Ophthalmic Genetics

ISSN: 1381-6810 (Print) 1744-5094 (Online) Journal homepage: https://www.tandfonline.com/loi/iopg20

CTNNB1 mutation associated with familial

exudative vitreoretinopathy (FEVR) phenotype

Maxwell W. Dixon, Maxwell S. Stem, Jane L. Schuette, Catherine E. Keegan &

Cagri G. Besirli

To cite this article: Maxwell W. Dixon, Maxwell S. Stem, Jane L. Schuette, Catherine E. Keegan
& Cagri G. Besirli (2016) CTNNB1 mutation associated with familial exudative vitreoretinopathy
(FEVR) phenotype, Ophthalmic Genetics, 37:4, 468-470, DOI: 10.3109/13816810.2015.1120318

To link to this article: https://doi.org/10.3109/13816810.2015.1120318

Published online: 11 Mar 2016.

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OPHTHALMIC GENETICS
2016, VOL. 37, NO. 4, 468–470
http://dx.doi.org/10.3109/13816810.2015.1120318
LETTER TO THE JOURNAL
CTNNB1 mutation associated with familial exudative vitreoretinopathy (FEVR)
phenotype
a
Maxwell W. Dixon , Maxwell S. Stemb, Jane L. Schuettec,d, Catherine E. Keeganc,d, and Cagri G. Besirlib
a
University of Michigan Medical School, Ann Arbor, MI, USA; bW.K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences,
University of Michigan, Ann Arbor, MI, USA; cDepartment of Pediatrics, Division of Genetics, University of Michigan, Ann Arbor, MI, USA;
d
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
Familial exudative vitreoretinopathy (FEVR) is a rare
genetic disorder of retinal vascular development that can
result in retinal detachment and blindness.1 A pathologic
hallmark of FEVR is peripheral retinal avascularity, which
promotes ischemia, neovascularization, and ultimately
vitreoretinal traction and detachment of the retina in severe
cases. Mutations in five genes2–7 have been associated with
the FEVR phenotype, and many of these genes play an
essential role in Wnt signaling. Wnts are glycoproteins
that bind to specific transmembrane receptors to initiate
intracellular signaling cascades,8,9 and normal Wnt signal-
ing within developing retinal endothelial cells is crucial to
the formation of a well-vascularized retina.
We report a patient with a heterozygous mutation in the
CTNNB1 gene, which codes for the protein beta-catenin.
Beta-catenin is the final mediator of gene transcription in
canonical Wnt signaling.10 To the best of our knowledge,
this is the first report of a CTNNB1 mutation that has been
linked to the FEVR phenotype.
A 22-month-old boy was referred to the W. K. Kellogg Eye
Center for evaluation of “depth perception problems.” The
patient’s past medical history included lipomyelomeningocele,
failure to thrive, short stature, developmental delay, and beha-
viors on the autism spectrum. The patient was born at 34 and
1/7 week gestation with a birth weight of 1842 g. Newborn
screening was normal. The patient had previously been eval-
uated by Pediatric Genetics and a heterozygous mutation in
the CTNNB1 gene was identified by clinical whole exome
sequencing (GeneDx, Gaithersburg, MD). The mutation was
characterized as an insertion of five base pairs
(c.2112_2116dupAGAAC; p.P706QfsX31), causing a frame-
shift of the protein and likely complete loss-of-function,
resulting in haploinsufficiency. The mutation was not found
in the mother, who was the only parent available for testing.
Based on the type of mutation and the patient’s clinical
features, it was presumed to be causative of his developmental
delay and congenital anomalies.
At his initial visit to the eye center at age 22 months, the
patient’s exam was notable for bilateral hyperopic
astigmatism. Spectacles were prescribed and the patient
was to follow-up in 6 months, but he was lost to follow-
CONTACT Cagri G. Besirli, MD, PhD cbesirli@med.umich.edu W. K. Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105, USA.
Color versions of one or more figures in the article can be found online at http://www.tandfonline.com/iopg.
© 2016 Taylor & Francis
up for over 14 months. On return visit, he was noted to
have a left eye preference and dilated examination revealed
an abnormality in the right eye concerning a retinal detach-
ment. Examination under anesthesia showed normal ante-
rior segments of both eyes. Fundoscopic examination of the
right eye revealed an exudative macular detachment with
retinal elevation in the peripapillary area extending to the
inferotemporal periphery (Figure 1A). Also present were
the initial stages of retinal fold formation in the posterior
pole with a falciform fold in the inferotemporal periphery.
Vitreous overlying this fold was abnormal and generating
traction, and exudates were present at the base of the fold.
The retinal periphery was markedly avascular. Fundoscopic
examination of the left eye revealed an elevated optic nerve,
a normal macula, and premature pruning of the temporal
retinal vessels (Figure 1C). Fluorescein angiography
revealed early leakage from the abnormal retinal vessels
(Figure 1B). The peripheral vessels were pruned off with
complete avascularity of the far periphery. The left eye
showed similar peripheral vascular pruning temporally
more than nasally (Figure 1D). The findings on EUA
were consistent with the FEVR phenotype. To prevent dis-
ease progression, the patient underwent laser photocoagula-
tion of the peripheral retina of the right eye during the
initial EUA. He subsequently underwent prophylactic laser
photocoagulation of the left eye several weeks later.
Our patient with a CTNNB1 mutation and intellectual
disability exhibited the ocular findings pathognomonic for
FEVR: peripheral retinal avascularity and retinal detachment
in a child whose natural history was not consistent with
retinopathy of prematurity (ROP). These findings are signifi-
cant because, to the best of our knowledge, this is the first
reported case of a CTNNB1 mutation associated with the
FEVR phenotype. Furthermore, as normal CTNNB1 expres-
sion is essential for proper canonical Wnt signaling, the com-
bination of the patient’s genotype and phenotype supports the
current paradigm that abnormal Wnt signaling contributes to
the development of FEVR.
The Wnt signaling pathway is a complex, highly conserved
pathway that regulates cellular differentiation and
proliferation.11 Traditionally, Wnt signaling has been

Figure 1. (A) Fundus photo of the right eye depicts a macula-off retinal detachment extending to the inferotemporal periphery with associated exudation. (B)
Fluorescein angiography of the right eye revealing early leakage from the abnormal retinal vessels. (C) F undus photo of the left eye depicts an elevated optic nerve,
normal macula, and premature pruning of the temporal retinal vessels. (D) Fluorescein angiography of the left eye shows vascular pruning temporally.
categorized as beta-catenin-dependent (canonical) or beta-
catenin-independent (non-canonical). Beta-catenin is a pro-
tein encoded by the CTNNB1 gene, and it regulates gene
transcription as the final effector molecule in canonical Wnt
signaling. Abnormal Wnt signaling has been implicated in
diseases ranging from colon cancer12 to developmental
anomalies such as FEVR, which highlights the important
role that this signaling pathway plays in regulating cellular
proliferation.
Mutations at nearly any point along the canonical Wnt
signaling cascade have been associated with FEVR. For exam-
ple, mutations in the Wnt ligand Norrin (NDP),4 Wnt recep-
tors such as Frizzled-4 (FZD4)2 and Lipoprotein receptor-
related protein 5 (LRP5),3 and other downstream mediators
of Wnt signaling such as Tetraspanin 12 (TSPAN12)5,6 have
all been linked to FEVR. While its mechanism is not yet fully
elucidated, mutations in zinc finger protein 408 (ZNF408) also
lead to the FEVR phenotype.7 Depending on the type of
mutation and the affected gene, FEVR can be inherited in
an autosomal dominant (FZD4, LRP5, ZN408), autosomal
recessive (FZD4, LRP5, TSPAN12) or X-linked recessive pat-
tern (NDP).1
Many of the reported mutations in CTNNB1 are somatic
gain-of-function mutations and typically related to
tumorigenesis.13 Germline loss-of-function mutations are rarer
and mostly correlated with intellectual disability, speech disor-
ders, motor dysfunction, and craniofacial abnormalities.14–16
The clinical presentation of FEVR can be highly variable
and the disease exists along a spectrum of different severities.-
1,8
At the most benign end of the spectrum, patients can be
asymptomatic with an area of retinal avascularity that is not
sufficiently large enough to cause neovascularization and its
OPHTHALMIC GENETICS 469
associated adverse sequelae. At the other end of the spectrum
is complete blindness secondary to total retinal detachment.
The current staging system for FEVR progresses through five
stages and follows a pattern of peripheral retinal avascularity
leading to neovascularization, retinal traction and exudation,
and ultimately retinal detachment.17
Treatment of FEVR is aimed at halting the relentless pro-
gression from neovascularization to retinal traction and
detachment. This is accomplished by destroying the area of
retinal non-perfusion/avascularity, most commonly via laser
photocoagulation. Ablating the ischemic retina reduces the
stimulus for neovascularization and helps to prevent progres-
sion to the later stages of FEVR.
In conclusion, we report a patient with a known CTNNB1
mutation causing the FEVR phenotype. Importantly,
CTNNB1 codes for beta-catenin, the final effector molecule
in canonical Wnt signaling. Abnormalities at nearly any point
along the canonical Wnt signaling pathway have been shown
to cause FEVR, and this case reinforces the current paradigm
of FEVR pathogenesis by linking a mutation in the beta-
catenin gene to the FEVR phenotype.
Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
ORCID
Maxwell W. Dixon http://orcid.org/0000-0002-3220-9656
470 M. W. DIXON ET AL.
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