Congenital hereditary endothelial dystrophy is a rare corneal dystrophy characterized by bilateral diffuse clouding of both corneas from infancy. CHED was first described in 1960 by Edward Maumenee, MD, who reported a series of cases of varying corneal clouding that was congenital and principally stationary.¹ The corneal clouding in CHED ranges from a mild haze to a ground glass, milky appearance. This clouding can lead to amblyopia. Patients present with a thickened cornea, with pachymetry readings two to three times normal, and a thickened Descemet’s membrane.²

The incidence of congenital corneal opacities, including congenital glaucoma, is six per 100,000. CHED makes up a small minority.³ Although the incidence of CHED is quite low, it is more common in places with higher consanguinity. In reviews from the Middle East and India, a diagnosis of CHED accounted for 21 percent of all pediatric keratoplasties.^4,5

Figure 1. A 3-year-old female with congenital hereditary endothelial dystrophy. The right eye is 1.5 months post-DSAEK without endothelial stripping. There is increased corneal clarity. The left eye has not been operated on yet. There is a mild but diffuse corneal clouding, which in this picture can best be appreciated over the pupil.

The corneal clouding and thickening seen in CHED is a result of a paucity of endothelial cells. In the healthy cornea, the endothelium exists as a monolayer of polygonal cells, which serves as a fluid “pump” to keep the stroma dehydrated and maintain corneal clarity. A healthy corneal endothelium in children and young adults is around 3,500 cells/mm².⁶ These cells work by a Na/K ATPase ion pump to remove water from the stroma and deposit it in the aqueous humor. Fluid can disrupt the highly organized lamellar collagen matrix and lead to a loss of corneal clarity. In CHED (and other endothelial dystrophies like Fuchs’ dystrophy), a loss of endothelial cells results in a buildup of fluid in the corneal stroma (edema). Electron microscopy studies have revealed severely reduced and atrophic endothelial cells in CHED patients.⁷

Until recently, CHED had been classified into two variants: 1) an autosomal dominant variant that presents after 1 year of age and is progressive (CHED1); and 2) an autosomal recessive variant that presents at birth and is stationary (CHED2). Patients with CHED1 are described as being born with clear corneas and develop clouding over the first few years of life. They complain of epiphora and photophobia, but do not have nystagmus. By contrast, CHED2 patients are described as having corneal clouding from birth with accompanying nystagmus. They do not complain of epiphora or photophobia. The corneal clouding in CHED2 is generally more advanced than in CHED1, and corresponds to a worse visual acuity. Recent genetic studies have mapped CHED1 to an area on chromosome 20 that overlaps with posterior polymorphous corneal dystrophy (PPCD).⁸ Additionally, a review of reported cases of CHED1 found considerable overlap in clinical, histopathologic and electron microscopic examinations between CHED1 and PPCD.⁹ Clinically, patients with both conditions have been described as having small flakes, spots and irregular white areas throughout the stroma. A review of histopathologic and electron microscopy studies of previously diagnosed CHED1 patients reveals multiple abnormal endothelial layers and microvilli, which can also classically be seen with PPCD.^10,11 Recently, the international classification of corneal dystrophies (IC3D) has been revised to eliminate CHED1 from classification, stating that, “There is no convincing published evidence to support the existence of AD CHED as a distinct entity.”¹² The autosomal recessive CHED (CHED2) is now renamed CHED.

Clinical Findings

In addition to corneal clouding and thickened pachymetry, patients with CHED may have an irregular or roughened appearance of their epithelium, suggestive of edema. This can be better delineated by the instillation of fluorescein. The clouding in CHED is diffuse (limbus to limbus) and relatively uniform. While the cornea can be quite cloudy, even milky, the iris is usually visible. This is in contrast to other etiologies of congenital corneal clouding like Peter’s anomaly or a limbal dermoid, which can vary in size/location and often obscure underlying iris. Aside from the corneal abnormalities, the structure of the eye in CHED patients is usually normal.

Figure 2. A 3-year-old female with CHED, three months after DSAEK without endothelial stripping of the left eye. Her corneal clarity is significantly improved and her visual acuity improved from 20/250 to 20/80.

It is important to differentiate congenital glaucoma from CHED, as both conditions can produce corneal clouding from infancy. Additionally, CHED patients often have relatively high intraocular pressure secondary to thick pachymetry.¹³ Clinicians should look carefully for signs of glaucoma including increased corneal diameter, increased cup-to-disc ratio, Haab’s striae and buphthalmos. However, there are several reports of concomitant CHED and glaucoma.^14,15 Some authors consider both CHED and congenital glaucoma neurocristopathies.^16,17 CHED may be secondary to a failure of regression of primordial endothelium during the development of the anterior chamber and congenital glaucoma may result from a sheet of primordial endothelium that fails to fenestrate appropriately within the angle, causing an abnormal insertion of the iris. To diagnose either condition, a careful exam is paramount, which can be difficult in young children. If necessary, an exam under anesthesia should be scheduled. Pre-intubation IOP, refraction, corneal diameter, axial length and gonioscopy should be documented.

Clinicians should also inquire about hearing loss, as several patients with CHED have been found to have Harboyan syndrome, also called corneal dystrophy and perceptive deafness. These patients have progressive post-lingual sensorineural hearing loss. The hearing loss typically becomes clinically apparent by 10 to 25 years old. Deficits start in the 20 to 25 dB range (mild to moderate) and occur at higher frequencies.18 More than 50 percent of cases have been associated with parental consanguinity.

Genetics

CHED has been mapped to chromosome 20 loci 20p13. The gene codes solute carrier family 4, sodium borate transporter member 11 (SLC4A11).⁸ Eranga Vithana and colleagues studied 10 families with CHED and found seven different mutations in the SLC4A11 gene.¹⁹ The gene encodes a sodium borate transporter. Transfection of an immortalized cell line with mutant SLC4A11 cDNAS resulted in little to no expression of transporter protein on the cell surface. The majority of pedigrees with CHED who have been screened demonstrate coding region mutations in the SLC4A11 gene.⁹ It is thought that the intracellular boron concentration plays a key role in the growth and terminal differentiation of neural crest cells. Therefore, loss of function of this transporter may result in abnormal corneal endothelial synthesis and differentiation.

Patients with Harboyan syndrome also have mutations in the SLC4A11 gene. The gene is expressed in the cochlea of adult mice and thought to play a role in the homeostasis of cochlear fluid and endolymph secretion.¹⁸ This may explain the concomitant corneal edema and hearing loss seen in patients with Harboyan syndrome.

Management

CHED patients have varying visual acuities depending on the degree of corneal clouding. A decision must be made whether to intervene or observe. If intervention is desired, surgery is required. The pathophysiology is a result of inadequate endothelium, and treatment therefore requires replacing the endothelium. This can be accomplished by either a full-thickness transplant (penetrating keratoplasty) or a partial-thickness transplant surgery, where only the endothelium is replaced (Descemet’s stripping endothelial keratoplasty). In all cases, patients should be carefully followed and amblyopia should be treated.

Penetrating Keratoplasty

PK in children can be challenging for a number of reasons: Children have higher rates of graft rejection than adults. Surgery is challenging because of lower scleral rigidity, increased fibrin reaction and positive vitreous pressure. Children may be difficult to examine and suture adjustments may necessitate multiple exams under anesthesia, all the while taking into account changing refractions and managing amblyopia.⁵

A multicenter retrospective study for PK in CHED by Debra A. Schaumberg, MPH, and colleagues found a first graft survival rate of 71 percent.20 Half of the children improved one or more Snellen lines, but only 40 percent ultimately achieved visual acuity of 20/200 or better.²¹ A second series from India found a 75 percent graft survival rate at four years for presumed AR CHED patients. Ali A. Al Rajhi, MD, and colleagues compared “early onset CHED,” formerly CHED2, to “delayed onset CHED,” formerly CHED1 but now considered part of the PPCD spectrum. They found better acuities and graft survival in the delayed onset group.²² Similarly, series where patients received grafts at later ages report improved visual acuity and graft survival.^23,24 However, this relative success may be a function of the fact that these patients have more mild disease/PPCD.

DSEK

Given the fact that CHED is primarily a disorder of the corneal endothelium and Descemet’s membrane, a DSEK is another good surgical option. Compared to PK, DSEK offers the advantage of faster visual recovery, a relatively closed system during surgery and fewer corneal sutures, producing less corneal astigmatism and necessitating less postoperative suture adjustment/removal. One challenge of DSEK in CHED is Descemet’s scoring and removing the corneal endothelium. Visibility is often compromised due to corneal clouding, and the endothelium has been found to be more adherent than in other cases of endothelial dysfunction, like Fuchs’ dystrophy.²⁵ A second challenge is the fact that CHED patients are often phakic and, therefore, causing a cataract is a significant risk during surgery. In adults, Janet Y.M. Tsui, MD, and colleagues found that the presence of an air bubble caused a premature cataract in 40 percent of phakic eyes.²⁶ In a study at L.V. Prasad Eye Institute, Jatin N. Ashar, MD, and colleagues did a paired comparison, where patients with CHED underwent PK in one eye and DSEK in the contralateral eye.²⁷ At one year, they found that all grafts were clear. In the DSEK group, the astigmatism was significantly lower and had faster stabilization of refraction. By contrast, grafts appeared overall clearer in the PK group, although final visual acuity was equivalent. Several case series have reported improved visual acuity and corneal clarity with a relatively short visual recovery in patients undergoing DSEK for CHED.^28,29

Figure 3. Performing a DSAEK with a Busin glide, anterior chamber maintainer and a miotic pupil.

Specific Considerations

Given the difficulty of Descemet’s stripping in the setting of reduced corneal clarity and adherent endothelium, several authors have completed DSEK in CHED without stripping and without removing the host endothelium. Massimo Busin, MD, and colleagues did not strip Descemet’s in patients less than 1 year old at the time of surgery because Descemet’s could not be identified. In all patients, the donor tissue ultimately attached and the cornea cleared completely by one week after surgery, although in four of the six eyes, re-bubbling was necessary.²⁹ Jatin N. Ashar, MD, and colleagues compared patients with CHED where Descemet’s was not stripped (nDSEK) to those where it was stripped (DSEK), and found comparable final visual acuities between the two groups.³⁰ One of the three patients with nDSEK needed to be re-bubbled compared to 0 with DSEK. Based on these findings, DSEK without stripping is a viable option for patients where there is poor visibility, who are very young and/or Descemet’s is difficult to identify and remove.

Several techniques have been described to minimize lens trauma in phakic pediatric DSEK patients. Mahmoodreza Panahi-Bazaz, MD, and colleagues describe a suture pull-through method, to minimize anterior chamber manipulation when visibility is poor.³¹ Additionally, topical pilocarpine was used to induce miosis. Dr. Busin and colleagues advocate moving the incision superiorly so that the pull-through method can be done over the superior iris, which protects the underlying crystalline lens.²⁹

Prognosis

Final visual outcomes in patients with CHED vary and depend on the degree of corneal clouding, the level of amblyopia and whether or not there was a successful surgical intervention. Compared to other etiologies of congenital corneal clouding, CHED patients tend to have better surgical outcomes.⁵ This is likely due to the fact that, in most circumstances, CHED patients have an otherwise healthy eye. The recent advent of DSEK offers a much less invasive alternative to PK surgery. Clinicians should screen carefully for concomitant conditions like glaucoma and hearing loss. Patients and family should be counseled on the necessity of long-term follow-up and should understand the genetic nature of this disease. REVIEW

Dr. Trief is an assistant professor of ophthalmology at the Edward S. Harkness Eye Institute, Columbia University Medical Center. Dr. Ritterband is a clinical professor of ophthalmology at the Icahn School of Medicine of Mt. Sinai, and the assistant director of the cornea service at the New York Eye and Ear Infirmary of Mt. Sinai. Dr. Seedor is a clinical professor of ophthalmology at the Icahn School of Medicine, and system director of cornea and external disease at NYEEI of Mt. Sinai. Dr. Waisbren is an assistant professor of ophthalmology at Icahn. Also contributing to the article were Luna Xu, MD, and Yijie Lin, MD, MBA, ophthalmology residents at NYEEI of Mt. Sinai.

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