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INTRODUCTIONThe effects of external trauma and of ophthalmic and systemic disease on human corneal endothelium are best understood by first reviewing the anatomy and physiology of the adult human endothelium. A com-prehensive review of this material can be found in Chapter 4-1.

FUCHS’ DYSTROPHYIntroductionFuchs’ endothelial corneal dystrophy (FD) is a bilateral, non-inflammatory, progressive loss of endothelial cells that results in cor-neal edema and reduction of vision. Its key features include the presence of central guttae, folds in Descemet’s membrane, stromal edema, and microcystic epithelial edema. Corneal endothelial degen-eration is the primary defect that leads to the development of corneal edema. Associated features include prominent corneal nerves, stromal opacification, recurrent corneal erosions, female gender and familial predisposition.

Epidemiology and PathogenesisFD is the most common corneal dystrophy to require keratoplasty, accounting for approximately 3.9% of all penetrating keratoplasties and 47.7% of all endothelial keratoplasties in the United States in 2011.1 Pedigree analysis suggests that FD is an inherited dystrophy with an autosomal dominant inheritance pattern, although the exact mode of inheritance in many cases remains unknown.2 FD is likely to be com-plex in etiology, with genetic as well as environmental factors playing a role in its pathogenesis.3 A significant variation occurs in expressivity between males and females, with a 4 : 1 female–male ratio recorded at the time of keratoplasty.4 It is equally common among whites and blacks who undergo keratoplasty, but is relatively rare in Asians.5

Development of guttae and the onset of symptoms are more com-mon in middle age.2 A variant of early-onset FD, which presents with corneal changes within the first few years of life, has been described.6 FD patients are believed to have an increased incidence of open-angle glaucoma.7 Short axial length, shallow anterior chamber, and

angle-closure glaucoma also have been seen in conjunction with FD.8 FD has been associated with keratoconus.9–11 The progressive loss of endothelial cell function is primary in nature rather than secondary to any alteration in aqueous humor flow rate12 or constituency.13 Endothe-lial dysfunction is mainly a result of a reduction in Na+,K+-ATPase pump activity,14 which leads to a reduction in ion flux across the endothelium.11 Molecular biological studies of corneal buttons from patients with FD suggest that apoptosis may play an important role in endothelial cell degeneration.15 Recent studies have demonstrated an oxidant–antioxidant imbalance in FD cells, which in turn leads to oxi-dative DNA damage and apoptosis.16

Mutations in the gene COL8A2 in chromosome 1p34.3-p32 that codes for the alpha2 chain of type VIII collagen have been reported in patients with early onset FD and in families with posterior polymor-phous corneal dystrophy.6,17 Several genetic loci have been identified in late-onset FD patients.3 The first genetic locus was mapped to chromo-some 13, called Fuchs’ corneal dystrophy locus 1 (FCD1).18 Subse-quently, two other loci, FCD219 and FCD3,20 were mapped to chromosomes 18 and 5 respectively. Additionally, other reports have provided evidence for potential linkage to chromosomes 1, 7, 15, 17 and X by genome-wide linkage analysis.21

Mutations in the Borate Cotransporter encoded by the SLC4A11 gene, also associated with congenital hereditary endothelial dystrophy, have been linked to the development of late-onset FD.22,23 Additionally, mutations in the TCF8 gene, associated with posterior polymorphous corneal dystrophy, have been identified in patients with late-onset FD.24 Recently, a strong association has been discovered between late-onset FD and sequence variants in the transcription factor 4 (TCF4) gene in chromosome 18.25–27 This gene encodes the E2-2 transcription factor which is involved in cellular growth and differentiation.25

Ocular ManifestationsThe earliest slit-lamp finding in FD is the presence of focal excres-cences of extracellular matrix in Descemet’s membrane, called guttae (cornea guttata). In the earliest stages of this disease, the guttae first emerge in the central corneal endothelium (Fig. 4-21-1). Guttae are not

Noel Rosado-Adames, Natalie A. Afshari 4.21 Corneal Endothelium

SECTION 6 Corneal Diseases

PART 4 CORNEA AND OCULAR SURFACE DISEASES

Associated feature■ A delicate tissue subject to alteration from age, trauma, systemic or

ocular disease, contact lens wear, surgery, intraocular solutions, and unique dystrophic conditions

Key feature■ A tissue containing large quantities of membrane-bound

Na+,K+-ATPases with specialized intercellular junctions that establish a pump–leak process integral to the maintenance of corneal deturgescence

Definition: Hexagonal nonreplicating monolayer of neural crest-derived tissue that regulates the hydration state of corneal stroma.

Fig. 4-21-1 Slit-lamp view of FD. Note the guttae on the specularly reflected image of the endothelium.

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PathologyLight microscopy findings include a thickened Descemet’s membrane, which may be laminated in appearance with buried guttae, guttae on the surface, or devoid of guttae but thickened (Fig. 4-21-3).4 The endothelial layer is attenuated. Histological comparison of normal, early-onset FD and late onset FD corneas have shown distinct histo-logical patterns, demonstrated by electron microscopy.3 Early-onset FD shows a markedly thickened Descemet’s membrane anterior banded layer (ABL). ABL is presumed to develop during early fetal life, thus suggesting that these changes in ABL may represent pathological pro-cesses that start in utero and continue to develop later during

specific to FD, and they may be seen in asymptomatic patients and in the setting of both uveitis and nonspecific superficial keratopathies. Up to 11% of eyes in patients older than 50 years of age have guttae.28 Pathologically identical lesions in peripheral Descemet’s membrane are known as Hassall–Henle warts and are part of the normal aging process (see Chapter 4-22).

The guttae initially appear on specular reflection as scattered, dis-crete, isolated dark structures, smaller than an individual endothelial cell.29 An associated fine pigment dusting may be observed within the central endothelium. At this stage, referred to as stage 1, the patient’s vision is usually normal, and the stroma and epithelium are unin-volved.3,28 Over time, these individual excrescences increase in number, enlarge, and fuse with adjacent guttae to disrupt the normal endothelial monolayer’s specular reflection.29 This produces a roughened surface with a specular reflection similar to beaten metal in appearance. Even-tually, this process expands from the center of the cornea to involve the corneal periphery as well. As the disorder progresses, the endothelial monolayer becomes attenuated in thickness, with an increase in aver-age cell size (polymegathism), a decrease in the percentage of hexagonal shaped cells and an increase in the coefficient of variation in cell size (pleomorphism). In the last stages of the dystrophy, effacement of the endothelium results in overlying stromal edema. At this point, the endothelium becomes more difficult to observe using conventional specular microscopy, but it may still be visualized using confocal microscopy.29

As endothelial function progressively declines, the fluid accumulat-ed in the stroma during night-time lid closure is removed at a reduced rate, which results in significant stromal edema upon awakening.30 This heralds the onset of stage 2.3,28 Patients note blurred vision, glare, and colored halos around lights. Initially, the stromal edema is local-ized in front of Descemet’s and behind Bowman’s membrane.31 Eventu-ally the entire stroma swells, taking on a ground-glass appearance. With the increase in corneal thickness, the posterior stroma and Descemet’s membrane are thrown into folds. Vision at this time is variable.

With progressive endothelial dysfunction, bulk fluid flow across the cornea results in microcystic and bullous epithelial edema. This devel-opment represents stage 3 of the disease.3,28 With involvement of the epithelial layer, the optical quality of the tear–air interface is severely degraded, which produces a profound reduction in vision. With the onset of epithelial edema, basal adhesion complexes become disrupted to produce recurrent corneal erosions. As a slit-lamp marker of recur-rent epithelial sloughing, duplication of basement layers occurs, which creates fingerprint and map changes.

If erosions are prominent, a vascular pannus between epithelium and Bowman’s membrane may be induced and results in an anterior stromal haze, with further reduction in vision, representing stage 4 of the disease.3 However, the associated secondary fibrotic layer produced within the pannus often reduces or eliminates the painful recurrent epithelial erosions experienced by the patient. With the increase in stromal edema, glycosaminoglycans elute from the stroma,32 causing disorganization of the collagen fibrils, which contributes to additional stromal opacification.

Diagnosis and Ancillary TestingThe earliest observable change suggestive of FD is the presence of gut-tae on slit-lamp examination (see Fig. 4-21-1). Specular microscopy provides endothelial cell counts, as well as a photographic record that can be a useful educational aid for the patient (Fig. 4-21-2). Subtle stro-mal edema can be observed using sclerotic scatter techniques. Corneal pachymetry documents increased corneal thickness. As the disease progresses, more obvious signs may develop, which include folds in Descemet’s membrane, stromal haze, microcystic and bullous epithe-lial edema, subepithelial fibrosis, and pannus formation. When corneal opacification precludes specular microscopy, confocal microscopy can be used to image the endothelium and obtain reliable endothelial cell counts.29,30

Differential DiagnosisDifferential diagnosis includes posterior polymorphous corneal dystro-phy, congenital hereditary endothelial dystrophy, aphakic or pseudo-phakic bullous keratopathy, and Hassall–Henle bodies. No associated systemic diseases exist.3,28

Fig. 4-21-2 Specular photomicrograph of FD. Note dark areas that represent guttae adjacent to areas of enlarged endothelial cells. (Spacing of grid 0.1 mm.)

Fig. 4-21-3 Characteristic wart-like bumps present within Descemet’s membrane. (A) Periodic acid-Schiff stain. (B) Scanning electron microscopy shows this better. (Courtesy of Dr R. C. Eagle, Jr.)

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CHED is believed to result from abnormal neural crest cell terminal induction during the late term to perinatal period. At this time, failure to complete final differentiation of the endothelial monolayer occurs, which results in a dysfunctional endothelium.45 This dysfunctional endothelium is believed to have faulty growth regulation mechanisms that lead to accumulation of a functionally abnormal and structurally exaggerated form of posterior nonbanded Descemet’s membrane.46

Ocular ManifestationsThe usual presentation is bilateral, symmetrically edematous, cloudy corneas evident at birth or early in the postnatal period.42 Examination reveals the corneas to have a diffuse gray–blue, ground-glass coloring.42 Corneal thickness is two to three times normal and often greater than 1 mm centrally. Both IOP and horizontal corneal diameter are normal. Rarely, CHED is associated with glaucoma and should be considered if corneal opacification fails to resolve after normalization of IOP.47

Closer examination reveals the texture of the epithelial surface to be irregular, with a diffuse pigskin-like roughness.42 Occasionally, discrete white dots also may be seen in the stroma. In areas where stromal opacification is less dense, Descemet’s membrane appears gray, and on specular reflection may have a peau d’orange texture.42 The endothelial layer may or may not be visualized. A fine corneal pannus may be seen, as well as low-grade inflammation.

DiagnosisA tentative diagnosis is usually possible when examination under anesthesia demonstrates the typical bilateral stromal opacification, gross corneal thickening, normal horizontal diameter, normal IOP, and absence of breaks in Descemet’s membrane.

Differential DiagnosisDifferential diagnosis includes congenital glaucoma without buphthal-mos, posterior polymorphous corneal dystrophy, macular stromal dys-trophy, mucopolysaccharidosis, intrauterine infection, and birth trauma from forceps. Harboyan syndrome is an entity defined as congenital hereditary endothelial dystrophy (CHED) accompanied by progressive, sensorineural hearing loss.48,49 This disorder has also been linked to the SLC4A11 gene mutation.49

PathologyLight microscopy shows epithelial atrophy with basal cell hydrops, subepithelial calcification or fibrosis, patchy loss of Bowman’s mem-brane, and variable vascularization or spheroidal degeneration of the stroma.46 Descemet’s membrane is thickened, often with discrete lami-nations. The endothelial layer is attenuated.46

TreatmentIf the edema is stationary and mild, use of hypertonics and desiccating measures may be employed. Usually, however, these patients require keratoplasty due to the bilateral nature of the corneal edema. Kerato-plasty in infants and children is a high-risk procedure and is technically difficult, and the long-term prognosis for graft clarity is worse than it is for adults. No definitive clinical guidelines have emerged regarding the timing of surgical intervention, due to significant heterogeneity in dis-ease severity, follow-up periods, and patient ages at both diagnosis and surgery, among the few published studies.50 Delayed penetrating kerat-oplasty (after age 12) may offer better graft outcomes and visual prog-nosis in CHED patients, even in the presence of nystagmus, according to a recent publication.51 DSAEK has been performed in recent years in a small series of patients as a therapeutic alternative for CHED. DSAEK performed in eyes with CHED has allowed rapid restoration of corneal clarity while minimizing intraoperative and postoperative complications normally associated with pediatric penetrating keratoplasty.52

The decision regarding surgery may be difficult, because despite significant corneal haze and absence of a red reflex, patients often seem to see much better than expected.53 If patients maintain good fixation with normal alignment, surgery may be delayed; loss of fixation or development of nystagmus may lead to earlier intervention.53

Course and OutcomeIn one large study, 38% of patients younger than 12 years of age who underwent penetrating keratoplasty had haze or opaque grafts at the

adulthood.3 In late-onset FD, the characteristic thickening of Descemet’s membrane is due to the deposition of an additional posterior banded layer (PBL), posterior to the posterior nonbanded layer. The PBL is markedly thickened and contains abnormally deposited collagen and the classic posterior excrescences, guttae.3 The production of this mor-phologically abnormal Descemet’s membrane serves as a marker for a dysfunctional endothelium.33

TreatmentEarly stages of the disease may be managed medically, temporizing the need for a keratoplasty. Medical management includes the use of hyper-tonic solutions or ointments and decreasing ambient humidity. If intraocular pressure (IOP) is above 20 mmHg (2.67 kPa), attempts to lower it may reduce the force that drives fluid into the stroma. Treat-ment measures for painful erosions include hypertonics, bandage con-tact lenses, anterior stromal puncture, and conjunctival flaps.With progressive corneal edema refractory to medical management, keratoplasty is usually offered. Penetrating keratoplasty was tradition-ally performed for the treatment of advanced cases.34 If the patient shows signs of visually significant cataracts, keratoplasty may be com-bined with cataract extraction.35 In recent years, posterior lamellar keratoplasty, most commonly Descemet stripping automated endothe-lial keratoplasty (DSAEK or DSEK) has been performed as an alterna-tive to conventional full-thickness corneal transplantation for the treatment of endothelial disorders.36-40 In fact, DSAEK represented 89% of the total keratoplasties performed in Fuchs’ endothelial dystrophy patients in 2011.1 This procedure involves replacing the diseased endothelium and deep stroma with a posterior lamellar disc of tissue, including donor corneal endothelium, Descemet’s membrane, and pos-terior corneal stroma. DSAEK has been demonstrated to be superior to penetrating keratoplasty in terms of earlier visual recovery, postopera-tive refractive outcomes, wound and suture-related complications, and intraoperative and late suprachoroidal hemorrhage risk.38

Course and OutcomeLong-term outcomes of FD patients undergoing penetrating kerato-plasty showed that graft clarity approached 90%, and approximately 60% of patients achieved 20/40 (6/12) or better visual acuity five years after transplantation.33 Results after Descemet stripping endothelial keratoplasty have shown that average best-corrected Snellen visual acu-ity (mean 9 months after surgery) ranged from 20/34 to 20/66.38 Reports of graft survival rates at 5 years for DSAEK were similar to those reported for penetrating keratoplasty (95% vs 93%) in FD patients.39

CONGENITAL HEREDITARY ENDOTHELIAL DYSTROPHYIntroductionFirst described by Maumenee41 in 1960, congenital hereditary endothe-lial dystrophy (CHED) is but one of the many causes of bilateral corneal clouding in full-term infants and usually requires keratoplasty. Key features of this autosomal dominant or recessive condition are a cor-neal thickness two to three times normal, normal IOP, and normal corneal diameter. Associated features are corneal pannus, nystagmus, and esotropia.

Epidemiology and PathogenesisPrevalence, incidence, and sex distribution for this disorder are unknown. The onset is usually at birth in a term infant; corneal cloud-ing may be maximal at birth or progress over a period of years. Family pedigree studies support that autosomal dominant (CHED1) and reces-sive (CHED2) forms exist, as well as sporadic occurrences. Autosomal recessive inheritance is associated with bilateral corneal edema without photophobia but with nystagmus that is present at birth.42 Autosomal dominant inheritance is associated with the progressive onset of corneal edema 1–2 years post partum with photophobia but without nystag-mus.42 Autosomal dominant and autosomal recessive forms of CHED have been linked to chromosome 20, mapped to the loci 20p11.2-q11.2 and 20p13, respectively.43 Mutations in the SLC4A11 gene in chromo-some 20 have been associated with the development of autosomal recessive CHED.43 A related X-linked endothelial dystrophy has been described in males that clinically resembles CHED very closely.44

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to create confluent geographic patches. Less common are band-shaped or ‘snail track’ areas, which typically have scalloped edges and are about 1 mm across (Fig. 4-21-5).75 Their length can range from 2 to 10 mm.76 In both vesicular and band presentations, the overlying stroma and epithelium are uninvolved, and vision is normal. The least common slit-lamp finding is placoid or diffuse involvement of the endotheli-um.75 Patients who have placoid-type PPCD often present with reduced vision. Specular microscopy of the presenting lesions shows them to be sharply demarcated from uninvolved endothelium. In this presenta-tion, Descemet’s membrane and the posterior stroma are hazy, and usually areas of corneal edema and iridocorneal adhesions occur.76

On specular microscopy the vesicles appear as circular dark rings around a lighter, though mottled, center in which some cellular detail is evident.75–79 These vesicles represent steep-sided, shallow depres-sions in the endothelium;75 the steep sides correspond to the peripheral dark ring seen on specular reflection, and the depressed center corre-sponds to the lighter, mottled central portion (Fig. 4-21-6). Specular microscopy of the band-shaped areas shows them to be composed of a chain of overlapping vesicles, which create a shallow trench with scal-loped borders that represent the edges of individual vesicles that have fused.75 Patients with PPCD may exhibit broad-based iridocorneal adhesions and peripheral anterior synechiae. These are most often seen in corneas with placoid areas of involvement.76 Elevation of IOP refrac-tory to medical measures is common in this group of patients. All patients who have PPCD have reduced endothelial cell counts com-pared with age-matched controls.75,77

most recent office visit. In the same study, the 5-year graft survival rate was about 50%.54 First graft survival rates range from 25% at 3 months in earlier studies to 62–90% at 2–3 years in more recent series.50,53

Results from a small series of patients older than age 12 months who underwent DSAEK revealed that best-corrected visual acuity of 20/40 or better was achieved in 8 of the 9 patients, and visual acuity of 20/70 was achieved in the remaining patient. In the infant group, the three patients that had DSAEK were able to Fix and Follow after the procedure.52

POSTERIOR POLYMORPHOUS CORNEAL DYSTROPHYIntroductionFirst described in 1916 by Koeppe, this rare dystrophy has a clinical spectrum that ranges from congenital corneal edema to late-onset cor-neal edema in middle age. Many cases are subclinical – the majority of patients have good vision and only subtle slit-lamp and specular micro-graphic abnormalities. Posterior polymorphous corneal dystrophy (PPCD) is a bilateral autosomal dominant disorder characterized by polymorphic posterior corneal surface irregularities with variable degrees of corneal decompensation. Key features consist of the following:

• Vesicular, curvilinear, and placoid irregularities found on slit-lamp examination

• Rounded dark areas with central cell detail that produce a doughnut-like pattern on specular microscopy

• Epithelial-like transformation of endothelium on histological examination

• Reduced vision from the corneal edema.Associated features are iridocorneal adhesions, peripheral anterior

synechiae, glaucoma, and a tendency to recur in graft patients. Some of these features overlap with iridocorneal endothelial (ICE) syndrome, Peters’ anomaly, and Axenfeld–Rieger syndrome, suggesting that PPCD may be part of a broader spectrum of disorders united by abnormalities of terminal neural crest cell differentiation.55,56 PPCD associated with posterior amyloid degeneration of the cornea, keratoconus, and Alport’s syndrome has been reported.55,57,58

Epidemiology and PathogenesisThe prevalence of this rare disorder in the general population is unknown. This autosomal dominant condition presents with variable genetic penetrance and expressivity.59,60 PPCD has been linked to three chromosomal loci: PPCD1 (OMIM 122000) on chromosome 20p11.2- q11.2, PPCD2 (OMIM 609140) on chromosome 1p34.3 – p32.3, and PPCD3 (OMIM 609141) on chromosome 10p11.2.60 Specific genes at each locus have been identified but some controversy exists regarding the role of these genes in the pathogenesis of this condition.61–66 Muta-tions in the homeobox gene VSX1 in PPCD1 were demonstrated in PPCD families,61,62 but other studies did not replicate these results.63,64 Reports have associated the COL8A2 gene within the PPCD2 locus, coding for the alpha2 chain of type VIII collagen, with PPCD,17,67 as well as contributing to the pathogenesis of Fuchs’ endothelial corneal dystrophy (FD). The contribution of this gene has also been questioned as additional studies have failed to identify similar mutations within analyzed PPCD or FD cohorts.67–69 Studies investigating a candidate gene at the PPCD3 locus demonstrated disease-causing mutations in the zinc finger E-box binding homeobox 1 gene ZEB1, previously known as TCF8.70–73

The pathogenesis of PPCD is thought to be due to focal metaplasia of endothelial cells into a population of aberrant keratinized epithelial-like cells.55,58 Immunohistochemical analyses of these transformed cells show that they contain antigens and cytokeratins that are usually asso-ciated with epithelial cells.74 The transformation of a single-cell layer of endothelium into a multilayered epithelium-like tissue is believed to be responsible for the loss of stromal deturgescence, the observed specular microscopic patterns, and the tendency toward synechiae formation.

Ocular ManifestationsThe most common finding is isolated vesicles bilaterally, which appear as circular or oval transparent cysts with a gray halo, diameters in the range of 0.2–1 mm, at the level of Descemet’s membrane, best viewed by retroillumination with a widely dilated pupil (Fig. 4-21-4).75,76 The cysts may be few or many, widely separated or clustered close together

Fig. 4-21-4 Slit-lamp appearance of vesicles in posterior polymorphous dystrophy. Note the small vesicular lesions on retroillumination. (Courtesy of Dr Richard Yee.)

Fig. 4-21-5 Slit-lamp appearance of the band form of posterior polymorphous dystrophy. Note the vertical serpentine band. (Courtesy of Dr Richard Yee.)

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endothelial cells adjacent to epithelial cell-like areas that show myriad surface microvilli.78,79 Transmission electron microscopy shows multi-layered cells that contain numerous desmosomes and intracytoplasmic filaments.78,79 Cell culture studies demonstrate features similar to cul-tured epithelial cell lines.79

TreatmentThe majority of patients require no treatment; those with corneal opacification are offered keratoplasty. Traditionally, penetrating kerato-plasty was performed in this group of patients. Recent reports have shown the implementation of endothelial keratoplasty with positive results.80,81

Course and OutcomeIn the majority of patients, PPCD is believed to be a nonprogressive type of dystrophy, usually without vision impairment. Those patients who require keratoplasty appear to be at risk for recurrence of this dys-trophy in the grafted cornea,82–84 as well as for the development of glaucoma.79 It is thought that the genesis of this behavior is due to the epithelial-like transformation and subsequent migration of host endothelium, which causes the endothelium to encroach on the donor corneal tissue and host angle structures.79

KEY REFERENCESAdamis AP, Filatov V, Tripathi BJ, et al. Fuchs’ endothelial dystrophy of the cornea. Surv

Ophthalmol 1993;38:149–68.Aldave AJ, Yellore VS, Principe AH, et al. Candidate gene screening for posterior polymorphous

dystrophy. Cornea 2005;24:151–5.Biswas S, Munier FL, Yardley J, et al. Missense mutations in COL8A2, the gene encoding the

alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet 2001;21:2415–23.

Busin M, Beltz J, Scorcia V. Descemet stripping automated endothelial keratoplasty for congenital hereditary endothelial dystrophy. Arch Ophthalmol 2011;129:1140–6.

Cremona FA, Ghosheh FR, Rapuano CJ, et al. Keratoconus associated with other corneal dystrophies. Cornea 2009;28:127–35.

Elhalis H, Azizi B, Jurkunas UV. Fuchs endothelial corneal dystrophy. Ocul Surg 2010;8:173–84.Gottsch JD, Sundin OH, Liu SH, et al. Inheritance of a novel COL8A2 mutation defines a distinct

early-onset subtype of Fuchs corneal dystrophy. Invest Ophthalmol Vis Sci 2005;46:1934–9.Krafchak CM, Pawar H, Moroi SE, et al. Mutations in TCF8 cause posterior polymorphous corneal

dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. Am J Hum Genet 2005;77:694–708.

Lee WB, Jacobs DS, Musch DC, et al. Descemet’s stripping endothelial keratoplasty: safety and outcomes: a report by the American Academy of Ophthalmology. Ophthalmology 2009:1818–30.

Merjava S, Malinova E, Liskova P, et al. Recurrence of posterior polymorphous corneal dystrophy is caused by the overgrowth of the original diseased host endothelium. Histochem Cell Biol 2011;136:93–101.

Ozdemir B, Kubaloğlu A, Koytak A, et al. Penetrating keratoplasty in congenital hereditary endothelial dystrophy. Cornea 2012;31:359–65.

Pineros O, Cohen EJ, Rapuano CJ, et al. Long-term results after penetrating keratoplasty for Fuchs’ endothelial dystrophy. Arch Ophthalmol 1996;114:15–18.

Price MO, Fairchild KM, Price DA, et al. Descemet’s stripping endothelial keratoplasty five year graft survival and endothelial cell loss. Ophthalmology 2011;118:725–9.

Riazuddin SA, Zaghloul NA, Al-Saif A. Missense mutations in TCF8 cause late-onset Fuchs’ corneal dystrophy and interact with FCD4 on chromosome 9p. Am J Hum Genet 2010;86:45–53.

Vithana EN, Morgan PE, Ramprasad V. SLC4A11 mutations in Fuchs’ endothelial corneal dystrophy. Hum Mol Genet 2008;17:656–66.

DiagnosisThe majority of patients are diagnosed using the slit lamp by observing vesicular, band-like, or placoid areas on the posterior corneal surface. The diagnosis of PPCD in patients with corneal edema of unknown cause is based on light and electron microscopy of the excised buttons obtained during keratoplasty.

Differential DiagnosisDifferential diagnosis includes tears in Descemet’s membrane, intersti-tial keratitis, FD, and iridocorneal endothelial (ICE) syndrome (ICE syndrome is discussed in detail in Chapter 10-20). As in PPCD, endothelial cells in ICE syndrome may show epithelial characteristics, leading to speculation that they represent a spectrum of the same dis-ease.56 However, unlike PPCD, ICE syndrome is unilateral, occurs sporadically, is more common in females, and is typically progressive and symptomatic. Glaucoma and iris changes can be found in PPCD but are much more prominent features of ICE syndrome. No systemic associations exist except for rare reports of PPCD associated with Alport’s syndrome.

PathologyLight microscopy shows pits in the posterior corneal surface, which correspond to the vesicles seen on slit-lamp examination. Descemet’s membrane in these areas is attenuated, and the endothelium may be multilayered.78,79 In other areas, Descemet’s membrane appears multi-layered, of variable thickness, and with attenuation or loss of endothe-lium. Discontinuities in Descemet’s membrane with anterior migration of cells to form slit-like structures or clefts in pre-Descemet’s stroma have been described.57 Scanning electron microscopy of keratoplasty buttons may show a striking juxtaposition of normal-appearing

Fig. 4-21-6 Specular photomicrograph of vesicles in posterior polymorphous dystrophy. Note the doughnut-like appearance of the vesicles. (Courtesy of Dr Richard Yee.)

Access the complete reference list online at

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REFERENCES1. Eye Banking Statistical Report. Washington, DC: Eye Bank Association of America; 2011.2. Wilson SE, Bourne WM. Fuchs’ dystrophy. Cornea 1988;7:2–18.3. Elhalis H, Azizi B, Jurkunas UV. Fuchs’ endothelial corneal dystrophy. Ocul Surf 2010;8:

173–84.4. Lang GK, Naumann GOH. The frequency of corneal dystrophies requiring keratoplasty in

Europe and the USA. Cornea 1987;6:209–11.5. Santo RM, Yamaguchi T, Kanai A, et al. Clinical and histopathologic features of corneal

dystrophies in Japan. Ophthalmology 1995;102:557–67.6. Gottsch JD, Sundin OH, Liu SH, et al. Inheritance of a novel COL8A2 mutation defines a

distinct early-onset subtype of Fuchs’ corneal dystrophy. Invest Ophthalmol Vis Sci 2005;46:1934–9.

7. Kolker AE, Hetherington Jr J. Becker–Shaffer’s diagnosis and therapy of the glaucomas. 5th ed. St Louis, MO: CV Mosby; 1983. p. 275.

8. Pitts JF, Jay JL. The association of Fuchs’ corneal endothelial dystrophy with axial hypermetropia, shallow anterior chamber, and angle closure glaucoma. Br J Ophthalmol 1990;74:601–4.

9. Lipman RM, Rubenstein JB, Torczynski E. Keratoconus and Fuchs’ corneal endothelial dystrophy in a patient and her family. Arch Ophthalmol 1990;108:993–4.

10. Orlin SE, Raber IM, Eagle Jr RC, et al. Keratoconus associated with corneal endothelial dystrophy. Cornea 1990;9:299–304.

11. Cremona FA, Ghosheh FR, Rapuano CJ, et al. Keratoconus associated with other corneal dystrophies. Cornea 2009;28:127–35.

12. Wilson SE, Bourne WM, O’Brien PC, et al. Endothelial function and aqueous humor flow rate in patients with Fuchs’ dystrophy. Am J Ophthalmol 1988;106:270–8.

13. Wilson SE, Bourne WM, Maguire LJ, et al. Aqueous humor composition in Fuchs’ dystrophy. Invest Ophthalmol Vis Sci 1989;30:449–53.

14. McCartney MD, Wood TO, McLaughlin BJ. Moderate Fuchs’ endothelial dystrophy ATPase pump site density. Invest Ophthalmol Vis Sci 1989;30:1560–4.

15. Borderie VM, Baudrimont M, Vallee A, et al. Corneal endothelial cell apoptosis in patients with Fuchs’ dystrophy. Invest Ophthalmol Vis Sci 2000;41:2501–5.

16. Szentmáry N, Szende B, Süveges I. Epithelial cell, keratocyte, and endothelial cell apoptosis in Fuchs’ dystrophy and in pseudophakic bullous keratopathy. Eur J Ophthalmol 2005;15: 17–22.

17. Biswas S, Munier FL, Yardley J, et al. Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet 2001;21:2415–23.

18. Sundin OH, Jun AS, Broman KW, et al. Linkage of late-onset Fuchs’ corneal dystrophy to a novel locus at 13pTel-13q1213. Invest Ophthalmol Vis Sci 2006;47:140–5.

19. Sundin OH, Broman KW, Chang HH, et al. A common locus for late onset Fuchs’ corneal dystrophy maps to 18q212-q2132. Invest Ophthalmol Vis Sci 2006;47:3919–26.

20. Riazuddin SA, Eghrari AO, Al-Saif A, et al. Linkage of a mild late-onset phenotype of Fuchs corneal dystrophy to a novel locus at 5q331-q352. Invest Ophthalmol Vis Sci 2009;50: 5667–71.

21. Afshari NA, Li YJ, Pericak-Vance MA, et al. Genome-wide linkage scan in Fuchs endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 2009;50:1093–7.

22. Vithana EN, Morgan PE, Ramprasad V. SLC4A11 mutations in Fuchs endothelial corneal dystrophy. Hum Mol Genet 2008;17:656–66.

23. Riazuddin SA, Vithana EN, Seet LF. Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs’ corneal dystrophy. Hum Mutat 2010;31:1261–8.

24. Riazuddin SA, Zaghloul NA, Al-Saif A. Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am J Hum Genet 2010;86:45–53.

25 Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N Engl J Med 2010;363:1016–24.

26. Li YJ, Minear MA, Rimmler J, et al. Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy. PloS One 2011;6:e18044.

27. Riazuddin SA, McGlumphy EJ, Yeo WS, et al. Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus. Invest Ophthalmol Vis Sci 2011;52:2825–9.

28. Wilson SE, Bourne WM. Fuchs’ dystrophy. Cornea 1988;7:2–18.29. Laing RA, Leibowitz HM, Oak SS, et al. Endothelial mosaic in Fuchs’ dystrophy. Arch

Ophthalmol 1981;99:80–3.30. Mandell RB, Polse KA, Brand RJ, et al. Corneal hydration control in Fuchs’ dystrophy. Invest

Ophthalmol Vis Sci 1989;30:845–52.31. Adamis AP, Filatov V, Tripathi BJ, et al. Fuchs’ endothelial dystrophy of the cornea. Surv

Ophthalmol 1993;38:149–68.32. Kangas TA, Edelhauser HF, Twining SS, et al. Loss of stromal glycosaminoglycans during

corneal edema. Invest Ophthalmol Vis Sci 1990;31:1994–2002.33. Levy SG, Moss J, Sawada H, et al. The composition of wide-spaced collagen in normal and

diseased Descemet’s membrane. Curr Eye Res 1996;15:45–52.34. Pineros O, Cohen EJ, Rapuano CJ, et al. Long-term results after penetrating keratoplasty for

Fuchs’ endothelial dystrophy. Arch Ophthalmol 1996;114:15–18.35. Payant JA, Gordon LW, VanderZwaag R, et al. Cataract formation following corneal

transplantation in eyes with Fuchs’ endothelial dystrophy. Cornea 1990;9:286–9.36. Terry MA, Ousley PJ. Deep lamellar endothelial keratoplasty in the first United States

patients: early clinical results. Cornea 2001;20:239–43.37. Busin M, Arffa RC, Sebastiani A. Endokeratoplasty as an alternative to penetrating

keratoplasty for the surgical treatment of diseased endothelium: initial results. Ophthalmology 2000;107:2077–82.

38. Lee WB, Jacobs DS, Musch DC, et al. Descemet’s stripping endothelial keratoplasty: safety and outcomes: a report by the American Academy of Ophthalmology. Ophthalmology 2009:1818–30.

39. Price MO, Fairchild KM, Price DA, et al. Descemet’s stripping endothelial keratoplasty five-year graft survival and endothelial cell loss. Ophthalmology 2011;118:725–9.

40. Patel SV. Graft survival and endothelial outcomes in the new era of endothelial keratoplasty. Exp Eye Res 2012;95:40–7.

41. Maumenee AE. Congenital hereditary corneal dystrophy. Am J Ophthalmol 1960;50: 1114–24.

42. Waring III GO, Rodrigues MM, Laibson PR. Corneal dystrophies II Endothelial dystrophies. Surv Ophthalmol 1978;23:147–67.

43. Hemadevi B, Veitia RA, Srinivasan M, et al. Identification of mutations in the SLC4A11 gene in patients with recessive congenital hereditary endothelial dystrophy. Arch Ophthalmol 2008;126:700–8.

44. Schmid E, Lisch W, Philipp W, et al. A new X-linked endothelial corneal dystrophy. Am J Ophthalmol 2006;141:478–87.

45. Bahn CF, Falls HF, Varley GA, et al. Classification of corneal endothelial disorders based on neural crest origin. Ophthalmology 1984;91:558–63.

46. Kirkness CM, McCartney A, Rice SC, et al. Congenital hereditary corneal oedema of Maumenee: its clinical features, management, and pathology. Br J Ophthalmol 1987;71: 140–4.

47. Mullaney PB, Risco JM, Teichmann K, et al. Congenital hereditary endothelial dystrophy associated with glaucoma. Ophthalmology 1995;102:186–92.

48. Harboyan G, Mamo J, Der Kaloustian V, et al. Congenital corneal dystrophy: progressive sensorineural deafness in a family. Arch Ophthalmol 1981;85:27–32.

49. Desir J, Abramowicz M. Congenital hereditary endothelial dystrophy with progressive sensorineural deafness (Harboyan syndrome). Orphanet J Rare Dis 2008;3:28.

50. Schaumberg DA, Moyes AL, Gomes JA, et al. Congenital hereditary endothelial dystrophy Multicenter Pediatric Keratoplasty Study. Am J Ophthalmol 1999;127:373–8.

51. Ozdemir B, Kubaloğlu A, Koytak A, et al. Penetrating keratoplasty in congenital hereditary endothelial dystrophy. Cornea 2012;31:359–65.

52. Busin M, Beltz J, Scorcia V. Descemet-stripping automated endothelial keratoplasty for congenital hereditary endothelial dystrophy. Arch Ophthalmol 2011;129:1140–6.

53. Sajjadi H, Javadi MA, Hemmati R, et al. Results of penetrating keratoplasty in CHED: congenital hereditary endothelial dystrophy. Cornea 1995;14:18–25.

54. Dana M-R, Moyes AL, Gomes JAP, et al. The indications for and outcome in pediatric keratoplasty. Ophthalmology 1995;102:1129–38.

55. Molia LM, Lanier JD, Font RL. Posterior polymorphous dystrophy associated with posterior amyloid degeneration of the cornea. Am J Ophthalmol 1999;127:86–8.

56. Anderson NJ, Badawi DY, Grossniklaus HE, et al. Posterior polymorphous membranous dystrophy with overlapping features of iridocorneal endothelial syndrome. Arch Ophthalmol 2001;119:624–5.

57. Feil SH, Barraquer J, Howell DN, et al. Extrusion of abnormal endothelium into the posterior corneal stroma in a patient with posterior polymorphous dystrophy. Cornea 1997;16: 439–46.

58. Ross JR, Foulks GN, Sanfilippo FP, et al. Immunohistochemical analysis of the pathogenesis of posterior polymorphous dystrophy. Arch Ophthalmol 1995;113:340–5.

59. Cibis GW, Krachmer JA, Phelps CD, et al. The clinical spectrum of posterior polymorphous dystrophy. Arch Ophthalmol 1977;95:1529–37.

60. Vincent AL, Niederer RL, Richards A, et al. Phenotypic characterization and ZEB1 mutational analysis in posterior polymorphous corneal dystrophy in a New Zealand population. Mol Vis 2009;15:2544–53.

61. Heon E, Greenberg A, Kopp KK, et al. VSX1: a gene for posterior polymorphous dystrophy and keratoconus. Hum Mol Genet 2002;11:1029–36.

62. Valleix S, Nedelec B, Rigaudiere F, et al. H244R VSX1 is associated with selective cone ON bipolar cell dysfunction and macular degeneration in a PPCD family. Invest Ophthalmol Vis Sci 2006;47:48–54.

63. Aldave AJ, Yellore VS, Principe AH, et al. Candidate gene screening for posterior polymorphous dystrophy. Cornea 2005;24:151–5.

64. Gwilliam R, Liskova P, Filipec M, et al. Posterior polymorphous corneal dystrophy in Czech families maps to chromosome 20 and excludes the VSX1 gene. Invest Ophthalmol Vis Sci 2005;46:4480–4.

65. Hosseini SM, Herd S, Vincent AL, et al. Genetic analysis of chromosome 20-related posterior polymorphous corneal dystrophy: genetic heterogeneity and exclusion of three candidate genes. Mol Vis 2008;14:71–80.

66. Yellore VS, Papp JC, Sobel E, et al. Replication and refinement of linkage of posterior polymorphous corneal dystrophy to the posterior polymorphous corneal dystrophy 1 locus on chromosome 20. Genet Med 2007;9:228–34.

67. Aldave AJ, Rayner SA, Salem AK, et al. No pathogenic mutations identified in the COL8A1 and COL8A2 genes in familial Fuchs corneal dystrophy. Invest Ophthalmol Vis Sci 2006;47:3787–90.

68. Kobayashi A, Fujiki K, Murakami A, et al. Analysis of COL8A2 gene mutation in Japanese patients with Fuchs’ endothelial dystrophy and posterior polymorphous dystrophy. Jpn J Ophthalmol 2004;48:195–8.

69. Yellore VS, Rayner SA, Emmert-Buck L, et al. No pathogenic mutations identified in the COL8A2 gene or four positional candidate genes in patients with posterior polymorphous corneal dystrophy. Invest Ophthalmol Vis Sci 2005;46:1599–603.

70. Aldave AJ, Yellore VS, Yu F, et al. Posterior polymorphous corneal dystrophy is associated with TCF8 gene mutations and abdominal hernia. Am J Med Genet A 2007;143A:2549–56.

71. Krafchak CM, Pawar H, Moroi SE, et al. Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. Am J Hum Genet 2005;77:694–708.

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72. Liskova P, Tuft SJ, Gwilliam R, et al. Novel mutations in the ZEB1 gene identified in Czech and British patients with posterior polymorphous corneal dystrophy. Hum Mutat 2007;28:638.

73. Yellore VS, Rayner SA, Nguyen CK, et al. Analysis of the role of ZEB1 in the pathogenesis of posterior polymorphous corneal dystrophy. Invest Ophthalmol Vis Sci 2012;53:273–8.

74. Ross JR, Foulks GN, Sanfilippo FP, et al. Immunohistochemical analysis of the pathogenesis of posterior polymorphous dystrophy. Arch Ophthalmol 1995;113:340–5.

75. Laganowski HC, Sherrard ES, Kerr Muir MG. The posterior corneal surface in posterior polymorphous dystrophy: a specular microscopical study. Cornea 1991;10:224–32.

76. Hirst LW, Waring III GO. Clinical specular microscopy of posterior polymorphous endothelial dystrophy. Am J Ophthalmol 1983;95:143–55.

77. Brooks AMV, Gillies WE. Differentiation of posterior polymorphous dystrophy from other posterior corneal opacities by specular microscopy. Ophthalmology 1989;96:1639–45.

78. Henriquez AS, Kenyon KR, Dohlman KH, et al. Morphologic characteristics of posterior polymorphous dystrophy: a study of nine corneas and review of the literature. Surv Ophthalmol 1984;29:139–47.

79. Krachmer JH. Posterior polymorphous corneal dystrophy: a disease characterized by epithelial-like endothelial cells which influence management and prognosis. Trans Am Ophthalmol Soc 1985;83:413–75.

80. Bromley JG, Randleman JB, Stone D, et al. Clinicopathologic findings in iridocorneal endothelial syndrome and posterior polymorphous membranous dystrophy after Descemet stripping automated endothelial keratoplasty. Cornea 2012;31:1060–4.

81. Studeny P, Jirsova K, Kuchynka P, et al. Descemet membrane endothelial keratoplasty with a stromal rim in the treatment of posterior polymorphous corneal dystrophy. Ind J Ophthalmol 2012;60:59–60.

82. Boruchoff SA, Weiner MJ, Albert DM. Recurrence of posterior polymorphous corneal dystrophy after penetrating keratoplasty. Am J Ophthalmol 1990;109:323–8.

83. Sekundo W, Lee WR, Aitken DA, et al. Multirecurrence of corneal posterior polymorphous dystrophy. Cornea 1994;13:509–15.

84. Merjava S, Malinova E, Liskova P, et al. Recurrence of posterior polymorphous corneal dystrophy is caused by the overgrowth of the original diseased host endothelium. Histochem Cell Biol 2011;136:93–101.