Ophthalmic Genetics

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

Juvenile cataract in association with tuberous

sclerosis complex

A. L. Geffrey, K. R. Geenen, E. Abati, S. H. Greenstein, D. K. VanderVeen, R. L.

Levy, S. L. Davidson, M. P. McGarrey, E. A. Thiele & M. E. Aronow

To cite this article: A. L. Geffrey, K. R. Geenen, E. Abati, S. H. Greenstein, D. K. VanderVeen,

R. L. Levy, S. L. Davidson, M. P. McGarrey, E. A. Thiele & M. E. Aronow (2020): Juvenile
cataract in association with tuberous sclerosis complex, Ophthalmic Genetics, DOI:
10.1080/13816810.2020.1755989

To link to this article: https://doi.org/10.1080/13816810.2020.1755989

Published online: 27 Apr 2020.

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OPHTHALMIC GENETICS
https://doi.org/10.1080/13816810.2020.1755989

CASE REPORT

Juvenile cataract in association with tuberous sclerosis complex

A. L. Geffreya, K. R. Geenena, E. Abatib, S. H. Greensteinc, D. K. VanderVeend, R. L. Levye, S. L. Davidsonf, M. P. McGarreyc,
E. A. Thielea, and M. E. Aronowc
a
Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; bNeurology
Unit, Department of Pathophysiology and Transplantation, University of Milan, IRCCS Policlinico Ca’Granda Foundation, Milan, Italy; cMassachusetts
Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA; dDepartment of Ophthalmology, Boston Children’s Hospital, Boston,
Massachusetts, USA; eDepartment of Ophthalmology, Weill Cornell Medical College, New York, New York, USA; fDepartment of Ophthalmology,
Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

ABSTRACT ARTICLE HISTORY

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized Received March 25, 2020
by benign hamartomas occurring in multiple organ systems including the brain, kidneys, heart, lungs, Accepted April 05, 2020
liver, skin, and the eyes. Typical retinal findings associated with TSC include astrocytic hamartoma and KEYWORDS
achromic patch. While rare cases of cataract occurring in the setting of TSC have been reported, this is Tuberous sclerosis complex;
the first analysis of a large series of individuals with TSC that aims to quantify the frequency of this cataract; juvenile
finding and to describe its clinical and genetic associations.
Materials and Methods: This is a retrospective chart review of 244 patients from the Herscot Center for
Tuberous Sclerosis Complex at the Massachusetts General Hospital who underwent complete ophthalmic
examination. We describe the clinical and genetic findings in five individuals with TSC and juvenile cataract.
Results: Four of five cases (80%) were unilateral. The cataract was described as having an anterior
subcapsular component in 3 of 5 cases (60%). Three individuals (60%) underwent lensectomy with
intraocular lens (IOL) implant and two individuals (40%) were observed. Genetic testing revealed
a known disease-causing mutation in TSC2 in 100% of cases.
Conclusions: Recent evidence suggests that mTOR signaling may play a role in cataract formation which
could explain the relatively high incidence of juvenile cataract in this population. Juvenile cataract is
a potentially under-recognized ocular manifestation of TSC.

Introduction analyze one of the largest hospital-based TSC populations in

Tuberous sclerosis complex (TSC) is an autosomal dominant
condition that arises sporadically in the majority of affected
individuals (1). TSC results from mutations in the TSC1 and
TSC2 genes, tumor suppressor genes that work together as
a complex in the mTOR pathway (2). TSC can affect any organ
or system in the body, but most commonly involves the brain,
kidneys, heart, lungs, liver, skin, and eyes (1). Commonly asso-
ciated ophthalmic manifestations of TSC include retinal astro-
cytic hamartoma, which occurs in up to 50% of individuals, and
retinal achromic patch (Figure 1) (3). Refractive error, strabis-
mus, and amblyopia can also occur (1).
While age-related cataract is common in middle-aged and
older adults, early onset (congenital and juvenile) cataract is
less prevalent and has been associated with underlying genetic
disease, infection, and trauma (4). Congenital or juvenile
cataract has been noted to occur in the setting of Down
syndrome, Lowe syndrome, galactosemia, and rubella,
among many other conditions (5–7). Although a formal asso-
ciation has not yet been established, there have been rare case
reports of cataract observed in individuals with TSC (8–12).
The frequency of occurrence of juvenile cataract in TSC
population is currently unknown. In the present series, we
the United States, from which five cases of juvenile cataract
are identified and described.
Materials and methods
Cases were identified from a retrospective chart review of
individuals followed at the Herscot Center for TSC at the
Massachusetts General Hospital. The Herscot Center for
TSC provides comprehensive multidisciplinary care for more
than 500 patients and families, making it one of the largest
subspecialty clinical centers of its kind in the United States.
Institutional review board (IRB) approval was obtained for
review of medical records. Of 561 individuals with definite
TSC by clinical diagnostic criteria (13), 244 underwent
a complete ophthalmic examination, of which five with juve-
nile cataract were identified. The clinical features of the five
cases and their associated genetic findings are described.
Results
Of the five individuals with juvenile cataract, four (80%) had
unilateral involvement. The cataract was described as having

CONTACT E. A. Thiele ethiele@mgh.harvard.edu Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital, 175 Cambridge Street,
Suite 340, Boston, MA 02114; M. E. Aronow mary_aronow@meei.harvard.edu Retina Service, Massachusetts Eye and Ear, Harvard Medical School, 243 Charles
Street, Suite 850A, Boston, MA 02114
© 2020 Taylor & Francis Group, LLC
2 A. L. GEFFREY ET AL.

Genetic testing was performed in all individuals and revealed

a known disease-causing mutation in TSC2 in 100% of cases
(Table 1). Each of the cases are individually described as
follows.

Case 1
A 7-week-old female presented to the emergency room with
infantile spasms (IS). Magnetic resonance imaging (MRI) of
the brain revealed cortical tubers in the right frontal lobe and
a subependymal nodule (SEN), leading to the clinical diagno-
sis of TSC. Genetic testing confirmed a disease-causing muta-
tion in TSC2 (c.4919 A > G substitution in exon 37; histidine
replaced by arginine). At 12 weeks of age, due to refractory
seizure activity, she underwent a right frontal craniotomy with
resection of a cortical tuber. Following admission for surgery,
she had a baseline in-office ocular examination in anticipation
(a) of initiating vigabatrin. Examination revealed a 1 mm central
opacity most consistent with an anterior subcapsular cataract
in the right eye. The remainder of the ocular examination,
including dilated fundus examination, was normal in both
eyes. Specifically, no astrocytic hamartomas or achromic
patches were observed. At 6 months follow-up, the cataract
was stable. She continues to have complete ophthalmic exam-
inations at regular intervals due to vigabatrin use and to
monitor the cataract and any signs of amblyopia.

(b)
Figure 1. Fundus photograph of the right eye demonstrating typical, subtle-
appearing retinal astrocytic hamartomas (superior and inferior to the optic
nerve) and a calcified astrocytic hamartoma superonasal to the optic nerve (a).
Fundus photograph of the right eye with a cluster of retinal achromic patches
inferonasal to the optic nerve (b).
an anterior subcapsular component in 3 of 5 cases (60%).
Three individuals (60%) had a visually significant cataract or
showed signs of evolving amblyopia, and therefore underwent
lensectomy with intraocular lens (IOL) implantantaion and
two individuals (40%) had mild findings and were observed.
Case 2
A 2.5-month-old female presenting with IS was diagnosed with
TSC after MRI of the brain showed multiple cortical tubers and
SENs. Genetic testing revealed a disease-causing mutation in
TSC2 (a heterozygous splice site mutation, c.2639 + 1 G > A
substitution). While this represents a novel mutation, a similar
mutation (c.2639 + 1 G > C), has been previously published in
association with TSC (14). She also had variants in MECP2 and
SPTAN1 of unknown significance. The MECP2 mutation was
R268 W (c.802 C > T) or (p.Arg268Trp), a missense change
reported as a de novo mutation in a female with Rett syndrome
(15). The patient also had a de novo nonsense mutation
(Arg270Term) in MECP2. The SPTAN1 mutation was
N1883 S (c.5648 A > G) or (p.Asn1883Ser), a missense muta-
tion not previously reported as either a disease-causing muta-
tion or as a benign polymorphism.
She was started on vigabatrin for IS, and at 5 months of
age, she underwent a complete baseline ophthalmic examina-
tion that revealed a right paracentral anterior subcapsular
cortical cataract. She had an intermittent accommodative

Table 1. Features of juvenile cataract observed in individuals with tuberous sclerosis complex.
Case Sex Age* Laterality Description Mutation Gene Treatment
1 F 9 Mo Right Anterior subcapsular c.4919 A > G TSC2 Observation
2 F 23 Mo Right Anterior subcapsular with cortical changes c.2639 + 1 G > A TSC2 Lensectomy with IOL implant
c.802 C > T MECP2
c.5648 A > G SPTAN1
3 M 13 Mo Bilateral Lamellar c.611 G > A TSC2 Lensectomy with IOL implant
4 F 30 Yr Right Anterior subcapsular and posterior subcapsular c.3759delG TSC2 Lensectomy with IOL implant
5 M 10 Yr Right Lenticular opacity c.4037 C > A TSC2 Observation
*Age at cataract diagnosis
F: female, M: male, Mo: month, Yr: year, IOL: intraocular lens

esotropia, anisometropic hyperopia, and amblyopia of the
right eye. At 23 months of age, her cataract progressed
(Figure 2) and she underwent lensectomy with insertion of
an intraocular lens (IOL) implant. Dilated fundus examina-
tion revealed a small astrocytic hamartoma in the superotem-
poral quadrant of the right fundus. The left fundus
demonstrated two astrocytic hamartomas, one located in the
superotemporal quadrant and one located in the inferotem-
poral quadrant. She also had several retinal achromic patches
in both eyes.
Case 3
A 5-month-old male presented with IS. An MRI of the brain
revealed scattered cortical tubers and a solitary SEN. Further
investigation demonstrated cardiac rhabdomyomas on echo-
cardiogram and bilateral renal cysts on abdominal imaging,
leading to the diagnosis of TSC. Genetic evaluation revealed
the presence of a known disease-causing TSC2 mutation
(c.611 G > A). At the age of 13 months, ocular examination
identified bilateral lamellar cataracts, worse in the right eye.
There had been no cataract in either eye at prior exam at age
of 8 months. The lamellar cataract was described as being in
the shape of a crescent moon, present inferiorly more than
superiorly, and with a clear central visual axis. Amblyopia was
not present at time of diagnosis and the cataracts were not
visually significant. He was followed closely and 17 months of
age, 1+ haze was present in visual axis of the right cataract
and mild amblyopia was present. Amblyopia therapy with
patching of the left eye was initiated. Over the next one
Figure 2. A 5-month-old female was noted to have a right paracentral anterior subcapsular cataract with additional cortical changes. Mild right esotropia with
anisometropia and amblyopia was noted. At 23 months of age, the amblyopia and esotropia worsened and lensectomy with intraocular lens implantation was
performed.
OPHTHALMIC GENETICS 3
month, the cataract progressed significantly in the right eye
and became dense and white. He underwent lensectomy with
the insertion of an IOL implant at 19 months of age. The
cataract in the left eye has been closely monitored and has
remained stable. There were no retinal astrocytic hamartomas
or achromic patches in either eye. No retinal toxicity related
to vigabatrin therapy for IS was observed.
Case 4
A 40-year-old woman was evaluated for TSC after an elective
oncology gene panel revealed a deletion in TSC2 (c.3759delG).
An MRI of the brain demonstrated scattered cortical tubers
and a solitary SEN. Dermatologic evaluation revealed
a shagreen patch on her left lower lumbosacral region and
hypopigmented macules, consistent with the diagnosis of
TSC. No retinal astrocytic hamartomas or achromic patches
were observed on dilated fundus examination. Prior to her
diagnosis of TSC, she had been diagnosed at age 30 years with
a combined anterior and posterior subcapsular cataract in the
right eye. There was no prior history of trauma. Given her
young age and the appearance of the lens opacity, the cataract
was presumed to be juvenile in onset. At the age of 36 years,
the patient underwent cataract extraction with insertion of an
IOL implant.
Case 5
A 7-month-old male presented with IS. MRI of the brain
demonstrated multiple cortical tubers and SENs, consistent
4 A. L. GEFFREY ET AL.
with the clinical diagnosis of TSC. Genetic evaluation revealed
the presence of a known disease-causing mutation in TSC2
(c.4037 C > A). He began taking vigabatrin for IS and there-
fore was seen for regular ophthalmic surveillance to monitor
for retinal toxicity. Neither astrocytic hamartoma nor achro-
mic patch was observed on dilated fundus examination. At the
age of 10 years, bilateral optic disc pallor was noted.
A lenticular opacity in the right eye was also observed at
that time. As the cataract was not visually significant, no
further intervention was required and this finding was
observed.
Discussion
TSC is a genetic disorder that occurs with a frequency of 1 in
6,000 live births and has a prevalence of 1 in 20,000 (16,17). It
is a multi-organ disease that results from mutations in TSC1
and TSC2, the protein products of which form a heterodimer
that interacts within the mTOR signaling pathway. mTOR is
a serine/threonine protein kinase which assembles into two
distinct complexes, mTORC1 and mTORC2. The TSC1/2
complex regulates downstream activation of mTORC1,
which plays a key role in cell cycle progression, cell growth,
and molecular biosynthesis (18). mTORC1 is also the target of
rapamycin, an mTOR inhibitor. mTOR signaling is altered in
many sporadic tumors and is believed to be responsible for
many of the clinical manifestations of TSC. Individuals with
TSC develop hamartomas throughout the body. Classic
ophthalmic features include retinal astrocytic hamartoma,
present in 30 % to 50% of affected individuals, and retinal
achromic patch (1,3). Astrocytic hamartoma is one of the
major diagnostic criterion for establishing diagnosis, while
retinal achromic patch is one of the minor diagnostic criterion
(3,4,13). Although these lesions are not typically visually sig-
nificant, their presence warrants further evaluation for TSC.
On histopathology, retinal astrocytic hamartoma resembles
cortical tubers and are comprised of aberrant astrocytes.
These lesions are believed to arise from abnormal migration
of cells of neural crest origin, due to a disruption in normal
mTOR pathway signaling(4).
While cataract has not previously been recognized as
a dominant clinical feature of TSC, its presence in this popu-
lation has been previously described in rare case reports. It
represents a potentially under-recognized association with
TSC (8–12). While age-related cataract is common in middle-
aged and older adults, the incidence of cataract in children has
been estimated to be approximately 72 per 100,000 in a recent
large cohort study (19). In comparison, within our population
of 561 individuals with TSC at the Herscot Center at the
Massachusetts General Hospital, of which 244 underwent
complete ophthalmic examination, five (2%) were noted to
have juvenile cataract. In comparison with the general popu-
lation, this represents a figure that is 100-fold higher than
would be expected. Interestingly, all patients in our series had
mutations in TSC2. This is consistent with the prior observa-
tion that ocular manifestations are statistically more common
in individuals who harbor mutations in TSC2 (3).
Genetic conditions associated with juvenile cataract, such
as Down syndrome, Lowe syndrome, galactosemia, and others
result from mutations in genes that affect multiple organs.
Genetic alterations can also affect the human crystalline lens
resulting in loss of transparency and refractive properties (7).
As mTORC is a known regulator of cell growth and prolifera-
tion, including protein biosynthesis, it is conceivable that
some patients with TSC would be prone to the development
of cataract. Meng et al. recently demonstrated that mTOR
activation induces posterior capsular lens opacification by
triggering TGF-β2-mediated epithelial-to-mesenchymal tran-
sition in human lymphatic endothelial cells (HLEC). The use
of rapamycin and other mTOR inhibitors, such as Ku-
0063794, could potentially prevent this process (20).
Additionally, Tian et al. demonstrated that rapamycin can
inhibit proliferation and induce apoptosis in human crystal-
line lens cells in vitro by downregulating the Akt/mTOR
pathway (21). In light of these mechanisms, and several
reports recognizing the occurrence of juvenile cataract in
individuals with TSC, it is possible that juvenile cataract is
an under-recognized ocular manifestation of the disease.
Cortical lens fibers continue to develop post-natally, and all
of the individuals in this series had cortical or subcapsular
lens changes. Thus, the current series of juvenile cataract in
individuals with TSC helps to further expand the phenotype
and could potentially lead to advancing our understanding of
TSC pathophysiology as well as improvement in clinical care.
Acknowledgments
The Herscot Center for Tuberous Sclerosis Complex at Massachusetts
General Hospital (MGH) supported this study.
Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
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