GRANULAR DYSTROPHY

Signs and Symptoms

Granular corneal dystrophy is a bilateral condition that affects the central regions of the corneal stroma while sparing the periphery.1-3 Two distinct classifications of this condition have been described: type 1 (GCD1), or classic granular dystrophy and type 2 (GCD2), more commonly known as Avellino corneal dystrophy.1,4 Clinically, both varieties present with multiple, discrete, white-to-gray corneal deposits that are non-uniform in size, most closely resembling snowflakes or breadcrumbs. Avellino dystrophy is distinguished by greater variability in the size of the opacities, as well as a tendency for the opacities to fuse and give rise to elongated and stellate shapes. In addition, Avellino dystrophy may present with amyloid lesions in the deeper stroma, a finding consistent with lattice corneal dystrophy.4

Patients with granular dystrophy may be diagnosed on routine examination during childhood or adolescence, although the condition does not typically become symptomatic until the third or fourth decade of life.1,4,5 Vision is usually not affected in the early stages; however, as the deposits become larger and more dense, visual acuity may drop off precipitously. It is not unusual to see older patients with this condition manifesting vision of 20/200 or worse. Patients may also report varying degrees of ocular irritation, ranging from a mild foreign body sensation to pronounced pain. The most significant complication, aside from reduced vision, is the propensity toward recurrent epithelial erosions.6,7

Pathophysiology

Corneal dystrophies are non-infectious, non-inflammatory, hereditary disorders that involve abnormal deposition or retention of material within the cornea, usually due to faulty cellular metabolism or nutrition. The underlying etiology is often related to a specific genetic mutation.8 Such dystrophies are categorized by the layer of the cornea in which they are found, including the superficial anterior layers (epithelium and epithelial basement membrane), Bowman’s layer, the corneal stroma, Descemet’s membrane or the endothelium. Granular dystrophy occurs at the level of the stroma, although it is not the most common stromal corneal dystrophy seen in clinical practice.9 In vivo confocal microscopy shows that the deposits in granular dystrophy vary in shape from round to trapezoidal, and in size from 50-500µm in diameter.2 The epithelial basement membrane and Bowman’s layer are also altered, and this can lead to recurrent corneal erosion.

Granular dystrophy displays an autosomal dominant inheritance pattern with variable penetrance.1 Both GCD1 and GCD2 are considered to be part of the TGFBI (Tissue Growth Factor Beta Inducible) dystrophies, along with lattice corneal dystrophy and Reis-Bucklers dystrophy.2,7 These conditions arise from mutations in the chromosome 5q31-related TGFBI gene.10 The majority of the mutations in TGFBI are located in the Fas1 domain 4 with the mutational hotspots being Arg124 and Arg555.7 Further studies suggest that GCD1 and GCD2 are primarily associated with accumulation of the R555W and R124H mutant TGFBI proteins in corneal stroma, respectively.11

Management

There is no recognized medical therapy for granular corneal dystrophy. Patients typically endure the situation, relying on ocular lubricants and perhaps hypertonic solutions for palliative relief of irritation. When significant visual compromise ensues, however, surgical intervention may become necessary.

Phototherapeutic keratectomy (PTK) has been effectively used for removing central superficial corneal opacities and improving visual acuity in patients with granular corneal dystrophy.4,12,13 Alcohol epitheliectomy with mechanical debridement can be used to treat cases with a superficial variant of granular dystrophy where phototherapeutic keratectomy is not available.14,15 More severe cases may warrant anterior lamellar keratoplasty or even penetrating keratoplasty.16 However, even after surgical intervention, granular dystrophy may recur in a significant proportion of patients. Published reports suggest that the use of soft contact lenses postoperatively may diminish the likelihood of recurrence.17

Conventional treatment of corneal erosions associated with granular dystrophy involves lubrication, bandage contact lenses, prophylactic antibiotics and topical anti-inflammatory agents as needed for pain. Anterior stromal puncture is not advisable for recurrent erosions secondary to corneal dystrophies, and should be employed only in those cases of erosion associated with prior ocular trauma. PTK, on the other hand, has been successfully used in recalcitrant recurrent corneal erosions independent of the etiology.18

Clinical Pearls

Since granular dystrophy is autosomal dominant, it is important to examine family members (especially siblings or children) for similar ocular findings.

In the palliative management of granular dystrophy, ocular lubricants are generally helpful. No published studies exist to demonstrate superiority of any particular product over the others; however, one of the authors (AGK) has had excellent success with FreshKote (Focus Laboratories), a product that has high oncotic pressure to reestablish the epithelial integrity and a lipid-restorative agent to increase lubricity and wettability.

1. Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009;4:7.

2. Shukla AN, Cruzat A, Hamrah P. Confocal microscopy of corneal dystrophies. Semin Ophthalmol. 2012;27(5-6):107-16.

3. Lee ES, Kim EK. Surgical do’s and don’ts of corneal dystrophies. Curr Opin Ophthalmol. 2003;14(4):186-91.

4. Han KE, Kim TI, Chung WS, et al. Clinical findings and treatments of granular corneal dystrophy type 2 (avellino corneal dystrophy): a review of the literature. Eye Contact Lens. 2010;36(5):296-9.

5. Moon JW, Kim SW, Kim TI, et al. Homozygous granular corneal dystrophy type II (Avellino corneal dystrophy): natural history and progression after treatment. Cornea. 2007;26(9):1095-100.

6. Han KE, Chung WS, Kim T, et al. Changes of clinical manifestation of granular corneal deposits because of recurrent corneal erosion in granular corneal dystrophy types 1 and 2. Cornea. 2013;32(5):e113-20.

7. Poulaki V, Colby K. Genetics of anterior and stromal corneal dystrophies. Semin Ophthalmol. 2008;23(1):9-17.

8. Vincent AL, Patel DV, McGhee CN. Inherited corneal disease: The evolving molecular, genetic and imaging revolution. Clin Experiment Ophthalmol. 2005;33(3):303-16.

9. Musch DC, Niziol LM, Stein JD, et al. Prevalence of corneal dystrophies in the United States: estimates from claims data. Invest Ophthalmol Vis Sci. 2011;52(9):6959-63.

10. Eiberg H, Moller HU, Berendt I, Mohr J. Assignment of granular corneal dystrophy Groenouw type I (CDGG1) to chromosome 5q. Eur J Hum Genet. 1994;2(2):132-8.

11. Han YP, Sim AJ, Vora SC, Huang AJ. A unique TGFBI protein in granular corneal dystrophy types 1 and 2. Curr Eye Res. 2012;37(11):990-6.

12. Mori H, Miura M, Iwasaki T, et al. Three-dimensional optical coherence tomography-guided phototherapeutic keratectomy for granular corneal dystrophy. Cornea. 2009;28(8):944-7.

13. Jung SH, Han KE, Stulting RD, et al. Phototherapeutic keratectomy in diffuse stromal haze in granular corneal dystrophy type 2. Cornea. 2013;32(3):296-300.

14. Garg P, Jabbar A. Alcohol epitheliectomy with mechanical debridement in a case of granular corneal dystrophy with r555w homozygous mutation of TGF B1 gene. Indian J Ophthalmol. 2010;58(4):328-9.

15. Ashar JN, Latha M, Vaddavalli PK. Phototherapeutic keratectomy versus alcohol epitheliectomy with mechanical debridement for superficial variant of granular dystrophy: a paired eye comparison. Cont Lens Anterior Eye. 2012;35(5):236-9.

16. Unal M, Arslan OS, Atalay E, et al. Deep anterior lamellar keratoplasty for the treatment of stromal corneal dystrophies. Cornea. 2013;32(3):301-5.

17. Roters S, Severin M, Konen W, Krieglstein GK. Treatment of granular dystrophy with soft contact lenses. Ophthalmologica. 2004;218(1):70-2.

18. Jain S, Austin DJ. Phototherapeutic keratectomy for treatment of recurrent corneal erosion. J Cataract Refract Surg 1999; 25(12):1610-4.