Familial Foveal Retinoschisis Richard Alan Lewis, MD; Gilbert B. Lee, MA; Csaba L. Martonyi; James M. Barnett, MD; Harold F. Falls, MD
\s=b\ Three young women, offspring of a nonconsanguineous marriage of normal
parents, manifested mild visual loss associated with a bilateral foveal dystrophy that resembled the macular involvement in juvenile sex-linked retinoschisis. Electrophysiologic and psychophysiologic tests showed less severe involvement than the gonosomal equivalent. An autosomal recessive inheritance is pro-
posed. (Arch Ophthalmol 95:1190-1196, 1977)
The
ophthalmoscopic abnormalities of the fovea associated with juve-
nile sex-linked retinoschisis were described and illustrated by Haas1 in the original report of the condition in two brothers. The foveal retinoschisis occurs in virtually every reported instance of the disorder, whether or not peripheral vitreoretinal degeneration ensues." An X-chromosomal recessive mode of transmission was proposed by Thomson' and more firmly established by Sorsby et al' and by others.'-7 To our awareness, Forsius et al"-'" have described the only affected homozygous female subject with sexlinked hereditary retinoschisis, who was the daughter of an affected man and his second cousin. The woman had both macular and peripheral retinal degeneration and progressive visual deterioration all her life. This article will describe foveal retifor publication Nov 1, 1976. From the Department of Ophthalmology (Drs Lewis and Falls and Mr Martonyi), and the Vision Research Laboratory (Mr Lee), University of Michigan Medical Center, Ann Arbor. Dr Barnett is in private practice in Muskegon, Mich. Read in part before the 12th annual residents' days meeting at the Bascom Palmer Eye Institute, Miami, June 6, 1976. Reprint requests to the Department of Ophthalmology, B-2964 Clinical Faculty Office Bldg, University of Michigan Medical Center, Ann Arbor, MI 48109 (Dr Lewis).
Accepted
noschisis in three
daughters of a nonconsanguineous marriage of ophthalmoscopically normal parents. METHODS In addition to complete ophthalmologic evaluation of available members of this
family (Fig 1), affected siblings had color and monochromatic fundus photography, stereoscopic fluorescein angiophotography, central visual field examination, color vision testing, subjective dark adaptation studies, photopic and scotopic electroretinography (ERG), and assessment of Stiles increment brightness thresholds. The electrophysiologic and psychophysiologic techniques have been described."" REPORT OF CASES
18-year-old white woman first seen at the University of Michigan Medical Center in August 1975 because of a recent disturbance in her central visual acuity and her color perception. In 1969, her corrected acuity was 6/7.5 (20/25) in each eye, but no abnormalities of her maculae were identified. In September 1974, she was admitted to the US Navy with correctable acuity of 6/7.5 (20/25) in each eye and "normal color vision." Four months later, she began to notice patchy metamorphopsia and difficulty reading both at distance and at near. Her visual acuity was recorded as 6/12 (20/40) in the right eye and 6/15 (20/50) in the left eye. Ophthalmoscopy revealed a lacy radial network in the foveal retina of each eye that resembled cystoid macular edema, but fluorescein angiography showed no retinal vascular or pigment epithelial abnormalities. Central visual field testing identified no scotoma in either eye. Dark adaptation tested on a Goldmann-Weekers apparatus showed a final cone threshold at 6.5 log units, a rod final threshold at 2.3 log units, and the cone-rod break at nine minutes, which data were interpreted as normal. An eleetro-oculogram yielded a normal lightpeak/dark-trough ratio of 2.4 in the right eye and 2.5 in the left eye. Shortly thereafter, she was discharged from the Navy and was evaluated by us. Cask l.-An
(III-l)
was
history was noncontaking an oral contraceptive medication but no proprietary drugs or vitamins. She did not complain of photophobia or nyctalopia. Her visual acuity was 6/15 (20/50) ( + 0.25 sph) in the right eye and 6/24 (20/ 80) ( + 0.25 sph) in the left eye. Without correction, she read Jaeger 0.5 with each Her past medical
tributory. She
eye at 14
cm.
was
She demonstrated 50 seconds
stereoacuity (Titmus test). The Amsler grid examination showed central metamorphopsia in each eye. A visual field test revealed a patchy relative
of
central scotoma to 1
mm
white and red test
objects at 1 meter. Results of motility and biomicroscopic examinations were normal except for flecks of developmental epicapsular pigment on the left crystalline lens. The anterior and posterior aspects of the
vitreous in each eye contained no veils or and only a few delicate vitreous fibrils. Retinal pathological findings in each eye were symmetrical, limited to an area about the size of the optic disc, and centered in the fovea. The internal limiting membrane and the innermost retina were elevated slightly. Highlights arising from the internal limiting membrane radiated from a smudged foveolar reflex in each eye. The underlying retina, best evaluated by narrow beam binocular biomicroscopy, was thickened by a cartwheel-like formation of delicate septae pointing toward the center of the fovea (Fig 2). Scattered extensively between the radial plicae and extending into the perifovea were many tiny round
punctiform opacities
microcysts.
Both optic discs, the retinal vasculature, and the retinal pigment epithelium appeared normal. Careful ophthalmoscopy with scierai indentation identified no peripheral retinal abnormalities in either eye. Fluorescein angiography detected only the faintest hyperfluorescence through the normally dark foveal pigment screen, suggesting a subtle abnormality in the retinal pigment epithelium (Fig 3). There was no leakage of dye into the subsensory retinal space; the cystoid spaces of the foveal dystrophy did not fluoresce at any time. The Nagel anomaloscope showed a
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borderline protanomalous trichromacy masked by an abnormally wide range of acceptable matches (Table). The HardyRand-Rittler (H-R-R), Isihara, Farnsworth Dichotomous D-15 panel, and Sloan achromatopsia tests were executed without defects. The Farnsworth-Munsell 100-hue test showed a low total error score with the few mistakes aligned roughly with a bipolar tritan axis (Fig 4, top left). The patient was unable to perceive Haidinger's brushes or Maxwell's spot with either
t_? L_? FOVEAL
II
_ _
eye.
Subjective foveal dark adaptation
ing demonstrated
that the final
testcone
threshold was at the upper edge of the normal range. The data were well described by a single exponential curve with a time constant of about 4.2 minutes, which is about one half the normal rate. A dark curve 15° in temporal retina normal final cone and final rod The cone-rod break time was
adaptation showed
plateau.
a
slightly prolonged (12 minutes). Photopic ERG gave a B-wave of 70 pW, and scotopic ERG yielded a maximal A-wave of 230 pV and B-wave of 260 fiV. The ERG response to flicker stimuli faltered above 25 Hz. Measurement of Stiles' increment brightness thresholds identified normal w,, (blue cone), 7t4 (green cone), and it, (red cone)
mechanisms. Case 2.-This young woman (III-2), one of monozygotic twins, is two years younger than the patient in case 1. She failed a school vision screening examination at age 8 years. At age 10 years, her visual acuity was recorded as 6/9 (20/30) ( + 1.00 sph) in each eye. A peculiar macular dystrophy was noted in each eye. At age 11 years, she was examined by one of us (H.F.F.) again with corrected acuity of 6/9 (20/30) in each eye. A reasonably well demarcated, bilateral, cystic dystrophy in each fovea resembled macular edema and showed glistening radial striae on the inner retinal surface. Color vision was normal when tested with the H-R-R plates and FarnsworthMunsell 100-hue test. The Nagel anomaloscope (Table) showed unequivocal protanomalous trichromatic responses. The final threshold of a subjective foveal dark adaptation was elevated about 0.5 log unit; the asymptotes of both the cone and rod portions of the peripheral (15° temporal) dark adaptation curve were similarly minimally elevated. When reexamined at age 16, she did not complain of changes in her visual acuity or nyctalopia, but did comment that her vision tended to "glare out" in intense sunlight and that red objects (eg, stop signs) tended to appear black until she was close to them. Her past medical history was unremark-
RETINOSCHISIS
III
y i]
Fig 1.—Pedigree of family with foveal retinoschisis. All represented persons have been consanguinity was found nor is there anamnestic evidence of visual problems through at least four generations prior to generation I.
examined. No
able. She was taking an oral contraceptive medication but no vitamins or other drugs. Her corrected visual acuity was 6/9 (20/30) ( + 0.75 sph +0.75 cyl axis 90°) in each eye. She demonstrated 60 seconds of stereoacu-
ity (Titmus test).
The results of the Amsler grid examination of each eye were normal. A central visual field examination of each eye revealed a patchy 4° relative scotoma to 2 mm red test object at 1 meter. Each lens had a Mittendorf's dot, but the vitreous contained only a few fine fibrils and no strands, veils, or cellular debris. No foveolar reflex could be seen in either eye. The fovea of each eye was slightly thickened by a striking intraretinal wheel-like formation about the size of the papilla (Fig 5). Interspersed among the spokes were multi-
ple tiny, round, transparent microcysts, entirely similar to the foveas of her older sibling. The optic disc, the retinal vasculature, and the retinal periphery were
normal in each eye. A 1 disc-diameter flat choroidal nevus was located in the inferior nasal quadrant of the left eye. Fluorescein angiography identified no retinal vascular abnormalities and no leakage of dye from the parafoveal capillaries. The retinal pigment epithelium of the posterior pole was normal (Fig 6). The patient could not see Haidinger's brushes or Maxwell's spot with either eye. The Nagel anomaloscope showed a slightly widened equation and a shift toward the red end of the instrument (Table). No abnormalities were detected on the various pigment tests. The few errors on the Farnsworth-Munsell 100-hue test aligned with the tritan axis (Fig 4, center). The threshold of subjective foveal dark adaptation testing was at the upper end of the normal range. A peripheral dark adaptation curve showed that both the cone and rod final thresholds were elevated about
half log units but that the cone-rod break time was normal (9 minutes). Photopic ERG yielded 110 uV B-wave amplitude. The scotopic maximal A-wave was 340 uV and maximal B-wave was 480 uV. The ERG followed flicker stimuli to 45 Hz. Measurement of Stiles' increment brightness thresholds disclosed normal ir, (blue cone), -n, (green cone), and it., (red cone) mechanisms. Cask 3.—This young woman (III-3), the identical twin sister of case 2 (II-2), had experienced some difficulty with school vision screening tests from age 8 years. At age 10 years, her acuity was documented as 6/12 (20/40) (0.75 sph + 0.25 cyl axis 90°) in the right eye and 6/9 (20/30) ( +1.00 sph) in the left eye. A bilateral foveal disorganization symmetrical with that seen in her twin was recognized in each eye. One year later, her visual acuity was essentially unchanged and one of us (H.F.F.) confirmed the presence of the cystic foveal dystrophy in each eye. Color vision was normal on various pigment tests. The Nagel anomaloscope revealed protanomalous responses like those of her twin sister. A foveal dark adaptation curve was elevated one-half log unit, but the peripheral retinal (15° temporal) curve was normal. In 1975, at age 16 years, she was unaware of any changes in her visual perception. She did not complain of photophobia, dyschromatopsia, or nyctalopia. She was taking an oral contraceptive but no vitamins or other medications. Her visual acuity was 6/9 (20/30) ( + 0.50 sph + 0.50 cyl axis 90°) in the right eye and 6/9 (20/30) ( + 0.75 sph) in the left eye. She demonstrated 40 seconds of stereoacuity (Titmus test). The Amsler grid examination results from each eye were normal. There was a patchy relative central scotoma to small red test objects on visual
one
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2.—Monochromatic photograph of foveae of right eye (left) and left eye (right) of proposita (III-1). The crescentic light reflex nasally in each eye (small arrows) is caused by retinal thickening centrally. Radial septae with Interspersed microcysts can best be seen on the temporal side (open arrows).
Fig
Fig 3.—Fluorescein angiogram of foveal area of right eye of II1—1. Neuroepithelial changes are similar to those In left eye (Fig 2, right), and retinal vasculature Is normal. Subtle hyperfluorescence (arrow) shows defect in pigment epithelium. field
testing.
Examination of the anterior
Color Vision Assessed by N
segment of each eye showed normal
findings.
Each fovea contained the characteristic cartwheel of radiating intraretinal, almost transparent, spokes and many fine microcysts, identical to her sisters (Fig 7). The foveolar reflex in each eye was absent, but the underlying pigment epithelium was uninvolved. The retinal vasculature and peripheral retina to the ora serrata and the optic nerve was normal in each eye. Fluorescein angiography disclosed no pigment epithelial or retinal vascular abnormalities (Fig 8) and no pooling in the cystoid retinal spaces in the late photo-
graphs. The patient could not recognize either Haidinger's brushes or Maxwell's spot with
either eye. The Farnsworth-Munsell 100hue test showed a low error score along the tritan axis (Fig 4, bottom). The Nagel
anomaloscope yielded a protanomalous (trichromatic) equation altered in part by a wide range of acceptable matches (Table). A subjective foveal dark adaptation
revealed the final asymptote elevated about one-half log unit. The peripheral
Subject HI I
~
III-2
Date Oct 1975 Feb 1971
July
»
¡gel Anomaloscope*
Range
±
.573 ± .028~ .601 ± .051 .528 ± .045 ± .034 .601 .028 .528 ± .034 ± .118 .494 ± .034
1972
^_^_Oct 1975_.562 III-3
Feb 1971 1972
July
_
_Oct 1975_.612 "Normalized
scores
(«I,,,,
+
a) l„,
(1
»
ß
±
Range_Diagnosis .028_Protanomaly
275 ± .404 ± .045 .365 + .006 .315 ± .376 ± .028
Protanomaly
.371
Protanomaly
.034_
.315_ .371
+
.011
Normal
ß !»„).
—
adaptation curve was normal. Photopic ERG yielded a B-wave amplitude of 120 /iV. The maximal scotopic A-wave was
dark
360 p\ and maximal B-wave 530 jaV. The ERG responses followed a flickered stimulus at 30 Hz but not 45 Hz. Measurement of Stiles' increment brightness thresholds confirmed normal rr, (blue cone), ir, (green cone), and w, (red cone) mechanisms.
COMMENT
The three affected young women in this pedigree demonstrated similarities in visual acuity, ophthalmoscopic
and
fluorescein
angiographie apelectrophysiologic and psychophysiologic performance. They are the offspring of a nonconsanguineous marriage of Pennsylvania Dutch (II-l) and English (II-2) lineages with no antecedent history of ocular problems through at least four generations. pearance, and
Each parent has visual acuity of 20/20 in each eye without correction and no pathological condition of the ocular fundus in either eye by indirect ophthalmoscopy with scierai depres-
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r„—_w
m
"
m
"
*
"
"^
Fig 4.—Farnsworth-Munsell 100-hue test results for top left 111—"I and her sisters, III-2 (top right), and III-3 (bottom). Total error score, appearing In center of each figure, is normal for each individual.
sion and fundus biomicroscopy. The two siblings (III-4 and III-5) of the affected patients and all four grandparents also were found to have normal corrected visual acuity and no foveal or peripheral retinal abnormali-
ties.
The ophthalmoscopic pathological condition in each affected sibling is limited to the fovea. An intraretinal malformation appeared to split the retina into two nearly optically empty zones. The inner retinal layer was very thin and demonstrated delicate,
radial plication and small folds in the internal limiting membrane and suppression or absence of the foveolar light reflex. Encompassing an area about the size of the optic nerve head and centered around the foveal avascular zone, the foveal retina was thickened by a wheel-like formation of radiating cystoid spaces divided by almost transparent, gossamer septae. Myriads of round microcysts, like fine spume, best seen in the proximal illumination of the fine beam of a biomicroscope, were scattered among the
out toward the indistinct limits of the lesion where the retina tapered off into its normal thickness and architecture. No abnormalities of
septae and
the optic disc, the retinal vasculature, or the retinal periphery were found in any affected eye. The foveal dystrophy in these three is morphologically indiswomen tinguishable from the foveal retinoschisis of the juvenile sex-linked variety (Fig 9), although in our patients the intraretinal septae and cystoid spaces may be somewhat more deli-
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Fig 5—Monochromatic photographs of foveae. Right eye (left) and between them, and fine corrugation of reflexes from surrounding
Fig 6.—Fluorescein angiograms
of
right
left eye (right) of III-2. Note intraretinal retinal surfaces.
fovea
(left) and
Fig 7.—Monochromatic photographs of foveae of right eye (left) neuroeplthelial dystrophy Is similar to her affected sisters.
left fovea
and left eye
(right)
(right)
of III-2
of 11-3.
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are
spoke-like septae, mlcrocysts
normal.
Ophthalmoscopic
appearance of
Fig 8.—Fluorescein angiograms
of
right
fovea
(left)
and left fovea
(right)
of III-3 are normal.
to the history of visual deterioration and the observed structural changes in the outer retina is uncertain. However, the mild foveal form of sex-linked retinoschisis manifests either no angiographie abnormalities or only subtle pigment epithelial changes resulting in similar
pigment epithelium
hyperfluorescence."'' Angiographically, the retinal vasculature was normal in all three patients reported and intraretinal pooling of dye did not occur.
Our patients had normal color vision when tested with the usual pigment plates. Each had a low total error score on the Farnsworth-Munsell 100-hue test, with a predilection for these mistakes to appear along the tritan axis.'" Responses on a Nagel anoma-
Fig
9.—Monochromatic photograph of foveal abnormalities In a 15-year-old boy with sex-linked retinoschisis. Morphologic changes are strikingly similar to those in 2, 5, and 7.
juvenile
Fig
cate than the appearance of the
macular changes in the usual affected male subject. The penetrance of X-chromosomal recessive retinoschisis is 100% in the hemizygous state." The macular retinoschisis in this disorder is present without peripheral vitreoretinal pathology in about 50% of affected male subjects and is so characteristic that Deutman- considers it pathognomonic of the syndrome. The sole reported homozygous female subject""' had severe foveal and peripheral retinal as well as pigment epithelial involve"'
ment in both eyes, with progressive visual deterioration most of her life. our three young women have modest visual involvement, that their father is normal ophthalmoscopically, and that there is no anamnestic evidence of central visual loss or retinal pathological condition make this pedigree unique. Fluorescein angiographie results in two of our patients were normal and in case 1 showed a barely discernible increased fluorescence through the macular pigment epithelium. The relationship of this abnormality in the
That
only
loscope suggested protanomalous trichromacy in all three affected women, which was not confirmed by other color tests. This slightly reduced sensitivity to red has been noted also
in sex-linked retinoschisis.-' Possible explanations for this behavior in our patients include the following: (1) an abnormal orientation of the retina such that foveal cones are pointed toward the edge rather than the center of the pupil; (2) an abnormal red-absorbing filter in the ocular media; or (3) the presence of a foveal cone pigment with an anomalous absorption spectrum. The normal performance of other tests of color perception and normal Stiles' increment brightness thresholds for all three cone mechanisms reasonably eliminate the latter two choices from consideration. None of the three affected young
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could perceive either Haidinger's brushes or Maxwell's spot, although both entoptic phenomena were perceived readily by unaffected siblings and by each parent. In our experience, men affected with juvenile sex-linked retinoschisis similarly are unable to recognize these phenomena, whereas unaffected family members including female carriers are able to perceive them. These observations may imply either a deficiency of macular xanthophyll in our subjects or a reduced sensitivity of the foveal blue cones. This latter premise is partly substantiated on the FarnsworthMunsell 100-hue test by the predominance of the few observed errors along the tritan axis. The dark adaptation curves in our patients showed either normal or slightly elevated final cone and rod thresholds. These responses are less affected than those in most individuals with X-linked retinoschisis.- However, finer assessments of cone and rod performance are described above. The ERG recordings of all affected women displayed normal photopic fawave amplitudes; the scotopic a-wave, b-wave, and b-wave implicit times were also normal, except for the scotopic b-wave of case 1, which was minimally subnormal." Whether this observation suggests a widespread structural defect in the neuroretina'7'" or a progressive involvement in the eldest sibling may only be answered by further examination. The eleetro-oculogram was normal in the only affected patient (III-l) on whom it was performed. The differential diagnosis of the ophthalmoscopic entity observed in our three patients is limited. Cibis'" reported a pair of female monozygotic twins with peripheral retinoschisis and proposed an autosomal recessive mode of inheritance. The bilateral involvement in each patient was discovered at age 19 and was associated with high myopia, a nonspecific macular pigmentary degeneration, and slightly reduced visual acuity, from 20/30 to 20/70 in different eyes. Unfortunately, this family has been lost to follow-up (Dean Burgess, MD, women
written communication, May 1976), and the evolution of the macular lesions is not available. Each of our
affected patients
minimally hyperipheral permétropie retinal pathological findings. Favre-Goldmann syndrome,-"-' an
This investigation was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, and by grant EY-00197-18 from the National Eye Institute (M Alpern, PhD). Mathew Alpern, PhD, gave counsel and criticism throughout this study. Bernard C. Wildgen, MI), and David Meyer, MD, shared their clinical
hood, cataracts, an extinguished ERG, and extensive vitreoretinal and pigment epithelial alterations. In general, the pattern of the foveal retinoschi-
gree.
and
was
none
had
autosomal recessive disorder, has severe night blindness even in child-
sis and edema is more extensive and much coarser than in our patients. Cystoid macular edema associated with a number of retinal diseases'-'2 may resemble the foveal dystrophy described above. However, the specific etiologic associations and classical fluorescein angiographie findings of petaloid intraretinal staining readily differentiate cystoid edema from foveal retinoschisis. Gass-:' described an atypical cystoid macular edema in three men who consumed toxic levels of nicotinic acid. In one of his patients, the macular changes resolved within one week of discontinuing the drug and promptly reoccurred when it was reinstituted on two separate occasions. Fluorescein angiography did not identify any diffusion of dye from the parafoveal retinal capillaries into the extracellular fluid of the cystoid spaces of the swollen maculae. None of our patients
taking any prescription or proprietary medication at the time of discovery of the foveal retinoschisis. Furthermore, the early age of onset in each patient, the symmetry of all was
affected eyes, the simultaneous involvement of both monozygotic twins, and the absence of involvement in the only male sibling, is best explained by an autosomal recessively inherited disorder. However, we are unable to explain the history of visual change in case 1 on an ophthalmoscopic basis only, although we were not able to examine her at the time of its onset. It would appear that this form of foveal retinoschisis represents a previously unreported macular dystrophy that closely resembles the sex-linked juvenile form (Fig 9). This disorder properly may be included in the differential diagnosis of foveal retinoschisis in a person of either sex when there is no antecedent family history of central visual loss or sexlinked inheritance.
evaluations of various members of this
pedi-
References 1. Haas J: Ueber das
Zusammenvorkommen
Veranderungen der Retina und Arch Augenheilkd 37:343-348, 1898. von
Choroidea.
2. Deutman AF: Sex-linked juvenile retinoschisis, in: The Hereditary Dystrophies of the Posterior Pole ofthe Eye. Assen, The Netherlands, Van Gorcum, 1971, pp 48-99. 3. Thomson E: Memorandum regarding a family in which neuroretinal disease of an unusual kind occurred only in the males. Br J
Ophthalmol 16:681-686,
1932. 4. Sorsby A, Klein M, Gann JH, et al: Unusual retinal detachment, possibly sex-linked. Br J Ophthalmol 35:1-10, 1951. 5. Levy J: Inherited retinal detachment. Br J Ophthalmol 36:626-636, 1952. 6. Jager GM: A hereditary retinal disease. Trans Ophthalmol Soc U K 73:617-619, 1953. 7. Bengtsson B, Linder B: Sex-linked hereditary juvenile retinoschisis. Acta Ophthalmol (Kbh) 45:411-423, 1967. 8. Forsius H, Vainio-Mattila B, Eriksson A: X\x=req-\ linked hereditary retinoschisis. Br J Ophthalmol 46:678-681, 1962. 9. Forsius H, Eriksson A, Vainio-Mattila B: Geschlechtsgebundene erbliche Retinoschisis in Zwei Familien in Finnland. Klin Monatsbl
Augenheilkd 143:806-816,
1963.
10. Forsius H, Krause U, Helve J, et al: Visual acuity in 183 cases of X-chromosomal retinoschisis. Can J Ophthalmol 8:385-393, 1973. 11. Krill AE, Lee GB: The electroretinogram in albinos and carriers of the ocular albino trait. Arch Ophthalmol 69:32-38, 1963. 12. Alpern M, Falls HF, Lee GB: The enigma of typical total monochromacy. Am J Ophthalmol 50:326-341, 1960. 13. Wald G: The receptors of human color vision. Science 145:1007-1016, 1964. 14. Krause U, Vainio-Mattila B, Eriksson A, et al: Fluorescein angiographic studies on X-chromosomal retinoschisis. Acta Ophthalmol (Kbh) 48:794-807, 1970. 15. Ewing CC, Cullen AP: Fluorescein angiography in X-chromosomal maculopathy with retinoschisis (juvenile hereditary retinoschisis). Can J Ophthalmol 7:19-28, 1972. 16. Helve J: Colour vision in X-chromosomal juvenile retinoschisis. Mod Probl Ophthalmol 11:122-129, 1972. 17. Krill AE: The electroretinogram and elec-
tro-oculogram: Clinical applications. Invest Ophthalmol 9:600-617, 1970.
18. Guyot-Sionnest M: A propos d'une famille atteinte de retinoschisis idiopathique recessif l[ill] au sexe. Ann Oculist 202:573-598, 1969. 19. Cibis PA: Retinoschisis\p=n-\retinal cysts. Trans Am Ophthalmol Soc 53:417-453, 1965. 20. Favre M: A propose de deux cas de degen-
hyaloideoretininenne. Ophthalmologica 135:604-609, 1958. 21. MacVicar JE, Wilbrandt HR: Hereditary retinoschisis and early hemeralopia: A report of two cases. Arch Ophthalmol 83:629-636, 1970. 22. Gass JDM: Macular dysfunction caused by retinal vascular disease, in: Stereoscopic Atlas of Macular Diseases. St Louis, CV Mosby, 1970, pp erescence
135-172. 23. Gass JDM: Nicotinic acid J Ophthalmol 76:500-510, 1973.
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maculopathy. Am
\s=b\ Three young women, offspring of a nonconsanguineous marriage of normal
parents, manifested mild visual loss associated with a bilateral foveal dystrophy that resembled the macular involvement in juvenile sex-linked retinoschisis. Electrophysiologic and psychophysiologic tests showed less severe involvement than the gonosomal equivalent. An autosomal recessive inheritance is pro-
posed. (Arch Ophthalmol 95:1190-1196, 1977)
The
ophthalmoscopic abnormalities of the fovea associated with juve-
nile sex-linked retinoschisis were described and illustrated by Haas1 in the original report of the condition in two brothers. The foveal retinoschisis occurs in virtually every reported instance of the disorder, whether or not peripheral vitreoretinal degeneration ensues." An X-chromosomal recessive mode of transmission was proposed by Thomson' and more firmly established by Sorsby et al' and by others.'-7 To our awareness, Forsius et al"-'" have described the only affected homozygous female subject with sexlinked hereditary retinoschisis, who was the daughter of an affected man and his second cousin. The woman had both macular and peripheral retinal degeneration and progressive visual deterioration all her life. This article will describe foveal retifor publication Nov 1, 1976. From the Department of Ophthalmology (Drs Lewis and Falls and Mr Martonyi), and the Vision Research Laboratory (Mr Lee), University of Michigan Medical Center, Ann Arbor. Dr Barnett is in private practice in Muskegon, Mich. Read in part before the 12th annual residents' days meeting at the Bascom Palmer Eye Institute, Miami, June 6, 1976. Reprint requests to the Department of Ophthalmology, B-2964 Clinical Faculty Office Bldg, University of Michigan Medical Center, Ann Arbor, MI 48109 (Dr Lewis).
Accepted
noschisis in three
daughters of a nonconsanguineous marriage of ophthalmoscopically normal parents. METHODS In addition to complete ophthalmologic evaluation of available members of this
family (Fig 1), affected siblings had color and monochromatic fundus photography, stereoscopic fluorescein angiophotography, central visual field examination, color vision testing, subjective dark adaptation studies, photopic and scotopic electroretinography (ERG), and assessment of Stiles increment brightness thresholds. The electrophysiologic and psychophysiologic techniques have been described."" REPORT OF CASES
18-year-old white woman first seen at the University of Michigan Medical Center in August 1975 because of a recent disturbance in her central visual acuity and her color perception. In 1969, her corrected acuity was 6/7.5 (20/25) in each eye, but no abnormalities of her maculae were identified. In September 1974, she was admitted to the US Navy with correctable acuity of 6/7.5 (20/25) in each eye and "normal color vision." Four months later, she began to notice patchy metamorphopsia and difficulty reading both at distance and at near. Her visual acuity was recorded as 6/12 (20/40) in the right eye and 6/15 (20/50) in the left eye. Ophthalmoscopy revealed a lacy radial network in the foveal retina of each eye that resembled cystoid macular edema, but fluorescein angiography showed no retinal vascular or pigment epithelial abnormalities. Central visual field testing identified no scotoma in either eye. Dark adaptation tested on a Goldmann-Weekers apparatus showed a final cone threshold at 6.5 log units, a rod final threshold at 2.3 log units, and the cone-rod break at nine minutes, which data were interpreted as normal. An eleetro-oculogram yielded a normal lightpeak/dark-trough ratio of 2.4 in the right eye and 2.5 in the left eye. Shortly thereafter, she was discharged from the Navy and was evaluated by us. Cask l.-An
(III-l)
was
history was noncontaking an oral contraceptive medication but no proprietary drugs or vitamins. She did not complain of photophobia or nyctalopia. Her visual acuity was 6/15 (20/50) ( + 0.25 sph) in the right eye and 6/24 (20/ 80) ( + 0.25 sph) in the left eye. Without correction, she read Jaeger 0.5 with each Her past medical
tributory. She
eye at 14
cm.
was
She demonstrated 50 seconds
stereoacuity (Titmus test). The Amsler grid examination showed central metamorphopsia in each eye. A visual field test revealed a patchy relative
of
central scotoma to 1
mm
white and red test
objects at 1 meter. Results of motility and biomicroscopic examinations were normal except for flecks of developmental epicapsular pigment on the left crystalline lens. The anterior and posterior aspects of the
vitreous in each eye contained no veils or and only a few delicate vitreous fibrils. Retinal pathological findings in each eye were symmetrical, limited to an area about the size of the optic disc, and centered in the fovea. The internal limiting membrane and the innermost retina were elevated slightly. Highlights arising from the internal limiting membrane radiated from a smudged foveolar reflex in each eye. The underlying retina, best evaluated by narrow beam binocular biomicroscopy, was thickened by a cartwheel-like formation of delicate septae pointing toward the center of the fovea (Fig 2). Scattered extensively between the radial plicae and extending into the perifovea were many tiny round
punctiform opacities
microcysts.
Both optic discs, the retinal vasculature, and the retinal pigment epithelium appeared normal. Careful ophthalmoscopy with scierai indentation identified no peripheral retinal abnormalities in either eye. Fluorescein angiography detected only the faintest hyperfluorescence through the normally dark foveal pigment screen, suggesting a subtle abnormality in the retinal pigment epithelium (Fig 3). There was no leakage of dye into the subsensory retinal space; the cystoid spaces of the foveal dystrophy did not fluoresce at any time. The Nagel anomaloscope showed a
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borderline protanomalous trichromacy masked by an abnormally wide range of acceptable matches (Table). The HardyRand-Rittler (H-R-R), Isihara, Farnsworth Dichotomous D-15 panel, and Sloan achromatopsia tests were executed without defects. The Farnsworth-Munsell 100-hue test showed a low total error score with the few mistakes aligned roughly with a bipolar tritan axis (Fig 4, top left). The patient was unable to perceive Haidinger's brushes or Maxwell's spot with either
t_? L_? FOVEAL
II
_ _
eye.
Subjective foveal dark adaptation
ing demonstrated
that the final
testcone
threshold was at the upper edge of the normal range. The data were well described by a single exponential curve with a time constant of about 4.2 minutes, which is about one half the normal rate. A dark curve 15° in temporal retina normal final cone and final rod The cone-rod break time was
adaptation showed
plateau.
a
slightly prolonged (12 minutes). Photopic ERG gave a B-wave of 70 pW, and scotopic ERG yielded a maximal A-wave of 230 pV and B-wave of 260 fiV. The ERG response to flicker stimuli faltered above 25 Hz. Measurement of Stiles' increment brightness thresholds identified normal w,, (blue cone), 7t4 (green cone), and it, (red cone)
mechanisms. Case 2.-This young woman (III-2), one of monozygotic twins, is two years younger than the patient in case 1. She failed a school vision screening examination at age 8 years. At age 10 years, her visual acuity was recorded as 6/9 (20/30) ( + 1.00 sph) in each eye. A peculiar macular dystrophy was noted in each eye. At age 11 years, she was examined by one of us (H.F.F.) again with corrected acuity of 6/9 (20/30) in each eye. A reasonably well demarcated, bilateral, cystic dystrophy in each fovea resembled macular edema and showed glistening radial striae on the inner retinal surface. Color vision was normal when tested with the H-R-R plates and FarnsworthMunsell 100-hue test. The Nagel anomaloscope (Table) showed unequivocal protanomalous trichromatic responses. The final threshold of a subjective foveal dark adaptation was elevated about 0.5 log unit; the asymptotes of both the cone and rod portions of the peripheral (15° temporal) dark adaptation curve were similarly minimally elevated. When reexamined at age 16, she did not complain of changes in her visual acuity or nyctalopia, but did comment that her vision tended to "glare out" in intense sunlight and that red objects (eg, stop signs) tended to appear black until she was close to them. Her past medical history was unremark-
RETINOSCHISIS
III
y i]
Fig 1.—Pedigree of family with foveal retinoschisis. All represented persons have been consanguinity was found nor is there anamnestic evidence of visual problems through at least four generations prior to generation I.
examined. No
able. She was taking an oral contraceptive medication but no vitamins or other drugs. Her corrected visual acuity was 6/9 (20/30) ( + 0.75 sph +0.75 cyl axis 90°) in each eye. She demonstrated 60 seconds of stereoacu-
ity (Titmus test).
The results of the Amsler grid examination of each eye were normal. A central visual field examination of each eye revealed a patchy 4° relative scotoma to 2 mm red test object at 1 meter. Each lens had a Mittendorf's dot, but the vitreous contained only a few fine fibrils and no strands, veils, or cellular debris. No foveolar reflex could be seen in either eye. The fovea of each eye was slightly thickened by a striking intraretinal wheel-like formation about the size of the papilla (Fig 5). Interspersed among the spokes were multi-
ple tiny, round, transparent microcysts, entirely similar to the foveas of her older sibling. The optic disc, the retinal vasculature, and the retinal periphery were
normal in each eye. A 1 disc-diameter flat choroidal nevus was located in the inferior nasal quadrant of the left eye. Fluorescein angiography identified no retinal vascular abnormalities and no leakage of dye from the parafoveal capillaries. The retinal pigment epithelium of the posterior pole was normal (Fig 6). The patient could not see Haidinger's brushes or Maxwell's spot with either eye. The Nagel anomaloscope showed a slightly widened equation and a shift toward the red end of the instrument (Table). No abnormalities were detected on the various pigment tests. The few errors on the Farnsworth-Munsell 100-hue test aligned with the tritan axis (Fig 4, center). The threshold of subjective foveal dark adaptation testing was at the upper end of the normal range. A peripheral dark adaptation curve showed that both the cone and rod final thresholds were elevated about
half log units but that the cone-rod break time was normal (9 minutes). Photopic ERG yielded 110 uV B-wave amplitude. The scotopic maximal A-wave was 340 uV and maximal B-wave was 480 uV. The ERG followed flicker stimuli to 45 Hz. Measurement of Stiles' increment brightness thresholds disclosed normal ir, (blue cone), -n, (green cone), and it., (red cone) mechanisms. Cask 3.—This young woman (III-3), the identical twin sister of case 2 (II-2), had experienced some difficulty with school vision screening tests from age 8 years. At age 10 years, her acuity was documented as 6/12 (20/40) (0.75 sph + 0.25 cyl axis 90°) in the right eye and 6/9 (20/30) ( +1.00 sph) in the left eye. A bilateral foveal disorganization symmetrical with that seen in her twin was recognized in each eye. One year later, her visual acuity was essentially unchanged and one of us (H.F.F.) confirmed the presence of the cystic foveal dystrophy in each eye. Color vision was normal on various pigment tests. The Nagel anomaloscope revealed protanomalous responses like those of her twin sister. A foveal dark adaptation curve was elevated one-half log unit, but the peripheral retinal (15° temporal) curve was normal. In 1975, at age 16 years, she was unaware of any changes in her visual perception. She did not complain of photophobia, dyschromatopsia, or nyctalopia. She was taking an oral contraceptive but no vitamins or other medications. Her visual acuity was 6/9 (20/30) ( + 0.50 sph + 0.50 cyl axis 90°) in the right eye and 6/9 (20/30) ( + 0.75 sph) in the left eye. She demonstrated 40 seconds of stereoacuity (Titmus test). The Amsler grid examination results from each eye were normal. There was a patchy relative central scotoma to small red test objects on visual
one
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2.—Monochromatic photograph of foveae of right eye (left) and left eye (right) of proposita (III-1). The crescentic light reflex nasally in each eye (small arrows) is caused by retinal thickening centrally. Radial septae with Interspersed microcysts can best be seen on the temporal side (open arrows).
Fig
Fig 3.—Fluorescein angiogram of foveal area of right eye of II1—1. Neuroepithelial changes are similar to those In left eye (Fig 2, right), and retinal vasculature Is normal. Subtle hyperfluorescence (arrow) shows defect in pigment epithelium. field
testing.
Examination of the anterior
Color Vision Assessed by N
segment of each eye showed normal
findings.
Each fovea contained the characteristic cartwheel of radiating intraretinal, almost transparent, spokes and many fine microcysts, identical to her sisters (Fig 7). The foveolar reflex in each eye was absent, but the underlying pigment epithelium was uninvolved. The retinal vasculature and peripheral retina to the ora serrata and the optic nerve was normal in each eye. Fluorescein angiography disclosed no pigment epithelial or retinal vascular abnormalities (Fig 8) and no pooling in the cystoid retinal spaces in the late photo-
graphs. The patient could not recognize either Haidinger's brushes or Maxwell's spot with
either eye. The Farnsworth-Munsell 100hue test showed a low error score along the tritan axis (Fig 4, bottom). The Nagel
anomaloscope yielded a protanomalous (trichromatic) equation altered in part by a wide range of acceptable matches (Table). A subjective foveal dark adaptation
revealed the final asymptote elevated about one-half log unit. The peripheral
Subject HI I
~
III-2
Date Oct 1975 Feb 1971
July
»
¡gel Anomaloscope*
Range
±
.573 ± .028~ .601 ± .051 .528 ± .045 ± .034 .601 .028 .528 ± .034 ± .118 .494 ± .034
1972
^_^_Oct 1975_.562 III-3
Feb 1971 1972
July
_
_Oct 1975_.612 "Normalized
scores
(«I,,,,
+
a) l„,
(1
»
ß
±
Range_Diagnosis .028_Protanomaly
275 ± .404 ± .045 .365 + .006 .315 ± .376 ± .028
Protanomaly
.371
Protanomaly
.034_
.315_ .371
+
.011
Normal
ß !»„).
—
adaptation curve was normal. Photopic ERG yielded a B-wave amplitude of 120 /iV. The maximal scotopic A-wave was
dark
360 p\ and maximal B-wave 530 jaV. The ERG responses followed a flickered stimulus at 30 Hz but not 45 Hz. Measurement of Stiles' increment brightness thresholds confirmed normal rr, (blue cone), ir, (green cone), and w, (red cone) mechanisms.
COMMENT
The three affected young women in this pedigree demonstrated similarities in visual acuity, ophthalmoscopic
and
fluorescein
angiographie apelectrophysiologic and psychophysiologic performance. They are the offspring of a nonconsanguineous marriage of Pennsylvania Dutch (II-l) and English (II-2) lineages with no antecedent history of ocular problems through at least four generations. pearance, and
Each parent has visual acuity of 20/20 in each eye without correction and no pathological condition of the ocular fundus in either eye by indirect ophthalmoscopy with scierai depres-
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r„—_w
m
"
m
"
*
"
"^
Fig 4.—Farnsworth-Munsell 100-hue test results for top left 111—"I and her sisters, III-2 (top right), and III-3 (bottom). Total error score, appearing In center of each figure, is normal for each individual.
sion and fundus biomicroscopy. The two siblings (III-4 and III-5) of the affected patients and all four grandparents also were found to have normal corrected visual acuity and no foveal or peripheral retinal abnormali-
ties.
The ophthalmoscopic pathological condition in each affected sibling is limited to the fovea. An intraretinal malformation appeared to split the retina into two nearly optically empty zones. The inner retinal layer was very thin and demonstrated delicate,
radial plication and small folds in the internal limiting membrane and suppression or absence of the foveolar light reflex. Encompassing an area about the size of the optic nerve head and centered around the foveal avascular zone, the foveal retina was thickened by a wheel-like formation of radiating cystoid spaces divided by almost transparent, gossamer septae. Myriads of round microcysts, like fine spume, best seen in the proximal illumination of the fine beam of a biomicroscope, were scattered among the
out toward the indistinct limits of the lesion where the retina tapered off into its normal thickness and architecture. No abnormalities of
septae and
the optic disc, the retinal vasculature, or the retinal periphery were found in any affected eye. The foveal dystrophy in these three is morphologically indiswomen tinguishable from the foveal retinoschisis of the juvenile sex-linked variety (Fig 9), although in our patients the intraretinal septae and cystoid spaces may be somewhat more deli-
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Fig 5—Monochromatic photographs of foveae. Right eye (left) and between them, and fine corrugation of reflexes from surrounding
Fig 6.—Fluorescein angiograms
of
right
left eye (right) of III-2. Note intraretinal retinal surfaces.
fovea
(left) and
Fig 7.—Monochromatic photographs of foveae of right eye (left) neuroeplthelial dystrophy Is similar to her affected sisters.
left fovea
and left eye
(right)
(right)
of III-2
of 11-3.
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are
spoke-like septae, mlcrocysts
normal.
Ophthalmoscopic
appearance of
Fig 8.—Fluorescein angiograms
of
right
fovea
(left)
and left fovea
(right)
of III-3 are normal.
to the history of visual deterioration and the observed structural changes in the outer retina is uncertain. However, the mild foveal form of sex-linked retinoschisis manifests either no angiographie abnormalities or only subtle pigment epithelial changes resulting in similar
pigment epithelium
hyperfluorescence."'' Angiographically, the retinal vasculature was normal in all three patients reported and intraretinal pooling of dye did not occur.
Our patients had normal color vision when tested with the usual pigment plates. Each had a low total error score on the Farnsworth-Munsell 100-hue test, with a predilection for these mistakes to appear along the tritan axis.'" Responses on a Nagel anoma-
Fig
9.—Monochromatic photograph of foveal abnormalities In a 15-year-old boy with sex-linked retinoschisis. Morphologic changes are strikingly similar to those in 2, 5, and 7.
juvenile
Fig
cate than the appearance of the
macular changes in the usual affected male subject. The penetrance of X-chromosomal recessive retinoschisis is 100% in the hemizygous state." The macular retinoschisis in this disorder is present without peripheral vitreoretinal pathology in about 50% of affected male subjects and is so characteristic that Deutman- considers it pathognomonic of the syndrome. The sole reported homozygous female subject""' had severe foveal and peripheral retinal as well as pigment epithelial involve"'
ment in both eyes, with progressive visual deterioration most of her life. our three young women have modest visual involvement, that their father is normal ophthalmoscopically, and that there is no anamnestic evidence of central visual loss or retinal pathological condition make this pedigree unique. Fluorescein angiographie results in two of our patients were normal and in case 1 showed a barely discernible increased fluorescence through the macular pigment epithelium. The relationship of this abnormality in the
That
only
loscope suggested protanomalous trichromacy in all three affected women, which was not confirmed by other color tests. This slightly reduced sensitivity to red has been noted also
in sex-linked retinoschisis.-' Possible explanations for this behavior in our patients include the following: (1) an abnormal orientation of the retina such that foveal cones are pointed toward the edge rather than the center of the pupil; (2) an abnormal red-absorbing filter in the ocular media; or (3) the presence of a foveal cone pigment with an anomalous absorption spectrum. The normal performance of other tests of color perception and normal Stiles' increment brightness thresholds for all three cone mechanisms reasonably eliminate the latter two choices from consideration. None of the three affected young
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could perceive either Haidinger's brushes or Maxwell's spot, although both entoptic phenomena were perceived readily by unaffected siblings and by each parent. In our experience, men affected with juvenile sex-linked retinoschisis similarly are unable to recognize these phenomena, whereas unaffected family members including female carriers are able to perceive them. These observations may imply either a deficiency of macular xanthophyll in our subjects or a reduced sensitivity of the foveal blue cones. This latter premise is partly substantiated on the FarnsworthMunsell 100-hue test by the predominance of the few observed errors along the tritan axis. The dark adaptation curves in our patients showed either normal or slightly elevated final cone and rod thresholds. These responses are less affected than those in most individuals with X-linked retinoschisis.- However, finer assessments of cone and rod performance are described above. The ERG recordings of all affected women displayed normal photopic fawave amplitudes; the scotopic a-wave, b-wave, and b-wave implicit times were also normal, except for the scotopic b-wave of case 1, which was minimally subnormal." Whether this observation suggests a widespread structural defect in the neuroretina'7'" or a progressive involvement in the eldest sibling may only be answered by further examination. The eleetro-oculogram was normal in the only affected patient (III-l) on whom it was performed. The differential diagnosis of the ophthalmoscopic entity observed in our three patients is limited. Cibis'" reported a pair of female monozygotic twins with peripheral retinoschisis and proposed an autosomal recessive mode of inheritance. The bilateral involvement in each patient was discovered at age 19 and was associated with high myopia, a nonspecific macular pigmentary degeneration, and slightly reduced visual acuity, from 20/30 to 20/70 in different eyes. Unfortunately, this family has been lost to follow-up (Dean Burgess, MD, women
written communication, May 1976), and the evolution of the macular lesions is not available. Each of our
affected patients
minimally hyperipheral permétropie retinal pathological findings. Favre-Goldmann syndrome,-"-' an
This investigation was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, and by grant EY-00197-18 from the National Eye Institute (M Alpern, PhD). Mathew Alpern, PhD, gave counsel and criticism throughout this study. Bernard C. Wildgen, MI), and David Meyer, MD, shared their clinical
hood, cataracts, an extinguished ERG, and extensive vitreoretinal and pigment epithelial alterations. In general, the pattern of the foveal retinoschi-
gree.
and
was
none
had
autosomal recessive disorder, has severe night blindness even in child-
sis and edema is more extensive and much coarser than in our patients. Cystoid macular edema associated with a number of retinal diseases'-'2 may resemble the foveal dystrophy described above. However, the specific etiologic associations and classical fluorescein angiographie findings of petaloid intraretinal staining readily differentiate cystoid edema from foveal retinoschisis. Gass-:' described an atypical cystoid macular edema in three men who consumed toxic levels of nicotinic acid. In one of his patients, the macular changes resolved within one week of discontinuing the drug and promptly reoccurred when it was reinstituted on two separate occasions. Fluorescein angiography did not identify any diffusion of dye from the parafoveal retinal capillaries into the extracellular fluid of the cystoid spaces of the swollen maculae. None of our patients
taking any prescription or proprietary medication at the time of discovery of the foveal retinoschisis. Furthermore, the early age of onset in each patient, the symmetry of all was
affected eyes, the simultaneous involvement of both monozygotic twins, and the absence of involvement in the only male sibling, is best explained by an autosomal recessively inherited disorder. However, we are unable to explain the history of visual change in case 1 on an ophthalmoscopic basis only, although we were not able to examine her at the time of its onset. It would appear that this form of foveal retinoschisis represents a previously unreported macular dystrophy that closely resembles the sex-linked juvenile form (Fig 9). This disorder properly may be included in the differential diagnosis of foveal retinoschisis in a person of either sex when there is no antecedent family history of central visual loss or sexlinked inheritance.
evaluations of various members of this
pedi-
References 1. Haas J: Ueber das
Zusammenvorkommen
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Choroidea.
2. Deutman AF: Sex-linked juvenile retinoschisis, in: The Hereditary Dystrophies of the Posterior Pole ofthe Eye. Assen, The Netherlands, Van Gorcum, 1971, pp 48-99. 3. Thomson E: Memorandum regarding a family in which neuroretinal disease of an unusual kind occurred only in the males. Br J
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1932. 4. Sorsby A, Klein M, Gann JH, et al: Unusual retinal detachment, possibly sex-linked. Br J Ophthalmol 35:1-10, 1951. 5. Levy J: Inherited retinal detachment. Br J Ophthalmol 36:626-636, 1952. 6. Jager GM: A hereditary retinal disease. Trans Ophthalmol Soc U K 73:617-619, 1953. 7. Bengtsson B, Linder B: Sex-linked hereditary juvenile retinoschisis. Acta Ophthalmol (Kbh) 45:411-423, 1967. 8. Forsius H, Vainio-Mattila B, Eriksson A: X\x=req-\ linked hereditary retinoschisis. Br J Ophthalmol 46:678-681, 1962. 9. Forsius H, Eriksson A, Vainio-Mattila B: Geschlechtsgebundene erbliche Retinoschisis in Zwei Familien in Finnland. Klin Monatsbl
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10. Forsius H, Krause U, Helve J, et al: Visual acuity in 183 cases of X-chromosomal retinoschisis. Can J Ophthalmol 8:385-393, 1973. 11. Krill AE, Lee GB: The electroretinogram in albinos and carriers of the ocular albino trait. Arch Ophthalmol 69:32-38, 1963. 12. Alpern M, Falls HF, Lee GB: The enigma of typical total monochromacy. Am J Ophthalmol 50:326-341, 1960. 13. Wald G: The receptors of human color vision. Science 145:1007-1016, 1964. 14. Krause U, Vainio-Mattila B, Eriksson A, et al: Fluorescein angiographic studies on X-chromosomal retinoschisis. Acta Ophthalmol (Kbh) 48:794-807, 1970. 15. Ewing CC, Cullen AP: Fluorescein angiography in X-chromosomal maculopathy with retinoschisis (juvenile hereditary retinoschisis). Can J Ophthalmol 7:19-28, 1972. 16. Helve J: Colour vision in X-chromosomal juvenile retinoschisis. Mod Probl Ophthalmol 11:122-129, 1972. 17. Krill AE: The electroretinogram and elec-
tro-oculogram: Clinical applications. Invest Ophthalmol 9:600-617, 1970.
18. Guyot-Sionnest M: A propos d'une famille atteinte de retinoschisis idiopathique recessif l[ill] au sexe. Ann Oculist 202:573-598, 1969. 19. Cibis PA: Retinoschisis\p=n-\retinal cysts. Trans Am Ophthalmol Soc 53:417-453, 1965. 20. Favre M: A propose de deux cas de degen-
hyaloideoretininenne. Ophthalmologica 135:604-609, 1958. 21. MacVicar JE, Wilbrandt HR: Hereditary retinoschisis and early hemeralopia: A report of two cases. Arch Ophthalmol 83:629-636, 1970. 22. Gass JDM: Macular dysfunction caused by retinal vascular disease, in: Stereoscopic Atlas of Macular Diseases. St Louis, CV Mosby, 1970, pp erescence
135-172. 23. Gass JDM: Nicotinic acid J Ophthalmol 76:500-510, 1973.
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maculopathy. Am
