- Email: [email protected]
Juvenile X-linked retinoschisis presenting as juxtapapillary retinal fold mimicking combined hamartoma of the retina and retinal pigment epithelium
Accepted Manuscript Juvenile X-linked retinoschisis presenting as juxtapapillary retinal fold mimicking combined hamartoma of the retina and retinal pigment epithelium Renelle Pointdujour-Lim, MD, Emil Anthony T. Say, MD, Carol L. Shields, MD PII:
S1091-8531(17)30065-4
DOI:
10.1016/j.jaapos.2016.11.022
Reference:
YMPA 2562
To appear in:
Journal of AAPOS
Received Date: 27 July 2016 Revised Date:
10 October 2016
Accepted Date: 6 November 2016
Please cite this article as: Pointdujour-Lim R, Say EAT, Shields CL, Juvenile X-linked retinoschisis presenting as juxtapapillary retinal fold mimicking combined hamartoma of the retina and retinal pigment epithelium, Journal of AAPOS (2017), doi: 10.1016/j.jaapos.2016.11.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Juvenile X-linked retinoschisis presenting as juxtapapillary retinal fold mimicking combined hamartoma of the retina and retinal pigment epithelium Renelle Pointdujour-Lim, MD, Emil Anthony T. Say, MD, and Carol L. Shields, MD
RI PT
Author affiliations: Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania Submitted July 27, 2016. Revision accepted November 6, 2016.
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Support provided by Eye Tumor Research Foundation, Philadelphia, PA (CLS). The funders had no role in the design and conduct of the study, in the collection, analysis and interpretation of the data, and in the preparation, review or approval of the manuscript. Carol L. Shields, MD, has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Hospital, 840 Walnut Street, Suite 1440, Philadelphia, PA 19107 (email: [email protected]).
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Word count: 892
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A 21-month-old boy presumptively diagnosed with combined hamartoma of the retina and
vitreomacular traction and prominent retinal folding.
RI PT
retinal pigment epithelium was found to have juvenile X-linked retinoschisis with
Combined hamartoma of the retina and retinal pigment epithelium (RPE) is a benign condition
SC
that can simulate intraocular tumors such as choroidal melanoma and retinoblastoma.1,2 Retinal folds, gliosis, traction, and a mossy green or charcoal gray color, often with focal, dense
M AN U
hyaloidal organization, are hallmark features of this lesion. Although combined hamartoma is considered to be congenital, an acquired variant has been reported,3 which alternatively could represent an atypical presentation of a vitreoretinopathy, such as familial exudative vitreoretinopathy (FEVR) or juvenile X-linked retinoschisis (JXLR). Specifically, FEVR is
TE D
known to characteristically manifest with varying degrees of vitreoretinal traction and folding, and retinal folding has been described in some patients with JXLR.4 Yonekawa and colleagues3 observed a single case of spontaneous formation of a pseudo-combined hamartoma over 3
EP
months in a patient with FEVR. Schachat and Glaser5 noted combined hamartoma in a patient that later demonstrated acquired retinoschisis. This report describes a single case of pseudo-
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combined hamartoma in a patient with JXLR. Case Report
A 21-month-old white boy with unremarkable past medical history and family history developed right esotropia for 8 months and was referred to Wills Eye Hospital for possible retinoblastoma. On examination, visual acuity was inability to fix or follow in the right eye and ability to fix and follow in the left eye. The anterior segment was normal in each eye. Limited clinical fundus
ACCEPTED MANUSCRIPT
examination revealed a charcoal gray retinal mass with overlying glial proliferation and vascular tortuosity in the right eye, suggestive of combined hamartoma of the retina and RPE. The left fundus appeared normal.
RI PT
Examination under anesthesia revealed bilateral temporal peripheral retinoschisis in both eyes with dense vitreomacular traction right eye, imparting the hamartomatous appearance
(Figure 1A,B). Fluorescein angiography (RetCam II, Clarity Medical Systems, Pleasanton, CA)
SC
revealed large, nonperfused retinoschisis cavities (Figure 1C,D). There was no
neovascularization or macular leakage. The “hamartoma” demonstrated hypofluorescence and
M AN U
vascular tortuosity.
Ultrasonography revealed bilateral, thin-walled retinoschisis cavities of both eyes with vitreoretinal traction of the right eye (Figure 1E) greater than the left eye (Figure 1F). Spectral domain optical coherence tomography (SD-OCT, Optovue, Freemont, CA) revealed macular
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retinoschisis involving multiple layers (Figure 2A, B) and peripheral retinoschisis at the level of the nerve fiber layer in both eyes without inner or outer retinal breaks. Horizontal and vertical SD-OCT scans (Figure 2C,D) through the “hamartomatous” mass showed vitreomacular traction
EP
with dense hyaloidal organization, inner retinal folding, and retinal thickening, similar to the SDOCT features of isolated combined hamartoma. The final diagnosis was JXLR (OMIM
AC C
#312700). Family history of JXLR was negative according to the mother’s history, but family evaluation was advised, and genetic testing was suggested. Observation of both eyes and amblyopia therapy was initiated. Discussion
JXLR is an inherited condition with bilateral macular dystrophy in young males. The worldwide prevalence is 1 in 20,000.6 Although its pathogenesis is not entirely elucidated, information
ACCEPTED MANUSCRIPT
about the molecular alterations responsible for JXLR is evolving. Initially, this dystrophy was believed to be related to dysfunctional Muller cells6; however, more than 191 mutations in the retinoschisin (RS1) gene on the short arm of the X chromosome (Xp22.1–p22.3) have been
RI PT
identified, and the locus is more likely localized in the bipolar and photoreceptors cells.6 Macular abnormalities include foveal schisis in young patients and atrophic foveal changes in older patients.7 Peripheral retinoschisis, present in approximately 50% of patients with JXLR, is
SC
associated with poorer visual outcomes when the macula is involved.7 Other clinical features include pre- and/or subretinal macular fibrosis with retinal folds in 17%, exudation in 31%,
sclerotic retinal vessels in 3%.4
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submacular hemorrhage in 11%, vascular sheathing in 8%, bridging retinal vessels in 8%, and
The introduction of SD-OCT has enhanced detection of JXLR. The appearance of the fovea on SD-OCT resembles cystoid macular edema; however, there is no macular leakage on
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fluorescein angiography, as in our case. SD-OCT can detect macular schisis, even in cases of normal-appearing fundus.4 By comparison, fluorescein angiography demonstrates less refined foveal features, such as an atypical foveal avascular zone in 19% but more panoramic peripheral
EP
features of leakage in 59% and nonperfusion in 11%.4 The primary defect in JXLR is in the retinoschisin gene, which functions to maintain
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intraretinal cell-to-cell adhesion and thus provide retinal integrity.6 Loss of function leads to cellular dehiscence and cystoid edema. Although retinoschisin is not expressed in the vitreous, Ikeda and colleagues8 reported resolution of foveal schisis after vitrectomy and gas tamponade. They speculated that the tight vitreous to retina adhesion might be a pathologic feature of JXLR, and that normal retinal structure is restored once the vitreoretinal traction is released.8 The tight vitreoretinal adhesion in JXLR can be managed with plasmin or related
ACCEPTED MANUSCRIPT
products to loosen tension. Patel and Morse9 described the use of ocriplasmin, known for its proteolytic activity against fibronectin and laminin, in a patient with JXLR and reported induction of posterior vitreous detachment and resolution of macular schisis. In our case, perhaps
RI PT
the tight vitreoretinal adhesion led to retinal traction with folding and an appearance similar to combined hamartoma. The development of a “pseudo-combined hamartoma” was previously described by Hrisomalos and colleagues10 in a patient with congenital hydrocephalus and
AC C
EP
TE D
M AN U
SC
papilledema. This “pseudo-combined hamartoma” was formed secondary to an inciting event.
ACCEPTED MANUSCRIPT
References 1.
Shields CL, Thangappan A, Hartzell K, Valente P, Pirondini C, Shields JA. Combined hamartoma of the retina and retinal pigment epithelium in 77 consecutive patients visual
RI PT
outcome based on macular versus extramacular tumor location. Ophthalmology 2008;115:2246-52. 2.
Arepalli S, Pellegrini M, Ferenczy SR, Shields CL. Combined hamartoma of the retina
tomography in eight eyes. Retina 2014;34:2202-7.
Yonekawa Y, Thomas BJ, Drenser KA, Trese MT, Capone A Jr. Acquired combined
M AN U
3.
SC
and retinal pigment epithelium: findings on enhanced depth imaging optical coherence
hamartoma of the retina and retinal pigment epithelium. JAMA Ophthalmol 2015;133:1085-6. 4.
Rao P, Robinson J, Yonekawa Y, et al. Wide-field imaging of nonexudative and
5.
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exudative congenital x-linked retinoschisis. Retina 2016;36:1093-100. Schachat AP, Glaser BM. Retinal hamartoma, acquired retinoschisis, and retinal hole. Am J Ophthalmol 1985;99:604-5.
Molday RS, Kellner U, Weber BH. X-linked juvenile retinoschisis: clinical diagnosis,
EP
6.
genetic analysis, and molecular mechanisms. Prog Retin Eye Res 2012;31:195-212. George ND, Yates JR, Moore AT. Clinical features in affected males with x-linked
AC C
7.
retinoschisis. Arch Ophthalmol 1996;114:274-80.
8.
Ikeda F, Iida T, Kishi S. Resolution of retinoschisis after vitreous surgery in x-linked retinoschisis. Ophthalmology 2008;115:718-22.
9.
Patel A, Morse L. Ocriplasmin for foveal schisis in x-linked retinoschisis. Retin Cases Brief Rep 2015;9:248-51.
ACCEPTED MANUSCRIPT
Hrisomalos NF, Mansour AM, Jampol LM, Fowell SM, Greenwald MJ. “Pseudo”combined hamartoma following papilledema: case report. Arch Ophthalmol
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SC
RI PT
1987;105:1634-5.
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10.
ACCEPTED MANUSCRIPT
Legends FIG 1. A 21-month-old boy with features of combined hamartoma of the retina and retinal pigment epithelium. A, Right eye, with charcoal gray retinal mass (arrow), vascular dragging and
RI PT
tortuosity, and overlying fibrosis. B, Left eye showing blunted foveal reflex. C-D, Fluorescein angiography revealed retinal vascular dragging and mild leakage temporally in the area of
retinoschisis in the inferotemporal quadrant of the right eye (C) but no leakage in the left eye
SC
(D). E-F, B-scan ultrasonography revealed a large echolucent schisis cavity (arrow) in the superotemporal quadrant of the right eye (E) and a smaller schisis cavity (arrow) in the
M AN U
inferotemporal quadrant of the left eye (F).
FIG 2. The features of juvenile X-linked retinoschisis were evident on spectral domain optical coherence tomography. Multilayer foveal schisis can be appreciated in the right eye (A) and left eye (B). Retinal thickening with retinal folds as the “hamartomatous” site with an associated
AC C
EP
TE D
hyaloidal organization are seen in the right eye on horizontal (C) and vertical (D) cuts.
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EP
TE D
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SC
RI PT
ACCEPTED MANUSCRIPT
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SC
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ACCEPTED MANUSCRIPT
S1091-8531(17)30065-4
DOI:
10.1016/j.jaapos.2016.11.022
Reference:
YMPA 2562
To appear in:
Journal of AAPOS
Received Date: 27 July 2016 Revised Date:
10 October 2016
Accepted Date: 6 November 2016
Please cite this article as: Pointdujour-Lim R, Say EAT, Shields CL, Juvenile X-linked retinoschisis presenting as juxtapapillary retinal fold mimicking combined hamartoma of the retina and retinal pigment epithelium, Journal of AAPOS (2017), doi: 10.1016/j.jaapos.2016.11.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Juvenile X-linked retinoschisis presenting as juxtapapillary retinal fold mimicking combined hamartoma of the retina and retinal pigment epithelium Renelle Pointdujour-Lim, MD, Emil Anthony T. Say, MD, and Carol L. Shields, MD
RI PT
Author affiliations: Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania Submitted July 27, 2016. Revision accepted November 6, 2016.
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SC
Support provided by Eye Tumor Research Foundation, Philadelphia, PA (CLS). The funders had no role in the design and conduct of the study, in the collection, analysis and interpretation of the data, and in the preparation, review or approval of the manuscript. Carol L. Shields, MD, has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Hospital, 840 Walnut Street, Suite 1440, Philadelphia, PA 19107 (email: [email protected]).
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Word count: 892
ACCEPTED MANUSCRIPT
vitreomacular traction and prominent retinal folding.
RI PT
retinal pigment epithelium was found to have juvenile X-linked retinoschisis with
Combined hamartoma of the retina and retinal pigment epithelium (RPE) is a benign condition
SC
that can simulate intraocular tumors such as choroidal melanoma and retinoblastoma.1,2 Retinal folds, gliosis, traction, and a mossy green or charcoal gray color, often with focal, dense
M AN U
hyaloidal organization, are hallmark features of this lesion. Although combined hamartoma is considered to be congenital, an acquired variant has been reported,3 which alternatively could represent an atypical presentation of a vitreoretinopathy, such as familial exudative vitreoretinopathy (FEVR) or juvenile X-linked retinoschisis (JXLR). Specifically, FEVR is
TE D
known to characteristically manifest with varying degrees of vitreoretinal traction and folding, and retinal folding has been described in some patients with JXLR.4 Yonekawa and colleagues3 observed a single case of spontaneous formation of a pseudo-combined hamartoma over 3
EP
months in a patient with FEVR. Schachat and Glaser5 noted combined hamartoma in a patient that later demonstrated acquired retinoschisis. This report describes a single case of pseudo-
AC C
combined hamartoma in a patient with JXLR. Case Report
A 21-month-old white boy with unremarkable past medical history and family history developed right esotropia for 8 months and was referred to Wills Eye Hospital for possible retinoblastoma. On examination, visual acuity was inability to fix or follow in the right eye and ability to fix and follow in the left eye. The anterior segment was normal in each eye. Limited clinical fundus
ACCEPTED MANUSCRIPT
examination revealed a charcoal gray retinal mass with overlying glial proliferation and vascular tortuosity in the right eye, suggestive of combined hamartoma of the retina and RPE. The left fundus appeared normal.
RI PT
Examination under anesthesia revealed bilateral temporal peripheral retinoschisis in both eyes with dense vitreomacular traction right eye, imparting the hamartomatous appearance
(Figure 1A,B). Fluorescein angiography (RetCam II, Clarity Medical Systems, Pleasanton, CA)
SC
revealed large, nonperfused retinoschisis cavities (Figure 1C,D). There was no
neovascularization or macular leakage. The “hamartoma” demonstrated hypofluorescence and
M AN U
vascular tortuosity.
Ultrasonography revealed bilateral, thin-walled retinoschisis cavities of both eyes with vitreoretinal traction of the right eye (Figure 1E) greater than the left eye (Figure 1F). Spectral domain optical coherence tomography (SD-OCT, Optovue, Freemont, CA) revealed macular
TE D
retinoschisis involving multiple layers (Figure 2A, B) and peripheral retinoschisis at the level of the nerve fiber layer in both eyes without inner or outer retinal breaks. Horizontal and vertical SD-OCT scans (Figure 2C,D) through the “hamartomatous” mass showed vitreomacular traction
EP
with dense hyaloidal organization, inner retinal folding, and retinal thickening, similar to the SDOCT features of isolated combined hamartoma. The final diagnosis was JXLR (OMIM
AC C
#312700). Family history of JXLR was negative according to the mother’s history, but family evaluation was advised, and genetic testing was suggested. Observation of both eyes and amblyopia therapy was initiated. Discussion
JXLR is an inherited condition with bilateral macular dystrophy in young males. The worldwide prevalence is 1 in 20,000.6 Although its pathogenesis is not entirely elucidated, information
ACCEPTED MANUSCRIPT
about the molecular alterations responsible for JXLR is evolving. Initially, this dystrophy was believed to be related to dysfunctional Muller cells6; however, more than 191 mutations in the retinoschisin (RS1) gene on the short arm of the X chromosome (Xp22.1–p22.3) have been
RI PT
identified, and the locus is more likely localized in the bipolar and photoreceptors cells.6 Macular abnormalities include foveal schisis in young patients and atrophic foveal changes in older patients.7 Peripheral retinoschisis, present in approximately 50% of patients with JXLR, is
SC
associated with poorer visual outcomes when the macula is involved.7 Other clinical features include pre- and/or subretinal macular fibrosis with retinal folds in 17%, exudation in 31%,
sclerotic retinal vessels in 3%.4
M AN U
submacular hemorrhage in 11%, vascular sheathing in 8%, bridging retinal vessels in 8%, and
The introduction of SD-OCT has enhanced detection of JXLR. The appearance of the fovea on SD-OCT resembles cystoid macular edema; however, there is no macular leakage on
TE D
fluorescein angiography, as in our case. SD-OCT can detect macular schisis, even in cases of normal-appearing fundus.4 By comparison, fluorescein angiography demonstrates less refined foveal features, such as an atypical foveal avascular zone in 19% but more panoramic peripheral
EP
features of leakage in 59% and nonperfusion in 11%.4 The primary defect in JXLR is in the retinoschisin gene, which functions to maintain
AC C
intraretinal cell-to-cell adhesion and thus provide retinal integrity.6 Loss of function leads to cellular dehiscence and cystoid edema. Although retinoschisin is not expressed in the vitreous, Ikeda and colleagues8 reported resolution of foveal schisis after vitrectomy and gas tamponade. They speculated that the tight vitreous to retina adhesion might be a pathologic feature of JXLR, and that normal retinal structure is restored once the vitreoretinal traction is released.8 The tight vitreoretinal adhesion in JXLR can be managed with plasmin or related
ACCEPTED MANUSCRIPT
products to loosen tension. Patel and Morse9 described the use of ocriplasmin, known for its proteolytic activity against fibronectin and laminin, in a patient with JXLR and reported induction of posterior vitreous detachment and resolution of macular schisis. In our case, perhaps
RI PT
the tight vitreoretinal adhesion led to retinal traction with folding and an appearance similar to combined hamartoma. The development of a “pseudo-combined hamartoma” was previously described by Hrisomalos and colleagues10 in a patient with congenital hydrocephalus and
AC C
EP
TE D
M AN U
SC
papilledema. This “pseudo-combined hamartoma” was formed secondary to an inciting event.
ACCEPTED MANUSCRIPT
References 1.
Shields CL, Thangappan A, Hartzell K, Valente P, Pirondini C, Shields JA. Combined hamartoma of the retina and retinal pigment epithelium in 77 consecutive patients visual
RI PT
outcome based on macular versus extramacular tumor location. Ophthalmology 2008;115:2246-52. 2.
Arepalli S, Pellegrini M, Ferenczy SR, Shields CL. Combined hamartoma of the retina
tomography in eight eyes. Retina 2014;34:2202-7.
Yonekawa Y, Thomas BJ, Drenser KA, Trese MT, Capone A Jr. Acquired combined
M AN U
3.
SC
and retinal pigment epithelium: findings on enhanced depth imaging optical coherence
hamartoma of the retina and retinal pigment epithelium. JAMA Ophthalmol 2015;133:1085-6. 4.
Rao P, Robinson J, Yonekawa Y, et al. Wide-field imaging of nonexudative and
5.
TE D
exudative congenital x-linked retinoschisis. Retina 2016;36:1093-100. Schachat AP, Glaser BM. Retinal hamartoma, acquired retinoschisis, and retinal hole. Am J Ophthalmol 1985;99:604-5.
Molday RS, Kellner U, Weber BH. X-linked juvenile retinoschisis: clinical diagnosis,
EP
6.
genetic analysis, and molecular mechanisms. Prog Retin Eye Res 2012;31:195-212. George ND, Yates JR, Moore AT. Clinical features in affected males with x-linked
AC C
7.
retinoschisis. Arch Ophthalmol 1996;114:274-80.
8.
Ikeda F, Iida T, Kishi S. Resolution of retinoschisis after vitreous surgery in x-linked retinoschisis. Ophthalmology 2008;115:718-22.
9.
Patel A, Morse L. Ocriplasmin for foveal schisis in x-linked retinoschisis. Retin Cases Brief Rep 2015;9:248-51.
ACCEPTED MANUSCRIPT
Hrisomalos NF, Mansour AM, Jampol LM, Fowell SM, Greenwald MJ. “Pseudo”combined hamartoma following papilledema: case report. Arch Ophthalmol
EP
TE D
M AN U
SC
RI PT
1987;105:1634-5.
AC C
10.
ACCEPTED MANUSCRIPT
Legends FIG 1. A 21-month-old boy with features of combined hamartoma of the retina and retinal pigment epithelium. A, Right eye, with charcoal gray retinal mass (arrow), vascular dragging and
RI PT
tortuosity, and overlying fibrosis. B, Left eye showing blunted foveal reflex. C-D, Fluorescein angiography revealed retinal vascular dragging and mild leakage temporally in the area of
retinoschisis in the inferotemporal quadrant of the right eye (C) but no leakage in the left eye
SC
(D). E-F, B-scan ultrasonography revealed a large echolucent schisis cavity (arrow) in the superotemporal quadrant of the right eye (E) and a smaller schisis cavity (arrow) in the
M AN U
inferotemporal quadrant of the left eye (F).
FIG 2. The features of juvenile X-linked retinoschisis were evident on spectral domain optical coherence tomography. Multilayer foveal schisis can be appreciated in the right eye (A) and left eye (B). Retinal thickening with retinal folds as the “hamartomatous” site with an associated
AC C
EP
TE D
hyaloidal organization are seen in the right eye on horizontal (C) and vertical (D) cuts.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
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M AN U
SC
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ACCEPTED MANUSCRIPT