Corneal dystrophies are fascinating to the ophthalmologist because of their striking clinical appearance and often challenging management. The corneal dystrophies likewise clearly hold a great deal of interest for affected patients and families. Their interest obviously is not based on fascination but rather on concern about the visual prognosis for themselves and prospects for involvement among their children.

The purpose of this chapter is to review each of the corneal dystrophies with particular emphasis on their inheritance pattern as well as their clinical presentation, appearance, and course. It is hoped that this will form the basis for intelligent diagnosis and treatment as well as rational discussion and counseling for patients and their families. Table 1 provides a quick reference detailing the inheritance pattern, mode of disability, treatment, and degree of visual disability for each of the corneal dystrophies.

TABLE ONE. Corneal Dystrophies: Summary of Inheritance, Mode of Disability, Treatment, and Extent of Visual Disability

EPITHELIAL BASEMENT MEMBRANE DYSTROPHY

Epithelial basement membrane dystrophy, also called map-dot-fingerprint or Cogan's microcystic epithelial dystrophy, is the most common anterior dystrophy seen by the ophthalmologist. It comprises a variety of corneal epithelial changes that were first described separately but later recognized as a spectrum of the same dystrophy.^1–16

The pattern of inheritance is not clear. It seems to follow a familial pattern. A report of autosomal dominance was described for the recurrent erosion syndrome.¹⁷ A familial pattern was described by Laibson and Krachmer in 1975.¹³ These researchers described three pedigrees including eight families in which changes were present in two generations, two families in which three generations were involved, and two families in which multiple siblings were involved. Although initial reports indicated that epithelial basement membrane dystrophy was a rare condition,³ later reports applying more careful examination techniques show a much higher prevalence, ranging from 6% to 42%^18,19 of the general population. A dominant inheritance pattern is suggested.

Epithelial basement membrane dystrophy is more common in females than in males and in whites than in other races. Patients most commonly present with typical dystrophic changes of the cornea as an incidental finding during routine examination. About 10% of patients will present with symptoms of recurrent erosions typically after age 30. Any patient presenting with recurrent erosions should have a careful examination of both eyes to search for the characteristic map, dot, or fingerprint line corneal changes.

The most common findings are the maplike opacities (Figs. 1 AND 2), which can be detected by wide oblique illumination.⁸ The dot changes (Fig. 3) are seen by direct illumination, and fingerprint lines (Fig. 4) often need indirect illumination from the iris or retroillumination for detection. The distribution of the lesions can change over time.

A separate clinical entity called dystrophic recurrent erosion was described by Chandler.² These patients present in the first decade of life with bilateral erosions. Studies of pedigrees show a dominant pattern of inheritance. The erosive attacks resolve with age, and vision is normal unless complicated by scarring. The pathologic basis of this entity is undefined.

Symptomatic patients can be treated with various modalities, which include hyperosmotic agents, lubricants, patching, and bandage contact lenses.²⁰ Since most patients respond to treatment with retention of good vision, the morbidity is low. For more severe cases debridement or anterior stromal puncture may be useful.^21,22

MEESMANN'S JUVENILE EPITHELIAL DYSTROPHY

Meesmann's dystrophy is a rare, slowly progressive, bilaterally symmetric dystrophy that develops in the first 1 or 2 years of life. Multiple tiny epithelial vesicles are detected on examination. Meesmann's dystrophy was first described by Pameijer in 1935,²³ who described many small punctate opacities in the cornea of a mother, son, the mother's sister, and two of three daughters. Only the adults had ocular discomfort and mild decrease in vision. It was recognized relatively late as a dystrophy because of minimal symptoms that did not require ophthalmologic care.

Inheritance is autosomal dominant, which has been well established in many pedigrees.²⁴ Meesmann described the condition in 1938 in two separate families.²⁵ Three nonrelated families in Germany with 34 patients were described in 1943 by Meesmann and Wilke.²⁶ For the rare case to be labeled sporadic all other available family members must be examined.

The uniform, tiny epithelial cysts have been described in a patient as young as 7 months.²⁷ These lesions gradually increase in number and density. In adults, the entire cornea is involved but the cysts are most noticeable in the interpalpebral zone. There may be a segmental pattern or a diffuse whorl distribution as well. The discrete dots are bubble like and are seen on direct illumination and retroillumination. They originate in the anterior epithelial layer and migrate to the surface. The patient is asymptomatic until middle age when the vesicles reach the surface and rupture causing irregular astigmatism with blurred vision, irritation, and photophobia. Only when the cysts rupture do they stain with fluorescein. Later, clinical findings may include lines and amorphous subepithelial opacities, which rarely require penetrating keratoplasty for improved vision. Visual acuity may be decreased to 20/40 to 20/60 and rarely to less than 20/400.²³ There are no known associated ocular or systemic findings.

When examined histopathologically, the cysts seen clinically are found most prominently in the anterior epithelium. The amorphous material within the cysts probably represents epithelial cell remnants. Histopathologic observations also show increased amounts of glycogen in the corneal epithelium. This led some observers to consider this dystrophy a glycogen storage problem. Later studies suggest that high epithelial turnover is the source of the abundant glycogen.²⁸ A characteristic fibrillar granular material called peculiar substance is seen within the cytoplasm of the epithelial cells.

A suggestion that the anterior stroma was involved in the pathogenesis was first made by Burns in 1968.²³ In 1987, Wittebol-Post and colleagues²⁹ suggested that the stroma is the cause of the dystrophy. They observed the presence of thinner corneas in affected patients in two different pedigrees when compared with nonaffected members and controls. These are statistically significant differences.

Most patients have minimal symptoms and require no treatment. In adulthood, symptomatic management may be necessary for erosive problems. In patients with severe symptoms, epithelial debridement may be indicated. Recurrence usually takes place but is usually slow and less severe. Rarely, patients may develop subepithelial scarring, necessitating a superficial, lamellar, or penetrating keratoplasty. Epithelial involvement has recurred after all of these procedures.

REIS-BUCKLERS DYSTROPHY

Reis-Bucklers dystrophy is a bilateral, symmetric central corneal dystrophy that presents in the first decade with reticular superficial corneal opacities and erosions. In 1917, Reis first described the condition in a family.³⁰ In 1949, Bucklers³¹ studied four successive generations of the family described by Reis and established the autosomal dominant inheritance. Many pedigrees have subsequently been studied, and the autosomal dominant pattern with complete and incomplete penetrance is well documented.^31–36 When patients are diagnosed with Reis-Bucklers dystrophy other family members should be examined and counseled about the autosomal dominant pattern of inheritance.

Patients typically present in the first decade of life with spontaneous painful erosions and a fine reticular superficial opacification. By the second and third decades central opacities develop in a fishnet or ringlike pattern that gradually moves out into the midperipheral cornea. A diffuse superficial stromal haze evolves with decreased corneal sensation. By age 30, erosions may decrease in frequency because of scarring but visual acuity decreases as well. Surface irregularity produces irregular astigmatism. Atrophic iris stroma, congenital corneal edema, and prominent corneal nerves may be associated.^35,37

Histopathologically, the basement membrane may be focally absent, thus accounting for the frequent epithelial erosions. Bowman's layer is replaced with a fibrocellular connective tissue that may extend into the anterior stroma. An amorphous material is part of the fibrous tissue. Ultrastructurally the amorphous material is composed of characteristic short, curled microfibrils.³⁸ The conjunctiva may also show reduplication of the basement membrane.

Management may be difficult since the erosions start at a very young age. Therapy generally consists of pressure patch, hypertonic solutions, and bandage contact lenses. As scarring develops with subsequent decrease in vision, a superficial keratectomy may be attempted, or, in more severe cases, a lamellar or penetrating keratoplasty may be performed.^39–41 Patients should be informed of the risk of recurrence in the graft.^39,41,42

Anterior membrane dystrophy and honeycomb dystrophy are clinical variants of Reis-Bucklers dystrophy.^43–46 Both are characterized by later onset, fewer erosions, and less effect on visual acuity because the epithelium remains smoother. Anterior membrane dystrophy was described in 1966 by Grayson and Wilbrandt³² in two generations of a single pedigree. Honeycomb dystrophy was documented in over 11 generations of a single pedigree by Thiel and Behnke.⁴² Clinically a characteristic honeycomb opacity develops in a subepithelial location in the second decade. Honeycomb dystrophy has been reported in a pedigree with other relatives having more typical Reis-Bucklers dystrophy⁴³

ANTERIOR MOSAIC DYSTROPHY

Anterior mosaic dystrophy is a bilaterally symmetric dystrophy that was first described by Vogt in 1930.⁴⁷ Multiple flat, gray, polygonal opacities with intervening clear spaces are seen at the level of Bowman's layer, giving a crocodile skin-like appearance to the cornea.⁴⁸ When these changes occur sporadically as a degenerative change, they are referred to as anterior crocodile shagreen. Visual acuity is generally not reduced but depends on the density of corneal changes.

Kopsa and Marusic described a dominant pattern of inheritance in two generations with anterior mosaic dystrophy.⁴⁹ In 1939, Valerio presented a family where anterior mosaic dystrophy was observed in a son whose father had band keratopathy.⁵⁰ Other ocular associations include X-linked recessive megalocornea,⁵¹ iris abnormalities⁵² with injury,⁵³ and phthisis bulbi.

INHERITED BAND-SHAPED KERATOPATHY

Band keratopathy resembling the pattern seen secondary to ocular disease has also been described as an inherited process. In inherited band keratopathy calcium deposits in Bowmans' layer in the interpalpebral region. It spreads diffusely from the limbus to form a fenestrated haze on the cornea. Visual acuity is markedly decreased.

Inherited band-shaped keratopathy has been described in both senile and infantile forms.^54–56 Opacities were detected at birth or at puberty.⁵⁶ Three of nine siblings of one family with consanguinity in their pedigree were described. In another report two brothers both older than 65 years of age had similar findings.⁵⁴

Inherited band-shaped dystrophy is an uncommon dystrophy that presents with interpalpebral keratopathy at various ages. Visual acuity may be profoundly decreased. The inheritance pattern is not well defined.

GRANULAR DYSTROPHY

Groenouw, in 1890, described two unrelated patients with “nodular corneal opacities.” He later reported a series of cases in four generations from the family of his first patient, remarking on its autosomal dominant inheritance pattern and its slowly progressive nature.^57–59

In 1938. Bucklers clarified the confusion existing about corneal dystrophies. He classified all known reported cases of hereditary dystrophy into three distinct separate categories: granular and lattice dystrophies with autosomal dominant inheritance and macular dystrophy with autosomal recessive inheritance.⁶⁰ He further concluded that Groenouw's first two patients consisted of one case of granular dystrophy (Groenouw type D and the second with macular dystrophy (Groenouw type II).

Since then. there have been numerous pedigrees with granular dystrophy documented in the literature,^61,62 the most recent and extensive one by Moller from Denmark, documenting 115 patients (91 living) in five different families. The largest family had 94 affected persons in seven generations. He confirmed the dystrophy's autosomal dominant inheritance and 100% penetrance and was able to trace the cases back to six different mutations for an estimated mutation rate of 0.3 per million.⁶³ Recent linkage analysis has suggested a possible locus for the granular dystrophy gene on the short arm of chromosome 12, but further studies are needed.⁶⁴

Other researchers have described pedigrees with granular dystrophy, albinism, and tapetoretinal degeneration.⁶⁵ Folberg and co-workers presented four cases with granular and lattice dystrophies in the same eye. All four patients could trace their families back to the Italian province of Avellino.⁶⁶ One additional patient with the same Italian heritage was described by Smith and colleagues with the triad of keratoconus, lattice, and granular dystrophies.⁶⁷ Moller and Ridgway reported a probable homozygous patient with severe granular dystrophy. This patient had an onset of the dystrophy at about 18 months of age and required two transplants in each eye before 17 years of age. She is one of three daughters of a consanguineous marriage whose parents have mild granular dystrophy not affecting vision. One other daughter has more typical mild granular dystrophy, while the third is unaffected.⁶⁸

Early on one finds bilaterally symmetric discrete white breadcrumb-like opacities (Fig. 5) within the central corneal stroma beneath Bowman's membrane. The intervening cornea is clear and vision remains normal. These “granules” usually appear within the first or second decades of life and can later coalesce to form a number of shapes, from dots to rings and radiating lines. The opacities eventually enlarge and spread to affect the peripheral and posterior stroma, clouding the once clear intervening stroma and variably decreasing vision to the 20/80 to 20/200 range by the fifth to sixth decades. The peripheral 1 to 3 mm of cornea always remains clear, differentiating this entity from macular dystrophy. Although interpedigree variations are common, members of the same family usually resemble one another.

Because of the predominant subepithelial location of the abnormal deposits, the epithelium may be irregular and epithelial erosions are possible yet infrequent. Again, painful erosive episodes may be frequent in some pedigrees and not in others (see superficial variant of granular dystrophy). Cornea hypesthesia may be present.

Histologically these granular deposits consist of eosinophilic “hyaline” and stain a bright red with Masson's trichrome.⁶⁹ Electron microscopic studies have noted an increase in the endoplasmic reticulum of the cells, cell degeneration, and clumps of elongated electron-dense bodies corresponding to the clinically apparent granules.^70,71 More recent studies have shown positive staining with Luxol-fast blue, a stain that probably binds to membrane-derived phospholipids.⁷² Immunohistologic stains have shown that some deposits contain microfibrillar proteins.⁷² This suggests to some that granular dystrophy may result from an abnormal manufacture or processing of cell membrane phospholipids or proteins.^73,74 The initial subepithelial location of these deposits early in the course of the dystrophy points toward the epithelial cell rather than the stromal keratocyte as the underlying abnormal cell.

Management consists of treating the recurrent erosions when they happen. Most patients with granular dystrophy have good vision throughout their life and do not require corneal transplantation. In those whose vision worsens, corneal transplantation is very successful. Recurrences in the graft are frequent and are seen usually from 1 to 19 years postoperatively.^75–77 Superficial keratectomy and debridement have achieved good results following superficial recurrences.⁷⁸

SUPERFICIAL VARIANT OF GRANULAR DYSTROPHY

Some controversy exists in the literature regarding this proposed subgroup of granular dystrophy (Groenouw type I). The first to give it this name was Haddad and associates, who described two cases, one in a 7-year-old boy and the other in an 18-year-old woman.⁷⁹

Like typical granular dystrophy, it is autosomal dominant and has similar electron microscopic findings. Sporadic cases are known.⁷⁹ Unlike typical granular dystrophy, it tends to present earlier in the first or second decade of life and have earlier visual impairment as well. It often presents with pain, redness, and photophobia secondary to recurrent epithelial erosion and on light microscopy may appear indistinguishable from Reis-Bucklers dystrophy.

Initially appearing as bilateral, small snowflakelike lesions in the superficial central corneal stroma, it progresses to coalescent opacification of the central anterior stroma with destruction of Bowman's membrane, epithelial irregularity and scarring, and peripheral and posterior spread. As in typical granular dystrophy, there is generally a clear corneal zone near the limbus.⁷⁹ Rodrigues and co-workers described one case of 53-year-old Japanese woman with a “superficial confluent form of granular dystrophy,” presumably offering an extreme view of this dystrophy's progressive nature.⁸⁰

Because of its early onset, atypical often reticular appearance, and frequent painful erosions, this dystrophy has frequently been confused and identified as the “geographic type” of Reis-Bucklers dystrophy.⁸¹ On light microscopy, the eosinophilic subepithelial deposits stain red with Masson's trichrome, which is true of both the deposits in Reis-Bucklers and granular dystrophy. Only the absence of deeper stromal involvement and the presence of curly filaments on transmission electron microscopy rather than electron-dense rods distinguishes Reis-Bucklers from the superficial variant of granular dystrophy.

In a review of the literature, Moller argues that the geographic form of Reis-Bucklers dystrophy is really a variant of granular dystrophy.⁸² In it he notes a study by Winkelman and co-workers that divided Reis-Bucklers dystrophy into two types based on electron microscopic findings.⁸³ The first group was “the honeycomb type” of Theil and Behnke,^42,84 which has “curly filaments” on transmission electron microscopy, and the second group was the geographic Reis-Bucklers type with “rod-shaped elements”-the same electron-dense rods as are found in classic and superficial granular dystrophy.⁷¹ In spite of the clinical similarities between Reis-Bucklers and superficial granular dystrophy, current linkage analysis has excluded a close linkage between Reis-Bucklers dystrophy (most likely on chromosome 6) and granular dystrophy.⁸⁵

Management consists of conservatively treating the erosive episodes with bland antibiotics, lubricants, patching, and occasionally bandage contact lenses. By the third and fourth decades of life, vision may have deteriorated enough owing to increased central corneal scarring, opacification, and epithelial irregularity to warrant superficial keratotomy or penetrating keratoplasty. Recurrence in the graft is common (Fig. 6).

PROGRESSIVE DYSTROPHY OF WAARDENBURG AND JONKERS

Waardenburg and Jonkers, in 1961, described 37 members of an affected family with this dystrophy.⁸⁶ Characterized by autosomal dominant inheritance, onset often in the first year of life includes painful attacks of photophobia, redness and tearing early in life and diminishing with age, and relatively good visual acuity. Many of their patients had “hailstone-like or snowflake-like opacities” in the superficial stroma while the cornea periphery remained clear. These researchers believed that this “new dystrophy” was possibly a subtype of Groenouw I or granular dystrophy. Indeed other authors have grouped this dystrophy under the heading of granular dystrophy.⁸⁷

Wittebol-Post and co-workers revisited the same family 25 years later and found 51 patients in seven generations. This time they obtained clinical pictures as well as tissues for light and electron microscopy. Their conclusion was that the progressive dystrophy of Waardenburg and Jonkers was equivalent to the honeycomb dystrophy of Thiel and Behnke^42,45,88 since their affected pedigree showed the typical curly filaments on transmission electron microscopy.

LATTICE DYSTROPHY

Lattice dystrophy, an autosomal dominantly inherited disorder, was first described by Biber in 1890. Biber presented the corneal findings in three unrelated persons, calling the abnormalities “gitterige keratitis.”⁸⁹ Haab, in 1899, expanded on these findings, documenting three additional cases within the same family.⁹⁰ His clinical description of this entity is still one of the best: “The lines… remind [s] one of twigs or the figures which one sees on a frosted window. Between the lines one sees small gray spots and points. The figures are transparent and light reflecting, so that the spots look like drops of water and the lines resemble threads of crystal.”⁹⁰ Within the same journal volume as Haab's study, Dimmer described three siblings with “gitterige keratitis” whose childhood was marked with episodic attacks of ocular pain, redness, and photophobia.⁹¹

Between 1899 and 1938, lattice dystrophy was often confused with the other autosomal dominant stromal dystrophy, granular dystrophy, because both appear quite similar early in their clinical course. In 1938, Bucklers laid to rest the debate after his survey on the corneal dystrophies, confirming three separate hereditary disorders.⁸¹ Franceschetti and Babel⁹² and Jones and Zimmerman⁶⁹ later described the histopathologic differences between these dystrophies, but it was not until the work of Seitelberger and Nemetz⁹³ and then of Klintworth⁹⁴ in the 1960s that amyloid was found to be the abnormal substance deposited in lattice dystrophy.

Lattice dystrophy has been noted as early as 2 years of age⁹⁵; however, most cases will show the first clinical signs and symptoms nearer the end of the first decade of life. Patients may come to the attention of the ophthalmologist with symptoms of recurrent erosions. Visual acuity is often very good early on; with progression of the dystrophy, vision diminishes, usually by the second or third decades of life.

Slit lamp examination of young patients may only reveal small white or refractile anterior stromal spots in the central cornea. These spots often confused early investigators, leading some to misidentify this disorder as granular dystrophy. Later, the branching icicle-like lines (Fig. 7) appear in the anterior and then posterior stromal levels. The subepithelial location of many of these deposits lead to erosion of the overlying epithelium. Subepithelial scarring with destruction of Bowman's membrane then may take place allowing further opacification of the cornea and obscuration of the original lattice pattern. With further scarring, erosive episodes are less and corneal hypesthesia occurs.⁷⁴ Other patients may have deeper stromal involvement, fewer epithelial erosions, and continued good vision until much later in life.

Unilateral and asymmetric cases are known, and superficial cases with little stromal involvement have been described.^96,97 One such case clinically resembled Reis-Bucklers dystrophy.⁹⁸ An unusual pedigree, tracing its roots to Avellino, Italy, has been described in which both granular and lattice dystrophies occur.⁶⁶

Lattice corneal dystrophy has been subdivided into three subsets. Lattice dystrophy type 1, or classic lattice dystrophy as described above, has no systemic involvement, an early onset with fairly early reduction in visual acuity, and a history of multiple erosive episodes. Corneal lattice lines are centrally located, and the peripheral 1 to 3 mm of the cornea is usually clear.

Lattice dystrophy type II is found in familial systemic amyloidosis (Meretoja's syndrome, type IV familial neuropathic syndrome). This is also an autosomal dominant disease, usually found in patients of Finnish, Dutch, or Scotch-Irish ancestry. Systemic involvement consists of progressive cranial and peripheral neuropathies, skin changes, and multisystemic involvement secondary to eventual deposition of amyloid throughout the body. The corneal changes are usually quite mild, presenting in the third decade or later. Corneal erosions and poor vision are uncommon. In contrast to type I lattice dystrophy, the refractlie lines are peripherally located, fewer in number, and larger. Open-angle glaucoma and pseudoexfoliation have been associated.^99–102

Type III has only recently been described in pedigrees from Japan, where lattice dystrophy types I and II are rare. Hida and co-workers presented five patients: three from two families and three sporadic cases.¹⁰³ All five patients were in the seventh to ninth decades of life before noting a gradual reduction in vision, and none had experienced recurrent erosions earlier in life. Clinically, there was no evidence of systemic amyloidosis. Histologically and by slit lamp, the amyloid lattice lines are larger than in type I and are most often located at midstromal depth. A band of sub-Bow-man's membrane amyloid was found in all cases with Bowman's membrane primarily intact.¹⁰⁴ Available family pedigree suggests an autosomal recessive inheritance pattern.

Other amyloid deposits may be found in the cornea, including secondary amyloidosis after inflammation and trauma,^105,106 gelatinous droplike dystrophy,¹⁰⁷ and polymorphic amyloid degeneration.¹⁰⁸

The management of lattice dystrophy consists of conservative treatment of the erosive episodes with patching, lubricants, and/or bandage contact lenses. When visual acuity worsens, corneal transplantation works well. Penetrating keratoplasty results are favorable, but recurrences in grafts occur and are more common and earlier than granular or macular dystrophies, occurring 2 to 14 years postoperatively.³⁷ Any patient presenting with abnormal systemic findings in conjunction with peripheral corneal lattice lines should be evaluated for systemic amyloidosis.

MACULAR DYSTROPHY

Groenouw, in 1890, described two patients with what he believed was the same corneal degenerative process of noduli corneae.⁵⁷ His error in classifying these two patients together was brought to light after Bucklers wrote his classic study on the corneal dystrophics in 1938.⁶⁰ After being commissioned by the health department of the German government to study the corneal dystrophies, Bucklers determined that one was indeed macular dystrophy of autosomal recessive inheritance (Groenouw II) and one was granular dystrophy (Groenouw I), an autosomal dominantly inherited disorder.

Typical of recessive disorders, macular dystrophy is the rarest of the stromal dystrophies. Its onset is early in life, and progression of the corneal changes is rapid, leading to earlier surgical intervention with corneal transplantation. Consanguinity or a common genealogy has been noted in several reported cases^109–111; however, the dystrophy often appears sporadic since carriers of the gene are not affected.

Corneal changes (Fig. 8) are usually noted within the first decade of life and consist initially as a diffuse, bilaterally symmetric anterior stromal clouding. Later, cloudy gray-white macular opacities appear. Unlike granular dystrophy, the “maculae” occur in all parts of the cornea and no peripheral or intervening clear zone is found. Additionally, corneal thinning is a typical finding in this dystrophy, serving to differentiate it from other stromal dystrophies in which pachymetry is usually normal.^112–114 With time, increased opacification of the cornea occurs with spread of the cloudy gray-white lesions peripherally, anteriorly, and posteriorly. Through the increasingly dense background fog, focal white aggregates are found and tend to be larger in the anterior axial cornea. Some of these superficial deposits may cause focal elevation of the epithelium, but epithelial erosions are uncommon. Descemet's membrane later appears hazy, and endothelial guttata are seen.^37,74

Patients commonly complain of photophobia perhaps from the increased scattering of light from the cloudy cornea or from discomfort from surface irregularities. By 20 to 40 years of life, vision has been reduced enough to warrant corneal transplantation.

Macular dystrophy now appears to be a systemic disorder of keratan sulfate metabolism.^115–118 Keratan sulfate is a sulfated glycoaminoglycan, one of several proteoglycans that make up the normal extracellular matrix of two tissues in the human body--cartilage and corneal stroma. Investigators have found that stromal keratocytes from corneas with macular dystrophy fail to manufacture a normal sulfated keratan, concluding that these patients are lacking in a particular sulfotransferase needed for transferring sulfate groups onto the keratan chain. This abnormal proteoglycan then accumulates in the keratocytes and extracellular space, leading to corneal opacification and keratocyte and endothelial cell degeneration.

Most of the body's keratan sulfate resides in cartilaginous tissues whose daily wear and tear is reflected by a measurable serum level of keratan sulfate. Using monoclonal antibodies that identify epitopes of keratan sulfate, investigators have found that some patients with macular dystrophy have immeasurable serum keratan sulfate levels. Similarly, their corneal tissue does not react with any anti-keratan sulfate antibody tested, nor in one study did their nasal cartilage.¹¹⁸ However, there was another group of patients whose serum keratan sulfate levels were normal and whose corneas did react with some or all of the monoclonal keratan sulfate antibodies tested, suggesting that this corneal disorder may be heterogenous.^119,120 Apparently keratan sulfate is not necessary for the normal make up and functioning of cartilaginous tissue, and no histopathologic abnormalities of the cartilage are found in any group of patients with macular corneal dystrophy.

Management consists of reducing the patient's photophobia with protective sunglasses when necessary. Penetrating keratoplasty is the surgical treatment of choice when vision is significantly affected. Lamellar keratoplasty is not effective since all corneal layers are involved in this dystrophy. Recurrence in the graft is less common than in the other stromal dystrophies, presumably because normal keratan sulfate-producing donor keratocytes are viable within the graft for a long period of time.¹²¹ When recurrences occur, the deposits are typically seen in the donor periphery.¹²²

SCHNYDER'S CRYSTALLINE DYSTROPHY

Central crystalline dystrophy of Schnyder is a rare, autosomal dominantly inherited corneal disorder in which cholesterol crystals and lipid deposits, absent at birth, develop bilaterally in the central corneal stroma within the first few years of life. Early on, the crystals may be undetectable except with slit lamp examination, often becoming grossly visible later in life in the third to fifth decades. Usually this disorder causes little or no visual disability.

This dystrophy was first described by Van Went and Wibaut in 1924.¹²³ These researchers presented eight family members in three generations with these crystalline changes; however, it was Schnyder, in 1927 and later, who determined its inheritance pattern and discussed the entity at length.^124–126 Franceschetti and Forni noted its 100% penetrance, and many authors have shown the dystrophy to be somewhat variable in appearance within the same family and with time.^127–130 Only three sporadic cases have been reported.¹³¹

Early gene linkage analysis has suggested a locus for this dystrophy on chromosome 9.¹³¹

Arcus senilis or juvenilis and limbal girdle of Vogt frequently coexist with this disorder, both presenting at an early age. Early arcus juvenilis has been reported at age 14 years and limbal girdle at age 7 years. Xanthelasma, genu valgum, and chondrodystrophy have been variably found in certain pedigrees but not with sufficient frequency to ascribe an absolute genetic linkage.^132–134, Hyperlipidemia and hypercholesterolemia occasionally have been associated with this dystrophy, not only in affected family members but also in the unaffected.^135,136 In those persons with abnormal blood lipid levels there was no correlation between extent of the disease and type or degree of hyperlipidemia. Some investigators have found no definite correlation between systemic lipid abnormalities and Schnyder's dystrophy.¹³⁰ However, most investigators believe that obtaining lipid profiles on affected persons is needed. In one reported case of a patient with hypercholesterolemia, lowering plasma cholesterol levels lessened the corneal lesions.¹²⁸

Typically, a patient with this dystrophy only presents to the ophthalmologist in the fifth or sixth decade of life when vision may be affected by the increasing central opacification of the corneal stroma. Since the epithelium remains intact and smooth and the early lesions are inconspicuous. younger patients remain asymptomatic and the disorder remains undetected. Corneal sensation may be reduced.

Clinically, younger patients may have small polychromatic refractlie crystals in the central stroma. Many may develop a C-shaped or ring-shaped pattern or a confluent central disc of these cholesterol crystals (Fig. 9). Varying amounts of diffuse stromal gray-white opacification may be seen extending posterior and peripherally with the increasing age of the patient. It is this later opacification that probably contributes to the decline in visual acuity of some of these patients.^130,137 Eighty percent of these patients will have a limbal girdle and corneal arcus. with the arcus becoming more confluent and dense with age.³⁷ The midperipheral stroma usually remains clear. No inflammation or vascularization is seen. Xanthelasma may be present.

Management consists of observation alone in the dystrophy's early stages. With visual acuity impairment. penetrating keratoplasty is quite successful. Lamellar keratectomy has been tried; however. recurrences of the crystalline deposits and intrastromal lipids occur sooner and more in tensely in lamellar than in full-thickness procedures. Decreased clarity of the tissue after lamellar keratectomy precludes good visual results in those cases with more extensive posterior stromal involvement.¹³⁸

CENTRAL CLOUDY DYSTROPHY

First described by François in 1956,¹³⁹ this autosomal dominant dystrophy appears in the central corneal stroma as small fluffy or cloudy gray areas in a cobblestone pattern separated from each other by lucent lines of clear stroma.

François described eight cases in patients 35 to 76 years of age. Two occurred in siblings, and the other six were sporadic cases; however, at that time the mode of inheritance was obscure. Other researchers were able to document the autosomal dominant nature of the dystrophy and its onset as early as the first decade of life.^140,141 It has been found unilaterally as well as coincidentally with other ocular disorders such as fleck and pre-Descemet's dystrophies, glaucoma, spherophakia, and pseudoxanthoma elasticum.^142–145

Cloudy dystrophy is usually an incidental finding since it causes no impairment of vision, is not or only minimally progressive, and is usually only visible by slit lamp examination. Corneal sensation and thickness are normal, and treatment is unnecessary.

Direct illumination, broad oblique illumination, or scleral scatter best reveals this dystrophy, showing involvement of the central two thirds of the corneal stroma and sparing of Descemet's and Bowman's membrane. Cloudy polygons with indistinct edges are separated by cracklike clear areas and are usually found in one or multiple stromal layers (Fig. 10).

Clinically, very little separates the appearance of this dystrophy from anterior or posterior crocodile shagreen of Vogt, which is believed to be a secondary or senile change.^146–149 Some investigators believe that unless many ages and generations of related persons are found, the lesion should be called crocodile shagreen rather than posterior cloudy dystrophy.⁸⁷

Little is known about the incidence or histopathology of this dystrophy. Krachmer and colleagues reported one case of cloudy dystrophy in which transmission electron microscopy showed a “sawtooth-like arrangement of collagen lamellae at right angles to others with the stroma.” Clumps of abnormal 100-nm banded collagen were also found in these areas.¹⁵⁰ Because there were no other affected family members, Krachmer and colleagues formally called this patient's lesion posterior crocodile shagreen. It is probably reasonable to say that cloudy dystrophy is little different from crocodile shagreen histopathologically as well as clinically.

POLYMORPHIC STROMAL DYSTROPHY

This bilateral corneal disorder is more aptly considered a degenerative finding associated with aging than a true dystrophy.¹⁰⁸ It will be considered in this section, however, because it shares in common with dystrophies the features of central corneal location, avascularity, bilaterality, and lack of associated primary inflammation.¹⁰⁸ It has historically been classified as a dystrophy.^151,152 The disorder is characterized by polymorphic punctate flecks and filamentous opacities axially located in the deep stroma.¹⁵¹ Histopathologic and ultrastructural analysis have shown these deposits to be amyloid, and hence the term polymorphic amyloid degeneration of the cornea is a more descriptive name for this disorder.^108,150

Studies of three families in the literature have failed to show heritability.^108,150 The disorder was not demonstrated in anyone younger than the age of 49 (range, 49–84), giving credence to the argument for designation as a degeneration. Stachen published the first incontestable description of this entity in 1968 and grouped it as a pre-Descemet's corneal dystrophy with unusual features.¹⁵² His family study included 26 relatives in three generations without corneal pathology. Mannis and associates reported on two family studies in 1981.¹⁰⁸ In the first family, 19 relatives in three generations failed to show corneal lesions. In the second family, 27 members spanning three generations were examined. Typical corneal findings for polymorphic stromal dystrophy were found in two older siblings of the proband. Two other siblings were normal, and no family member outside of the proband's generation demonstrated corneal pathology.¹⁰⁸ It is plausible that more extensive pedigrees may demonstrate a heritable process. The literature to date, however, does not support this essential requirement for classification as a dystrophy.

The clinical picture of polymorphic stromal “dystrophy” is notable because the morphology of the corneal deposits are similar to the small refractive opacities seen with the larger branching filaments in lattice, a true amyloid autosomal dominant dystrophy.^108,151 The clinical history serves to distinguish these two entities. Lattice is characterized by onset early in life (first to fourth decade), anterior stromal involvement with recurrent erosions, decreased acuity, and clear autosomal dominant pedigree. Polymorphic stromal “dystrophy” conversely shows onset after age 50, prominent deep stromal involvement, no loss of vision or erosion symptoms, and no demonstrable inheritance.¹⁰⁸ Slit lamp examination will reveal both punctate polymorphic flecks and filamentous opacities that are gray-white and slightly refractlie with wide slit lamp illumination. These opacities have a predication for the axial posterior stroma but may be seen more anteriorly or involving full-thickness stroma. The stroma between each opacity is normal, as is the corneal thickness and epithelium. Deep pre-Descemet's dystrophic opacities may cause characteristic indentations of Descemet's membrane. The endothelial mosaic is normal, however.¹⁵¹ Affected patients are asymptomatic and without visual disability attributable to the corneal pathology. The disorder is nonprogressive over longitudinal follow up of 6 years, and no treatment is indicated.¹⁵¹

FLECK DYSTROPHY

This uncommon autosomal dominant dystrophy is characterized by discrete flat, subtle, gray-white opacities throughout the corneal stroma. François and Neetens first described this entity in 31 members of one family as hérédo-dystrophie mouchetée.¹⁴⁴ It has been called fleck or speckled dystrophy in the English literature.^153–161 Several reports have demonstrated the histologic and ultrastructural findings in this dystrophy to consist of isolated abnormally distended keratocytes, which probably correspond to the flecks seen clinically.^154,158,159 These distended keratocytes are filled with intracytoplasmic vacuoles that stain positive for lipid and acid mucopolysaccharide, These isolated involved keratocytes may be found at any stromal level. The intervening stroma and other keratocytes are normal.

Since the original description in 1957, many pedigrees have been published corroborating the autosomal dominant inheritance of fleck dystrophy.^{153–157,159,160} As with other autosomal dominant traits, fleck dystrophy can demonstrate variable expression. Asymmetric involvement of the two eyes in a patient has been documented.^153,157 Unilateral nonpenetrance manifested as monocular involvement has also been noted.^{153,155,157,160} The number of fleck opacities in a cornea may vary within a given pedigree from less than 4 to more than 500.¹⁵⁵ In each person, however, the number of opacities appears to remain relatively constant throughout life.³⁷ Evidence for the nonprogressive nature of this disorder can be inferred from several pedigrees showing the presence of typical fleck dystrophy at ages 2 to 4 years that is not phenotypically different in fleck size or number from patients aged over 70 years.^144,160 The histologic finding of isolated keratocytes distended with mucopolysaccharide and lipid suggests that fleck dystrophy may represent an inherited storage disorder confined to the cornea.^154,158,159 Extensive laboratory evaluation has failed to detect any systemic mucopolysaccharide disorder in those patients tested.¹⁵⁵ The metabolic basis for this abnormality of isolated keratocytes is unknown. Inherited metabolic disorders, however, characteristically show recessive inheritance. Fleck dystrophy may be distinct genetically as an autosomal dominantly inherited mucopolysaccharide and lipid storage disorder.

Clinically, the corneal manifestations are subtle and will be missed without careful slit lamp examination. The flecks are best appreciated using high magnification with direct illumination or retroillumination. Individual fleck morphology reveals variable small discrete oval, comma-shaped, or wreathlike opacities with relatively transparent centers. The opacities appear flat or platelike and are distributed in all levels of the corneal stroma extending to the limbus. The intervening stroma is normal, as are epithelium, Bowman's layer, Descemet's membrane, and endothelium.

A typical patient will present on routine examination since no symptoms are attributable to the corneal pathology. Visual acuity is not affected. Usually 30 to 100 discrete flecks may be seen in each cornea, although the number may vary from 1 to more than 500. Typical findings have been present in children as young as 2 years of age, raising speculation that the disorder may be congenital.¹⁴⁴ Usually manifestations are essentially symmetric bilaterally.

PRE-DESCEMET'S DYSTROPHY

Pre-Descemet's dystrophy represents a spectrum of disease with the common finding of numerous fine pleomorphic dots in the deep corneal stroma. Various descriptions of this heterogeneous group of disorders have included cornea farinata, deep filiform dystrophy, and deep punctiform dystrophy. Although the clinical findings resemble a familial dystrophy, a reliable inheritance pattern has not been established. Most observers consider this group of diseases to represent a spectrum of age-related deep stromal degeneration rather than a true dystrophy.¹⁶²

Histopathology reveals normal cornea except for vacuolated keratocytes just anterior to Descemet's membrane. Special stains and ultrastructural analysis identified these abnormal keratocytes to contain lipid-dense cytoplasmic membrane-bound vacuoles.¹⁶² Curran and coworkers suggest that this accumulation of neutral fats and phospholipids in abnormal keratocytes is not unlike lipofuscin found in other tissues associated with age-related degenerative processes.

Grayson and Wilbrandt offer a clinically useful classification of the various pre-Descemet opacities.¹⁶³

Cornea farinata, the most common of these disorders, is generally held to be a normal involutional change associated with aging. It is characterized by diffuse deep stromal involvement of fine dustlike opacities. These are most prominent centrally and best seen by retroillumination.

In pre-Descemet's “dystrophy,”³⁷ discrete, minute opacities are larger than those of cornea farinata. Various shapes have been described, including dendritic, boomerang, circular, linear, comma, and filiform. A combination of these shapes may be seen in the same cornea. Patterns of involvement may be annular, sparing central and limbal cornea, may diffusely involve posterior stroma from limbus to limbus, or may be confined to the axial cornea.¹⁶³ Three pedigrees are reported showing pre-Descemet's opacities in two generations.¹⁶³ Also reported are typical findings in two sisters. Most reports, however, are sporadic. Invariably, patients are older than 30 years of age. Cornea farinata may coexist with the large opacities of pre-Descemet's dystrophy in the same cornea, again raising the hypothesis that these two entities may represent a spectrum of degenerative posterior stromal changes rather than a true dystrophy.¹⁶³ A genetic predisposition in certain families however cannot be excluded.

Pre-Descemet's dystrophic opacities may be associated with other ocular and systemic diseases. Typical pre-Descemet's dystrophic opacities have been noted in affected male and female carriers of X-linked recessive icthyosis¹⁶⁴ and in association with pseudoxanthema elasticum.¹⁴³ Reports of coexistent ocular disorders include posterior polymorphous dystrophy, anterior basement membrane dystrophy, keratoconus,¹⁶³ and juvenile asteroid hyalosis.

Visual acuity is not reduced, and the disorder will be found incidentally on careful slit lamp examination and is usually bilaterally symmetric. No medical or surgical intervention is necessary.

CONGENITAL HEREDITARY STROMAL DYSTROPHY

This rare congenital dystrophy manifesting nonprogressive corneal clouding appears to result from disordered stromal fibrillogenesis. A report by Witschel and associates in 1978 defined congenital hereditary stromal dystrophy as a separate entity from congenital hereditary endothelial dystrophy and other causes of congenital corneal opacification on the basis of distinct clinical findings and characteristic electron microscopy.¹⁶⁶ In congenital hereditary stromal dystrophy the epithelium, Bowman's layer, and endothelium are ultrastructurally normal. The stroma, however, consists of two distinctly abnormal collagen fibrillar arrays. Small tightly packed highly ordered fibrils alternate with loosely packed haphazardly arranged fibrils in a lamellar pattern.

The inheritance of this disorder is autosomal dominant. Only two pedigrees have been reported in the literature.¹⁶⁶ In one of these, 20 affected members in four generations were described.

All reported cases have a characteristic clinical appearance and course. Children present at birth with bilateral diffuse corneal clouding. This appears as a flaky haze that is more pronounced in the central anterior stroma than in the periphery. The cornea is of normal thickness with a smooth regular epithelium. Erosions and epithelial edema do not occur. Descemet's membrane and the endothelium appear normal. The corneal clouding is not progressive. Without surgical intervention. patients may achieve visual acuities. ranging from 20/100 to 20/500. Early sensory deprivation in these patients will often result in nystagmus. strabismus and amblyopia. In Witschel's series. penetrating keratoplasty performed in seven eyes (five patients aged 4 to 11 years) was delayed until childhood when they presented. Post-keratoplasty visual acuities ranged from 20/40 to 20/100. representing improvement to the limit of the preexisting sensory deprivation amblyopia in all cases. Long-term graft survival is good. There is no evidence of recurrence in the graft. Theoretically, early penetrating keratoplasty in the first weeks to months after birth may result in improved visual rehabilitation.

POSTERIOR AMORPHOUS CORNEAL DYSTROPHY

This heredofamilial posterior corneal disorder is characterized by bilateral diffuse gray-white sheetlike deep stromal opacities with decreased central corneal thickness. Two reported pedigrees are found in the literature.^167,168 The earliest, a report by Carpel in 1977, describes the large irregular sheetlike areas of opacification in the posterior stroma as well as the prominent central corneal thinning. These features differ dramatically from the other posterior stromal dystrophies.¹⁶⁷ No histologic studies are available.

The inheritance of this disorder is autosomal dominant. The earliest pedigree described by

Carpel shows a consanguineous marriage in the first generation. However, seven affected members spanning three generations argues for an autosomal dominant mode.¹⁶⁷ More recently, eight members of a family spanning five generations were affected, confirming the inheritance as autosomal dominant.¹⁶⁸ In addition, the nonprogressive nature of this disorder was emphasized, citing as evidence the presence of characteristic peripheral posterior corneal opacities in the youngest (6 months) and oldest (80 years) members of the pedigree.¹⁶⁸ Important additional observations by Dunn and associates include the findings of hyperopia, flattened corneal topography, and iris stromal anomalies.¹⁶⁸ The features of both corneal and iris stromal anomalies, a nonprogressive course, and demonstration of the disorder in an infant raises the possibility that posterior amorphous corneal dystrophy might be more appropriately classified as a heritable dysgenesis of embryonic mesoderm rather than a dystrophy.¹⁶⁸

Patients with posterior amorphous corneal dystrophy will likely present as an incidental finding on slit lamp examination. Visual acuity is affected minimally or not at all (20/20 to 20/30).^167,168 Examination will show sheetlike areas of opacification that may be contiguous with Descemet's membrane or may have clear stroma interposed. The opacities usually extend from central cornea to the limbus, but a variant may only show peripheral involvement. Central corneal thinning (0.25 to 0.47 mm) is uniform and does not cause irregular astigmatism. 168 Ghost vessels are not present, distinguishing this entity from interstitial keratitis. Iris abnormalities include collarette strands, spongy tufts of anterior iris stroma, corectopia, and iris processes extending to Schwalbe's line.¹⁶⁸

GELATINOUS DROPLIKE DYSTROPHY

Gelatinous droplike dystrophy is best documented in the Japanese literature with over 60 cases since its first report in 1914 by Nakaizumi.¹⁶⁹ Only a few reports of this rare familial disorder appear in the occidental literature.^107,170,171 The condition has been called primary familial amyloidosis of the cornea with the histopathologic finding of multiple subepithelial and anterior stromal deposits having the typical polarization and ultrastructural characteristics of amyloid.¹⁷⁶

The inheritance of this disorder is most consistent with an autosomal recessive mode. In all cases reported, only one generation is affected with the trait, involving both sexes. Three of seven siblings¹⁷² and three of ten siblings.¹⁰⁷ respectively, had the typical corneal findings in two well-researched pedigrees. Gartry and associates reported a pedigree in which three of four siblings had gelatinous droplike dystrophy whose parents were first cousins.¹⁷¹ Neither the parents nor other relatives were affected. Consanguinity provides further support for an autosomal recessive mode. Other reports have documented isolated cases.^170,173,176 Kanai and Kaufman report two brothers with a family history of consanguineous marriage with gelatinous droplike dystrophy.¹⁷¹ One of the brothers, however, developed the typical subepithelial amyloid deposits after superficial keratectomy for primary band-shaped keratopathy. The family association of primary band-shaped keratopathy and gelatinous droplike dystrophy has been made.¹⁷⁷

A typical patient will present in the first decade of life with bilateral decreased acuity ranging from 20/50 to hand motions. Photophobia and tearing may be extreme. Examination reveals bilateral central protuberant multinodular subepithelial mounds. These mulberry-like excrescences may be translucent milky white on retroillumination. Vascularization is minimal or not present except secondarily in advanced cases. There is progressive central clouding of the corneas. Extent of corneal involvement may not be symmetric.¹⁷⁰ Superficial keratectomy is followed by recurrence of the lesions.¹⁷² Lamellar keratoplasty is possible¹⁷⁰ but may not reliably remove the pathology, which can extend deep to the mid stroma.¹⁷² Penetrating keratoplasty may be the treatment of choice for visually debilitating symptoms.^172,176 However, superficial recurrence in the graft has been reported.^178,179

FUCHS' DYSTROPHY

Without the assistance of a biomicroscopy, Fuchs first described this corneal dystrophy in 1910, based on its epithelial changes. Although he postulated an endothelial cause, subsequent clinical and histopathologic studies established the primary pathology was endothelial and the epithelial and stromal changes simply the sequelae.

Fuchs' dystrophy is a bilateral, symmetric endothelial dystrophy that presents with corneal guttata and may lead to corneal edema. Some researchers use the term endothelial dystrophy when a greater than expected number of central guttata are seen in a particular age-group. The term Fuchs' dystrophy is reserved for guttata seen in conjunction with corneal edema.¹⁸⁰

Fuchs' dystrophy accounts for approximately 10% of all penetrating keratoplasties. The pattern of inheritance is not yet well defined. Multiple reports have been published^181,182 that suggest an autosomal dominant pattern. Increased frequency in females and possible incomplete penetrance suggest that other factors may influence the final expression. In 1978, Krachmer and co-workers studied several families who had endothelial dystrophy.¹⁸⁰ They examined 284 relatives and found a strong familial tendency. The severity of involvement and number of relatives affected increases with age.

Patients with Fuchs' dystrophy rarely present with symptoms until after 50 years of age. Patients progress through three phases. In phase one, patients are asymptomatic and simply have guttata (Fig. 11) and pigment dusting of the endothelium. Patients who progress to phase two present with complaints of hazy vision and glare as stromal and epithelial edema develop. Epithelial edema progresses to bullae that may rupture and may cause severe pain. In phase three, subepithelial connective tissue develops and edema decreases. Patients become more comfortable but have a significant decrease in vision.

Guttata are not specific for Fuchs' dystrophy. They are products of abnormal endothelial cells can be present with inflammation, trauma, or aging. Up to 70% of the population over the age of 40 may have guttata.¹⁸³

Fuchs' dystrophy is more frequent in postmenopausal women and is rare in the Japanese.¹⁸¹ There are no associated systemic diseases. Open-angle glaucoma and ocular hypertension as well as a predisposition to angle-closure glaucoma may be seen.¹⁸¹ Advanced corneal edema may lead to erosions, ulcers, vascularization, and calcific degeneration.

Histopathology reveals markedly thickened Descemet's membrane and guttae in its posterior portion. More recent studies suggest an altered arrangement of collagen molecules and a possible defective fibrinolytic system.¹⁸⁴ Aqueous amino acid levels are abnormal in this dystrophy, but no systemic problems have been detected.¹⁸⁵ Endothelial viral particles were reported in Fuchs' dystrophy, suggesting that a vital infection leads to endothelial failure.¹⁸⁶

No treatment is necessary in the presence of guttata without edema. As edema develops, 5% NaCl ointment or drops may be used with some success. Corneal edema may be decreased by using a hair dryer directed toward the eyes in the morning. A bandage contact lens may provide comfort in the presence of bullae. With severe visual loss a penetrating keratoplasty needs to be done. Ideally, surgery is performed prior to involvement of the peripheral cornea for the best outcome.^187,188 There is approximately an 80% success rate with surgery.

POSTERIOR POLYMORPHOUS DYSTROPHY

The literature contains many descriptions and names for posterior polymorphous dystrophy owing to the variety of clinical findings.^189–193 Koeppe is credited with the first description in 1916 of six patients with congenital pits on the posterior surface of the cornea. Subsequently, multiple clinical and histopathologic reports described this generally bilateral, asymmetric, or even unilateral dystrophy. Although vesicles (Fig. 12) at the level of Descemet's membrane are traditionally described, clinical examination reveals a variety of opacifications of the posterior corneal layers.¹⁹²

Multiple family studies elucidated the usual autosomal dominant pattern of inheritance.^190,191 McGee and Falls first documented autosomal dominance with good penetrance.¹⁹² Autosomal recessive patterns may occur, but consanguinity may be a factor in its presentations.¹⁹² Grayson¹⁹³ examined three generations of one pedigree that illustrated the disease spectrum from early minimal findings. Slow progressive involvement was documented. There was evidence of the anterior chamber cleavage syndrome in this family.

The age at onset is difficult to determine since patients are usually asymptomatic and the dystrophy is detected on routine examination. Visual acuity is usually normal. Clinical findings range from vesicles to geographic blisters to broad bands and sheets of grayish material in Descemet's membrane. Broad peripheral anterior synechiae extending around the angle for 60° to 120° in conjunction with secondary edema have been described.^194,195 Glaucoma is present in about 15%. Elevated intraocular pressure is difficult to manage secondary to overgrowth of abnormal endothelium in the angle and over open surgical sites.

Other ocular findings include glaucoma, pupillary ectropion, “glass” membranes of the anterior iris surface, and bands in Descemet's membrane.¹⁹⁶ Rarely stromal opacities may be found.

Occasionally the changes can progress with development of stromal and epithelial edema and bullous keratopathy requiring penetrating keratoplasty. The severity of the dystrophy varies even within the same pedigree.

Corneal changes can be sectoral or peripheral. Secondary edema can prevent evaluation of Descemet's membrane and prevent the diagnosis of posterior polymorphous dystrophy. In these cases it is important to examine other family members. No definite systemic pathology is described except for vitiligo of brows and lashes. Occasionally it can present with corneal edema at birth similar to congenital hereditary endothelial dystrophy. Some believe that congenital hereditary endothelial dystrophy is part of the spectrum of posterior polymorphous dystrophy.¹⁹⁶ The differential diagnosis also includes Chandler's syndrome.¹⁹⁵ An association with band keratopathy was present in several cases, but no systemic mineral imbalances were found.

Histopathology shows epithelial cells on the posterior cornea that may produce abnormal collagen.¹⁹⁷ Staining with antikeratin antiserum, a marker for epithelial cells, is positive in posterior polymorphous dystrophy. This suggests a gestational alteration after the fifth month of pregnancy of the normal endothelial cells into epithelial cells.¹⁹⁸

Management is usually simple observation. Since the majority of patients are asymptomatic, penetrating keratoplasty is indicated only when the visual acuity is compromised by corneal edema. Recurrence in the graft has been reported.¹⁹⁹

CONGENITAL HEREDITARY ENDOTHELIAL DYSTROPHY

Congenital hereditary endothelial dystrophy was first described by Laurence²⁰⁰ in 1863 as “corneitis interstitalis in utero.” In 1960, Maumenee defined the clinical characteristics of congenital hereditary endothelial dystrophy.²⁰¹ A variety of names (degenerative congenital corneal dystrophy, congenital macular opacity) have been used in the early literature to describe this bilateral, symmetric, diffuse opacification of the cornea. It presents at an early age with marked corneal edema but no vascularization. In 1969, Pearce and associates²⁰⁰ presented a pedigree in which 39 family members were examined. An autosomal dominant pattern was described.

A review of the subsequent literature suggests two patterns of inheritance that differ clinically.^202–204 The autosomal recessive pattern usually presents at birth with nystagmus and cloudy corneas. It is asymptomatic, and stationary. The autosomal dominant type presents in the first or second year of life with photophobia, tearing, but no nystagmus. It slowly progresses over 5 to 10 years.

Clinically, the cornea has a ground-glass appearance owing to significant stromal edema, but the epithelium only shows a granular appearance without staining (Fig. 13). No bullous changes are seen. Band keratopathy may be an associated finding. Erosions are unusual. Visual acuity ranges from 20/50 to light perception. No consistent systemic findings have been demonstrated. However, one family displayed an autosomal dominant pattern in which high-tone sensory deafness was present. The parents were first cousins.²⁰⁵ Family history and clinical findings are important in differentiating this dystrophy from other diseases.^206,207 It is especially important to rule out congenital glaucoma which requires different management. Consanguinity may increase risk of systemic problems.

In older patients a trial of hypertonic ointment at bedtime and the use of a hair dryer to dehydrate the cornea may be of limited help. In the early amblyogenic age patients may require a penetrating keratoplasty. Initial long-term graft survival rates were very low, but now a higher rate of success is reported, possibly owing to improvements in technique.

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