British Journal of Ophthalmology, 1989, 73, 661-664

Primary gelatinous drop-like keratopathyD S GARTRY,' M G FALCON,' AND R W COX2From the 'Department of Ophthalmology, St Thomas's Hospital, London SE] 7EH, and the 2Institute ofOphthalmology, 17-25 Cayton Street, London EC]V 9AT

SUMMARY This paper describes three siblings, the only affected members of the family, withgelatinous drop-like keratopathy. This rare form of primary corneal amyloidosis has been reportedalmost exclusively in Japanese literature, and to our knowledge this is the first report of thecondition seen in the United Kingdom. Clinical and histological details are presented. The natureand possible aetiology of the amyloid deposits are discussed and the literature is fully reviewed.

The family described here came originally fromTeheran and consisted of four siblings whose parentswere first cousins. Two of the three boys and the onlygirl were affected, but no other members of thefamily or their relatives had a history of eye disease.The clinical presentation in the three patients was

strikingly similar. In each of the three children visualdifficulties had begun at the age of 6 years and theyhad become virtually blind within the ensuing 10years. There was also extreme photophobia and acharacteristic tendency to sneeze violently andrepeatedly on exposure to light. There appeared tohave been no other history of eye disease or trauma.All three siblings had had a corneal graft in 1981, theoldest boy at that time being 20, his brother 12, andhis sister 17. Full clinical details are not available, but'failure' was said to have occurred after two years inthe case of the young men and after only two monthsin the case of the girl.At the time of presentation in 1986 the older

brother was aged 26, the younger 18, and their sister24. The clinical features in all six eyes were verysimilar, but examination was extremely difficult(even under local anaesthesia) because of the intensephotophobia. Vision was reduced to barely naviga-tional levels. Both the grafted and non-graftedcorneae were opaque, with confluent jelly-likenodules extending throughout, and superficialvascularisation (Fig. 1). The grafted eye in the girlwas more opaque than the other eye and wastherefore regrafted; in the two men the converse wasthe case.

All three siblings underwent penetrating kerato-plasty. The operations were uneventful except that itwas considered helpful to excise the peripheralCorrespondence to Dr D S Gartry.

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nodules in the host anterior stroma to reduce thegross corneal thickness (which was approximatelytwice normal) to a manageable level. There was astriking early improvement not only in vision but alsoin the disabling photophobia that existed preopera-tively, in spite of one eye still being involved with thekeratopathy in each patient.Two of the three excised discs were fixed in formol

saline and examined histologically.

Histology

Microscopic examination of the two corneal discsdisclosed areas of irregular epithelial hyperplasia,areas of epithelial atrophy, epithelial oedema,destruction of Bowman's layer, stromal fibrosis,stromal vascularisation and large, mainly superficial,deposits of hyaline, eosinophilic material that gave

rig. I rreoperative appearance ofgelatinous drop-likekeratopathy (the sister).

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D S Gartry, M G Falcon, and R W Cox

Fig. 2 Corneal discfrom the sistershowing epithelial atrophy,epithelial hyperplasia, and theconsiderable extent ofthesubepithelial and superficialstromal deposits ofhyalinematerial. (Haematoxylin and eosin,x 90).

the reactions of amyloid, namely, positive stainingwith the periodic acid Schiff and Congo red methods,orange-green dichroism with Congo red whenexamined in polarised light, and bright greenishyellow fluorescence with thioflavin T. In the secondof the discs examined (the brother) the eosinophilicdeposits penetrated as deeply as two-thirds ofthe corneal thickness. There was evidence of theprevious corneal graft in the first disc examined, andDescemet's membrane and associated endothelialcells were clearly visible in both cases. Electronmicroscopy in the second specimen revealed fibrilsthat measured 10 nm in diameter and were consistentwith amyloid. The morphological findings in bothpatients were considered to be compatible with thediagnosis of primary gelatinous drop-like cornealdystrophy (Figs. 2, 3).

.....:..:*.:

Fig. 3 Higherpower view ofsubepithelial accumulations ofhyaline material with atrophy of theAoverlying epithelium. It is this type /ofmorphology that produces thegelatinous drop-like appearanceseen clinically. (Haematoxylin and leosin, x195).

Discussion

Primary gelatinous drop-like dystrophy is a rareform of primary familial corneal amyloidosis firstdescribed in Japan by Nakaizumi in 1914.' About 60cases have been reported in the Japanese literaturesince then,'-2' and various names have been given tothe condition, such as diffuse gelatinous punctatekeratitis,2 gelatinous drop-like corneal dystrophy,3familial diffuse gelatinous drop-like cornealdystrophy,4 and colloid drop-shaped familialdegeneration of the cornea.1

Outside Japan reports of the condition areextremely rare, the first being that by Lewkojewawriting from the Helmholtz Institute in Moscow.22Since then only a handful of clearly indisputableoccidental cases of gelatinous drop-like dystrophy

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Primary gelatinous drop-like keratopathy

have been reported, including three cases from theUSA,'23 one from Switzerland,) and one fromFrance.'7 In the Swiss case, the patient was a 12-year-old Tunisian boy, and no family history was found.Other reports of proved corneal amyloidosiswith appearances similar to gelatinous drop-likedystrophy seem to have been secondary to pre-existing disease. Stafford and Fine2' reported on an11-year-old girl in whom an eye that was enucleatedbecause of retrolental fibroplasia was found to havegelatinous drop-like amyloid deposits. McPherson etal.29 reported similar bilateral corneal changes in a 20-year-old Negress and included four further casereports of similar changes, concluding that all weredue to pre-existing chronic corneal disease. Interest-ingly, they went on to examine 200 eyes submitted forpathological examination for other reasons andfound that 3-5% had corneal amyloidosis which hadnot been apparent prior to removal. SimilarlyGarner6" reported five cases of corneal amyloidosisrelated to previous corneal pathology. Two ofthese were related to trauma, one to trichiasisand senescent change, one was found to be latticedystrophy, and the fifth had an atypical sub-epithelialfibrous plaque. Kanai and Kaufman' likewisereported on a patient who developed gelatinousdrop-like amyloid following primary band-shapedkeratopathy. The amyloid was not found histologic-ally in the first specimen but was present two yearslater in the subsequent corneal disc. One of twoNorth African patients presented by Pouliquen etal.'7 developed gelatinous drop-like keratopathyafter long-standing trachoma, while the otherappeared to be a case of primary gelatinous amyloid.

Parents of affected patients are rarely affected,and the inheritance of the condition is regarded asbeing autosomal recessive with a low degree ofpenetrance.'3 14 The clinical manifestations usuallybegin between the ages of 8 and 18 and initiallyconsist of photophobia, lacrimation, redness, asensation of grittiness, and intermittently blurredvision. On examination of the cornea numerous smallsubepithelial gelatinous excrescences are seen acrossthe corneal surface, giving the whole an appearancevariously described as 'mulberry like' or 'toad skin'like. In advanced cases (often before age 20), thesymptoms are very severe, with profound photo-phobia and visual loss. At this stage there may bestromal neovascularisation. No systemic associationshave been reported.

It was not possible, with such advanced cases asours, to comment on the possible origin of theamyloid fibrils other than to state that the histologysuggested that the major site of deposition wasanterior stroma with erosion of Bowman's layer.There has been some debate as to the origin of the

amyloid. Hohki et al. have postulated that it may beproduced by both keratocytes (as would appear to bethe case with lattice dystrophy) and basal epithelialcells. Nagataki et al.' consider that the keratocytesare not involved, and along with Ohnishi et al."consider that the basal epithelial cell layers are solelyresponsible.Some of the reports discussed above have clouded

the issue by describing conditions similar to primarygelatinous drop-like keratopathy, but there is nodoubt that this strange and most disabling conditionis a discrete entity that can be separated from otherforms of familial amyloidosis by the absence ofsystemic involvement, the unique ocular appear-ances (which occur early and advance rapidly),32 andthe characteristic localisation of the larger amyloiddeposits in the superficial cornea.The precise type of amyloid found in gelatinous

drop-like keratopathy has yet to be fully elucidated.Further definition of chemical structure may bepossible by immunohistochemical techniques such asthose applied by Hida et al. 33 to lattice dystrophytypes I and II and a newly recognised form, type III.So far attempts at precise chemical description oflattice dystrophy type I by these techniques haveproduced conflicting results, which are thought93 tobe due to differences in immunohistochemical tech-niques and the antibodies used or to reflect hetero-geneity inherent in type I. Evolution of newermethods applied to unfixed, freshly excised corneaemay allow further definition of the amyloid material,including the deposits of gelatinous dropletkeratopathy.

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Acceptedfor publication 29 December 1988.

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