Diagnostic features of the Favre-Goldmann syndrome · Brit. Y. Ophthal. (1976) 6o, 345 Diagnostic features ofthe Favre-Goldmann syndrome GERALDA. FISHMAN, LEE M. JAMPOL, AND MORTONF

Brit. Y. Ophthal. (1976) 6o, 345

Diagnostic features of the Favre-Goldmann syndrome

GERALD A. FISHMAN, LEE M. JAMPOL, AND MORTON F. GOLDBERGFrom the Department of Ophthalmology, University of Illinois Eye and Ear Infirmary,Chicago, Illinois

Traditional descriptions of the Favre-Goldmannsyndrome include early onset of night blindness;atypical pigmentary dystrophy of the retina;degenerative changes of the vitreous humour(including both liquefaction and the presence ofmicrofibrillar strands); peripheral and, less often,central retinoschisis; lens opacities; striking elec-troretinographic (ERG) abnormalities; and auto-somal recessive inheritance. We noted previouslyunreported diffuse leakage from retinal vessels onfluorescein angiography. Electroretinographyshowed cone and rod responses which we believeare characteristic in the earlier stages of the disease.

Case reportsCASE I

A 27-year-old White woman (the proband) wasfirst seen at the University of Illinois Eye and EarInfirmary in December I974 for investigation of poorvision in her right eye and decreased night vision for aslong as she could remember. Neither symptom hadworsened. The patient had no other subjective com-plaints. She had completely recovered from hepatitistwo years previously. The patient was not taking anymedications, although she had taken oral contraceptivesin the past. Two younger brothers, aged i8 and 22years, were reported also to have poor night vision. Ai6-year-old sister had no ocular complaints. Parentalconsanguinity was not noted. The case of another youn-ger sister who also complained of poor night vision isdescribed later. Fig. i illustrates this pedigree. Thepatient's two-year-old daughter and five-month-oldson were ophthalmoscopically normal.The patient's best corrected visual acuity was 20/200

in the right eye with -4oo sph. +I125 cyl. X IIS,and 20/20 in the left eye with -I-25 sph. +i oo cyl.x 300. External examination showed a mild blepharop-tosis on the left; the conjunctiva and cornea of botheyes were normal. The patient's right pupil was slightlysmaller than the left; no Marcus Gunn phenomenonwas demonstrated, and both pupils reacted normally toboth direct and consensual light stimuli. The left irishad a more greenish hue than the blue right iris. Motilityexamination showed a right hyperphoria and slight

Address for reprints: G. A. Fishman, MD, University of IllinoisEye and Ear Infirmary, I855 West Taylor Street, Chicago, Illinois6o6I2, USA

3,I2 3 4 53,4,5 not examined

D

FIG. I Pedigree of cases i and 2. Arrow identifiesproband.

overaction of the right inferior oblique muscle. Onslit-lamp examination the cornea and anterior chamberwere normal. The right lens showed a i+ posteriorsubcapsular lens opacity while the left lens was clear.The vitreous humour of both eyes was optically emptyposteriorly, while anteriorly microfibrillar strandsof condensed vitreous were noted. Intraocular pressureswere normal in both eyes. Visual field testing showed asymmetrical constriction to within 20° of fixation witha 4 mm white test object in the right eye and to withinI5° to 200 of fixation with a 2 mm white test object inthe left eye.The right fundus showed extensive peripheral

retinoschisis beginning between the equator and oraserrata and extending posteriorly to the superior andinferior temporal vessel arcades. Nasally, the schisisdid not extend more than I disc diameter posterior tothe equator. Clumping of retinal pigment was seenpredominantly in areas of retinoschisis. The schisisand pigmentation were greater temporally than nasally.The optic disc appeared normal. The macula hadminimal but definite cystoid changes. In the posteriorpole, but not in the macula, subtle, white, thread-likeopaque changes were noted within the retinal vessels.As peripheral, more highly raised areas of schisis wereapproached these opaque changes became more evidentin small retinal vessels and often assumed a dendriticappearance (Fig. 2). Similar but less extensive changeswere noted in the patient's left eye. In addition to theareas of extensive schisis and opaque vascular changes afull-thickness retinal hole with an operculum wasnoted at i i o'clock near the equator in the left eye.A small vitreous traction band extended from the oper-culum over the ora serrata.A dark-adaptation study with a Goldmann-Weekers

dark adaptometer showed monophasic curves in botheyes. Final cone thresholds were normal, while a rodcomponent to the dark-adaptation curve was non-detectable. An electro-oculogram (EOG) showed

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346 British Journal of Ophthalmology

subnormal light-peak to dark-trough ratios of I-7I andI-62 in the right and left eyes, respectively. An ERGshowed cone responses that were normal in amplitudebut much prolonged in implicit time in both eyes (Fig.3a). During a 15-minute period of dark adaptation theresponses did not change in either implicit time oramplitude. A small b2 (probable rod component of thescotopic ERG) was noted (Fig. 3b). A 1-4 blue stimulusfrom a Grass photostimulator was implemented toisolate rod responses and showed a minimal 25 [LVb-wave deflexion from the baseline while an 1-I6 redstimulus showed only cone (x-wave) responses in botheyes. Flicker fusion frequency testing of both eyeswith a high-intensity stimulus showed fusion at 30cycles/s. Normal fusion frequency rates are 55 cycles/sor higher.A fluorescein angiogram accentuated the opaque

retinal vessels in the temporal periphery of the patient'sright eye. Within areas of most advanced schisis opaqueretinal vessels were not perfused (Fig. 4a). In lessraised areas delayed perfusion of some remaining opaquevessels was seen (Fig. 4a). Vessel perfusion often appear-

FIG. 3a Case i. Light-adapted ERG. Both right(upper) and left eye (lower) tracings show prolongedimplicit times of 50 ms. Vertical squares representIOO ,uV, horizontal squares 20 ms. Normal cone implicittime, from vertical line, lower left, to b-wave peakis 28 ms

FIG. 3b Case i. Dark-adapted ERG. Note similaramplitudes and implicit times to those in Fig. 3a:

development of b2 (rod) portion of ERG scotopicresponse is only noticeable difference

ed to end just posterior to extensive raised areas ofschisis (Fig. 4a). Fluorescein leakage occurred fromopaque retinal vessels at the margin of perfused andnon-perfused retina (Fig. 4b). These leaking vesselsdid not represent neovascular tissue. A late-phasefluorescein study of the patient's right macula showedsubtle but definite leakage from perifoveal capillaries(Fig. 5) and throughout the posterior pole.

CASE 2

The 26-year-old sister of case i was seen in January1975 for investigation of poor night vision since earlychildhood. The patient's general health was good. Herbest corrected visual acuity was 20/25 in the right eyewith +5-75 sph. and 20/30 in the left eye with +3"25sph. +0o25 cyl. x IO0. External examination was normal.Versions were full in all directions of gaze. The pupilsreacted normally to both direct and consensual-lightstimuli. Although orthotropic for near, the patient didhave a variable 25 to 30 prism dioptre alternatingesotropia for distance. Slit-lamp examination of thecornea and anterior chamber was normal in both eyes.There was no evidence of any iris heterochromia. Thepatient had I+ bilateral posterior subcapsular lensopacities and I + cells in the mid-vitreous cavity. Thevitreous humour in both eyes appeared optically emptyposteriorly while the anterior vitreous showed degenera-tive microfibrillar strands. On gonioscopy the anteriorchamber angles were normal. Fundus examinationrevealed subtle cystoid changes. The larger retinalvessels appeared to be normal in both calibre andcourse. An extensive shallow retinoschisis was notedthroughout the mid-periphery of both eyes. The schiticchanges, which were associated with a moderate amountof black pigment clumping, were present both nasallyand temporally. Opaque vessel changes were presentthroughout the mid-periphery extending anteriorlybetween the equator and ora serrata (Fig. 6).

Visual field testing with a Goldmann perimetershowed relative symmetrical constriction to withinI5° of fixation in each eye. Results of a dark-adaptationtest were similar to those in case i in showing only amonophasic recording with normal final cone thresholds.Colour vision testing with the Farnsworth-Munsellioo-hue test showed a mild blue defect in the patient'sright eye and normal colour perception in the left.An EOG showed significantly abnormal light-peak todark-trough ratios of I 33 and 1-05 in the right andleft eyes, respectively. (Normal values for her age fromour laboratory would be I-75 or greater.) An ERGshowed cone responses that were both reduced inamplitude and prolonged in implicit time. After a20-minute period of dark adaptation there was essen-tially no change from photopic values in either ampli-tudes or implicit times in either eye, reflecting an appar-ent absence of detectable rod activity. Rod responseswere also non-detectable with a low-intensity 1-4 bluestimulus. Flicker responses with a high-intensitystimulus were non-detectable at 30 cycles/s.A fluorescein angiogram of the patient's right eye

showed extensive leakage from retinal capillariesthroughout the posterior pole (Fig. 7). Leakage waspresent in the mid-periphery in association with vessels



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FIG. 2 Case I, right eye. Opaque,dendritic appearance of peripheralvessels

FIG. 6 Case 2. Opaque vessels withinmid-periphery of right eye



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FIG. 4a Case I. Fluoresceinangiogram of temporal periphery fromright eye showing opaque, dendriticretinal vessels. Non-perfused retina isnoted within areas of marked schisis(larger arrows). Note delayed fillingof retinal vessel (smaller arrows)

FIG. 4b Leakage of dye from opaqueretinal vessels at margin of perfusedand non-perfused retina. Note samevessel in Fig. 4a is now perfused(arrows)



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that ophthalmoscopically were opaque. Less leakageoccurred in areas where retinoschisis was most evidentclinically. Areas of early hyperfluorescence noted inthe posterior pole and mid-periphery were associatedwith retinal pigment epithelial atrophy while spottyregions of hypofluorescence were caused by pigmentclumping. In later stages of the angiographic studychanges of cystoid oedema were noted in the rightmacula (Fig. 7).

CASE 3

A 56-year-old White man, who was unrelated to thepatients in cases i and 2, complained of decreasednight vision and poor peripheral vision for as long as

he could remember. The central vision in his left eye

had also been poor since about age 20. Vision in theright eye had been good until about Io years previously,when he began to notice a slow but progressive de-crease in acuity. The patient's general health was good.A 55-year-old sister, unavailable for examination, alsocomplained of poor night vision since childhood.Parental consanguinity was not noted.

Visual acuity was 20/60 in the right eye with +6 75

sph. + -75 cyl. x I80° and 5/200 in the left eye with+ 6-oo sph. Extemal and motility examinations were

normal. Slit-lamp examination of the cornea, iris, andanterior chamber of both eyes was normal. Both pupilsreacted normally to direct and consensual light stimuli.Ocular pressure was i I mmHg in each eye. There were

bilateral 2+ posterior subcapsular lens opacities. Thevitreous humour in both eyes was optically emptyposteriorly from extensive liquefaction, while in theanterior vitreous chamber there were spidernet fibrillarstrands. Fundus examination showed a bilateral waxy-type atrophy of the optic discs and constricted retinalvessels. The foveal reflex was absent in both eyes.Within the superior and inferior temporal mid-peri-phery of the right eye was a highly raised retinoschisis(Fig. 8). In some areas the schisis extended posteriorly,and ophthalmoscopically appeared to end just posteriorto the arcade formed by the large superior and inferiortemporal arterioles (Fig. 9). The schisis was progres-sively less raised posteriorly as it approached the bordersof the superior and inferior temporal vessels. All schitic

FIG. 5 Case i. Late-phase fluoresceinangiogram from the posterior pole.

*~~.... Note leakage from perifoveal(arrows) and other capillaries

areas were associated with round black clumps ofretinal pigment (Figs 8, 9). On slit-lamp examinationof the posterior pole with a contact lens subtle opaquechanges were noted within smaller retinal vessels notassociated with areas of schisis. These opaque changesbecame more evident as the vessels approached regionsof shallow schisis. At the posterior border of moreraised schitic areas the opaque vessels were mostevident and appeared dendritic. Although areas ofschisis were not noted nasal to the optic disc minimalopaque changes within smaller retinal vessels were alsopresent in these areas. Fundus changes in the left eyewere essentially the same as those in the right.

Visual field testing with 4e-III and 4e-IV isopters onthe Goldmann perimeter showed an absolute symme-



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350 British journal of Ophthalmology

FIG. 7 Case 2. Extensive leakagefrom retinal capillaries throughoutposterior pole. Note leakage fromperifoveal capillaries (arrows)

trical constriction to within I5° of fixation in each eye.Dark-adaption thresholds measured on the right eyeshowed a monophasic curve with a normal cone thres-hold. In both eyes ERG responses were non-detectable,while an EOG showed light-peak to dark-trough ratiosof i-io and I-I5 in the right and left eyes, respectively.On fluorescein angiography leakage from retinal capil-laries was evident even in areas which ophthalmoscopi-cally either appeared normal or showed only subtleopaque changes within retinal vessels. Extensive capil-lary leakage was noted posteriorly in areas of low schisis(Fig. io). Retinal capillaries were non-perfused in areaswhere schisis was much raised in the mid-periphery.

Discussion

Favre (1958) reported vitreoretinal degenerationand the early onset of poor night vision in a i6-year-old boy and his I5-year-old sister. Vitreouschanges included both liquefaction and fibrillardegeneration. Fundus changes included equatorialchorioretinal atrophy and pigment clumping.Peripheral and macular retinoschisis was alsonoted. Ophthalmoscopically the schisis of themacula was reminiscent of microcystic oedema.The boy also had posterior cortical lens opacities.In both cases visual field testing showed annularscotomas, while dark-adaptation studies revealedmonophasic curves with normal cone but absentrod thresholds. Their 13-year-old sister was normal,and a paternal grandmother, although not examinedby Favre, was reported by the family to have had

poor night vision. Ricci (I960) found that ERGresponses were non-detectable in Favre's twopatients. He reported similar findings in a 41-year-old woman and emphasized the absence of anERG response. Ricci suggested an autosomalrecessive pattern of inheritance.

In the majority of similar cases subsequentlyreported (Blanck, Polliot, and Bernard, 1973;Carr and Siegel, I970; Francois, De Rouck, andCambie, 1974; Frangois and Van Oye, I967;MacVicar and Wilbrandt, 1970; Maraini, I967;Stankovic, Kecmanovic, and Drincic, I973) ERGresponses were non-detectable. Dark-adaptationfindings generally included monophasic curves withnormal cone thresholds or biphasic curves withmuch raised rod final thresholds. Recordable ERGresponses were noted by Carr and Siegel (1970)in an i i-year-old boy with Favre-Goldmannsyndrome. The photopic a- and b-waves weredescribed as 'near normal'; a scotopic incrementwas not observable. No mention was made ofimplicit time values. The same authors reportedan additional case of a 22-year-old man who had anormal ERG photopic and scotopic a-wave butan absence of any positive b-wave response. Sinceselective absence of an ERG b-wave is charac-teristic of juvenile X-linked retinoschisis it was notclear from their description how they eliminatedthis diagnostic possibility.

Recordable but markedly reduced a- and b-waveERG responses were obtained from a single case



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FIG. 8 Case 3.Highly raisedretinoschisis intemporal peripheryfrom right eye(arrows).Clumping ofretinal pigmentepithelium is seen

FIG. 9 Case 3.Posterior extensionof schisis to withininferior vasculararcade (arrows)



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FIG. 10 Case 3. Extensive leakagefrom retinal capillaries in posteriorpole. Note leakage from perifovealcapillaries (arrows)

reported by Blanck and others (I973). Implicittime values were not cited. In three cases reportedby Frangois and others (I974) photopic responsesof either normal or subnormal amplitudes werenoted. Photopic implicit times were prolongedin two of the three cases. Scotopic recordingsshowed either absent or much decreased b-waveamplitudes. Scotopic a-waves were recordablebut reduced in amplitude. In our two youngerpatients, on whom ERG responses were stillrecordable, photopic and scotopic amplitudes wereessentially identical. The photopic responseswere either normal or subnormal in amplitudeand prolonged in implicit time. Prolonged cone(photopic) implicit times have also been notedin most genetic patterns of retinitis pigmentosa(Berson and Kanters, 1970). In our patients ERGrod responses either failed to develop or developedminimally after I5 minutes of dark adaptation. Thescotopic responses in Fig. 3b are presumablypredominantly from cone activity, thus accountingfor the almost identical responses under both light-and dark-adapted conditions. Highly abnormalflicker fusion frequency responses in the vresenceof normal or slightly subnormal ERG single-flashphotopic amplitudes were an unexpected findingin two of the three cases. This discrepancy betweensingle-flash photopic amplitudes and flicker fusionfrequency has not been previously emphasizedand may be characteristic of this disease.Two reports of fluorescein angiographic findings

in patients with Favre-Goldmann syndrome madeno mention of either leakage from or non-perfusionof retinal vessels (MacVicar and Wilbrandt, 1970;Stankovic and others, 1973). The diffuse vascularleakage noted in our patients is unique amongretinal dystrophies and has not been reported inassociation with peripheral or macular changes inX-linked juvenile retinoschisis. Isolated reports havedescribed perifoveal capillary leakage and cystoidmacular oedema in patients with retinitis pigmen-tosa (ffytche, I972; Gass, 1970). Since cystoidmacular oedema was present in varying degreesin all three of our patients we suspect that at leastsome previously reported cases of Favre-Goldmannsyndrome with 'macular schisis' may have hadmicrocystic oedema from leaking perifoveal capil-laries.

Dendritic opaque vessels similar to those seenin our cases have been noted in patients withjuvenile X-linked retinoschisis. We observed acorrelation between the presence of schitic changesand the development of vessel opacity, leakage,and non-perfusion. No retinoschisis was presentin the posterior pole and only subtle opaquevascular changes were noted on contact lensexamination. Even these mildly opaque retinalvessels were, however, incompetent, as evidencedby leakage of fluorescein. Moderate retinoschisiswas present within the mid-peripheral retina inassociation with marked opaque vascular changesand extensive leakage of fluorescein dye. In areas



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with the most extensive schitic changes retinalvessels no longer appeared opaque but were non-perfused. A cause and effect relationship betweennon-perfusion and opaque retinal vessels and thedevelopment of retinoschisis cannot be supportedwith certainty by our findings. However, possiblythose areas with extensive ischaemia of the innerretina are most susceptible to the development ofschisis. An equally tenable explanation mightimplicate the schisis as causing secondary non-perfusion of retinal vessels. Other forms of retino-schisis do not cause a similar diffuse vascularleakage, and therefore another sequence of events(vascular leakage causing perivascular fluid accu-mulation and thereby retinoschisis) may apply tothe Favre-Goldmann syndrome and may beanalogous to the pathogenesis of cystoid macularoedema in this syndrome. In this disorder, asexemplified by case 2, ultimate occlusion of pre-viously leaking vessels may result in a clinicalsituation characterized by maximum raising ofschitic areas with absence of leakage (owing tototal non-perfusion of previously involved vessels).A diagnosis of Favre-Goldmann syndrome

should be considered in patients presenting with anearly history of poor night vision, bilateral atypicalpigmentary changes of the retina, and degenerativechanges in the vitreous humour. Additional diag-nostic findings include retinoschisis, opaque retinal

vessels, diffuse leakage from retinal capillaries, andcystoid macular oedema. Electroretinographic res-ponses are either non-detectable or, if present, mayshow almost identical responses under both light-and dark-adapted conditions. In addition, highlyabnormal flicker fusion frequency responses in thepresence of relatively normal single-flash photopicamplitudes may be seen.

Summary

Extensive retinal vascular disease was noted inthree patients from two families with Favre-Goldmann syndrome. In addition to classicalfeatures they had pronounced leakage from someretinal vessels. Vessels were either opaque ('sclero-tic') or non-perfused. Cystoid macular oedemawas a contributing cause of decreased vision.Two of the three patients showed a discrepancyon electroretinography between single-flash photo-pic amplitudes and flicker fusion frequency. Thismay be characteristic of Favre-Goldmann syn-drome.

This investigation was supported in part by the NationalRetinitis Pigmentosa Foundation, training grantEY24-I6 from the National Eye Institute, and anunrestricted award from Research to Prevent Blindness,Inc.

References

BERSON, E. L., and KANTERS, L. (1970) Arch. Ophthal. (Chic.), 84, z88BLANCK, M. F., POLLIOT, L., and BERNARD, P. (I973) Bull. Soc. fran,. Ophtal., 86, 242CARR, R. E., and SIEGEL, I. M. (1970) Arch. Ophthal. (Chic.), 84, 436FAVRE, M. (1958) Ophthalmologica (Basel), I35, 604FFYTCHE, T. J. (I 972) Trans. ophthal. Soc. U.K., 92, 265FRANCOIS, J., DE ROUCK, A., and CAMBIE, E. (1974) Ophthalmologica (Basel), z68, 8i

and VAN OYE, R. (I967) Ann. Oculist. (Paris), 2oo, 664GASS, J. D. M. (1970) 'Stereoscopic Atlas of Macular Disease', p. 154. Mosby, St LouisMACVICAR, j., and WILBRANDT, H. (I970) Arch. Ophthal. (Chic.), 83, 629MARAINI, G. (I967) Ann. Ottal., 93, 343RICCI, A. (I960) Ophthalmologica (Basel), 139, 338STANKOVIC, I. V., KECMANOVIC, Z., and DRINCIC, V. (I973J Bull. Soc. franc. Ophtal., 86, 246



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Diagnostic features of the Favre-Goldmann syndrome · Brit. Y. Ophthal. (1976) 6o, 345 Diagnostic features ofthe Favre-Goldmann syndrome GERALDA. FISHMAN, LEE M. JAMPOL, AND MORTONF