Granular Corneal Dystrophy

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Article initiated by:
Amr K. Hassan, Oscar Chen
All contributors:
Anne Kim, Christina Moon, M.D., Colleen Halfpenny, M.D., Oscar Chen, Amr K. Hassan
Assigned editor:
Maria D. Bernal, MD
Review:
Assigned status Update Pending
 by Christina Moon, M.D. on November 9, 2023.


Disease Entity

Granular Corneal Dystrophy [ICD 10: H18.539 - Granular corneal dystrophy, unspecified eye]

Disease

Granular corneal dystrophy (GCD) is a rare, inherited condition characterized by granular deposits in the stromal layer of the cornea, leading to slow progression of visual impairment due to loss of corneal transparency. These opacities typically present in the first decade of life, as early as 3 years of age. As this condition progresses, the bilateral granules increase in size and number but do not extend to the peripheral limbus. There are two types of GCD, which are distinguished by their clinical appearance and composition of corneal deposits.[1]

Etiology

GCD is inherited in an autosomal dominant pattern. It is caused by a point mutation in the transforming growth factor β induced (TGFBI) gene located on chromosome 5q31 locus, also known as BIGH3. This gene encodes transforming growth factor beta induced protein (TGFBIp), also known as the protein kerato-epithelin.[2]

Risk Factors

Due to autosomal dominant inheritance, positive family history increases the risk of GCD. Homozygote individuals tend to have more severe phenotype with larger and confluent corneal opacities than heterozygotes.[3] GCD type 1 is reportedly more prevalent in Europe.[4] GCD type 2 was first described from the first four patients in the original study, each tracing their ancestry from the Italian province of Avellino.[5][6] However, studies have demonstrated that it has been seen in populations without Italian ancestry. It is currently the most common type of TGFBI corneal dystrophy in certain countries in Asia, specifically Korea and Japan.[7][8] Granular dystrophy is less prevalent in the US, occurring in an estimated 1% or less of the population.[8]

General Pathology

Granular corneal dystrophy is a part of a group of epithelial-stromal TGFBI dystrophies, but the epithelium and Bowman layer may be affected in late disease. Granular corneal dystrophy is categorized into two subtypes:  

Granular corneal dystrophy type 1

GCD Type 1 (GCD1) is also known as classic granular or Groenouw corneal dystrophy type 1. The onset of GCD1 occurs early in life with development of white opacities in the superficial cornea. The disease initially appears as lesions separated by spaces of clear cornea, resembling breadcrumbs or snowflakes, and can coalesce to form larger deposits with disease progression. Lesions appear in the central cornea and may not extend to the limbus. Because GCD1 is a slowly progressive condition, most patients can experience glare and photophobia but can typically maintain good visual acuity until the fifth decade of life. Granular deposits, which may derive from corneal epithelium or keratocytes, stain positive as bright red for hyaline using the Masson trichrome stain. Amyloid is not present, differentiating it from GCD2 and lattice corneal dystrophy. Electron microscopy reveals rod shaped or trapezoidal deposits. [9][10]

These deposits may cause recurrent corneal erosions due to breakdown of cells on the corneal epithelial layer or Bowman’s layer. This results in sharp pain on the corneal surface, particularly during sleep or upon awakening, and may involve blurred vision, tearing, redness, and/or photophobia.[11]

Granular corneal dystrophy type 2

GCD type 2 (GCD2) is also known as Avellino corneal dystrophy or combined granular-lattice corneal dystrophy. Clinically, patients present similarly to those with GCD1. However, patients with GCD2 present in childhood or early adulthood with white dots progressing to stellate-shaped opacities later in age. GCD2 tends to present with fewer corneal deposits than GCD1. Deep lattice-like amyloid lesions can be seen after the appearance of granular deposits, which tend to be more common. Unlike type 1, both hyaline and amyloid deposits can be present with positive staining on Masson trichome and Congo red stains, respectively. Electron microscopy reveals rod shaped deposits and possible fibrils of amyloid. These deposits can cause recurrent corneal erosions and lead to decreased visual acuity due to increasing corneal opacity in later stage of the disease. [12]

Pathophysiology

GCD is caused by mutations in the TGFBI gene, which encodes transforming growth factor beta induced protein (TGFBIp), also known as kerato-epithelin.  Mutations of the gene may lead to accumulation of protein deposits in the cornea, leading to corneal clouding and reduced vision.[2]

GCD1 is associated with mutations on TGFB1 gene, predominantly arginine replacing tryptophan at position 555 (Arg555Trp).[13]  One study suggests hereditary mutations in the TGFBI gene decreases susceptibility to proteolysis, causing abnormal degradation of TGFBIp and accumulation in the cornea.[14] Another study of a large Tunisian family described presentation of GCD1 for homozygous mutation of arginine to serine in codon 124 (R124S).[15]

GCD2 is almost exclusively caused by substitution of arginine to histidine in codon 124 (R124H) of the TGFBI gene.[16] This point mutation of the TGFB1 gene can activate extracellular protein accumulation in the cornea and ultimately lead to corneal clouding. One study proposes that GCD2 is associated with impaired autophagy that leads to accumulation of TGFBIp, while another study suggests mitochondrial dysfunction may be involved.[17][18] The pathogenesis of GCD is currently not well understood.

Primary Prevention

There are no known preventative strategies for GCD that have been studied to date.  

Diagnosis

History

Patients who are homozygous for GCD present earlier and symptomatically with recurrent corneal erosions in the first decade of life.[19] Otherwise in heterozygotes, patients are often asymptomatic but can experience glare and photophobia. Decreased visual acuity and recurrent corneal erosions tends to present after the 4th or 5th decade of life.  

Physical examination

The lesions consist of bilateral, discrete, small, white granular lesions in the anterior stroma with clear areas between these deposits. The granules are primarily located in the central cornea, with an absence of these deposits in the periphery. The deposits resemble crushed breadcrumbs or snowflakes. The deposits become larger and increase in number as the disease progresses. Eventually, the intervening clear areas develop a corneal haze, which opacify with age. This late opacification is usually much more superficial than the longstanding, dense white granules. Vision dramatically declines when the clear spaces opacify.

Signs and Symptoms

Patients are most often asymptomatic but may experience glare and reduced vision. Patients may form corneal erosions, which can cause decreased visual acuity and result in corneal clouding later in life. Other symptoms in addition to visual impairment include eye discomfort or pain.  

Clinical Diagnosis

Clinical diagnosis is primarily based on observation of multiple irregular, discrete, crumb or flake-like opacities or subtle white dots in the anterior stroma on slit-lamp biomicroscopy in addition to a positive family history. The deposits may become numerous, enlarge, and coalesce in Type 1, whereas deposits may progress to larger stellate lesions with lattice lines in the deeper stroma in Type 2.  

Diagnostic procedures

Various imaging modalities may be useful in determining size, location, and depth of corneal opacities, including deposits from GCD. Anterior segment coherence tomography (AS-OCT) will often show hyperreflective opacities in the anterior stroma in GCD. AS-OCT can also be useful in guiding therapeutic procedures such as phototherapeutic keratectomy (PTK).[20] Confocal microscopy will demonstrate irregular highly reflective crumb-like opacities between the epithelium and Bowman’s layers. Superficial corneal layers will show flat deposits compared to deeper layers.[21] Ultrasound biomicroscopy of GCD shows hyperreflective hyaline granules within the superficial stroma of the cornea.[22] Corneal topography can also provide additional information regarding density of the opacities, which can be helpful for PTK or anterior lamellar keratoplasty (ALK). [23]

Differential Diagnosis

Lattice corneal dystrophy type 1 (LCD)

Lattice corneal dystrophy type 1 is a rare, slow-progressive condition. Similar to GCD, it is inherited in an autosomal dominant pattern and caused by a mutation in the TGFBI gene on 5q31. Onset begins in the first decade and can cause visual impairment after the fourth decade of life.  Slit lamp examination shows amyloid deposition and linear lattice-like opacities in the anterior central cornea. Unlike GCD, LCD type 1 presents with multiple amyloid protein deposits between the epithelium and Bowman’s layer and reveal an atrophic epithelium on optical computed tomography due to disruption of the Bowman’s layer.[1][12]

Macular Corneal Dystrophy (MCD)

Macular corneal dystrophy is a rare corneal stromal dystrophy caused by mutation in the CHST6 gene of the 16q22 locus. Dysfunction in proteoglycan synthesis of keratan sulfate in the stroma and epithelium lead to deposition of abnormal proteoglycans, causing decreased vision over time.[24] Similar to GCD, it first appears as small bilateral irregular opacities, which become gray-white within a hazy stroma. These opacities gradually extend throughout the central and peripheral corneal stroma and coalesces until the entire stroma is opacified. Patients with MCD can experience decreased vision before the fifth decade of life. Unlike GCD or other corneal dystrophies, MCD has an autosomal recessive inheritance, and histopathology shows distinct intracytoplasmic deposits within stromal keratocytes and the corneal endothelium, consisting of glycosaminoglycans. Corneal thinning is also associated with MCD, which is not yet shown in GCD.[1][25]

Fleck Corneal Dystrophy (FCD)

Fleck corneal dystrophy is an autosomal dominant corneal dystrophy associated with mutations in the enzyme phosphatidylinositol 3-phosphate 5-kinase type III (PIP5K3) gene. These mutations may affect the trafficking of peripheral endosomes, which lead to the pathologic appearance of vacuolated keratocytes containing lipids and glycosaminoglycans in the stroma.[26] On examination, numerous small white “dandruff-like” flecks are distributed throughout the corneal stroma, including the periphery. Unlike GCD, FCD is usually asymptomatic and vision is often maintained due to its nonprogressive nature.[1]

Schnyder Corneal Dystrophy (SCD)

Schnyder corneal dystrophy is caused by mutations in the UbiA prenyltransferase domain containing 1 (UBIAD1) gene, which is involved in lipid metabolism.[27][28] Mutations lead to cholesterol and lipid deposition in the cornea, leading to slowly progressive corneal opacification, increased glare, and decreased visual acuity, specifically photopic vision.[29] Systemic findings associated with SCD include dyslipidemia and genu valgum. SCD can appear early in life with corneal clouding or crystalline deposits in the central cornea within a diffuse haze, which can progress to a ring-shaped structure or arcus lipoides.[1][29] It is an autosomal dominant corneal dystrophy similar to GCD, but the characteristic features of cholesterol and lipid deposits are more specific to SCD.

Posterior amorphous corneal dystrophy (PACD)

Posterior amorphous corneal dystrophy is an autosomal dominant, nonprogressive condition involving the posterior stroma, Descemet’s membrane, and iris. It presents early in the first decade of life and has been considered a congenital disorder. PACD is characterized by sheet-like opacities on the posterior stroma. Unlike GCD, PACD is notable for corneal flattening and thinning, iridocorneal adhesions, corectopia, and other abnormalities.[1][11][19]

Management

Medical therapy

Medical therapy involves treating the symptoms and delaying progression of the disease. No treatment is required early disease unless there is reduced vision or presence of corneal erosions. Medical treatment for recurrent erosions from granular corneal dystrophy may include artificial lubrication to reduce dryness and irritation. Bandage soft contact lenses with prescribed antibiotic drops and ointments to protect the eye and promote healing.[30]  

Surgery

If recurrent corneal erosions occur despite preventive or conservative management, surgical interventions may be considered. Excimer laser ablation with PTK can also remove superficial opacities by smoothening irregularities of corneal surface.[31][32] One case report suggests alcohol epitheliectomy with mechanical debridement may show similar visual outcomes as PTK for superficial GCD.[33] Penetrating Keratoplasty (PK) or Deep Anterior Lamellar Keratoplasty (DALK) may be required for loss of vision and in severe and late cases with profound lesions. Recent research has also shown that femtosecond laser-assisted anterior lamellar keratoplasty (FALK) is also safe and effective method for recurrent GCD, especially in post–penetrating keratoplasty and post-PTK eyes.[34]

Patients should be made aware that GCD is a contraindication for laser refractive surgery laser, including in situ keratomileusis (LASIK), and photorefractive keratectomy (PRK), due to risk of worsening corneal opacity after surgery.

Prognosis

There is a good prognosis for GCD after PTK, ALK, or DALK procedures. According to a retrospective review of patients with GCD1, recurrence occurred most rapidly after PTK, ALK, and DALK, at median time 2.7, 3.7, and 3.2 years, respectively. Recurrence was most delayed after penetrating keratoplasty, which had a median time of 13.7 years. All groups achieved a similar median best corrected visual acuity (20/25-20/30).[35]

Additional Resources

https://webeye.ophth.uiowa.edu/eyeforum/cases/43-corneal-stromal-dystrophies.htm

https://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/Granular-corneal-dystrophy/index.htm

https://www.aao.org/Assets/5fc86c03-e31b-4502-9177-789629b1eed1/637151444264670000/k42u-pdf?inline=1

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Klintworth, G.K., Corneal dystrophies. Orphanet J Rare Dis, 2009. 4: p. 7.
  2. ↑ 2.0 2.1 Munier, F.L., et al., Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet, 1997. 15(3): p. 247-51.
  3. ↑ Okada, M., et al., Granular corneal dystrophy with homozygous mutations in the kerato-epithelin gene.Am J Ophthalmol, 1998. 126(2): p. 169-76.
  4. ↑ Lang, G.K. and G.O. Naumann, The frequency of corneal dystrophies requiring keratoplasty in Europe and the U.S.A. Cornea, 1987. 6(3): p. 209-11.
  5. ↑ Folberg, R., et al., Clinically atypical granular corneal dystrophy with pathologic features of lattice-like amyloid deposits. A study of these families. Ophthalmology, 1988. 95(1): p. 46-51.
  6. ↑ Holland, E.J., et al., Avellino corneal dystrophy. Clinical manifestations and natural history.Ophthalmology, 1992. 99(10): p. 1564-8.
  7. ↑ Cho, K.J., et al., TGFBI gene mutations in a Korean population with corneal dystrophy. Mol Vis, 2012. 18: p. 2012-21.
  8. ↑ 8.0 8.1 Mashima, Y., et al., Association of autosomal dominantly inherited corneal dystrophies with BIGH3 gene mutations in Japan. Am J Ophthalmol, 2000. 130(4): p. 516-7.
  9. ↑ Akiya, S. and S.I. Brown, Granular dystrophy of the cornea. Characteristic electron microscopic lesion.Arch Ophthalmol, 1970. 84(2): p. 179-92.
  10. ↑ Brownstein, S., et al., Granular dystrophy of the cornea. Light and electron microscopic confirmation of recurrence in a graft. Am J Ophthalmol, 1974. 77(5): p. 701-10.
  11. ↑ 11.0 11.1 Sacchetti, M., et al., Pathophysiology of Corneal Dystrophies: From Cellular Genetic Alteration to Clinical Findings. J Cell Physiol, 2016. 231(2): p. 261-9.
  12. ↑ 12.0 12.1 Siebelmann, S., et al., Anterior segment optical coherence tomography for the diagnosis of corneal dystrophies according to the IC3D classification. Survey of Ophthalmology, 2018. 63(3): p. 365-380.
  13. ↑ Chakravarthi, S.V., et al., TGFBI gene mutations causing lattice and granular corneal dystrophies in Indian patients. Invest Ophthalmol Vis Sci, 2005. 46(1): p. 121-5.
  14. ↑ Underhaug, J., et al., Mutation in transforming growth factor beta induced protein associated with granular corneal dystrophy type 1 reduces the proteolytic susceptibility through local structural stabilization. Biochim Biophys Acta, 2013. 1834(12): p. 2812-22.
  15. ↑ Phenotype-genotype correlation of p.R124S mutation in granular type 1 corneal dystrophy of Tunisian origin. Acta Ophthalmologica, 2018. 96(S261): p. 38-38.
  16. ↑ Lakshminarayanan, R., et al., Clinical and genetic aspects of the TGFBI-associated corneal dystrophies. Ocul Surf, 2014. 12(4): p. 234-51.
  17. ↑ Kim, T.I., et al., Altered mitochondrial function in type 2 granular corneal dystrophy. Am J Pathol, 2011. 179(2): p. 684-92.
  18. ↑ Choi, S.I., et al., Impaired autophagy and delayed autophagic clearance of transforming growth factor β-induced protein (TGFBI) in granular corneal dystrophy type 2. Autophagy, 2012. 8(12): p. 1782-97.
  19. ↑ 19.0 19.1 Kim, M.J., et al., Posterior amorphous corneal dystrophy is associated with a deletion of small leucine-rich proteoglycans on chromosome 12. PLoS One, 2014. 9(4): p. e95037.
  20. ↑ Mori, H., et al., Three-dimensional optical coherence tomography-guided phototherapeutic keratectomy for granular corneal dystrophy. Cornea, 2009. 28(8): p. 944-7.
  21. ↑ Shukla, A.N., A. Cruzat, and P. Hamrah, Confocal microscopy of corneal dystrophies. Semin Ophthalmol, 2012. 27(5-6): p. 107-16.
  22. ↑ Heur, M. and B.H. Jeng, Ultrasonography of the Anterior Segment. Ultrasound Clin, 2008. 3(2): p. 201-206.
  23. ↑ Kocluk, Y., et al., Corneal topography analysis of stromal corneal dystrophies. Pak J Med Sci, 2015. 31(1): p. 116-20.
  24. ↑ Nakazawa, K., et al., Defective processing of keratan sulfate in macular corneal dystrophy. J Biol Chem, 1984. 259(22): p. 13751-7.
  25. ↑ Aggarwal, S., et al., Macular corneal dystrophy: A review. Survey of Ophthalmology, 2018. 63(5): p. 609-617.
  26. ↑ Li, S., et al., Mutations in PIP5K3 are associated with François-Neetens mouchetée fleck corneal dystrophy. American journal of human genetics, 2005. 77(1): p. 54-63.
  27. ↑ Du, C., et al., A mutation in the UBIAD1 gene in a Han Chinese family with Schnyder corneal dystrophy. Mol Vis, 2011. 17: p. 2685-92.
  28. ↑ Weiss, J.S., et al., Mutations in the UBIAD1 gene on chromosome short arm 1, region 36, cause Schnyder crystalline corneal dystrophy. Investigative ophthalmology & visual science, 2007. 48(11): p. 5007-5012.
  29. ↑ 29.0 29.1 Weiss, J.S., Visual morbidity in thirty-four families with Schnyder crystalline corneal dystrophy (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc, 2007. 105: p. 616-48.
  30. ↑ Roters, S., et al., Treatment of granular dystrophy with soft contact lenses. Ophthalmologica, 2004. 218(1): p. 70-2.
  31. ↑ Stewart, O.G., et al., Visual and symptomatic outcome of excimer phototherapeutic keratectomy (PTK) for corneal dystrophies. Eye (Lond), 2002. 16(2): p. 126-31.
  32. ↑ Fagerholm, P., Phototherapeutic keratectomy: 12 years of experience. Acta Ophthalmol Scand, 2003. 81(1): p. 19-32.
  33. ↑ Ashar, J.N., M. Latha, and P.K. Vaddavalli, 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): p. 236-9.
  34. ↑ Taneja, M., et al., Femtosecond Laser-Assisted Anterior Lamellar Keratoplasty for Recurrence of Granular Corneal Dystrophy in Postkeratoplasty Eyes. Cornea, 2017. 36(3): p. 300-303.
  35. ↑ Lewis, D.R., et al., Recurrence of Granular Corneal Dystrophy Type 1 After Phototherapeutic Keratectomy, Lamellar Keratoplasty, and Penetrating Keratoplasty in a Single Population. Cornea, 2017. 36(10): p. 1227-1232.
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