Genetics of the Corneal Dystrophies What We Have Learned in the Past Twenty-Five Years

Genetics of the Corneal Dystrophies What We Have Learned in the Past Twenty-five Years

Anthony J. Bron, F.R.C.S.

Purpose. To indicate important changes in our understanding of The term corneal dystrophy will be used here to define primary, the corneal dystrophies. Methods. A review of the literature of the inherited, bilateral disorders of the cornea affecting transparency last quarter of a century. Results. The earliest clinical classifica- or refraction. Such disorders may or may not disturb vision. At tions of the corneal dystrophies were based on the application of various times in the past they have been said to be of early onset, clinical, biological, histochemical, and ultrastructural methods. axially symmetrical, slowly progressive, or stationary. Earlier defi- Since then, the first great impetus to our understanding has come nitions also required that the affected corneas be free from vascu- from the application of techniques to map disorders to specific chromosome loci, using polymorphic markers. More recently, us- larization and not associated with systemic disease. These are rea- ing candidate gene and related approaches, it has been possible to sonable guidelines, which draw attention to the possibility of a identify genes causing several of the corneal dystrophies and the corneal dystrophy in a given clinical situation. But there are ex- mutations responsible for their phenotypic variation. A notable ceptions to each of these characteristics in conditions generally success has been to show that several important “stromal” dystro- accepted to be corneal dystrophies. Thus, asymmetrical or even phies result from mutations in the gene ␤ig-h3, which encodes for unilateral Meesmann’s and lattice dystrophy are reported, and vas- the protein keratoepithelin (␤ig-h3). Conclusions. For the corneal cularization is a characteristic of autosomal dominant keratitis and, dystrophies, as with other inherited disorders, there is room for two eventually, a feature of gelatinous drop-like dystrophy (GDLD). sorts of classification system, one based mainly on clinical pre- Haugen and Bertelsen3 have described a condition in a mother and sentation and the other on an up-to-date understanding of the ge- two sons in whom a dysplastic fibrovascular condition of the cor- netic mechanisms. They are not mutually exclusive. Some developmental corneal disorders are also discussed. neas is accompanied by keloidal deformities of the hands. Cornea Key Words: Corneal dystrophies—Genetics—Developmental guttata and Fuchs’ dystrophy are late in presentation, and lattice disorders. corneal dystrophy (LCD) type II is a manifestation of an inherited, systemic, amyloid polyneuropathy. Macular corneal dystrophy (MCD) is accompanied by changes in levels of antigenic serum Our perceptions of the corneal dystrophies have changed, dra- keratan sulfate, implying extraocular involvement. Other corneal matically over the past quarter of a century, as new genetic infor- disorders, too, are recognized features of systemic diseases, such mation has become available. Over 10 chromosome loci have been as X-linked ichthyosis (steroid sulfatase deficiency),4 ceramide linked to specific corneal dystrophies, and mutations in four genes trihexosidase deficiency (Fabry disease),5 the mucopolysacchari- are known to be responsible for some of these. Multiple mutations doses, and the mucolipidoses. in the gene ␤ig-h3, which encodes for the protein keratoepithelin (␤ig-h3), have been invoked to explain the phenotypic diversity of the classical stromal dystrophies and are providing insights into KERATOEPITHELIN DYSTROPHIES their mechanisms. With these new findings and the expectation of further developments in this field, there has been a call for a Considerable interest has focused on mutations in the kerato- revised classification of the corneal dystrophies, substituting a ge- epithelin gene (␤ig-h3) as the basis for several, phenotypically notypic for a phenotypic approach. Some valuable genotypic clas- distinct corneal dystrophies. Keratoepithelin is an adhesion pro- 1,2 sifications have been published recently. However, the two ap- tein, which is strongly expressed by the corneal epithelium and, to proaches are not mutually exclusive and the phenotypic approach, a lesser extent, by other corneal cells. It is secreted by the epithe- based on an assessment of clinical and structural features, is likely lium and is present in normal stroma, covalently bound to type VI to continue to provide the most comprehensive clinical account of collagen. A study by Streeten et al.6 showed the strongest immu- these disorders for some time to come. The genotypic approach noreactivity for keratoepithelin in Bowman’s layer, at an interla- will provide increasing understanding and, in the long term, the mellar location (to a lesser extent), and at the interface between opportunity for medical intervention, using conventional pharma- stromal collagen and Descemet’s layer (to a minor degree). cologic approaches, or gene therapy. The keratoepithelin molecule is about the size of albumin and, therefore, is sufficiently small to diffuse across the stroma from its Submitted March 7, 2000. Accepted April 30, 2000. epithelial source. Mutated keratoepithelins are of similar size and From Nuffield Laboratory of Ophthalmology, University of Oxford, their diffusability could explain the slow anterior-to-posterior evo- Oxford, U.K. Address correspondence and reprint requests to Dr. Anthony J. Bron, lution of granular, lattice, and Avellino corneal dystrophies over Nuffield Laboratory of Ophthalmology, University of Oxford, Walton time. Although it is not excluded that keratocytes and endothelial Street, Oxford OX2 6A W, U.K. cells may contribute to the formation of deposits in the keratoepi-

699 700 A.J. BRON thelin dystrophies, one of the strongest pieces of evidence support- and where they aggregate or co-aggregate to form amyloid or other ing a major epithelial origin is the initial confinement of recur- deposits. In the case of Thiel-Behnke dystrophy, which is confined rences to the epithelium, after keratoplasty or phototherapeutic to Bowman’s layer, it must be assumed that the aggregates, or the keratoplasty (PTK).7 This has been confirmed ultrastructurally.8 mutated keratoepithelin itself, either have a high affinity for Bow- With time, recurrences spread to affect the stroma.9 man’s layer or that their diffusion is limited by size constraints. It Between 1994 and 1996, four reports appeared, linking granular, may be relevant that immunolocalization of native keratoepithelin lattice,10 granular-lattice (or Avellino dystrophy),11 and Reis- is strongest at the level of Bowman’s layer in the normal cornea.6 Bu¨cklers’ dystrophy,12 to chromosome 5q31.13 It was mooted that The keratoepithelin dystrophies have in common a clear zone of these disorders, hitherto regarded as discrete clinical entities, unaffected, peripheral corneal stroma about 1–2 mm wide. The might be allelic forms. Korvatska et al.14 refined the locus of an basis for this is not known but may reflect removal of the diffusing, assumed allelic gene to a 1CM region of 5q (5q22–5q32) and mutated keratoepithelin by the limbal blood vessels or, alterna- excluded SPARC and LOX as relevant candidate genes. Later, the tively, that epithelial keratoepithelin expression is lower in the same group reported missense mutations in BIGH3, in family periphery, where the mitotic rate is high, than in the central cornea. members of each of the dystrophies mapping to 5q.15 Mutations at This deserves further study. codon 124 were associated with LCD (arginine to cysteine) and Table 1 offers a phenotypic classification of the corneal dystro- Avellino dystrophy (arginine to histidine), whereas mutations at phies supplemented with information about linkage, or genetic codon 555 were associated with granular corneal dystrophy (GCD) information where it is available. This approach has the benefit of type I (arginine to tryptophan) and Reis-Bu¨cklers’ dystrophy (ar- providing a comprehensive account of the dystrophies, which can ginine to glutamine). These studies have been confirmed and ex- be added to in the future. tended by others, and it is apparent that there are mutation hot spots at codons 124 and 555 but that mutations involving other codons are also associated with dystrophies within the same group. EPITHELIAL CORNEAL DYSTROPHIES These include mutations Arg124Leu (in GCD III, a superficial 16,17 18 Recurrent Corneal Erosion form of GCD ), Leu527Arg (in LCD IV ), and Pro501Thr 28 (LCD IIIA19). The mechanisms leading to the formation of depos- Franceschetti described recurrent corneal erosion occurring as its in these conditions is still under debate. To understand them, it a dominant trait over six generations. Onset was spontaneous or is useful to consider GCD I and LCD I as models for the kerato- was triggered by minor trauma between the ages of 4–6 years. Attacks diminished in frequency and severity by the fifth decade. epithelin dystrophies. In GCD, it has been shown that the deposits 29 contain keratoepithelin,6 together with nonkeratoepithelin pro- Other reports have also appeared. The condition is bilateral and teins, such as vimentin (an intermediate filament protein),20 cyto- characterized by microcystic epithelial lesions. Sporadic cases of keratin 18 (an epithelial protein),20 immunoglobulin (IgG) ␬ and ␭ bilateral recurrent corneal erosion are also seen, lacking the fea- light chains,21 and microfibrillar protein.22 The inference is that tures of map-dot-fingerprint disorder, in which an inherited basis mutated keratoepithelins, diffusing predominantly from the epithe- may be suspected; but, in the absence of a family history, the lium, coaggregate with an assortment of other proteins over a long likelihood of finding features in family members is small. period of time to form the deposits characteristic of the disorder. The aggregation process may also involve some environmental Meesmann’s Epithelial Corneal Dystrophy influences, as suggested by a report in which recurrence of GCD This is a rare, juvenile, autosomal dominant disorder with in- in a patient who had been grafted bilaterally only occurred in the complete penetrance, which was first described by Pameijer in cornea that was not subjected to postoperative contact lens wear.23 1935,30 and later, more fully, by Meesmann and Wilke.31 In its LCD is characterized by the formation of intracorneal amyloid most developed form, the corneal epithelium of each eye is stud- deposits. Some, but not all, of the mutations occurring at the codon ded with minute (10–50 ␮m), spherical microcysts, disposed with 124 hot spot appear to induce structural changes that favor amyloid varying symmetry. Distribution may be random, whirled, sectoral, formation. But mutations at eight other sites have also been re- interpalpebral, or unilateral. Vision may be unaffected or there sponsible (Table 1). Amyloid itself is not a single chemical entity may be attacks of discomfort and visual disturbance in the fourth and is encountered in a wide variety of chronic disorders. There are or fifth decade. Pedigrees are described with a more severe form of at least 16 forms of amyloid; each form is chemically different but the disorder.32 shares a tertiary structure that is rich in B-pleated sheets. It is this Ultrastructural studies have shown irregular basal laminar thick- feature that is responsible for its staining properties and for the ening, epithelial disorganization with frequent mitoses, and intra- typical birefringence in polarized light. It appears that mutations epithelial microcysts. The presence of an electron-dense “peculiar leading to the keratoepithelin LCDs favor the formation of kera- substance”33 is now recognized to be the morphologic counterpart toepithelin-amyloid. However, other materials are also found of an aggregated, mutated cytokeratin. Meesmann’s dystrophy has within aggregates, including amyloid P protein24,25 and native gel- been shown to be caused by mutations in genes (KRT3 at 12q13 solin.26 In Avellino dystrophy where both granular and lattice and KRT12 at 17q12) encoding two, cornea-specific cytokeratins lesions occur in combination, the granular lesions appear earliest (CK 3 and CK12, respectively).34,35 Mutations in KRT12 have and the lattice lesions appear later in the course of the disease. This been reported in the highly conserved, alpha-helix, initiation, or is a reminder that earlier histologic accounts of GCD drew atten- termination domains of the gene, which are regarded as essential tion to the occasional presence of amyloid among the deposits.27 for cytokeratin filament assembly.35 Not surprisingly, given the In summary, these disorders are thought to be due to the diffu- epithelial origin of the dystrophy, the condition has been reported sion of mutated keratoepithelin proteins from the corneal epithe- to recur after corneal grafting.36 lium where they originate, across Bowman’s layer and the stroma, A mutation in KRT 12 has been described in affected members

Cornea, Vol. 19, No. 5, 2000 GENETICS OF THE CORNEAL DYSTROPHIES 701 of the more severe, Stocker and Holt variety of Meesman dystro- local ocular disease, such as uveitis, rather than to the more pe- phy.37 ripheral forms associated with hypercalcemia. Calcareous band- keratopathy may occur as a secondary change in other inherited 43 Epithelial Rosette Dystrophy disorders, such as Norrie’s disease and congenital hereditary 8 This is a bilateral disorder described in a mother and two daugh- endothelial dystrophy (CHED). ters that is characterized by sparse, tiny, elevated, focal, poorly- staining epithelial lesions with a rosette appearance. The locations Honeycomb Corneal Dystrophy of the lesions alter, so that over a period of time, they may be Thiel and Behnke44 described an autosomal dominant dystrophy found in any region, except the far periphery. The condition may affecting Bowman’s layer in 55 members of a family traced over cause minor irritation without visual loss and appears to be non- 11 generations. The dystrophy presented in childhood with infre- 38 progressive. quent recurrent erosions in early life, which petered out in the fourth decade. A characteristic, bilateral, honeycomb arrangement Map-Dot-Fingerprint Dystrophy of subepithelial corneal opacities appeared between the ages of This is a bilateral epithelial disorder, characterized by a dis- 10–20 years, affecting all but a peripheral 1–2 mm of the cornea. turbed synthesis of the epithelial basal lamina. Linear prolonga- The opacities increased with time but did not affect stroma deep to tions of basal laminar material give rise to the fingerprint lines of Bowman’s layer. Generally, the corneal surface was smooth, sen- the disorder, whereas sheet-like extensions explain the presence of sation was normal, and vision was reduced only a moderate maps. The epithelium may be almost doubled in thickness in the amount. Nonetheless, corneal grafting may be indicated in some region of the maps, due to the presence of a two-tiered epithelium, patients. a feature readily detected by fluorescein. Epithelial microcysts, Confusion has arisen regarding this condition and the superficial trapped behind sheets of intraepithelial basal lamina, are respon- corneal dystrophy originally described by Reis45 and Bu¨cklers.46 sible for the white dots of the disorder. These large and smoothly The latter condition was described as disorder presenting in child- rounded microcysts, packed with degenerate epithelial cells, show hood that was associated with frequent recurrent erosion attacks, a degree of opacity quite distinct from the microcysts of traumatic progressive subepithelial opacification, and severe visual loss. recurrent corneal erosion. Thickenings of basal lamina at the basal Weidle47–49 indicated that the condition described by Reis and aspect of epithelial basal cells give rise to other features, visible as Bu¨cklers is a superficial form of GCD, sometimes termed geo- net and bleb patterns. The disorder is associated with defective graphic GCD, whose ultrastructural hallmark, as in other forms of epithelial attachment that is responsible for recurrent erosion at- GCD, is the presence of pseudocrystalline, rod-shaped deposits.50 tacks. The majority of cases are sporadic, but the condition has Many early reports of “Reis-Bu¨cklers’ dystrophy,” actually de- been reported as a dominant disorder.39 scribe the Thiel-Behnke condition, characterized by the ultrastructural presence of electron-dense, “curly filaments.” Okada et al.51 reported a BIGH3 mutation (Arg555Glu) in a patient with clinical, DYSTROPHIES OF BOWMAN’S LAYER AND honeycomb dystrophy; therefore, this dystrophy may be accepted THE STROMA as one of the keratoepithelin dystrophies. It is likely that at least some of the mutations attributed to “Reis-Bu¨cklers’ dystrophy” in Bowman’s layer, the anterior limiting membrane of the cornea, the past will be reassigned to Thiel-Behnke dystrophy. Recently, is an acellular collagenous layer, which is destroyed in several affected members in a family with Thiel-Behnke dystrophy have forms of corneal dystrophy and is irregularly replaced by scarring been mapped to chromosome 10q23-24, which does not carry the or specific deposits. The changes induced are secondary to events keratoepithelin gene.52 Thus, it appears that mutations in at least occurring in the epithelium or subjacent stroma, so that, in this two separate genes can give rise to the Thiel-Behnke phenotype, an sense, there are no primary dystrophies of Bowman’s layer. example of genetic heterogeneity in the corneal dystrophies. Grayson-Wilbrandt dystrophy is an autosomal dominant, ante- Anterior Crocodile Shagreen rior-limiting membrane dystrophy, resembling Thiel-Behnke dys- The sporadic occurrence of an axial, mosaic disturbance at the trophy in appearance. Onset is late, at the end of the first decade, 53 level of Bowman’s layer was first described by Vogt40 in an 80- and there are mild recurrent erosion symptoms. The extent of year-old man who showed flat, gray polygonal opacities at this subepithelial opacity is variable in different family members and level. The effect on vision was small. It has also been reported as vision ranges from 20/20 to 20/200. a dominant disorder over two generations41 and in a family in which the father exhibited a band keratopathy and the son, croco- Primary Gelatinous Drop-like Dystrophy dile shagreen, calcified as in band keratopathy itself. Anterior GDLD is an autosomal recessive disorder reported chiefly from crocodile shagreen has been associated with megalocornea, which Japan, but also sporadically and in affected families outside of is inherited as an X-linked trait. Japan. It has recently been mapped to chromosome 1p where mutations have been detected in the M1S1 gene encoding a tumor- Inherited Band-Shaped Keratopathy associated antigen. The mutations (Q118X, 632delA, Q207X, and Inherited band-shaped keratopathy may occur as a bilateral dis- S170X0) result in a form of corneal amyloidosis.54 Mutations in order presenting at birth, puberty, or in later life. It was found in the keratoepithelin gene55 or the gene for lactoferrin56 have been three out of nine siblings in a family reported by Streiff and excluded as a basis for this disease. Zwahlen42 and in two brothers, aged 66 and 71 years. The appear- GDLD presents in the first or second decade of life with mul- ances correspond to those found in band-keratopathy secondary to tiple, bilateral, mulberry-like, superficial, axial elevations of the

Cornea, Vol. 19, No. 5, 2000 702 A.J. BRON

TABLE 1. Corneal dystrophies

Dystrophy Inherit Locus Mutation Reference Epithelial Dystrophies Recurrent corneal erosion AD Franceschetti28 Meesmann (KRT3 gene) AD 12q13 Glu509Lys Irvine et al.34 (KRT12 gene) AD 17q12 Val143Leu Irvine et al.34 Arg135Gly Nishida et al.35 Arg135Thr Nishida et al.35 Arg135Ile Nishida et al.35 Tyr429Asp Nishida et al.35 Leu140Arg Nishida et al.35 Stocker-Holt 17q12 Arg19Ile Klintworth et al.37 Rosette dystrophy AD Bron and Burgess38 Map-dot-fingerprint AD Laibson and Krachmer39 Dystrophies of Bowman’s layer and the stroma Anterior crocodile shagreen AD Kopsa and Marusic41 Band keratopathy AD Streiff and Zwahlen42 Thiel-Behnke (␤ig-h3 gene) AD 5q31 Arg555Gln Okada et al.51 Thiel-Behnke (mapped) AD 10q23-q24 Yee et al.52 Grayson-Wilbrandt AD Grayson and Wilbrandt53 GDLD AD 1p Gln118X Tsujikawa et al.54 (M1S1 gene) 1p 632delA 1p Gln207X Familial corneal scarring AD Hirst et al.61 Subepithelial mucinous dystrophy AD Feder et al.62 Granular dystrophy (BIGH3) Type I AD 5q31 Arg555Trp Munier et al.15 Okada et al.51 Korvatska et al.14 Konishi et al.70 Othenin-Girard et al.180 Yamamoto et al.74 Fujiki et al.17 Mousala et al.181 Type II (Avellino) AD 5q31 Arg124His Munier et al.15 Mashima et al.182 Okada et al.51 Konishi et al.70 Korvatska et al.14 Sommer et al.16 Othenin-Girard et al.180 Yamamoto et al.74 Fujiki et al.17 Mousala et al.181 Type III GCD (geographic) AD 5q31 Arg124Leu Sommer et al.16 Okada et al.51 Dighiero et al.183 Mashima et al.184 Mousala et al.181 Fujiki et al.17 Yamamoto et al.74 Arg555Gln Munier et al.15 Fujiki et al.18 Korvatska et al.14 Othenin-Girard et al.180 Yamamoto et al.74 Mousala et al.181 LCD Type I (␤ig-h3) AD 5q31 Arg124Cys Munier et al.15 Mashima et al.182 Meins et al.185 Gupta et al.186 Sommer et al.16 Korvatska et al.14 Othenin-Girard et al.180 Yamamoto et al.74 Fujiki et al.17 Mousala et al.181 Arg124Leu Mashima et al.182 Leu518Pro Yamamoto et al.74 Endo et al.187 Ala546Asp Sommer et al.16 Pro551Gln Sommer et al.16 Type II (Meretoja syndrome) (gelsolin) AD 9q34 Asp187Asn Hiltunen et al.82 de la Chapelle et al.188 Steiner et al.84 Asp187Tyr de la Chapelle et al.188 Type III AR

(Table 1 continues)

Cornea, Vol. 19, No. 5, 2000 GENETICS OF THE CORNEAL DYSTROPHIES 703

TABLE 1. (Continued)

Dystrophy Inherit Locus Mutation Reference Type IIIA (␤ig-h3) AD 5q31 Pro501Thr Yamamoto et al.19 Yamamoto et al.74 Kawasaki et al.60 Ala622His Stewart et al.75 His626Ala Stewart et al.75 Type IIIA-like (␤ig-h3) AD 5q31 Ser538Cys Othenin-Girard et al.180 Type IV—deep (␤ig-h3) AD 5q31 Leu527Arg Fujiki et al.18 MCD Type I AR 16q21 Vance et al.93 Type IA AR 16q21 Klintworth et al.189 Type II AR 16q21 Jonasson et al.190 Klintworth et al.189 Liu et al.94 Central crystalline (Schnyder) AD 1p36 Shearman et al.95 Marginal crystalline (Bietti) AD Lee et al.98 Marginal crystalline (Barraquer) AD Barraquer99 Central cloudy AD Francois100 Speckled corneal dystrophy AD Francois Neetens101 Progressive dystrophy AD Waardenburg Jonkers103 Pre-Descemet’s dystrophies AD Paufique Etienne104 With itchyosis XR Xp22.32- Alperin Shaprio4 Posterior amorphous dystrophy AD Grimm et al.105 Enodothelial Corneal Dystrophies Posterior polymorphous dystrophy AD 20q11 Heon et al.110 Congenital hereditary endothelial Type I AD 20p Toma et al.117 Type II AR 20tel Hand et al.118 Corneal guttata With anterior polar cataract AD Dohlman121 Late hereditary endothelial dystrophy AD Ectatic corneal dystrophies Keratoconus AD 21 Rabinowitz et al.146 AR Developmental corneal disorders Megalocornea-with arcus, mosaic XR Xq12-26 Mackey et al.162 dystrophy, and cataract XR Xq21-q22 Meire et al.163 Megalocornea-with congenital miosis AD Meire and Delleman191 Megalocornea-mental retardation syndrome AD Barisic et al.165 Peters anomaly (PAX6) AD 11p13 Val → Asp Azuma et al.172 codon 7 exon 5a (RIEG1) AD 4q25 Doward et al.173 Chromosomal abnormalities 5p Partial trisomy Dichtl et al.192 Autosomal Dominant Kerititis (PAX6) AD 11p13 Splice acceptor site Mirzayans et al.170 exon 11 cornea, due to subepithelial accumulations of amyloid. It has been Subepithelial Mucinous Corneal Dystrophy reported unilaterally in a patient presenting later in life, at the age An autosomal dominant corneal dystrophy was described with of 61 years. Epithelial permeability is increased over the lesions frequent recurrent corneal erosions in the first decade followed by and they accumulate lactoferrin and other tear proteins. Symptoms decreased vision in adolescence.62 Biomicroscopy showed bilat- include photophobia, irritation, redness, and blurred vision. The eral, subepithelial haze that is densest axially but that affects the condition progresses to invade the anterior stroma and causes pro- entire corneal extent. Structural studies demonstrated a subepithe- found visual loss by the age of 20 years. Recurrence is the rule lial band of eosinophilic material staining positively with periodic after corneal grafting. acid–Schiff reagent, which was Alcian blue-positive and hyaluron- There is an uncertain relationship between this condition and idase-sensitive. Immunohistochemical studies supported the pres- primary spheroidal degeneration of the cornea, which is usually ence of a combination of chondroitin-4 sulfate and dermatan sul- regarded as an age-related degeneration. However, spheroidal de- fate in the deposits. The condition was said to resemble Grayson- generation has been described in a familial form57,58 and has been Wilbrandt dystrophy. reported in combination with GDLD.59,60 The association may be fortuitous. Granular Corneal Dystrophy GCD is an autosomal dominant, keratoepithelin dystrophy with Familial Corneal Scarring 100% penetrance.63 It is characterized by bilateral, symmetrically Hirst et al.61 reported bilateral, localized, opaque, nodular el- grouped, breadcrumb-like stromal opacities separated from one evations of the cornea in a patient with corneal anesthesia and dry another and from the limbus by clear stroma. Initially, subepithe- eyes. Similar lesions were found in four additional members of the lial lesions are flattened and placoid in appearance and opacities family in the absence of corneal anesthesia. Histologically, the increase in number and size with age. Weidle47,48 has documented appearances were of nonspecific, corneal scarring. an early-onset form (in 60% of his series) that presents in child-

Cornea, Vol. 19, No. 5, 2000 704 A.J. BRON hood with erosive attacks and leads to significant visual loss disorder characterized by recurrent corneal erosions and the onset (20/40 or worse) after the age of 40 years. A milder form, with of visual failure between the fourth to sixth decade. Lattice-like superficial discoid lesions and stellate stromal lesions, presents in lines are characteristically thick and ropy, like the lines of LCD III the second decade of life. Klintworth1 uses the abbreviation GCD (see Lattice Dystrophy Type III section below). Amyloid deposits I to describe the classical stromal form of GCD, GCD II to de- are found in the anterior to mid-stroma, including deposits between scribe granular-lattice (Avellino) dystrophy, and GCD III to de- Bowman’s layer and the stroma, also resembling those found in scribe “true” Reis-Bu¨cklers’ dystrophy, This severe, superficial, or LCD III.73 Mutations have been demonstrated in ␤ig-h3 at codon geographic variant presents in infancy with painful erosions and is Pro501Thr.19,60,74 The mutated protein colocalizes with amyloid associated with fine granular, subepithelial opacities that spread deposits in corneal specimens. Stewart et al.75 described a variant and become confluent with time.64 of LCD IIIA due to ␤ig-h3 mutations at Asn622His and Severe, early-onset, superficial forms of GCD have also been His626Arg with onset between the fourth and fifth decades. Af- described as a homozygous manifestation in the offspring of a fected members exhibited marked asymmetry between the two consanguineous marriage in which both affected parents suffered eyes, with lattice changes occurring in those corneas that had from a milder form of the disease.65,66 The absence of nonocular suffered recurrent erosions. The authors emphasize that keratoepi- disease in affected children reinforces the view that keratoepithelin thelin is expressed during corneal wound healing76 and is induc- does not play a critical role in noncorneal tissues. The homozygous ible by TGF-␤, which plays an important role in epithelial wound form is associated with early recurrence after surgery.51 healing.77 This observation is important because it implies that although the mutations may be directly responsible for defective epithelial adhesion, the lattice-like stromal lines may depend on a LATTICE CORNEAL DYSTROPHIES reactive response to the erosions, possibly involving over- The LCDs, including Avellino dystrophy, derive their name expression of the mutated protein by the epithelium in response to from the presence of branching, refractile, amyloid-containing fila- injury. This may have implications for clinical management. A ments in the corneal stroma. further, dominant form of late-onset, deep LCD (LCD IV) due to a Leu527Arg mutation was described by Fujiki et al.17 Avellino Dystrophy Granular-lattice, or Avellino dystrophy, is an autosomal domi- Lattice Dystrophy Type III nant corneal dystrophy expressing both the clinical and histologic LCD III is an autosomal recessive disorder, first described in a features of GCDs and LCDs. As noted earlier, Klintworth1 clas- Japanese pedigree. It is associated with relatively thick, mid- 78,79 sifies the dystrophy as a GCD, GCD II. The original families can stromal, lattice-like lines that extend from limbus to limbus. 80 be traced to the Campania region of Northern Italy, which includes Recurrent erosion is relatively infrequent and the condition the town of Avellino.67,68 Since these early reports, the dystrophy presents between the ages of 60 and 80 years. The gene has not yet has been reported from many countries and, in Japan, it appears to been mapped. be more common than LCD itself.69,70 Avellino dystrophy is caused by an Arg124His mutation in the keratoepithelin Lattice Dystropy Type II gene.15,66,71 The dystrophy presents in the first and second decade LCD II is an autosomal dominant form of LCD, which accom- of life with flat, subepithelial, or crumblike stromal lesions. Lattice panies the Finnish type of familial systemic amyloidosis of the lines appear in later life. The proportions of each type of lesion Meretoja syndrome or type IV familial polyneuropathy.81 It occurs vary widely within a sibship. The disorder is milder than LCD I. due to mutations in the gelsolin gene (Asp187Asn and Asp187Tyr) Vision varies between 20/20 and 20/400 and may sometimes war- that is located on chromosome 9q34.82–84 Paunio et al.85 have rant keratoplasty. Recurrent corneal erosions are infrequent. A demonstrated that cells of neural origin have a greater ability to homozygous form of the dystrophy is a severe disorder presenting process mutant gelsolin into an amyloid precursor protein than by the age of 6 years and leading to keratoplasty in the first or nonneural tissues, which may be relevant to the clinical manifes- second decade.18,51,66 tations of the disorder. Patients exhibit a progressive cranial and peripheral neuropathy with dry skin, blepharochalasis, protruding lips, and a mask-like facies. Lattice-like lines, thicker but less KERATOEPITHELIN LATTICE DYSTROPHIES dense than those of LCD I, appear in the corneal stroma after the LCD I is the classic form of LCD, inherited as an autosomal age of 20 years, spreading centripetally from the limbus. Erosive dominant trait. It presents at the end of the first decade with erosive symptoms may be a presenting feature in the third decade of life. symptoms and visual difficulty. Lattice-like lines occur anteriorly Visual loss is late and is aggravated by the effects of lagophthal- mos. and axially and spread posteriorly and centrifugally with time, 86 leaving the peripheral 1-mm clear. Erosive attacks are associated Tsunoda et al. described a nonfamilial form of amyloid A with increasing central stromal clouding, visual loss, and loss of amyloidosis in conjunction with LCD, polyneuropathy, and a pro- corneal sensation. Keratoplasty is frequently indicated. In two sis- found autonomic neuropathy. The disorder showed some similari- ters grafted for LCD I, Brodovsky and Taylor72 reported the oc- ties to the Meretoja syndrome. currence of macro-erosions on the grafts in the absence of clinical recurrence. LCD I may be caused by mutations at codon 124 and Macular Corneal Dystrophy at several other sites along the keratoepithelin gene (Table 1). MCD is an autosomal recessive disorder characterized by dif- Late-onset forms of the keratoepithelin LCDs have been de- fuse stromal corneal clouding that appears in the second 5 years of scribed, including LCD IIIA, which is an autosomal dominant life. Unlike the situation in the keratoepithelin dystrophies, the

Cornea, Vol. 19, No. 5, 2000 GENETICS OF THE CORNEAL DYSTROPHIES 705 corneal changes extend to the corneal limbus, without a clear zone. proteins.98 An inherited marginal crystalline dystrophy has been With time, the opacity increases in density and is accompanied by reported in the absence of retinal changes.99 dense superficial macules, which elevate the corneal surface and contribute to the visual loss. Thinning of the cornea occurs, which Central Cloudy Stromal Dystrophy 87 is attributed to a decreased separation of collagen fibrils and This takes the form of a cloudy, axial, posterior stromal haze possibly to altered swelling properties of the stromal gly- broken up into diffuse blocks by intervening clear tissue.100 The cosaminoglycans. Vision fails significantly by the second to third appearance probably has the same basis as Vogt’s crocodile decade and keratoplasty may be indicated by the third to fifth shagreen. The condition has been described in siblings in two 88 decade. Recurrence after keratoplasty is rare. In some individu- families. Vision is unaffected. als, late presentation in the fifth or sixth decade occurs and keratoplasty is delayed accordingly.89,90 Speckled Corneal Dystrophy MCD is a disorder of glycosaminoglycan metabolism involving This congenital, stationary, autosomal dominant disorder has a keratan sulfate and accompanied by abnormal intra- and extracel- distinctive appearance, with small, translucent, discoid opacities lular deposition of proteoglycans. Two major forms of MCD exist. scattered sparsely throughout otherwise clear stroma.101 There is The majority of patients have MCD I, in which neither the cornea no effect on vision. It has been reported with cloudy dystrophy in nor the serum contains normally sulfated keratan sulfate, deter- different members of the same family.102 mined by antibodies directed against sulfated keratan sulfate. In MCD II, there are normal amounts of antigenic keratan sulfate in both the serum and the cornea.91 Both subtypes may be found Progressive Corneal Dystrophy 103 within the same pedigree, suggesting that they may be variants of Waardenburg and Jonkers described an autosomal dominant dystrophy starting in childhood with painful attacks in the first the same disorder. In MCD IIA, there is immunochemical evidence of keratan sulfate in the cornea but not serum keratan sulfate. It has year of life and accompanied by reduced visual acuity and corneal been suggested that MCD may be due to a defect in a keratan sensation. Fine snowflake or hailstone stromal opacities increase in sulfatase, but detailed evidence is still lacking. Hasegawa et al.92 number with age and finally affect the epithelium. found no abnormality of serum sulfotransferase activity in patients with MCD. MCD has been mapped to chromosome 16q22.93,94 Pre-Descemet’s Dystrophies Various forms of pre-Descemet’s change have been described with particular attention to the varied morphology of the opacities CRYSTALLINE STROMAL that occur. Cornea farinata is common in the older population, so CORNEAL DYSTROPHIES that an inherited form is still uncertain.104 A deep punctiform A small number of crystalline stromal dystrophies are described, change is reported as part of the X-linked form of ichthyosis, a of which Schnyder’s corneal dystrophy is the most common. condition resulting from mutations in the gene for steroid sulfatase.4 Central Crystalline Corneal Dystrophy Schnyder’s crystalline corneal dystrophy is a bilateral, autoso- Posterior Amorphous Corneal Dystrophy mal dominant dystrophy showing a discoid or ring-shaped accu- Posterior amorphous corneal dystrophy is a congenital, bilateral mulation of polychromatic needles in the anterior stroma beneath autosomal dominant corneal disorder characterized by a sheet-like a smooth epithelium. It is variably accompanied by a presenile opacification of the posterior stroma extending across its width. It lipid arcus. The deposited lipid is chiefly unesterified cholesterol is associated with corneal flattening, variable thinning, and sometimes progressive ectasia.105,106 The endothelium is normal. and phospholipid, with sphingomyelin being the predominant 105 phospholipid. Schnyder’s dystrophy is usually, but not always, Grimm et al. proposed that it is a form of corneal dysgenesis. highly symmetrical. There may be slow progression and a development of a stromal haze, and some family members may show ENDOTHELIAL CORNEAL DYSTROPHIES crystal-free opacities alone. An association with hyperlipoprotein- emia in some pedigrees is unexplained but probably reflects that Posterior Polymorphous Corneal Dystropy the dystrophy is a disorder of lipid metabolism and that there may This bilateral, but often asymmetrical, endothelial dystrophy is be local or systemic forms. The dystrophy has been mapped to inherited as an autosomal dominant disorder. It is often asymp- chromosome 1 (1p34-p36) to a region that bears a gene whose tomatic and diagnosed by chance; but, when involvement of the 95 product is associated with lipid metabolism and transport. endothelium is extensive, there may be progressive corneal edema, leading to visual loss and necessitating keratoplasty.107 Early onset Marginal Crystalline Corneal Dystrophy of corneal edema is occasionally recorded.108 Features include Bietti crystalline dystrophy is an autosomal recessive tapetoreti- circumscribed vesicular, snailtrack, and diffuse changes at the nal degeneration characterized by glittering intraretinal and peril- level of the endothelium with characteristic appearances on specu- imbal corneal lipid inclusions.96,97 There is progressive develop- lar microscopy. Posterior polymorphous corneal dystrophy has ment of night blindness, field constriction, and pigmentary retinal been regarded as a disorder of neural crest endothelial cells, giving change, succeeded by choriocapillary atrophy. The amplitude of rise to a progeny that has some structural and immunohistochem- the electroretinogram is reduced. The disorder is thought to in- ical features of epithelial cells.109 Like CHED type I, the condition volve a defect in lipid metabolism, and lymphocytes from patients maps to the pericentromeric region of chromosome 20,110 raising with this disorder have been shown to lack two fatty acid-binding the question of whether the conditions may be allelic. Blood rela-

Cornea, Vol. 19, No. 5, 2000 706 A.J. BRON tives of patients with posterior polymorphous corneal dystrophy dence of increased proteolytic activity in keratoconus cornea and may have CHED I. changes in proteoglycan composition, which may explain the evo- lution of the disease. Zhou et al.126 demonstrated increased ca- Congenital Hereditary Endothelial Dystrophy thepsin B and G activity in affected corneas and associated gelati- CHED is inherited in recessive and dominant forms.111–113 In nase and caseinase activity, shown in situ by zymography. An each form, corneal edema results from a failure of endothelial increased activity of gelatinase A, released by corneal fibroblasts function.114 The dominant form (CHED I), presents in infancy; from keratoconus corneas, has also been reported.127 Other studies and, although the severity varies, it may progress to cause pro- have shown a marked decrease in the immunolocalized anti- found visual loss. Corneas are clear at birth and nystagmus is proteases, ␣1–anti-protease and ␣2–macroglobulin, at the level of absent. The recessive form (CHED II) is present at birth or devel- the epithelium in keratoconus. The decrease in ␣2–macroglobulin ops in the neonatal period. It shows minimal progression but is has been confirmed by western blot assay.128 There is no evidence usually of sufficient severity in infancy to induce nystagmus and of increased matrix metalloproteinase activity in keratoconus cor- amblyopia. Both forms have been treated successfully by corneal neas; and, apart from a focal decrease in the tissue inhibitor of grafting.115,116 The gene for CHED I has been mapped to a peri- metalloproteinase type 3 confined to breaks in Bowman’s layer, no centromeric region of chromosome 20 (20p11.2-q11.2) in an area general decrease in the tissue inhibitor of metalloproteinase 117 overlapping the gene for posterior polymorphous dystrophy. A (TIMP) activity has been found. The earliest ultrastructural studies gene for CHED II has been mapped to the telomeric portion of the of keratoconus suggested that its development might be related to 118 same chromosome. A study using homozygosity mapping and changes in the corneal epithelium. Such changes would be in keep- linkage analysis has confirmed that autosomal recessive CHED is ing with the view that excessive eye rubbing or atopic eye disease genetically distinct, both from dominant CHED and from posterior might induce keratoconus by inducing epithelial damage. 119 polymorphous corneal dystrophy. Baum,129 recalling that corneal epithelial cells originate at the limbus and age as they migrate centripetally, has suggested that the Cornea Guttata periaxial location of the cone apex reflects the greater age and This is a disorder of the corneal endothelium characterized by vulnerability of epithelial cells in this region. numerous fine excrescences in Descemet’s membrane that appear Wilson et al.130,131 has provided a plausible link between epi- axially and that spread to the periphery with age. It is common in thelial events and stromal tissue loss through an interleukin 1 the general population, with an equal gender incidence and a (IL-1)-dependant mechanism. Keratocytes possess IL-1 receptors 120 prevalence that increases with age. Cornea guttata is associated and their number is increased 4-fold in keratoconus corneas.132 with an increase in permeability of the endothelium and may be a IL-1 is expressed by the corneal epithelium and it has been shown precursor of Fuchs’ corneal dystrophy. However, normal corneal experimentally that keratocyte apoptotic death is inducible by IL-1 thickness may be maintained for decades. It may occur as an through a fas-ligand mechanism. According to this hypothesis, autosomal dominant disorder, sometimes congenitally in associa- epithelial stress could lead to an increased keratocyte turnover and tion with anterior polar cataract.121 It has been reported in the 122 loss in the cornea and associated changes that could influence the siblings of unaffected parents. composition of the stromal matrix. Such a mechanism could har- monize our ideas of the interaction of environmental and genetic Late Hereditary Endothelial Dystrophy mechanisms in keratoconus. Although keratoconus is encountered This bilateral endothelial dystrophy (Fuchs’ endothelial dystro- chiefly as a sporadic disorder, a genetic component is well recog- phy) is associated with cornea guttata, endothelial cell loss, a dis- nized and is supported by its occurrence in monozygotic twins and torted specular mosaic, increased endothelial permeability with by reports of a positive family history in 6–15% of cases.133–135 decreased pumping function, and the progressive development of The bilaterality of the disorder (96%) and the nonsuperimposable, corneal edema. Visual loss occurs with the onset of epithelial mirror-image symmetry of the shape changes are also in keeping edema, sometimes compounded by the effects of pigmentary de- with a genetic mechanism.136 Amsler137 pointed out the occur- posits on the endothelium. Presentation is after the fourth decade. rence of formes frustes of the disorder detectable by keratometry in Overall, the condition is more common in women, in the ratio of family members. 3:1. Fuchs’ dystrophy may be inherited as an autosomal dominant Since that time, the detection of affected family members has trait and has been reported in conjunction with Leber’s hereditary been greatly facilitated by the development of modern videokera- optic atrophy, a mitochondrial disorder.123 tographic techniques and diagnostic indices capable of identifying keratoconus in the absence of other clinical signs.138 The majority ECTATIC CORNEAL DYSTROPHIES of studies support an autosomal dominant mode of inheritance with variable expression.136,139–141 Reports of keratoconus in the Keratoconus siblings of unaffected parents have also suggested the possibility Keratoconus is a bilateral, noninflammatory, corneal ectasia of recessive inheritance.142 Rabinowitz cites eight instances of with a prevalence of about 1 in 2,000 of the general population. keratoconus occurring in monozygotic twins; in two sets, the sec- The biochemical basis for this progressive corneal disorder is not ond affected twin was only diagnosed with the help of videokera- fully understood. Apart from its occurrence as a feature of Ehlers toscopy.136,143–145 In one report in which only one twin was ap- Danlos type VI, where there is a defect in lysine hydroxylation of parently affected, videokeratography had not been performed.136 collagen, collagen composition generally appears to be unaltered A gene for an autosomal dominant form of keratoconus was in unscarred, keratoconus cornea.124 A change in collagen type VI mapped to a region on chromosome 21, close to the centromere.146 expression has been noted, however.125 Nonetheless, there is evi- This is of interest, given the association between keratoconus and

Cornea, Vol. 19, No. 5, 2000 GENETICS OF THE CORNEAL DYSTROPHIES 707 trisomy 21 (Down syndrome). The prevalence of keratoconus in the corneal endothelium. These changes are frequently accompa- Down syndrome is reported variably to be between 0.5–15% (i.e., nied by iris abnormalities and cataract. Peters anomaly may be 10–300 times more common than in the general population).136 caused by PAX6 mutations in a small proportion of cases.168,171,172 Keratoconus has also been reported in association with many Azuma et al.172 detected a splice-site mutation in four pedigrees of inherited disorders, including GCD,147,148 pre-Descemet’s corneal Peters anomaly with cataract, Axenfeld anomaly, and/or foveal dystrophy,149 Leber’s congenital amaurosis,150 dominant anterior hypoplasia. A missense mutation in exon 5a resulted in a polar cataract,151 blue sclerotics,152 osteogenesis imperfecta,153 Val→Asp substitution at the 7th codon of the alternative splice Ehler’s Danlos syndrome type VI,154 the Marfan syndrome,155 and region. Exon 5a of the PAX6 gene encodes a small peptide, op- atopic eczema.156 Many of these associations are assumed to have erating a molecular switch that specifies different target genes. occurred by chance, although the high frequency in Leber amau- Insertion of the peptide into the N-terminal subdomain of the rosis (up to 30% in those who are >15 years old) suggests that a paired box abolishes the DNA-binding activity of this domain and genetic mechanism may still be a possibility. The proposal that unmasks the binding activity of the C-terminal subdomain. Peters keratoconus in Leber disease is the consequence of frequent eye anomaly has also been reported to result from a splice-site muta- rubbing in these blind children (the oculo-digital sign) was not tion in the gene for unilateral Rieger syndrome (RIEG1-4q25).173 borne out in a study by Elder157 who confirmed the high frequency of keratoconus in children with Leber amaurosis in comparison to Autosomal Dominant Keratitis its frequency in children with other forms of blindness. A high Pearce et al.169 described autosomal dominant keratitis as a incidence of mitral valve prolapse in patients with keratoconus (up circumferential, anterior stromal, perilimbal, corneal opacification to 58%) has suggested that keratoconus might be part of a gener- 158,159 with vascularization and histologic signs of inflammation. There is alized connective tissue disorder. A similar proposal, made centripetal progression in some cases. Foveal hypoplasia is re- with respect to the finding of joint hypermobility in keratoconus 160 ported in both aniridia and autosomal dominant keratitis. In the patients, has not been supported by more recent studies. family reported by Mirzayans et al.,170 a splice-acceptor site mutation in exon 11 of the PAX6 gene was assumed to be responsible DEVELOPMENTAL CORNEAL DISORDERS for truncation of the proline-serine-threonine activation domain of the gene product. Megalocornea Megalocornea is a congenital condition of corneal enlargement, not associated with raised intraocular pressure in which the hori- TREATMENT OF THE CORNEAL DYSTROPHIES zontal diameter of the cornea exceeds 13 mm, ranging 13–16 mm. The corneal radius is shorter than normal and the anterior chamber There are no specific medical therapies for the corneal dystro- is consequently deep, with the iris–lens diaphragm displaced back- phies. Topical, hypertonic sodium chloride may offer limited vi- 161 sual assistance in the early stages of Fuchs’ dystrophy; and, simi- wards at the expense of the vitreous space. It occurs as an larly, bandage contact lenses may provide visual and symptomatic X-linked recessive disorder associated with lipid arcus, corneal support in Fuchs’ dystrophy and the anterior-limiting membrane mosaic dystrophy, pigment dispersion, and cataract and has been 162,163 dystrophies. In the past, lamellar or penetrating keratoplasty has mapped to the long arm of the X chromosome (Xq21.3-q22). provided the only long-term treatment of those forms of corneal It has also been described as an autosomal dominant disorder, with dystrophy giving rise to significant visual loss. Lamellar kerato- four affected members in two generations, associated with iris plasty has been favored by some in those situations where the stromal hypoplasia, miotic pupils, and defects in the pigment epi- endothelium is not affected in the disorder,174 thelium. One family member exhibited buphthalmos and a germ- such as keratoconus 164 or the anterior limiting membrane disorders. However, recurrences line mutation was mooted as a possible basis at that time. An of the dystrophy, particularly of the keratoepithelin dystrophies but autosomal recessive syndrome of megalocornea, psychomotor re- also in GDLD, has led to a search for other modes of treatment that tardation, seizures, hypotonia, short stature, and dysmorphism is 165 can be repeated and that carry less risk. This need has been satis- described. fied in part by the use of PTK, which has been used successfully in the treatment of granular-, lattice-, and anterior-limiting mem- PAX6 DISORDERS brane dystrophies and in GDLD and various causes of recurrent corneal erosion, including map-dot-fingerprint disorder.175,176 The PAX6 gene, located on chromosome 11p13, is involved in Success has also been reported in the treatment of MCD.177 Vision ocular morphogenesis. It encodes a transcriptional regulator that has been improved and the frequency of painful attacks has been recognizes target genes through its paired-type DNA-binding do- reduced by such treatments, although there is some risk of induc- 166 main. Mutations affecting the paired box region of the gene lead ing a hypermetropic shift.178 Such treatment has the attraction of to many congenital developmental abnormalities, including anirid- offering almost immediate benefit to the patient, although, as with 167 168 ia, Peters anomaly, autosomal dominant keratitis, and famil- keratoplasty, there is an expectation (e.g., in the keratoepithelin 169,170 ial foveal hypoplasia. In general, the disorders result from a dystrophies) that the dystrophy will recur as early as 30 months haplo-insufficiency of the gene, i.e., an absence of one functional after surgery,179 or certainly by 47 to 7 years63 after surgery. Early copy. Variable expression is common in these disorders. recurrence after PTK for GDLD and in the homozygous forms of the keratoepithelin dystrophies is also reported. PTK can be re- Peters Anomaly peated a limited number of times. Epithelial abrasion as a mode of Peters anomaly is an autosomal dominant, congenital corneal therapy, based on the same principles, has proved disappointing opacity with defects in the posterior stroma, Descemet’s layer, and because of an accelerated progression after recurrence.21,179

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