AMERICAN JOURNAL VOLUME 68
HEREDITARY D E E P DYSTROPHY O F T H E CORNEA ( P O L Y M O R P H O U S ) MICHAEL J. HOGAN, M.D.
AND GIAMBATTISTA BIETTI,
San Francisco, California
Approximately 60 cases of hereditary deep dystrophy of the cornea have been re ported, principally in the American and Ger man literature. The lesions consist of poly morphic opacities located in the central re gion of the cornea at the level of the endothelium, Descemet's membrane and deep stroma. These changes are most often de scribed as vesicular, with the anterior wall of the vesicle extending into the corneal stroma. They are of varying size, the small ones measuring 0.08 mm and the large ones 0.75 mm in diameter. They may be irregular in shape, smooth and rounded, or somewhat el liptical. Berliner1 believes them to be nodules or thickened depressions rather than vac uoles. Most authors have also described gray opacification of the stroma and Descemet's membrane around the circumference of the lesions, and some have commented on altera tions in the deep corneal stroma. The cor neas may exhibit ridgelike structures, pro jecting into the anterior chamber, the ridges being long and quite often concentric with the limbus.2'3 The corneal tissues in unaf fected areas are normal, even in patients who have had the condition for many years. However, visual acuity is somewhat reduced, even in young individuals, if there are many From the Department of Ophthalmology and the Francis I. Proctor Foundation for Research in Ophthalmology, University of California Medical Center, San Francisco, and the Department of Ophthalmology, University of Rome. This work was supported by USPHS Grant 06207. Presented at the meeting of the American Ophthalmological Society, Hot Springs, Virginia, May, 1969. Reprint requests to Michael J. Hogan, M.D., De partment of Ophthalmology, University of Califor nia Medical Center, San Francisco, California 94122.
lesions in the pupillary region. It is almost always diminished in patients who have had the disease for many years. Most often both eyes are equally affected, with a striking symmetry of the lesions in the eyes of some patients. The changes in the cornea seem to be nonprogressive. Forme fruste lesions have been described in one or both eyes.2 Corneal sensation and the intraocular pres sure are normal, except for an occasional pa tient with nonrelated open-angle glaucoma. The disease is probably congenital; many cases have been described in children 4-10 years of age. One patient had congenital opacities.2 It is also hereditary; nine kin ships have been reported in which two or more generations exhibited the disease. It seems likely that this condition is transmit ted as an autosomal dominant with fairly good penetrance. Theodore 2 noticed that the corneal lesions were more pronounced in succeeding generations, but Magruder 4 was unable to confirm this. Magruder performed bilateral cataract extractions on one patient, employing alpha-chymotrypsin, without af fecting the corneal lesions or corneal trans parency. Because of the good vision and nonprogression of the lesion, it is rare to obtain corneas with this disease. The only previous pathologic report was made in 1966 by Mor gan and Patterson 5 who obtained corneal tis sue in this condition from a 46-year-old man after penetrating keratoplasty for a postherpetic corneal scar. Both eyes of this patient showed multiple grayish opacities of various shapes and sizes at the level of Descemet's membrane, con fined to the central 7.0 mm of the cornea.
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T h e opacities were not too thick and pro jected into the anterior chamber in a ser rated fashion. T h e anterior edge of the opac ity on the corneal side was smooth, in con trast to other reported cases. Microscopic changes were confined to Descemet's membrane and the endothelium, with approximately four excrescences on Descemet's membrane in each section. They are fusiform in shape, bulged into the ante rior chamber and were PAS-positive ; each swelling showed, at a maximum, two dozen irregular empty vacuoles. Descemet's mem brane between the excrescences was normal in some places and thickened in others. T h e endothelium was very thin over the excres cences and its nuclei were flattened. W e have studied a patient with this type of deep dystrophy and his corneal tissue was examined by light and electron microscopy. A brief clinical report on this case was pre sented in the Italian literature by Bucci 3 in 1960. C A S E REPORT
The patient was a healthy married university
professor, aged 47 years, who had been followed since the age of 31 years for a bilateral corneal condition. At the time it was discovered, there was a deep corneal dystrophy, almost identical in the two eyes, characterized by polymorphous and quite translucent vesicular changes in the region of Des cemet's membrane. The endothelium appeared to be absent, especially in the right eye, which had slightly worse vision. The cornea of this eye showed a roundish zone of edema with some degree of deep stromal opacification slightly below the pu pillary area. These findings were furnished by a re ferring ophthalmologist. By 1959 the vision in the right eye had become worse because of increased edema, the acuity varying somewhat with use of the eyes and improving toward the end of the day. At this time the patient was first seen by one of us (G.B.). On examination, the visual acuity with correc tion in the right eye was 7/10 and in the left 10/10. The refractive error was: R.E., —4.0D sph C +2.0D cyl ax 170°; L.E., -4.0D sph C + 1.0D cyl ax 170°. The right eye showed no abnormality except for the cornea. Slightly below the pupillary area was an edematous process which was fairly circumscribed, characterized by epithelial and stromal edema and thickening so that the corneal thickness was in creased by approximately 30%. The principal dystrophic lesions occurred in the deep cornea, primar ily involving Descemet's membrane and the endo thelium, but there were areas of change in the ad jacent stroma. The changes were polymorphous, with small roundish areas of bullous appearance
Fig. 1 (Hogan and Bietti). Drawing of the right and left corneas. The right cornea shows the poly morphous lesions in the region of Descemet's membrane and deep stroma, as well as a grey central zone of edema and thickening. The left cornea shows only the plaques.
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Fig. 2 (Hogan and Bietti). Drawing of the left cornea, similar to that seen in Figure 1. The slitlamp microscopic drawing to the right depicts the changes in the deep stroma, Descemet's membrane and the endothelium. The excavated areas probably represent zones where endothelium has been lost. and other areas where these seemed to have co alesced to give rise to a ridgelike pattern or snailtrail appearance (fig. 1) with irregularly sinuous margins. Descemet's membrane was involved in these lesions and showed a concavity which was generally somewhat rough and slightly sparkling when viewed by the slitlamp beam in varying inci dences. A very thin edge of nonhomogeneous thick ness, also of sparkling appearance, limited the zones affected by the degenerative process. The zones of endothelium between these lesions appeared to have a normal mosaic. The left eye showed almost identical lesions, ex cept that there was no corneal edema or change in
thickness (fig. 2). General Hùtory. The patient had bronchial asthma during World War II and an appendectomy at the age of 37 years. He had been found to have oligospermia. Three brothers were living and healthy. The father, who died of cerebral thrombo sis, had had good vision. Family Htrfory.There was no history of any he reditary eye disease in the family. The three broth ers and a cousin were examined and found to have no eye disease. Because of the oligospermia there was no progeny. Course. The patient was followed regularly be tween 1959 and 1968, when the zone of opacifica-
Fig. 3 (Hogan and Bietti). Note central area of stromal and epithelial edema, as well as deep lesions in right cornea, prior to keratoplasty.
Fig. 4 (Hogan and Bietti). Postoperative appear ance of same eye after corneal grafting.
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Fig. S (Hogan and Bietti). Gross view of the deep side of the corneal button, demonstrating large and smaller nodular lesions, as well as the ridges. (Xl2.) tion and thickening of the cornea of the right eye had increased in size and amount and there were bullas present in the epithelium. Vision had fallen to 1/10 (fig. 3). The left eye was unchanged; the deep dystrophy in the right also showed no alter ation from that seen in 19S9. Corneal sensation was normal in both eyes. A full-thickness keratoplasty was performed on July 3, 1968. A 7.0-mm graft was placed in the recipient eye and held with 12 edge-to-edge virgin silk sutures. The final condition was satisfactory, and the eventual visual result was 1.0 with the following correction: R.E., - 4 . 0 sph C —3.0D cyl ax 115° (fig. 4). PATHOLOGY
The excised corneal tissue was immedi ately fixed in cold buffered 4% glutaraldehyde and sent to San Francisco. On July 15, it was placed in 2 % glutaraldehyde and then in 1% paraformaldehyde with C.P.C, on July 22. Gross Pathology. With the dissecting mi croscope at high magnification, all the lesions which were seen with the slitlamp micro scope could be visualized on viewing the inner surface of the cornea. Four types of lesions were identified: (1) deep stromal
nodules of approximately 0.25 to 0.75 mm size, which elevated the inner surface of the cornea and extended into the adjacent cor neal stroma (fig. 5), and which were gray and solid, with a smooth surface, and were scattered throughout the central cornea ; (2) ridges, corresponding to those seen clinically, and not seeming to be secondary to conflu ence of nodules, but rather forming their own circular patterns in the deep stroma; (3) a diffuse alteration of the deepest cor neal lamellas characterized by an increased gray haze; and (4) typical warts of cornea guttata. The corneal button was divided into two parts so that lesions were present in each portion, one for routine pathology and the other for electron microscopic study. The portion for eye pathology was embed ded in bioloid and the following stains were used : hematoxylin-eosin, Masson, PAS, amyloid, alcian blue, colloidal iron, von Kossa and alizarin red. After being embed-
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ded in epoxy resin, the half retained for electron microscopy was sectioned on the Porter-Blum microtome (MT-2) to show the principal lesions, some areas selected to show nodules and others to show ridges and deep stroma One-micron and ^o-micron sec tions were studied. The RCA 3E electron microscope was used to view and photograph the specimens. Light Microscopic Pathology. The endothelium of the entire specimen was either ab sent or very thin with a coarsely granular cytoplasm and a displaced nucleus. The classic findings of cornea guttata were seen in the central areas, but the warts were more clustered and less diffuse than in the senile type of cornea guttata (fig. 6 ) . Descemet's membrane showed diffuse thick ening and irregularity, forming small, smooth, dome-shaped protrusions into the anterior chamber; most had no endothelial cover. The membrane lacked its usual bril liant PAS stain, and seemed to be formed of several alternating dark and light zones (fig. 7)· The nodules which could be seen clinically and at gross examination were found in the deep stroma. In hematoxylin-eosin stained sections they were reminiscent of the plaques of focal senile translucency which occur in the sclera. They took a faint basophilic stain, were granular and the corneal lamellas were intact within them (fig. 8 ) . They stained positively with the alizarin red and von Kossa stains (figs. 9, 10) but were negative with the PAS, colloidal iron, alcian blue and amyloid stains. A pronounced folding of the deep corneal tissues into the anterior chamber produced the ridges which were seen clinically. These ridges contained normal corneal tissues for the most part, with nodules and deep lamel lar changes in many areas. The endothelium was usually thin over their apices, and Descemet's membrane was thickened. The deepest five to ten lamellas of the stroma stained much lighter with eosin than did the more superficial ones. At higher
Fig. 6. (Hogan and Bietti). Microphotograph, showing the warts characteristic of cornea gut tata and the lighter eosin staining of many of the deep corneal lamellas. (χ700.)
magnification, these layers appeared granu lar, and with the alizarin red and von Kossa stains they were positive for calcium, but showed no abnormality with the other stains (figs. 11,12). The corneal stroma showed the usual changes due to edema, with swelling and de generation of many of the fibröblasts, lamel lar separation by edema fluid and a weaker affinity for eosin. Bowman's membrane was intact and showed no important change. The epithelium showed the usual changes due to edema. Electron Microscopic Pathology. Electron micrographs confirmed the findings of light microscopy with respect to the nodules, ridges, deep changes in the stroma and Des cemet's membrane and the warts. In most blocks examined, the endothelium was absent or else it appeared to show de generative changes. The nuclei were pyknotic and the cytoplasm appeared unusually dense and reduced in size (fig. 13). In some areas between the warts, cells were present but, upon reaching warts themselves, only mem-
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Fig. 7 (Hogan and Bietti). A light micrograph, made from a 1μthick plastic-embedded specimen, shows the alternating striations found in Descemet's membrane over one of the ridges. The endothelium is missing. Note also the nodule in the deep stroma with a more dense periphery. (Richard son méthylène blue, reduced from X800.)
branous remnants and nuclei were present (fig. 14). Descemet's membrane showed two types of change, a diffuse thickening and warts. The wart stucture was found to be the same as that described by other authors0"8 and will not be discussed. The diffuse thickening was characterized by an addition of a less dense uniformly structureless substance to the membrane, increasing its thickness to 13μ in many areas. The thickening was produced by the addition of material with the same struc ture as Descemet's membrane but not as tightly organized (fig. 15). Externally, there
Fig. 8 (Hogan and Bietti). A nodule in the deep stroma shows a fine granularity due to the de position of crystals. Note the changes in Descemet's membrane. (Richardson méthylène blue, re duced from X800.)
was an increase of collagen in the membrane and this area contained many crystals. The nodules contained many long elliptic crystals which were dispersed diffusely or arranged in rosettelike structures, like a ray fungus (fig. 16) ; the crystals were most nu merous at the center of the nodules with fewer toward their periphery. They seemed to be deposited among the lamellas without affecting the collagen, whose fibers coursed through the area without interruption and showed no evidence of degeneration. The corneal ridges often contained nodules near their apices, but otherwise showed mainly a
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Fig. 9 (Hogan and Bietti). Microphotograph of a nodule in corneal tissue embedded in liioloid. The peripheral dense rim is basophilic. (Reduced from X/00.) directional change of the deep layers toward the anterior chamber. Within them, the deep est corneal layers also showed crystals. Those deep corneal layers which were positive for calcium with the von Kossa and alizarin red stains showed a diffuse, very dense deposition of crystals like those seen in the nodules, but the}· appeared to be more closely packed than those of the nodules (figs. 17, 18). T h e collagen here was also not altered by the crystal deposition.
Fig. 11 (Hogan and Bietti). von Kossa stain of the lesion in Figures 9 and 10. It too is positive for calcium. (χ700.) alteration of the collagen. T h e corneal fibroblasts showed various stages of degenera tion ; some were deeply osmiophilic, others had slight degeneration of the cytoplasm and organelles. Bowman's membrane and the epi thelial basement membrane showed very lit—
T h e corneal stroma showed some edema with separation of the layers from each other by the fluid, but there was very little
Fig. 10. (Hogan and Bietti). Alizarin red stain of the lesion shown in Figure 9. The stain is posi tive for calcium. (Reduced from X700.)
Fig. 12 (Hogan and Bietti). Alizarin red stain of the deeper lamellas of the cornea which appear darker in this photograph. (χ600.)
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Fig. 13. (Hogan and Bietti). von Kossa stain of the same specimen in Figure 12, showing a positive stain for calcium. (χ600.) s /////
tie change. The epithelium showed the changes expected from long-standing edema. DISCUSSION
This cornea showed deep dystrophic changes involving the endothelium, Descemet's membrane and the deep stroma near Descemet's membrane. The cornea guttata, we believe, was secondary to the localized
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Fig. IS (Hogan and Bietti). Endothclium between two warts. The cell is diminished in size, shows a greater structural density and is depleted of organelles. (X 18,200.)
endothelial disease and chronic edema pres ent during the 16 years prior to keratoplasty. The left eye of this patient showed no evi dence of cornea guttata, sustaining the premise that this condition found in the grafted eye is secondary, as in some inflam mations and after trauma. It might be thought that the process in both corneas was due to cornea guttata. However, in addition
to the absence of clinical evidence of guttata in the left eye, the plaque formation and deep stromal change do not support this con clusion. Also, we and others have not found crystal deposition in eyes with cornea gut tata. The nodules, ridges and deep stromal changes resemble those described clinically in many other presentations ; therefore, the
Fig. 14 (Hogan and Bietti). Electron micrograph of the inner part of Descemet's membrane. The thick ening is apparently produced by addition of new layers of material resembling Descemet's membrane itself, but orienteid in tight or loose layers. (X 18,200.)
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^ Fig. 16 (Hogan and Bietti). Fine structure of one of the nodules showing the deposition of crystals in the stroma and lack of change in the collagen. (X 18,200.) disease in this case can be related closely to all previous reports. The nodules' translu cency and their vesicular appearance have been commented on by all authors and, in view of their composition, this appearance would seem to arise from the localized de position of the crystals among the lamellas. In this respect, the findings are not unlike those in focal senile translucency of the sclera,10 in which deposits of calcium apatite among the scierai fibers render them more transparent. It was surprising to us to see the extensive deposition of calcium crystals in the deep lamellas of the cornea. This change was not as evident clinically because of its diffuseness, but the sparkling appear ance of the deep cornea was probably due to these particles. Because the histologie findings are so dis
similar, it is impossible to relate our case to that of Morgan and Patterson. Yet, both cases are examples of deep dystrophy of the cornea that probably differ in origin. Mor gan reported to us in a personal communica tion that the tissue lesions in their cornea were not positive for calcium. Magruder made an interesting observation on this dis ease when he considered the possibility of a similarity to hypophosphatasia, a syndrome most often seen in infants and children and inherited as a recessive disorder. His patient had a positive urine Sulkowitz test for cal cium, a serum calcium of 11.7 mg%, a low ered serum alkaline phosphatase of 0.6 Bodansky units and a serum phosphorus of 5.0 mg%. These tests were repeated and the re sults remained the same. With hypophos phatasia, a syndrome characterized by ab-
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normal mineralization of bone, the serum alkaline phosphatase decreases and phosphorylethanolamine increases in the urine. Magruder's patient did not have all these find ings, but the laboratory data clearly suggested a metabolic disorder. T h e brother of the propositus (less than 15 years of age) of the family reported by Snell and Irwin 1 1 showed an early band keratopathy of the corneas with no ocular inflammation, but metabolic studies apparently were not carried out. Cer tainly, most of these cases of deep dystrophy are of congenital origin and, therefore, some might be the result of a metabolic disorder related to calcium metabolism. In our pa tient, as with many other cases reported in the literature, the condition occurs sporadi cally. Individuals with this type of eye dis
ease should be scrutinized for other signs of metabolic disorder. SUMMARY
1. A case of hereditary deep dystrophy of the cornea (polymorphous) is reported. A keratoplasty was necessary in one eye be cause of corneal edema. 2. T h e corneal button was studied by light and electron microscopy and showed four types of lesions, including nodules, ridges, diffuse deep corneal lamellar changes and cornea guttata. 3. Crystals were found in the nodules and deep corneal lamellas, and were identified as calcium by the von Kossa and alizarin red stains. Their presence was confirmed by electron microscopy in all these locations.
Fig. 17 (Hogan and Bietti). Deep corneal lamellas, showing deposition of crystals in the region of Descemet's membrane. Some crystals can be seen in the membrane itself. (X13.500.)
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Fig. 18 (Hogan and Bietti). Higher power micrograph of the crystals observed in Figure 17. They are needlelike and more densely packed than in the nodules. (X 34,400.) The findings suggest that this is a hereditary metabolic disorder, possibly related to a dis turbed calcium metabolism. ACKNOWLEDGMENT
We thank Mrs. I. Wood for her technical assis tance in preparing the specimens and micrographs. REFERENCES
1. Berliner, M. L. : Biomicroscopy of the Eye : Slit Lamp Microscopy of the Living Eye. New York, Hoeber, 1949, p. 322. 2. Theodore, F. H. : Congenital type of endothelial dystrophy. Arch. Ophth. 21:626, 1939. 3. Bucci, M. G. : Su un caso di distrofia poli morfa giovanile dell'endotelio corneale. Boll. Ocul. 39 :384, 1960. 4. Magrudcr, G. B. : Lens extraction in heredi tary deep corneal dvstrophy. Am. J. Ophth. 52 :677, 1961.
5. Morgan, G. and Patterson, A. : Pathology of posterior polymorphous degeneration of the cornea. Brit. J. Ophth. 51:433, 1967. 6. Feeney, M. L. and Garron, L. K. : Descemet's membrane in the human peripheral cornea. A study by light and electron microscopy. In The Structure of the Eye. (G. K. Smelscr, ed.) New York, Aca demic Press, 1961, p. 367. 7. Jakus, M. A. : Further observations on the fine structure of the cornea. Invest. Ophth. 1:202, 1962. 8. Chi, H., Teng, C. and Katzin, H. : Histopathology of primary endothelial-epithelial dystrophy of the cornea. Am. J. Ophth. 45:518, 1958. 9. Kayes, J. and Holmberg, A. : The fine struc ture of the cornea in Fuchs' endothelial dystrophy. Invest. Ophth. 3 :47-67, 1964. 10. Cogan, D. G. and Kuwabara, J. : Focal senile translucency of the sclera. Arch. Ophth. 62:604, 1959. 11. Snell, A. C. and Irwin, E. S.: Hereditary deep dystrophy of the cornea. Am. J. Ophth. 45 :636, 1958.