Corneal Amyloidosis Associated with CongenitalHereditary Endothelial Dystrophy

Muneera A. Mahmood, M.D., F.R.C.Ophth., andKlaus D. Teichmann, M.D., F.R.C.S.C., F.R.A.C.O.

Purpose. To report the unusual occurrence of corneal amyloidosisindistinguishable from primary gelatinous drop-like dystrophy inthree members of a family with congenital hereditary endothelialdystrophy (CHED). Method. Case study of three patients. Results.Three patients, a 5-year-old girl, her 21-year-old maternal aunt,and a 16-year-old paternal uncle, presented with bilateral cornealedema and opacification secondary to CHED. All three underwentpenetrating keratoplasty, cases 1 and 3 in one eye and case 2 inboth eyes. Histopathology confirmed the diagnosis of CHED in allthree patients but also revealed multiple subepithelial nodular de-posits of amyloid, consistent with the diagnosis of primary gelati-nous drop-like dystrophy, in all four specimens. Three other mem-bers of the same family underwent penetrating keratoplasty withhistologic confirmation of CHED with no deposits of amyloid.Conclusion. To our knowledge, this is the first report of subepi-thelial corneal amyloid deposits in association with CHED. Thismay represent the concurrence of two primary dystrophies, al-though secondary amyloidosis cannot be ruled out. Early manifes-tation and absence of amyloid in three other family members withCHED lends more weight to a primary etiology.Key Words: Amyloidosis—Corneal amyloidosis—Congenital he-reditary endothelial dystrophy—Primary gelatinous drop-like dys-trophy.

Amyloidosis results from the abnormal deposition of an amor-phous, eosinophilic, acellular proteinaceous material (amyloid) ofan unknown origin, in various tissues in a variety of conditions.Amyloid deposits do not provoke an inflammatory response. Thedeposits stain positive with Congo red and exhibit an apple-greenbirefringence and dichroism with Congo red staining and polarizedlight. Amyloidosis can be localized or systemic, primary or sec-ondary. Localized corneal amyloidosis may be primary or second-ary.1

Localized corneal amyloidosis occurs in two main forms: latticecorneal dystrophy and primary gelatinous drop-like dystrophy(PGDD). PGDD is a rare corneal dystrophy, most probably auto-somal recessive in nature, which was first described in Japan in1914 followed by other reports.2–5 There are a few case reports in

the western literature and we have described one case of PGDDfrom Saudi Arabia. PGDD presents with photophobia, foreignbody sensation, and decreased visual acuity in the second and thirddecade of life. There is a high incidence of recurrent disease afterlamellar or penetrating keratoplasty (PKP).4 In PGDD, amyloid isdeposited in the subepithelial region of the cornea in the form ofelevated grayish-white nodules with occasional vascularizationand involvement of the superficial stroma.

Secondary corneal deposits of amyloid may take differentforms. They may occur as subepithelial masses that producemarked irregularity and opacification of the cornea often with avascular pannus, also termed secondary cobblestone amyloid de-generation. They may take the form of lamellar deposits occurringonly in the deep stroma or perivascular deposits associated withcorneal vascularization.1,6 The second and third types are usuallyidentified by histopathology. Secondary amyloidosis has been de-scribed in corneal disorders such as trauma, trachoma, lipoid pro-teinosis, leprosy, phlyctenulosis, lipoidal degeneration, keratoco-nus, climatic droplet keratopathy, and bullous keratopathy.

Congenital hereditary endothelial dystrophy (CHED) is a cor-neal dystrophy that presents at birth, or shortly thereafter, withmild to severe bilateral corneal edema, varying from a blue-grayground-glass appearance to total corneal opacification.1,7–9 Thedisease may be autosomal recessive or autosomal dominant. Thepathogenesis is not known but could be the result of degenerationof corneal endothelial cells during or after the fifth month of ges-tation.8 It is a common childhood dystrophy of the cornea in SaudiArabia.9

We report the unusual occurrence of corneal amyloidosis indis-tinguishable from PGDD associated with CHED in three membersof a family.

CASE REPORTS

Case 1A 5-year-old girl presented on October 28, 1992 with poor

visual acuity that she had experienced since birth. Family historywas significant for CHED in her siblings and her parents’ siblings.Visual acuity was 3/200 in the right eye and 20/300 in the left eye.Intraocular pressure was normal. There was right esotropia. Bilat-eral corneal edema with bullae and a few central subepithelialgrayish-white elevations were evident (Figs. 1 and 2). A PKP ofthe right eye was performed one week after presentation.

Histopathology of the corneal button confirmed the diagnosis ofCHED; in addition, it showed that the subepithelial zone was

Submitted July 30, 1999. Revision received December 15, 1999. Ac-cepted December 28, 1999.

From King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.Address correspondence and reprint requests to Dr. M.A. Mahmood,

10056 Oakley Court, Vienna, VA 22181-5354, U.S.A.Presented in part as a scientific poster at the XII Congress of the Euro-

pean Society of Ophthalmology, Stockholm, Sweden, June 27 to July 1,1999.

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partially occupied by large acidophilic deposits. These depositsstained positive with Congo red and polarized light with a dichroiccharacter and exhibited birefringence that confirmed their amyloidnature (Figs. 3A–3C). A histologic diagnosis of PGDD was made.

To date, the child has kept a clear graft in the right eye withvisual acuity of 20/125. The last follow-up was on January 27,1999. The patient is awaiting a PKP in the similarly affected lefteye.

Case 2A 21-year-old woman, a maternal aunt of case 1, presented on

August 29, 1995 with poor vision that she had experienced since

birth. Her vision was counting fingers near her face in both eyes.Intraocular pressure was normal. Examination revealed bilateraldiffuse corneal edema with multiple grayish-white nodular eleva-tions, almost from limbus to limbus (Fig. 4). The patient under-went a successful PKP in the left eye on May 20, 1996.

Histopathology of the corneal button showed an atrophic cor-neal epithelium with thick subepithelial deposits of a coarse, amor-phous acellular material. The anterior structures of the cornea werereplaced by fibrosis, while the posterior lamellae were relativelypreserved. Only a segment of thickened Descemet’s membranewas visible with no corneal endothelium, consistent with the di-agnosis of CHED. The subepithelial deposits stained positive with

FIG. 2. Case 1, OS. Clinical appearance similar to the righteye.

FIG. 3. (A) Case 1, OD. Nodular subepithelial amorphous de-posits stain positive with Congo red. Original magnification ×100. (B) Nodular subepithelial deposits exhibit birefringencewith polarized light and confirm the presence of amyloid. Origi-nal magnification × 100. (C) Thickened stroma and a paucity ofendothelial cells confirms the diagnosis of CHED (Periodic acid-Schiff). Original magnification × 100.

FIG. 1. Case 1, OD. Diffuse corneal edema with focal grayish-whitenodular elevations in the central area.

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Congo red and exhibited dichroism and birefringence with polar-ized light. The subepithelial deposits were deemed compatiblewith the diagnosis of PGDD (Figs. 5A–5C).

The patient did well postoperatively with an increase in vision to20/80 OS. She underwent a PKP in the right eye 14 months later.Histopathology of the right eye again confirmed the diagnosis ofCHED and revealed subepithelial amyloid deposits similar to theother eye, strongly suggesting the diagnosis of PGDD.

Case 3Chart reviews of other members of this family who had under-

gone PKP for CHED revealed that a paternal uncle of case 1underwent surgery in the left eye in 1985 at the age of 16 years. Healso gave history of poor vision in both eyes since birth withnormal intraocular pressures. The patient had undergone PKP inthe right eye three years earlier elsewhere. Clinical drawings of theleft eye showed multiple nodular elevations all over the corneaalong with corneal edema. The histopathology report described athickened Descemet’s membrane with few, if any, endothelialcells, confirming the diagnosis of CHED. In addition, the reportdescribed extensive subepithelial and superficial stromal depositsof amyloid. The histopathology slides were not available for re-view.

Other Family Members with CHEDA further review of family history revealed that three sisters of

case 1, nieces of cases 2 and 3, had undergone PKP for cornealedema. In all cases, histopathology confirmed the diagnosis ofCHED but showed no subepithelial amyloid deposits. A maternaluncle of case 1, brother of case 2, and a paternal aunt of case 1,sister of case 3, had CHED with no evidence of amyloidosis(Fig. 6).

DISCUSSION

We have described three related cases of CHED with subepi-thelial amyloid deposits. Cases 2 and 3 are the maternal aunt andpaternal uncle of case 1, respectively. Three other family memberswho underwent PKP for CHED do not show similar deposits. The

question arises as to whether these amyloid deposits are primary orsecondary. The presence of this condition in three different familymembers at an early age and the typical bilateral symmetricalsubepithelial nodular deposition of amyloid without any other de-generative changes suggest the presence of a second dystrophy.The absence of amyloid in other family members with CHED alsospeaks for two separate dystrophies. Unfortunately, we did notobserve PGDD without CHED in this family, which would haveproven the presence of two independent dystrophies. However,

FIG. 5. (A) Case 2, OS. Subepithelial amorphous nodular amyloiddeposits stain positive with Congo red. Original magnification × 100.(B) Subepithelial nodular deposits exhibit birefringence under polar-ized light. Original magnification × 100. (C) Note segment of thick-ened Descemet’s membrane and total absence of corneal endothe-lium (Periodic acid-Schiff). Original magnification × 20.

FIG. 4. Case 2, OD. Diffuse corneal edema with multiple whitishelevated nodules.

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none of these cases have suffered a recurrence, although PGDD isnotorious for repeated and early recurrences.

It is conceivable that long-term corneal edema may have led tosecondary degenerative changes. However, adults with chronicedema usually do not develop similar amyloidosis and none of ourother numerous CHED patients have these deposits.

Case 1 was only 5 years old when she underwent surgery. Heramyloid deposits were more localized than case 2, who had sur-gery at age 21 and had extensive limbus to limbus deposits. Theprogression with age could be a feature of both a progressivedystrophy and a worsening degeneration.

CONCLUSION

To our knowledge, this is the first report of subepithelial cornealamyloid deposits in association with CHED. This may represent aconcurrence of two primary dystrophies, though secondary amy-loidosis cannot be ruled out. The early occurrence of amyloid insome family members and the absence of amyloidosis in otherswith CHED lends more weight to a primary etiology.

REFERENCES

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2. Nagataki S, Tanishima T, Sakimoto T. A case of primary gelatinousdrop-like corneal dystrophy. Jpn J Ophthalmol 1972;16:107–16.

3. Akiya S, Ito K, Matsui M. Gelatinous drop-like dystrophy of thecornea. Light and electron microscopic study of superficial stomallesion. Jpn J Clin Ophthalmol 1972;26:815–26.

4. Santo RM, Yamaguchi T, Kanai A, Okisaka S, Nakajima A. Clinicaland histopathologic features of corneal dystrophies in Japan. Ophthal-mology 1995;102:557–67.

5. Mahmood MA, Cavender JC. Primary gelatinous drop-like dystrophy:penetrating keratoplasty vs phototherapeutic keratectomy. Middle EastJ Ophthalmol 1997;5:130–3.

6. Waring GO III, Mbekanni JM. Corneal degenerations. In: LeibowitzHM, Waring GO III, eds. Corneal disorders, clinical diagnosis andmanagement. 2nd ed. Philadelphia: Saunders, 1998:287–338.

7. Maumanee AE. Congenital hereditary corneal dystrophy. Am J Oph-thalmol 1960; 50:1114–24.

8. Kenyon KR, Antine B. The pathogenesis of congenital hereditary en-dothelial dystrophy of the cornea. Am J Ophthalmol 1971;72:787–95.

9. Al-Rajhi AA, Wagoner MD. Penetrating keratoplasty in congenitalhereditary endothelial dystrophy. Ophthalmology 1997;104:956–61.

Editor search: The Castroviejo Cornea Society is seeking applications for the position of Editor-in-Chief of the journal Cornea to succeed Dr. Mannis whose term ends at the end of 2001. Theeditor must have clinical and research expertise in the area of cornea and external ocular disease.Submit applications to Joel Sugar, M.D., Search Committee Chair, 1855 W. Taylor, Chicago, IL60612, U.S.A. Applications with CV should be received before October 1, 2000.

FIG. 6. Pedigree of cases withamyloidosis and CHED. Black-ened = cases with CHED. Striped= cases with CHED and amyloid-osis. Open = unaffected.

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