Granular Corneal Dystrophy 

Updated: May 02, 2018
Author: Jean Deschênes, MD, FRCSC; Chief Editor: Hampton Roy, Sr, MD 

Overview

Background

Granular corneal dystrophy (GCD), an IC3D category 1 dystrophy, is an autosomal-dominant, bilateral, noninflammatory condition that results in deposition of discrete, irregularly shaped opacities in the cornea by adulthood. It specifically affects the middle portion of the cornea (stroma) and can eventually cause decreased vision and eye discomfort.

There are two clinically separate types: granular corneal dystrophy type 1 (classic type) and granular corneal dystrophy type 2 (Avellino corneal dystrophy), which tends to have fewer corneal deposits, potentially resembling a combination of lattice corneal dystrophy and granular corneal dystrophy. Severe cases of granular dystrophy can be treated with either excimer laser ablation or by replacing cornea (corneal transplant). An example is shown in the image below.

Granular dystrophy. Image courtesy of James J Reid Granular dystrophy. Image courtesy of James J Reidy, MD, FACS, Associate Professor of Ophthalmology, State University of New York, School of Medicine & Biomedical Sciences, Buffalo, New York.

Pathophysiology

The cornea is the clear outer coat of the front of the eye. A dystrophy of the cornea is defined as a bilateral noninflammatory clouding of the cornea. Corneal dystrophies can be divided into 3 categories based on their location within the cornea, as follows: (1) anterior corneal dystrophies affect the corneal epithelium and may involve the Bowman layer, (2) stromal corneal dystrophies affect the central layer of cornea (the stroma), and (3) posterior corneal dystrophies involve the Descemet membrane and the endothelium. Granular corneal dystrophy is a stromal dystrophy, but the epithelium and Bowman layer may be affected in late disease.

The age of onset for most corneal dystrophies is before 20 years (exceptions include map-dot-fingerprint dystrophy and Fuchs corneal dystrophy). Most corneal dystrophies are inherited in a dominant pattern. Exceptions include macular corneal dystrophy, type-3 lattice dystrophy, and the autosomal-recessive form of congenital hereditary endothelial dystrophy.

Granular corneal dystrophy types I and II result from mutations in the TGFBI (BIGH3) gene.[1, 2] Depending on the specific mutation in the TGFBI gene, phenotypes of corneal dystrophy may differ.[3, 4]  R124H and R555W are mutation hotspots of the TGFBI gene.[5, 6] The R124H mutation of TGFBI is highly correlated with granular corneal dystrophy type 2 (GCD2). 

In a 2017 Chinese cohort study of 24 patients with clinically apparent granular corneal dystrophy, the R124H mutation was identified in 37.5% of cases; R555Q, 16.7%; R124L, 25%; R555W, 20.8%, and R124C, 0%. In 13 subjects with a positive family history of granular corneal dystrophy but no clinical signs of the disease, the mutation rate was 69.2%.[6]  

Two 2017 studies demonstrated that granular corneal dystrophy type 22 corneal fibroblasts were more susceptible to oxidative stress–induced cell death than were wild-type cells, suggesting that oxidative stress is involved in the corneal pathogenesis of granular corneal dystrophy type 2.[7]  Melatonin might have potential as a therapeutic agent by reducing endoplasmic reticulum (ER) stress.[8, 9]  

Extinguishing or shortening of the meibomian glands was also observed in patients with granular corneal dystrophy type 2.[10]

Epidemiology

Frequency

United States

Although granular corneal dystrophy type 2 is more common than granular corneal dystrophy type 1 in the United States, both are rare.

International

Granular corneal dystrophy is uncommon worldwide. Granular corneal dystrophy type 1 is more common in Europe, while granular corneal dystrophy type 2 is more prevalent in Japan, Korea, and the United States.[11]

Mortality/Morbidity

Corneal changes generally first become visible during the second decade of life, but vision may not be affected until the fourth to fifth decade of life. Eye pain from recurrent corneal erosions also can occur.

Sex

No sexual predilection has been reported.

Age

In granular corneal dystrophy type 1, corneal changes appear within the first decade of life but may not be visible until the second decade of life.[11] Visual acuity usually remains good until the fourth or fifth decade of life, once the opacities become confluent. Granular corneal dystrophy type 2 is usually diagnosed during early adulthood.[2]

Prognosis

The prognosis of granular corneal dystrophy is good, with symptomatic patients being eligible for either laser phototherapeutic keratectomy (PTK) or corneal transplant.

For granular corneal dystrophy type 1, recurrence occurred most rapidly after PTK (median, 2.7 years), deep anterior lamellar keratoplasty (DALK; median, 3.2 years), and anterior lamellar keratoplasty (ALK; median, 3.7 years). Recurrence was most delayed after penetrating keratoplasty (median, 13.7 years). All groups in this study achieved a similar median best corrected visual acuity (BCVA); 20/25-20/30).[12]

 

Presentation

History

Patients with granular corneal dystrophy (GCD) may have decreased vision, photosensitivity, and/or eye pain (from recurrent corneal erosions). Visual acuity decreases with age. As the pattern of inheritance for this dystrophy is autosomal dominant, one of the parents of the patient likely also has granular corneal dystrophy.

Physical

Granular corneal dystrophy is characterized by bilateral formation of discrete, focal, white granular deposits in the anterior stroma of cornea with clear areas between these deposits. The granules are primarily located in the central cornea, with an absence of these deposits in the peripheral cornea. The deposits can resemble crushed breadcrumbs or snowflakes.

As patients advance in age, the deposits become larger and increase in number. Eventually, the intervening clear areas develop a mild-to-severe corneal haze. When there are clear spaces between the deposits, vision generally is not severely affected. However, over time, the clear spaces become opacified. This late opacification is usually much more superficial than the longstanding, dense white granules. Vision dramatically declines when the clear spaces opacify.

Causes

Granular dystrophy is an autosomal-dominant condition that affects the TGFBI (BIGH3) gene; its genetic defect has been mapped to chromosome 5q.

Complications

Complications of granular corneal dystrophy include loss of vision and recurrent corneal erosions.

Complications of recurrent erosions include corneal infection and scarring, which can lead to significant decreased vision.

 

DDx

 

Workup

Procedures

Corneal biopsy, which is not clinically indicated in patients with granular corneal dystrophy (GCD), reveals eosinophilic hyaline deposits in corneal stroma. When a corneal transplant is performed, the specimen is submitted for histopathologic evaluation

Optical coherence tomography (OCT) has been used in assessing granular corneal dystrophy[13] and has been used to guide phototherapeutic keratectomy (PTK).[14, 15, 16]

Histologic Findings

When corneal specimens are obtained, light microscopy reveals eosinophilic hyaline deposits in the corneal stroma; the source of hyaline material is still unknown.

Masson trichrome stains the deposits bright red.

Pathologic deposits react with antibodies to keratoepithelin.[2]

 

Treatment

Medical Care

When recurrent erosions occur with granular corneal dystrophy (GCD), they are treated like any other form of recurrent erosions. Under care of an ophthalmologist, bandage contact lens along with antibiotic drops can be prescribed; alternatively, patching with an antibiotic ointment can be used. Some physicians treat recurrent erosions with frequent antibiotic ointments while awake.

Once the acute episode of recurrent erosions has resolved, preventive treatment may include sodium chloride 5% drops (eg, Muro 128) or artificial tear lubricating drops during the day and lubricating ointment at bedtime. If recurrent corneal erosions occur despite medical therapy, corneal punctures or excimer laser phototherapeutic keratectomy (PTK) may be considered.

Surgical Care

Excessive corneal erosions or visual decrease from superficial opacities can be treated with PTK. Excimer laser PTK removes superficial opacities, smooths the corneal surface, and allows the epithelium to re-adhere more tightly. When deep opacities are causing significant visual symptoms, corneal transplantation may be required.

If visual acuity worsens and most of the opacities are deep, lamellar or full-thickness corneal transplantation can be performed. Although the success rate for corneal transplantation is very high, granular deposits recur with time. Fortunately, when the deposits recur, they tend to be superficial, and amenable to treatment with excimer laser PTK. A study showed that multiple PTK procedures can be safely performed in grafts without compromising graft survival and with improved visual acuity.[17]

For cases in which all of these therapies fail, sutureless femtosecond laser-assisted anterior lamellar keratoplasty (FALK) is recommended as a safe and effective technique for the management of recurrent granular corneal dystrophy in post–penetrating keratoplasty and post-PTK eyes.[18]

Two long-term case reports have suggested that the simultaneous transplantation of healthy donor limbus when performing penetrating keratoplasty (ie, limbo-keratoplasty) may prolong recurrence in granular corneal dystrophy.[19]

Long-Term Monitoring

Patients with corneal epithelial defects due to recurrent erosions need to be observed every few days to make certain the defect is healing.

Inpatient & Outpatient Medications

Patients with corneal epithelial defects from recurrent erosions require treatment with topical antibiotics to prevent infection.

 

Medication

Medication Summary

Medical therapy for recurrent corneal erosions includes hypertonic saline, which is believed to increase adherence of epithelium to the underlying stroma. Lubrication, especially at bedtime, also may help prevent further corneal erosions.

Hypertonic saline drops

Class Summary

This agent dehydrates the epithelium, allowing it to better adhere to underlying stroma.

Sodium chloride hypertonic, ophthalmic (Adsorbonac, Afrin Saline Mist, Muro 128)

Used for temporary relief of corneal edema.

Lubricating agents

Class Summary

These agents can moisten ocular surface and decrease the frequency of recurrent erosions.

Artificial tears (Celluvisc, Murine, Refresh, GenTeal, Refresh PM, Lacri-Lube)

Contains equivalent of 0.9% NaCl and are used to maintain ocular tonicity. Acts to stabilize and thicken precorneal tear film and prolong tear film breakup time, which occurs with dry eye states.