PSEUDOINFLAMMATORY FUNDUS DYSTROPHY WITH AUTOSOMALRECESSIVE INHERITANCE
HENRIK R. FORSIUS, M.D.Oulu, Finland
ALDUR W. ERIKSSON, M. D.Amsterdam, The Netherlands
ERKKI A. SUVANTO, M.D.Pori, Finland
HANNU I. ALANKO, M.D.Oulu, Finland
A family in southwest Finland with bilateral hemorrhagic degenera-tion of the retina and choroid was followed up for more than 16 years.The maculas showed subretinal hemorrhages, glial cicatrization of theouter retinal layers, and profound choroidal atrophy, particularly inthe advanced stages of the disease. Fluorescein angiography demon-strated leakage through the pigment layer in the retinal tissue. The ageof onset varied from the second to the fourth decade. The clinicalpattern was similar to Sorsby's pseudoinflammatory dominant fundusdystrophy, except that the disorder appeared earlier in this Finnishfamily, the members of which show secondary dyschromatopsia, manydeep hyaloid bodies in the retina, disturbed dark adaptation (1 to 4 logunits), subnormal Iight-peak/dark-trough ratios, progressive myopia,and a mode of inheritance which is probably autosomal recessive. Theaffected parents are consanguineous in many ways and each of theireight children is affected.
In 1940 Sorsby' described an apparent-ly autosomal dominant disease with bilat-eral hemorrhages and exudates in the
Accepted for publication July 23, 1982.From the Department of Ophthalmology, Univer-
sity of Oulu, Oulu, Finland (Drs. Forsius and Alan-ko), the Institute of Human Genetics, Free Universityof Amsterdam, Amsterdam, The Netherlands (Dr.Eriksson); the Eye Department, Satakunta CentralHospital, Pori, Finland (Dr. Suvanto), and the Popu-lation Genetics Unit, Folkhiilsan Institute of Genet-ics, Helsinki, Finland (Drs. Forsius and Eriksson).This study was supported in part by grants from theFoundation for Medical Research FUNGO, subsi-dized by the Dutch Organization for the Advance-ment of Pure Research (Z.W.O.), The Netherlands,and the Sigrid [uselius Foundation, Helsinki, Fin-land.
Reprint requests to Henrik R. Forsius, M. D.,Department of Ophthalmology, University of Oulu,Kajaanintie 50, SF-90220 Oulu 22, Finland.
fundi as the most prominent features.The disease is known as Sorsby's pseudo-inflammatory macular dystrophy, domi-nantly inherited disciform macular dys-trophy," or hereditary hemorrhagicmacular dystrophy.j The disease beginsto appear when the patient is about 40years old and follows a progressivecourse.
The first symptoms are retinal lesionswith edema, hemorrhages, and exudatesin the macular area. Later, there is con-siderable scarring, with sclerosis in thechoroidal vessels associated with pigmen-tary proliferation which is sometimesmassive. Some months or years later, theother eye develops the same symptoms.The terminal stage, reached after the
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disease has run its course for about 30years, is a more or less uniform, wide-spread atrophy of the choroid with somepigmentation. In some cases the fundishow glistening colloid bodies around theoptic disk and macula."? Myopia occurs insome members of the affected family, butmost patients are hyperopic or astigmat-ic. There are no symptoms of night blind-ness or constriction of the visual fieldearly in the course, but color vision andvisual acuity are markedly disturbed. 1
Ashton and Sorsby" made a histologicstudy of the eyes of two elderly sisterswho probably had this disease. The mainpathologic changes can be summarized asfollows: sclerosis and atrophy of the cho-roid with fibrous mural degeneration ofthe remaining vessels; many ruptures ofBruch's membrane in the posterior fun-dus with degeneration of the elastic layerin the same area; newly formed subreti-nal vascular tissue originating from thechoroid and related to the dehiscences inBruch's membrane; disturbance of thepigmentary epithelium; and destructionof the outer layers of the retina with glialreplacement. Babel" found similar chang-es in one eye of a 52-year-old man withthe same disease.
A number of families with Sorsby'sinflammatory dystrophy with autosomaldominant inheritance have been stud-ied. 3-7,l(}'16
It has also been suggested that thepseudoinflammatory dystrophy of Sorsbycan be inherited autosomal recessively.One family, first described by Sorsby;!showed autosomal recessive inheritance.Two children, 8 and 12 years old at theonset of the disease, whose parents werefirst cousins, had round, mostly whitemasses of exudate at both maculas. Thisfamily was not included in the later de-scription of inflammatory dystrophy bySorsby, Joll-Mason, and Cardener."
Francois" reported a pedigree in whichtwo brothers, 41 and 37 years old, had
the disease, and in which the inheritancewas probably autosomal recessive. Themother still had normal eyes when exam-ined at the age of63 years; the father diedat the age of 32 years. The clinical de-scriptions of affected family memberswere not given in this report, but Fran-cois later described the same brothers.There was an irregular white-yellow areasurrounded by innumerable small yellowpoints in the macula of the older brother.Aplasia of the pigment epithelium waspresent in the periphery, with manysmall pigment points. In the youngerbrother, the periphery was normal butthere was a diffuse disturbance of thepigment layer equatorially and in thecentral parts of the fundus and also yellowpoints combined with a gray-yellow areain the macula, with unclear borders. Theelectroretinogram was subnormal in bothpatients.
SUBJECTS AND METHODS
One of us (E.S.) found changes in theposterior part of the fundi in severalmembers of one family in the Pori regionof Finland in 1965 (Fig. 1). The familywas examined by our team in 1966 andhas been closely followed since then. In1966 we found that the parents had pig-mented scars in both fundi and that someof the children had a hemorrhagic diseasein their fundi. The youngest childrenwere at first thought to be unaffected.Our diagnosis was pseudoinflammatorydystrophy of the Sorsby type with domi-nant inheritance. The mother, in whomthe changes were in the central part ofthe fundus, was believed to be the carrierof the disease, and the father, who hadscars throughout the fundus, was thoughtto have had another disease, probablychoroiditis disseminata. During the last15 years all eight children developedchanges in their eyes, and those in thefundus of the mother now closely resem-ble those which the father had at the
AMERICAN JOURNAL OF OPHTHALMOLOGY
10 11 12 13 14 15 16
Fig. 1 (Forsius and associates). Pedigree of a family with probable autosomal recessive pseudoinflammatoryfundus dystrophy. The parents (and their parents) are related in several ways and all the children are affected.So far we have no genealogical evidence that the parents of III -4 and IV-1 have common ancestors, but most oftheir ancestors carne from the same region, which remained a sparsely populated and isolated area until the19th century. Open squares and circles, unexamined males and females; solid squares and circles, affectedmales and females; slash, examined, unaffected; thick vertical line, consaguinity.
same age. We are now convinced that allthe family members have the same dis-ease but at different stages.
The father (II-7) and the mother (II-8)are both the youngest of several children(Fig. 1). The father (index case) is theonly one in his sibship known to havedecreased visual acuity. We examinedtwo brothers and two sisters of PatientII-7 and found them to be normal. Fourother siblings died at the ages of 31, 47,58, and 89 years with normal visual acu-ity. All five surviving members have beenexamined in the mother's sibship. Onlyone, Patient II-14, had any degenerativechanges in the fundi. Three brothers diedbetween the ages of 51 and 60 years butwere said to have had good vision. Theparents of Patients II-7 and II-8 had goodvisual acuities until they died (Fig. 1, 1-1,1-2, 1-3, and 1-4).
Methods-Dark adaptation was studiedwith the Goldmann-Weekers device.
We studied color vision with a Nagelanomaloscope and Ishihara, AOH-R-R,Bostrom-Kugelberg, and Bostrom pseu-doisochromaticplates. The plates were ex-amined with a daylight illuminator. Weused the same illumination for the Farns-worth panel 0-15 and the Farnsworth-
Munsell 100-hue tests. In the 100-huetest the upper limit of total error scores isset to 100 for subjects with an averageability to discriminate colors.
Visual fields were studied with a Gold-mann perimeter and a visual field analyz-er.
Fundus photographs were taken with aZeiss fundus camera and also with aCanon 60-degree fundus camera (in 1980and 1981).
We recorded lower eyelid electroretin-ograms with ten flashes (1,500 lux) at15-second intervals after 30 minutes ofdark adaptation and visual-evoked poten-tials with reverse-pattern stimulation(256 reversals, 1 Hz) in three subjects.
The electro-oculographic tests wereperformed by a semiautomatic method.After a pre-adaptation period of ten min-utes (3,700 lux at the pupillary plane), thestanding potentials were recorded everysecond minute during 12 minutes of darkadaptation. Then, light-adaptation re-cordings were made at 3,700 lux duringthe next 12 minutes. The time constantwas five seconds. The dark-trough andlight-peak amplitudes were measured inmicrovolts, and Arden ratios (light peak-+- dark trough) were calculated for each
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eye. The normal value for our laboratoryis 2.21 0.35.
Case 1 (1l-7)-This man, born in 1903, was thefather of the eight affected children. He had beentreated in 1953, when he was 50 years of age, for asudden decrease in the visual acuity of his left eye.There were large and small, partly pigmented, exu-dative, inHammatory colonies in both the macularregion and the periphery of the right eye. Thehospital's journal seven months later also noted oldscars in the choroid of the left eye.
The patient has been studied by our group for thelast 15 years, during which time the fundus degener-ation progressed (Fig. 2). Between 1965 and 1980 hisvisual acuity decreased from R E.: 20/40 with - 1.50x 150 and L.E.: 20/50 with -1.50 -1.00 x 20 tocounting fingers at 1 m in the right eye and at 30 cmin the left eye.
At his last examination, scattered atrophy of theretina and choroid in both fundi was observed with aGoldmann three-mirror lens, but there was somenormal-appearing choriocapillaris between the atro-phied areas. There were also changes in the extremeperiphery. In the left eye the optic nerve head wasatrophic and the retinal blood vessels were attenuat-ed. There were many lens opacities in both eyes.Dark adaptation was normal for his age in 1966. Hemade one error on the AOH-RR and Ishihara pseudo-isochromatic plates. On the Farnsworth panel D-15test he arranged the cups in the following order: 1-5,7, 6, 12, 14, 15, 13, 10, 11, 9, 8. The iris wasatrophic, especially in the pupillary region.
Fig. 2 (Forsius and associates). Patient 11-7. Leftfundus in 1968 at the age of 65 years. There are largeatrophic retinochoroidal areas and the retinal vesselsare attenuated.
Case 2 (1l-8)-The mother of the affected childrenwas born in 1919. At the age of 33 years she had hadan inflammation in the central fundus in both eyes;when she was 36 years old large pigmented areaswere found in both maculas and her visual acuity was20/60 in both eyes. At 38 years of age her visualacuity was RE.: 201150 with -7.00 and L.E.: 20/60with -6.00. The hospital journal noted central pig-mented areas a little larger than the optic nerve headin both fundi.
When we first examined her, when she was 46years old, her visual acuity was 20/150 with -7.50 inthe left eye. The optic nerve head was normal andthe retinal arteries appeared to be somewhat attenu-ated. There were large areas of retinal and choroidalatrophy (Fig. 3). There were some large and smallpigment flecks in the periphery. Dark adaptation wasnormal for her age. Defects were observed in thecentral visual fields. In 1980, when she was 60 yearsold, her visual acuity was counting fingers at 20 cm inthe right eye and at 30 em in the left eye. The nervefiber layer was normal. Choroidal atrophy was almosttotal in both eyes.
Case 3 (IIl-7)-This patient, the oldest child ofPatients 11-7 and 11-8, was born in 1942. We havestudied her since 1965, when her visual acuity wasnormal with RE.: -1.50 -1.50 x 175 and L.E.:-1.25 -1.00 x o.
When she was 23 years old, the visual acuity in herright eye suddenly decreased to R E.: 20/50 with-2.00 -0.75 x 3 and L.E.: 20/25 with -2.00 -0.75x 167. There was a large pigmented scar surroundedby exudation in the right macular area. A month laterthe exudation had disappeared. In the periphery thepigmentation in both the choroid and retina wasmissing (Fig. 4, top left). In all the other parts of the
Fig. 3 (Forsius and associates). Patient 11-8. Fundusof the right eye at the age of 47 years shows a largescar with glial formation in the macular area.
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fundus the pigment layer was even. Dark adaptationhad decreased by 2 log units. Color vision testsshowed changes in tritan direction on the Farnsworthpanel D-15 test. The Farnsworth-Munsell loo-huetest showed disturbances without any clear directionand a total error score of 101 with both eyes studiedtogether.
When she was 26 years old, her visual acuity wasR.E.: counting fingers at 0.5 m and L. E.: 20/20 with-3.50 -0.75 x 165. There was a hemorrhage in thecenter of the scar in the right eye. The central fundusin the left eye still had only small defects in thepigment layer (Fig. 4, top right).
Ten years later, the visual acuity of her right eyewas hand movements with -5.0. The retina wasdetached with radially formed folds in the maculararea and large pigment clumps in a fibrotic gray area
Fig. 4 (Forsius and associates). Patient 111-7. Topleft, Retinal periphery of the right eye at the age of26years. There are large pigment defects in the retinaand choroid. Top right, Left fundus at the age of 26years. The retinal pigment layer in the macular areais uneven. Visual acuity is still normal. Bottom left,Left fundus ten years later. An exudative hemorrhag-ic process has developed in the macular region,probably from newly formed subretinal capillaries.
were noted subretinally. The visual acuity of her lefteye was counting fingers at 2.5 m with -6.50 -1.25x 150. There was a hemorrhagic exudative process inthe macular area, surrounded by a pigment ring(Fig. 4, bottom left). The total error score on theFarnsworth-Munsell loo-hue test had increased to406.
Photocoagulation of the borders of this area with anargon laser had no effect. The central visual fieldshowed defects in both eyes and a nasal defect in theleft eye.
One year later the exudation and hemorrhage haddisappeared. The pigment layer of the retina wasuneven throughout the fundus. Th...