Granular Corneal Dystrophy

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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.

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]

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]

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.

No sexual predilection has been reported.

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]

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]

Grunauer-Kloevekorn C, Brautigam S, Wolter-Roessler M. Molecular genetic analysis of the BIGH3 gene in lattice type I (Biber-Haab-Dimmer) and granular type II (Avellino) corneal dystrophy: is indirect mutation analysis for hot spots recommended?. Klin Monatsbl Augenheilkd. 2005 Dec. 222(12):1017-23. [Medline].

Weiss JS, Møller HU, Lisch W, Kinoshita S, Aldave AJ, Belin MW, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008 Dec. 27 Suppl 2:S1-83. [Medline]. [Full Text].

Choi SI, Kim BY, Dadakhujaev S, Oh JY, Kim TI, Kim JY, et al. Impaired autophagy and delayed autophagic clearance of transforming growth factor ß-induced protein (TGFBI) in granular corneal dystrophy type 2. Autophagy. 2012 Sep 20. 8(12):[Medline].

Cho KJ, Mok JW, Na KS, Rho CR, Byun YS, Hwang HS, et al. TGFBI gene mutations in a Korean population with corneal dystrophy. Mol Vis. 2012. 18:2012-21. [Medline]. [Full Text].

Kannabiran C, Klintworth GK. TGFBI gene mutations in corneal dystrophies. Hum Mutat. 2006 Jul. 27 (7):615-25. [Medline].

Zeng L, Zhao J, Chen Y, Zhao F, Li M, Chao-Shern C, et al. TGFBI Gene Mutation Analysis of Clinically Diagnosed Granular Corneal Dystrophy Patients Prior to PTK: A Pilot Study from Eastern China. Sci Rep. 2017 Apr 4. 7 (1):596. [Medline].

Choi SI, Kim TI, Kim KS, Kim BY, Ahn SY, Cho HJ, et al. Decreased catalase expression and increased susceptibility to oxidative stress in primary cultured corneal fibroblasts from patients with granular corneal dystrophy type II. Am J Pathol. 2009 Jul. 175 (1):248-61. [Medline].

Choi SI, Lee E, Akuzum B, Jeong JB, Maeng YS, Kim TI, et al. Melatonin reduces endoplasmic reticulum stress and corneal dystrophy-associated TGFBIp through activation of endoplasmic reticulum-associated protein degradation. J Pineal Res. 2017 Oct. 63 (3):[Medline].

Ahn JH, Kim HD, Abuzar SM, Lee JY, Jin SE, Kim EK, et al. Intracorneal melatonin delivery using 2-hydroxypropyl-β-cyclodextrin ophthalmic solution for granular corneal dystrophy type 2. Int J Pharm. 2017 Aug 30. 529 (1-2):608-616. [Medline].

Sakimoto T. Granular corneal dystrophy type 2 is associated with morphological abnormalities of meibomian glands. Br J Ophthalmol. 2015 Jan. 99 (1):26-8. [Medline].

Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009 Feb 23. 4:7. [Medline]. [Full Text].

Lewis DR, Price MO, Feng MT, Price FW Jr. Recurrence of Granular Corneal Dystrophy Type 1 After Phototherapeutic Keratectomy, Lamellar Keratoplasty, and Penetrating Keratoplasty in a Single Population. Cornea. 2017 Oct. 36 (10):1227-1232. [Medline].

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

Dalton K, Schneider S, Sorbara L, Jones L. Confocal microscopy and optical coherence tomography imaging of hereditary granular dystrophy. Cont Lens Anterior Eye. 2009 Nov 27. [Medline].

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 Oct. 35(5):236-9. [Medline].

Jung SH, Han KE, Stulting RD, Sgrignoli B, Kim TI, Kim EK. Phototherapeutic Keratectomy in Diffuse Stromal Haze in Granular Corneal Dystrophy Type 2. Cornea. 2012 Apr 21. [Medline].

Rathi VM, Taneja M, Murthy SI, Bagga B, Vaddavalli PK, Sangwan VS. Phototherapeutic keratectomy for recurrent granular dystrophy in postpenetrating keratoplasty eyes. Indian J Ophthalmol. 2016 Feb. 64 (2):140-4. [Medline].

Taneja M, Rathi VM, Murthy SI, Bagga B, Vaddavalli PK. Femtosecond Laser-Assisted Anterior Lamellar Keratoplasty for Recurrence of Granular Corneal Dystrophy in Postkeratoplasty Eyes. Cornea. 2017 Mar. 36 (3):300-303. [Medline].

Lang SJ, Eberwein P, Reinshagen H, Reinhard T, Sundmacher R. Simultaneous transplantation of limbal stem cells may reduce recurrences of granular dystrophy after corneal transplantation: 2 long-term case reports. Medicine (Baltimore). 2015 May. 94 (20):e789. [Medline].

Das S, Langenbucher A, Seitz B. Excimer laser phototherapeutic keratectomy for granular and lattice corneal dystrophy: a comparative study. J Refract Surg. 2005 Nov-Dec. 21(6):727-31. [Medline].

Albert D, Jakobiec F. Principles and Practice of Ophthalmology. 1994. Vol 1: 26-49.

Jung SH, Han KE, Sgrignoli B, Kim TI, Lee HK, Kim EK. Intraocular lens power calculations for cataract surgery after phototherapeutic keratectomy in granular corneal dystrophy type 2. J Refract Surg. 2012 Oct. 28(10):714-24. [Medline].

Klintworth GK. Advances in the molecular genetics of corneal dystrophies. Am J Ophthalmol. 1999 Dec. 128(6):747-54. [Medline].

Krachmer J. Cornea. Vol 2: 1996.

Yamamoto S, Okada M, Tsujikawa M, et al. The spectrum of beta ig-h3 gene mutations in Japanese patients with corneal dystrophy. Cornea. 2000 May. 19(3 Suppl):S21-3. [Medline].

Jean Deschênes, MD, FRCSC Professor, Research Associate, Director, Uveitis Program, Department of Ophthalmology, McGill University Faculty of Medicine; Senior Ophthalmologist, Clinical Director, Department of Ophthalmology, Royal Victoria Hospital, Canada

Jean Deschênes, MD, FRCSC is a member of the following medical societies: American Academy of Ophthalmology, Association for Research in Vision and Ophthalmology, Canadian Medical Association, Canadian Ophthalmological Society, International Ocular Inflammation Society, Quebec Medical Association

Disclosure: Nothing to disclose.

Susan Ruyu Qi  University of Montreal Faculty of Medicine, Canada

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Christopher J Rapuano, MD Professor, Department of Ophthalmology, Sidney Kimmel Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Hospital

Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, American Ophthalmological Society, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Cornea Society, Eye Bank Association of America, International Society of Refractive Surgery

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cornea Society, AAO, OMIC, Allergan; Avedro; Bio-Tissue; GSK, Novartis; Shire; Sun Ophthalmics; TearLab<br/>Serve(d) as a speaker or a member of a speakers bureau for: Avedro; Bio-Tissue; Shire.

Hampton Roy, Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy, Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

William Lloyd Clark, MD Palmetto Retina

William Lloyd Clark, MD is a member of the following medical societies: Alpha Omega Alpha, Association for Research in Vision and Ophthalmology, American Academy of Ophthalmology

Disclosure: Nothing to disclose.

Fernando H Murillo-Lopez, MD Senior Surgeon, Unidad Privada de Oftalmologia CEMES

Fernando H Murillo-Lopez, MD is a member of the following medical societies: American Academy of Ophthalmology

Disclosure: Nothing to disclose.

William B Trattler, MD Ophthalmologist, The Center for Excellence in Eye Care; Volunteer Assistant Professor of Ophthalmology, Bascom Palmer Eye Institute

William B Trattler, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery

Disclosure: Received consulting fee from Allergan for consulting; Received consulting fee from Alcon for consulting; Received consulting fee from Bausch & Lomb for consulting; Received consulting fee from Abbott Medical Optics for consulting; Received consulting fee from CXLUSA for none; Received consulting fee from LensAR for none.

Natalie A Afshari, MD, MA, FACS Stuart I Brown, MD, Chair in Ophthalmology In Memory of Donald P Shiley, Professor of Ophthalmology, Chief of Cornea and Refractive Surgery, Director of Education, Fellowship Program Director in Cornea and Refractive Surgery, Shiley Eye Center, University of California, San Diego, School of Medicine

Natalie A Afshari, MD, MA, FACS is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Association for Research in Vision and Ophthalmology, Heed Ophthalmic Foundation

Disclosure: Nothing to disclose.

Joanne W Ho University of California, San Diego, School of Medicine

Disclosure: Nothing to disclose.

Granular Corneal Dystrophy

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