Corneal dystrophies

DEFINITION The cornea is the most anterior clear structure of the eye, analogous to a windshield. From anterior to posterior, the cornea contains epithelium, Bowman’s membrane, stroma, Decemet’s membrane, and endothelium. Corneal dystrophy describes primarily bilateral, often inherited, noninflammatory corneal disorders that are not related to systemic disease. The ICD 3 classification of corneal dystrophies was published in 2008 in the journal Cornea. Older classification schemes use anatomic location, whereas newer classification uses genetics to categorize corneal dystrophies into four categories.

Category 1 includes well defined dystrophies with known genes. Category 2 disorders are well defined with a known gene locus but no specific gene identified. Category 3 encompasses well-defined dystrophies with no known gene or locus. Dystrophies in Category 4 are poorly defined disorders with no known gene or locus. As the genetics of corneal dystrophies become more defined, these poorly defined disorders may be identified as variants of known dystrophies. Ophthalmologists will likely continue using anatomic classifications, however, as more genes are identified a new classification scheme may develop to include both anatomic and genetic features.

Risk Factors

Family history is the risk factor for corneal dystrophy. Unfortunately, symptoms are often subtle and may appear later in life or may be misdiagnosed because of the rarity of corneal dystrophies.

Etiology and Genetics

Autosomal dominant conditions in which 50 percent of children may inherit the disorder include epithelial basement membrane dystrophy (map-dot-fingerprint, Cogan’s microcystic), Meesmann dystrophy (juvenile hereditary epithelial dystrophy), and Thiel-Behnke dystrophy (Vogt anterior crocodile-shagreen, corneal dystrophy of Bowman layer type II). Epithelial basement membrane disorders may be found in up to 2 percent of the population.

The autosomal dominant stromal dystrophies include granular corneal dystrophy (Groenouw type 1), lattice corneal dystrophy (Biber-Haab-Dimmer), Avellino corneal dystrophy, and superficial granular corneal dystrophy (Bowman type 1 corneal dystrophy, Reis-Bucklers). These disorders are associated with TGFBI gene mutations. There are several variants of lattice type corneal dystrophy that are autosomal dominant and are associated with the TGFBI gene.

Additional autosomal dominant corneal dystrophies affecting the stroma are Meretoja, central corneal crystalline dystrophy (Schnyder), Fleck corneal dystrophy (Francois and Neetens), central cloudy corneal dystrophy (posterior crocodile-shagreen), congenital hereditary stromal dystrophy, and posterior amorphous corneal dystrophy. Many of these conditions are not linked to a specific gene or locus, and some may be variants. Posterior autosomal dominant disorders that involve the epithelium are congenital hereditary corneal edema type 1, polymorphous deep corneal dystrophy of Schlichting, and Fuchs endothelial corneal dystrophy.

Autosomal recessive corneal dystrophies include the anterior stromal dystrophies macular corneal dystrophy, gelatinous droplike dystrophy, and lattice corneal dystrophy type 3. In the anatomic area of the endothelium, the congenital hereditary corneal edema (CHED type 2) is also autosomal recessive. There are several other corneal dystrophies that are not yet defined as dominant or recessive. The penetrance (degree) of both the dominant and recessive dystrophies can be variable.

Disorders such as keratoconus and pellucid degeneration may be hereditary and can cause progressive corneal irregularity. These disorders are not generally considered corneal dystrophies. There are also systemic disorders that can affect the cornea. By definition, corneal dystrophies not associated with systemic disorders.

There was a rapid increase in the understanding of the genetics of corneal dystrophies in the late twentieth and early twenty-first centuries, and the understanding of these disorders from a genetics standpoint will likely continue to evolve as more research is undertaken. The first major breakthrough came in the 1990s, when Robert Folberg and associates identified mutations of the 5q31 chromosome as the cause for some forms of lattice degeneration. The majority of the classic autosomal dominant stromal corneal dystrophies have been shown to involve this chromosome. Several genes have been identified in these disorders.

In the epithelial dystrophies, the KRT12 gene at 17q12, the KRT3 gene at 12q13, and the CDB2 gene at 10q24 locations have been identified. Some form of Meesmann dystrophy may also be X-linked. Several stromal mutations have been associated with the TGFBI gene mutations. For autosomal recessive dystrophies, the 16q22 with mutations at the CHST6 gene and 1p32 with mutations at the M1S1 gene has been identified. Additional chromosomes that have been identified in corneal dystrophies include 9p34, 1p34.1,2q35, 20p12-q13.1, 20p13, 20p11.2, and 1p34.2-p32.

In 2016, researchers at the UCL Institute of Ophthalmology and Moorfields Eye Hospital London discovered new links between specific genes and certain types of corneal dystrophies. The discovery tied alterations in a DNA sequences that regulates the genes OVOL2 with incidents of CHED1 and PPCD1 corneal dystrophy.

Symptoms

The main symptoms of corneal dystrophies include blurred vision, pain, or spontaneous corneal abrasions also known as recurrent erosions. Symptoms may have a sudden onset such as in the case of an epithelial dystrophy, where a sudden spontaneous abrasion may occur upon awakening. Others may have a more subtle onset and can be mistaken for other corneal disorders such as herpes simplex infection. Dystrophies such as Fuchs corneal endothelial dystrophy may cause fluctuation of vision with a worsening of vision in the morning and improvement in vision later in the day.

Screening and Diagnosis

Family history of corneal dystrophies may be unknown due to either advanced age of onset or misdiagnosis. The most important screening test is a careful slit-lamp examination with a qualified ophthalmologist. An ophthalmologist trains as a medical doctor with a residency in ophthalmology. An optometrist is also qualified to do a slit-lamp examination and can refer the patient to an ophthalmologist for further diagnosis and treatment as needed.

Screening and Diagnosis

Discoveries of specific genes and mutations responsible for corneal dystrophies are very recent, so genetic screening is not yet standard of care in the diagnosis and treatment of most corneal dystrophies.

Treatment and Therapy

Depending on the type of corneal dystrophy, anatomic area affected, and severity of symptoms, treatment will range from observation to treatment with drops or ointments to corneal transplant. In severe cases, a fellowship-trained corneal specialist, an ophthalmologist with specialized corneal training, will be involved in diagnosis and treatment. Many corneal dystrophies have symptoms that are so mild that the dystrophy is never diagnosed. For those who are diagnosed, many retain functional vision throughout their lives. Severe cases may require corneal transplant for vision improvement.

Prevention and Outcomes

No specific preventive measures are available for corneal dystrophies. For dystrophies that appear in infancy and childhood, treatment of the corneal disorder is important to avoid amblyopia, in which the visual system does not develop properly. Recognizing early-onset corneal dystrophy requires vigilance from parents, family physicians, obstetricians, or pediatricians. Warning signs might include white opacities on the cornea or apparent white pupil (leukocoria), family history of corneal disorders, failure of the infant to fixate properly, or deviation of the eyes such as turning in or turning out. Older patients may seek care for eye discomfort or blurred vision.

Bibliography

"Breakthrough Discovery in the Genetics of Corneal Dystrophies." UCL, 25 Feb. 2016, www.ucl.ac.uk/ioo/news/2016/feb/breakthrough-discovery-genetics-corneal-dystrophies. Accessed 4 Sept. 2024.

Cummings, Thomas J. Ophthalmic Pathology: A Concise Guide. New York: Springer, 2013. Print.

Krachmer, Jay H., Mark J. Mannis, and Edward J. Holland. Cornea. St. Louis: Elsevier Mosby, 2004. Print.

Merin, Saul. Inherited Eye Diseases Diagnosis and Management. 2nd ed. Boca Raton: Taylor, 2005. Print.

Reinhard, Thomas, and Frank Larkin, eds. Corneal Disease: Recent Developments in Diagnosis and Therapy. New York: Springer, 2013. Print.

Traboulsi, Elias I., ed. Genetic Diseases of the Eye. 2nd ed. New York: Oxford UP, 2012. Print.

Wall, Sarah, et al. "The Need for Corneal Dystrophy Genetic Testing." Corneal Physician, 1 Apr. 2024, www.cornealphysician.com/issues/2024/april/the-need-for-corneal-dystrophy-genetic-testing/. Accessed 4 Sept. 2024.