GRANULAR CORNEAL DYSTROPHY WITH LATE MANIFESTATION

XXVl MEETING OF NORDIC OPHTHALMOLOGISTS

ACTA OPHTHALMOLOGICA VOL. 61 1983: 514-528

Stockholm, Sweden 9-11 May 1983

Deparhnent of Ophthalmology' (Head: H. Forsaw), University of Oulu, Finland, Imtatute of Human Genetics2 (Head: A. W . Enkson),

Free University of Amsterdam, The Netherlank, Department of Ophthalmology3 (Head: S . Vannas), University of Helsinki,

Eye Department of the Centralh~spital~ (Head: H. Aurekoski), Kokkola and The Folkhiilsan Institute of Genetics,

Population Genetics Unit5 (Head: J . Fellman), Helsinki, Finland

GRANULAR CORNEAL DYSTROPHY WITH LATE MANIFESTATION

HENRIK FORSIUS', ALDUR W. ERIKSSON2, JUSSI URNA',

AHTl TARKKANEN3, HElKKl AUREKOSKI4, RUNE R. FRANTS2

and MARGARETA DAMSTEN5

Ninety-two cases of granular corneal dystrophy, most of them belonging to 5 pedigrees are described. The age of manifestation in this Finnish type of granular dystrophy is first in the end of the second decade, and visual acuity is in mean normal through the whole life. An autopsy study showed no changes outside cornea elsewhere in the eyeball. In one family with granular dystrophy, another type of dystrophy, hereditary fleck dystrophy of the cornea, was accidentally found.

Key words: granular corneal dystrophy - fleck dystrophy of the cornea - histology of cornea.

In 1890, Groenouw described 2 new corneal dystrophies, of whiGh one has later been named granular corneal dystrophy and the other macular corneal dystrophy. They are often also called Groenouw I and Groenouw I1 corneal dystrophy, respectively, in accordance with their discoverer. Later on, in 1933, he completed his description and pedigree of a family with granular dystrophy, which he, by that time had been following for 43 years through 4 generations. The disease is autosomally dominantly inherited, and its only sign is found in the eye. The first signs of degeneration are seen at the age when the child starts school in the form of

5 14

Forsius et al. Granular corneal dystrophy

superficial white flecks in the parenchyma beneath Bowman’s membrane. These are often composed of radiating, superficial, semitranslucent lines in the shape of a tree, which, at high magnification, can be seen to consist up of small white crystals (Bucklers 1938). The youngest child described to have the formation was 2-years- old (Saebo 1936). The flecks increase rapidly in size before the age of 20. By that time, visual acuity has often decreased markedly, requiring corneal transplantation. The youngest child with granular dystrophy described in the literature to have a corneal graft performed was 7 years of age (Haddad et al. 1977).

At this state the changes are seen as flat, round or annular crescents or flecks right beneath Bowman’s membrane, but also as white points or flecks in the parenchyma, sometimes reaching up to the endothelium. The peripheral third part of the cornea remains free from flecks. The epithelium is normal at young age, but often uneven in adults, as the flecks elevate the epithelium and cause thinning of Bowman’s membrane.

Many of the patients describe acute episodes of lacrimation and pain, which are caused by recurrent erosions. These begin around puberty and cease to occur in the fifties. In young patients the white flecks are often small, but grow by and by over the decades with the centers of the flecks losing their white colour and turning gray.

Genetically, the condition is an autosomal dominant disease with 100% penetrance. Males and females are equally affected and the disease has been followed for up to 4 successive generations. Some patients are less affected than the others, and occasionally the children are more severely affected than their parents. About 80 pedigrees have been published, and several careful histological studies by light and electron microscopy have been made. The granules contain homogeneous material with sharp-edged fragments resembling crystals.

The largest pedigree published by Bucklers (1938) is from Germany with 57 personally investigated cases, making up a pedigree through 10 generations. His monography was a follow-up study of the families which Gilch (1937) and other German investigators had collected. The second largest family study was made in Switzerland by Bourquin et al. (1954) and later completed by Potter & Mattingley (1969) and Scouras et al. (1969). In addition to these works, we can mention Morra (1967), who followed a large family through 4 generations.

At least 10 pedigrees where the disease has been seen in 3 generations have been published.

Material and Methods

In our files up to 1980, we had 20 cases diagnosed as granular corneal dystrophy. Most of those affected had their roots in the same region in Central Finland close to the Gulf of Bothnia. A field expedition to this region in 1980 resulted in 50 new

515


cases, and later on we have completed the study of some families in the department of Ophthalmology, University of Oulu. We have personally seen alltogether 92 cases, most of them belonging to 5 pedigrees, and anamnestically 4 more. In addition, we studied 136 relatives, whom we established as non-affected. Of these, 30 were less than 17 years of age. We assumed initially that all the cases in western Finland would be derived from the same mutation and made genealogical studies to testify this. Sweden and Finland have the oldest parish registers in the world and we were able to follow nearly all those affected back to the 17th century. The mutation seems, however, to be older than that, as we have not been quite successful, but most of these affected have turned out to be related to each other.

Clinical picture

The families we have studied suffer from a disease which is histologically definitely granular corneal dystrophy. The cases from the coastal area differ, however, markedly from the cases earlier published with regard to the age of manifestation. Our youngest patient affected was a 16-year-old boy, in whom we saw in the

Fig. 1. The first signs of granular dystrophy are seen as small superficial flecks and short lines

(Pedigree 1 , X/43). Right eye of a 20-year-old male.

5 16


Fig. 2. Crystalline formations in rows and circles in a cornea of a 19-year-old girl. All formations are

superficial. Left eye. Pedigree 1, X/10.

pupillary region some bow-like subepithelial opaque lines which ended in white crystals situated slightly below the line.

The first signs of the disease (Figs. 1 and 2) are usually seen in the form of subepithelial white flecks. With increasing age the formations grow and increase in number, and at the age of 40-60 (Figs. 3 and 4) they reach their maximum of manifestation, after which some resorption takes place (Figs. 5A and 5B), and the crystalline structure of the flecks disapRears. The outer third of the cornea is free from flecks, and the largest formations usually occur in the lower part of the pupillary are. The subepithelial flecks are flat, round and often annular. The central area of these rings is not so close to Bowman’s membrane as the crystals themselves. Most of those affected have changes only in the superficial 1/3 of the parenchyma. Ten patients showed needle- or sword-like formations passing obliquely through the corneal parenchyma. Twenty-two patients also showed white formations in the central or deeper parts of the corneal parenchyma, and in 10 of these, small white flecks were seen close ot the endothelium in the parenchyma.

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Fig. 3. Left eye of a 48-year-old female with granular corneal dystrophy with unusually numerous

small flecks, one of the few who required a corneal graft. Vision 0.15. Pedigree 5, l/IV.

Fig. 4. The left eye of a 47-year-old male with rings and lines and an irregular fleck seen

superficially in his cornea. Pedigree 1, IX/52.


Fig. 5. Left cornea of a female (Pedigree 4, IV/8) with sword-like granular formations in the parenchyma of the cornea. We have followed the woman, who was born in 191 1, since 1959, when her corrected vision was 0.67 in left eye. The picture A was taken, in 1975. The crystals have greatly decreased since that time, only opaque scars were seen in left eye in 1980, when the picture B was taken. Her vision in 1980 was 0.2. The epithelium was irregular. She had

earlier often had acute episodes of lacrimation.

Corneal nerves

We have studied the relationship between corneal nerves and crystals. Corneal sensibility is normal or nearly normal in the affected subjects. Probably by a coincidence, crystals may grow at a point where a nerve is passing. We have frequently seen that the crystals extend their direction along the nerves. It is probably easier for the crystal to grow for some distance along the nerve than in other directions. Where the formation ends, the nerve is surrounded by small crystals.

We have divided our patients into 3 groups, depending on how many nerves can be seen in the pupillary region. No correlation between the number of nerves and the number of crystals has been found. On male had an oblique needle-like wound penetrating through the superficial parts of the parenchyma. The scar had been partially crystallized.

Recurrent erosions

We have asked the patients about symptoms of recurrent erosions, which are very common in families with granular dystrophy according to the literature. Only 3

519


such cases have been verified. By a curious coincidence (?), a sister to a patient with granular dystrophy has been treated in our hospital for recurrent erosions. She is marked as non-affected in our pedigree, because no crystals could be seen in the corneas. Many of the patients report frequent itching of their eyes in the mornings. Some of the older patients have superficial opacities in their corneas, and some also have superficial blood vessels in the periphery. We consider them to be caused by phlyctenular keratitis, a disease previously very common in these areas. None of the younger subjects have scars in the cornea from diseases.

Corneal thickness

In 44 patients we have measured the thickness of the cornea with Haag-Streit’s device. The thickness for the 20 males was 0.503 mm, their mean age being 38.5 years, and that for the 24 females 0.504 mm, their mean age being 45.7 years.

We divided the patients into a group with a small number of flecks (17 males, 1 1 females), thickness 0.503 mm, and a more severely affected group with 0.504 mm thickness (3 males, 13 females). The difference is neglible. The mean age for the former group was, as is was to be expected, lower or 37.0 years than that for the latter, 5 1.9 years.

Arcus senilis,

was studied in 57 affected subjects classified into 4 degrees of seventy. The distribution was normal compared with a normal population and the relatives (Forsius 1954).

We also regularly noted the existence of a b o t o x o n conzeae posterior and the white limbus girdle of Vogt. They do not seem to be correlated to Groenouw I dystrophy.

Other eye diseases in the family

One patient had retinitis pigmentosa combined with congenital deafness and visual acuity of 0.5 in both eyes. N o other cases of this retinal disease in his family are known. It can be mentioned that there is also another report of retinitis pigmentosa (Nizetic et al. 1957) and granular dystrophy in the same family. In a 58-year-old affected female a retinal disease diagnosed as dominant drusen was seen. Some of the oldest patients had macular degenerations of other types, also probably without connection with the corneal disease.

Hereditary fleck dystrophy of the cornea

When studying one family with granulate corneal dystrophy, we observed cases in which the distribution and shape of the flecks were different from those usually seen in this family. A careful analysis of this family showed that another type of

520


Fig. 6. Slit-lamp view of the cornea of a 50-year-old man (Pedigree 2, VII/12) with fleck dystrophy of cornea (Francois & Neetens 1957). Flat flecks of 0.1 mm are seen in all the corneal layers,

even in periphery, and are constant throughout life.

dystrophy, namely hereditary fleck dystrophy of the cornea (Francois & Neetens 1957) was also accidentally found in this family. The mother (Fig. 6) had Groenouw I dystrophy and the father the Francois-Neetens form of corneal dystrophy, see pedigree 11. This family and some other families in our files with Fleck dystrophy will be analyzed more closely in another study.

Visual acuity

Even many of the adult patients were unaware of their flecks before they were told about them, and most of those affected have normal visual acuity. Several other patients only complained about haze in bright sunlight (Table 1). We have suggested corneal transplantation to some patients, but only 3 patients have consented. One of them, a woman aged 48 years had visual acuity readings of 0.4 and 0.15, respectively, and corneal transplantation was performed on her left eye, resulting in a visual acuity of 0.8, see Fig. 3. The graft was histologically investigated

52 1


Table 1. Corrected visual acuity in patients with granular corneal dystrophy.

~ ~ ~~

Age groups 16-29 30-39 40 -49 50-59 60-

1.34162 1.06122 0.94116 0.82130 0.80134 Visual acuity1 No. eyes

and changes typical of granular dystrophy of the cornea were found. In her family (Pedigree 5) we studied the appearance of the flecks in 4 generations. They were smaller than those in our other patients and also much more numerous. This family lives in the central part of Finland, and it is possible that their case is yet another mutation.

In one 68-year-old female (Figs. 5A and 5B) the visual acuity was 0.2 in both eyes. We have followed her since 1959, but as she was satisfied with her vision and able to read, she was not interested in a graft. Over the past few years her vision has been subjectively better, as the corneal formations have clearly decreased.

Ocular pathology

The literature contains several reports on histological examinations of discs derived from corneal transplantations. We have, however, been able to obtain from a 76-year-old man who died of cancer, a whole eye for a histological examination.

The eye was fixed in neutral formalin, embedded in paraffin and sectioned at a thickness of 5p. Haematoxylin and eosin, Van Gieson, Periodic acid-Schiff, Masson trichrome, Wilder silver stain, colloidal iron. alcian blue and toluidine blue stains were performed.

Macroscopically, the left eye was of normal size. The cornea showed some grayish granules mainly in the central portion. The eye was opened through the horizontal plane. The vitreous was clear and the fundus appearance was within the normal limits. Microscopically, the corneal epithelium varied in thickness, but no epidermalization was found. The superficial stromal layers were found to involve focal lesions containing granular material (Fig. 7A,B). The material was eosinophilic, and stained brilliantly red with Masson’s trichrome.

Furthermore, the affected areas gave a much less intense periodic acid-Schiff reaction than did the surrounding involved stroma. the alcian blue, the toluidine blue and the colloidal iron stains were negative, while the silver stain revealed some argyrophilic fibrils. Descemet’s membrane and the endothelium appeared normal. The sclera was of normal thickness. The structure was well preserved throughout the globe. The findings are compatible with granular corneal dystrophy (Groenouw T y p e I) (Jones & Zimmerman 1959,1961; Garner 1969).

522


Fig. 7A. Granular material is present in the anterior stromal layers. Haernatoxylin and eosin x 140.

Fig. 7B. Granular material is seen to replace the Bowman's membrane in part. Haernatoxylin and

eosin x 140.

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In our hospital we have earlier studied an eye from a man with Schnyder’s crystalline corneal dystrophy and found crystals even in other parts of the eye apart from the cornea (Crop 1973). I t was therefore with great interest that in granular dystrophy we only verified changes in the cornea.

Heredity

The disease is autosomally dominantly inherited. Not in one single case have we been able to note that one generation would have been skipped, which means that the penetrance is 100%.

Of the personally investigated 92 affected subjects. Most of them belong to 5 pedigrees: 50 to pedigree 1 from Pedersore, 19 to pedigree 2 from Alavieska, 2 to pedigree 3 from Lapua, 8 to pedigree 4 from Oravais and 5 from pedigree 5 from Kuhmoinen. 39 of these were males and 45 females. In addition, 7 affected subjects descend from families of the coastal region, but hitherto we have not been able to connect them ot the other subjects affected. There is one family (pedigree 5) living in the central part of the country with a different clinical picture and, in addition, one patient in inner part of Finland, whose family not yet has been investigated. We know from the population history of Finland that 300-400 years ago there were people living mainly on the coast and along the rivers of the Gulf of Bothnia. The inner part of the country has derived its population from the south and southeast. This might explain the concentration of the granular dystrophy of this special type in the region where it has been found and suggests that the family with the more severe manifestation involves another mutation.

Pedigree I

524

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PEDIGREE FROM ALAVIESKA

m a ,I .. .. F L E C K I F R A N O O I S - N E E T E N S 1

A F F E C T E D M A L E , F E M A L E WITH G R A N U L A R C O R N E A L DYSTROPHY I G R O E N O U W I 1

,o I N V E S T I G A T E D CASE

Pedigree 2

PEDIGREE F R O M L A P U A [ G R A N U L A R C O R N E A L D Y S T R O P H Y 1

P -1707

$1928 z

Pedigree 3

525


.*-5+.fj Pedigree 4

P E D I G R E E F R O M K U H M O l N E N

G R A N U L A R C O R N E A L D Y S T R O P H Y

( @ C O R N E A L G R A F T P E R F O R M E D

t 1952

Pedigree 5

Discussion

The shape of the flecks varies according to their location. The deepest formations and the most peripheral ones are regularly small, white and round. Most of the flecks are superficial and often large. The flecks can probably be formed more easily between Bowman’s layer and the corneal parenchyma and therefore become 2-dimensional. 3-dimensional formations were never seen superficially. In the deeper levels the flecks seem to have possibilities to grow in all directions. No tree-like superficial formations, which Bucklers (1938) described to be the first changes in children, were observed, but the first changes were very often quite

526


GRANULAR CORNEAL DYSTROPHY IN FINLAND

Fig. 8. Large circles: > 10 affected, smaller circles: 2-9 affected, dark points: 1 affected.

superficial probably just below Bowman’s layer in the form of bows or lines. They were not white, and the parenchyma could be examined through them. At the end of these lines small white crystals could sometimes by seen, which the largest possible magnification showed to be slightly deeper than the lines. We got the impression, studying several generations, that the next stage may be crystallization of the lines or rings in a row along them. In old people the rings are large, probably because they have grown in diameter dyring the years, and the central area is more translucent, probably because absorption has taken place there. The formations, when followed for some years, retain their shape, but undergo slow development, as Bucklers (1938) has been able to show during an observation time of 27 years. We were able to give photographic documentation showing that resorption can take place in old subjects (Fig. 5A,B).

Nearly all the subjects in the pedigrees I-IV, even the most severely affected ones, were able to read with normal reading glasses, which also indicates that this Finnish variant differs from the cases described in the literature.

527


Acknowledgments

This study was supported in part by FUNGO, subsidized by the Dutch 01 (Z.W.O.), The Netherlands, and the Sig

From the Foundation for Medical Research on for the Advancement of Pure Research ius Foundation, Helsinki, Finland.

References

Bourquin J B, Babel J & Klein D (1954): Nouvel arbre genealogique de dystrophie corneenne

Bucklers M ( 1938): Die erblichen Hornhautdystrophien. Dystrophia corneae hereditariae.

Forsius H (1954): Arcus senilis corneae, its clinical development and relationship to serum

Francois J & Neetens A (1957): Nouvelle dystrophie heredo-familiale du parenchyme

Garner A (1969): Histochemistry of corneal granular dystrophy. Br J Ophthalmol 53:

Gilch T (1937): Uber die Verbreitung und Vererbung der familiaren Hornhautentartung in

Groenouw A (1933): Knetchenformige Hornhauttrubungen vererbt durch vier Genera-

Crop K ( 1973): Clinical and histological findings in crystalline corneal dystrophy. Acta

Haddad R, Font R C & Fine B S (1977): Unusual superficial variant of granular dystrophy of

Jones S T & Zimmerman L E (1959): Macular dystrophy of the cornea (Groenouw type 11).

Jones S T & Zimmerman L E (1961): Histopathologic differentiation of granular, macular

Morra M ( 1967) : Contributo clinico e genetic0 alla degenerazione corneale eredofamiliare

Nizetic B & Sakic D (1957): Degeneration nodulaire de la cornee (Groenouw liee a la coulene

Potter D & Mattingley J (1969): Hereditary granular corneal dystrophy and associated

Saebo J (1936): Uber hereditare Hornhautentartungen (Groenouw). Acta Ophthalmol

Scouras J, Cuendet J F & Streiff E B (1969): Une nouvelle famille de dystrophie granuleuse

granuleuse (Groenouw I). J Genet Hum 3: 137- 146.

Bucherei d Augenarztes, H 3. Ferdinand Enke Verlag, Stuttgart.

lipids, proteins and lipoproteins. Acta Ophthalmol (Copenh). Suppl42.

corneen (Heredo-dystrophie mouchetee). Bull SOC Belge Ophthalmol 114: 64 1-646.

799-807.

Wurttenberg. Z Mensch Vererbungs Konstitutionslehre 2 1 : 1-54.

tionen. Klin Monatsbl Augenheilkd 90: 577-580.

Ophthalmol (Copenh). Suppl 120: 52-57.

the cornea. Am J Ophthalmol83: 213-218.

Am J Ophthalmol47: 1 - 16.

and lattice dystrophies of the cornea. Am J Ophthalmol5 1 : 394-410.

tipo I de Groenouw. Boll Oculist Oculistica 46: 902-919.

de I’iris (pedigree d’une famille). Acta Genet (Basel) 7: 274-276.

arninoaciduria. Trans Aust Coll Ophthalmol 1 : 45-52.

(Copenh) 14: 98-99.

de la cornee (Groenouw I). J Genet Hum 17: 47 1-474.

Author’s address.

Prof. Hennk Forsius, Department of Ophthalmology, University of Oulu, SF-90220 Oulu 22, Finland.

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GRANULAR CORNEAL DYSTROPHY WITH LATE MANIFESTATION