnt signaling pathway. The results
of these mutations are peripheral ischemia and the
subsequent development of neovascularization and
traction detachment.
Dr. G. B. Hubbard notes differences between the
clinical manifestations and course of FEVR and ROP.
This patient has features of FEVR, but also ROP. Her
age at presentation is unusual for ROP and has had
a course that suggests long periods of inactivity. Both
of these issues speak to a diagnosis of FEVR. But she
was born at 26 weeks and almost certainly had ROP as
an infant.
He surmises that perhaps the patient has a FEVR
mutation that might otherwise been destined to have
a mild phenotype, but has more severe disease because
of the premature birth. This same scenario has been
used to explain patients with severe ROP but only mild
prematurity.
Dr. G. B. Hubbard suggests genetic testing, laser,
and anti-VEGF medication, and consideration of
vitrectomy for the macular traction. Importantly, he
notes that negative genetic testing does not rule out
FEVR, as known mutations account for approximately
50% of FEVR cases.
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
We thank Y. Zhang and Dr. A. H. Kashani for this
interesting case, and Dr. G. B. Hubbard for his
consultation.
References
1. Gilmour DF. Familial exudative vitreoretinopathy and related
retinopathies. Eye (Lond) 2015;29:1–14.
2. Benson WE. Familial exudative vitreoretinopathy. Trans Am
Ophthalmol Soc 1995;93:473–521.
3. Ranchod TM, Ho LY, Drenser KA, et al. Clinical presentation
of familial exudative vitreoretinopathy. Ophthalmology 2011;
118:2070–2075.
4. Ells A, Guernsey DL, Wallace K, et al. Severe retinopathy of
prematurity associated with FZD4 mutations. Ophthalmic Genet
2010;31:37–43.
5. Shastry BS, Pendergast SD, Hartzer MK, et al. Identification of
missense mutations in the Norrie disease gene associated with
advanced retinopathy of prematurity. Arch Ophthalmol 1997;
115:651–655.
6. Kondo H, Kusaka S, Yoshinaga A, et al. Genetic variants of
FZD4 and LRP5 genes in patients with advanced retinopathy of
prematurity. Mol Vis 2013;19:476–485.
7. Quiram PA, Drenser KA, Lai MM, et al. Treatment of vascu-
larly active familial exudative vitreoretinopathy with pegaptanib
sodium (Macugen). Retina 2008;28:S8–S12.
8. Henry CR, Sisk RA, Tzu JH, et al. Long-term follow-up of
intravitreal bevacizumab for the treatment of pediatric retinal
and choroidal diseases. J AAPOS 2015;19:541–548.
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