Posterior Amorphous Corneal Dystrophy

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Disease Entity

Posterior Amorphous Corneal Dystrophy (ICD-10 # H18.593, H18.599 - Other hereditary corneal dystrophies)

Disease

Posterior amorphous corneal dystrophy (PACD) is a rare disorder that involves the posterior stroma, Descemet’s membrane, and sometimes the iris. It falls into a category of stromal corneal dystrophies which are then characterized by pathognomonic patterns of corneal deposition and changes in morphology. PACD is specifically characterized by bilateral sheet-like opacification of the posterior stroma in association with corneal flattening and thinning.[1][2] Flattening of the corneal surface can result in a hyperopic refractive status.

Etiology

PACD is inherited in an autosomal dominant pattern. The chromosomal locus of the gene responsible for PACD has not been fully elucidated, but it has been reported to be associated with contiguous gene deletion of chromosome 12q21.33.[3][4] Recent research has been able to find an association between PACD and a deletion in the four genes encoding small leucine rich proteoglycans (SLRPs): KERA, LUM, DCN, and EPYC. These proteins are involved in collagen formation and matrix assembly which are involved in the maintenance of corneal transparency.[5] Therefore, any combination of deletions of this family of four proteins can lead to impaired corneal transparency.  

Risk Factors

PACD is understood to have an autosomal dominant pattern of inheritance therefore having a family history is an associated risk factor.[6]

General Pathology

PACD has not been well studied or documented due to the rareness of the disease. One study documents the ultrastructural changes of a corneal button from a patient with PACD who underwent penetrating keratoplasty.[7] Fracturing of the most posterior collagen layers of the stroma and focal attenuation of endothelial cells with no signs of edema, inflammation, or vascularization was seen on light microscopy. Furthermore, the Descemet’s membrane was uniformly thin with no irregular folds or thickenings. Electron microscopy showed disorganized collagen fibers in the posterior stromal lamellae with loss of endothelial cells. Overall, this study shows that there is a developmental abnormality in the formation of the posterior stroma and Descemet’s membrane in PACD.[7]

Pathophysiology

Genome-wide linkage analysis on families with a history of PACD demonstrated linkage to a region on chromosome 12q21.33 which includes four genes: keratocan (KERA), lumican (LUM), decorin (DCN), and epiphycan (EPYC). These proteins are involved with encoding small leucine rich proteoglycans (SLRPs) which are involved with collagen fibrillogenesis and matrix assembly. Mutations in the SLRPs can show abnormalities in the curvature and clarity of the cornea. For example, a mutation in KERA is associated with autosomal recessive corneal plana and a nonsense mutation in DCN is connected to congenital hereditary stromal dystrophy. A study that performed copy number analysis in affected families with PACD showed that deletions in these four genes have been associated with PACD although it is not definitively known which gene, or combination of genes are essential to the pathophysiology of PACD.[4][5]

Primary prevention

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

Diagnosis

Diagnosis of PACD is accomplished by slit lamp biomicroscopy and can be supplemented with additional imaging modalities including anterior segment optical coherence tomography or confocal microscopy. Histopathological staining can also be used to confirm the diagnosis.  

History

The onset of PACD can happen as early as 16 weeks and usually occurs within the first decade of life, suggesting that it is congenital in nature. The disease is typically non-progressive or slowly progressive and can have a mild effect on visual acuity.[8]

Physical examination

A careful slit lamp examination will show large amorphous sheet-like opacifications in the posterior stroma and Descemet’s membrane typically with decreased corneal thickness and flattening. Additionally, non-corneal findings have been also reported including iris abnormalities such as iridocorneal adhesions, corectopia, and pseudopolycoria.[9] Individuals with PACD are usually asymptomatic but can have changes in visual acuity and are usually hyperopes due to changes to the corneal curvature.[10]

Clinical diagnosis

Clinical diagnosis is primarily based on observing pathognomonic diffuse sheet-like opacifications in the posterior corneal stroma seen on slit lamp biomicroscopy and a positive family history.[1][2]

Diagnostic procedures

Anterior segment optical coherence tomography and confocal microscopy can be used to help supplement the diagnosis of PACD. Affected individuals classically demonstrate decreased corneal thickness and flattening of the corneal curvature that is shown in the OCT. (Johnson) On confocal microscopy, it can show microfolds and hyper-reflective layers at the posterior stroma just adjacent to the endothelial layer.[11]

Laboratory test

There have not been sufficient tissue specimens to characterize the histopathology of PACD. However, studies show that individuals with PACD have disorganized posterior stromal collagen lamellae and an attenuated corneal endothelium with extracellular colloidal iron stains in the posterior stroma.[9]

Differential diagnosis

Macular Corneal Dystrophy

Macular corneal dystrophy is an autosomal recessive condition of the corneal stroma where there is an irregularity in proteoglycan synthesis of keratan sulfate. This irregularity leads to deposition of abnormal proteoglycans leading to loss of corneal transparency and decreased vision. It presents similarly to PACD because it can appear with corneal thinning. However, unlike PACD, it is a progressive disease where it can lead to progressive vision loss due to spreading of opacifications involving Descemet’s membrane as well as the corneal endothelium.[12]

Fleck Corneal Dystrophy

Fleck Corneal Dystrophy (FCD) is also another inherited rare disease of the corneal stroma characterized by a mutation of the gene encoding for the enzyme phosphatidylinositol 3-phosphate 5-kinase type III (also known as PIP5K3 or PIKFYVE). Disruption in this enzyme can result in endomembrane and endosome carrier vesicle dysfunction causing increasing intracytoplasmic accumulation of glycosaminoglycans and complex lipids in regions of the stroma.[13] This condition presents similarly to PACD because it can cause opacities of the stroma and is inherited in an autosomal dominant fashion. However, instead of being able to appreciate sheet-like opacification of the posterior stroma with corneal flattening and thinning that is associated with PACD, FCD presents with small, non-progressive opacities within the stromal layer of the cornea which can have numerous dandruff-like features.[14][15]

Schnyder Corneal Dystrophy

Schnyder Corneal Dystrophy (SCD) is another inherited rare dystrophy of the corneal stroma caused by a mutation in UbiA prenyltransferase domain containing 1 (UBIAD1) gene, which plays a role in cholesterol metabolism. Disruption in this enzyme results in accumulation of unesterified cholesterol and phospholipids near the stroma, leading to occasional central crystalline subepithelial deposits with stromal haze and progressive corneal opacification.[16] This condition presents similarly to PACD because it can cause opacities of the stroma and is inherited in an autosomal dominant fashion. Furthermore, the onset of SCD typically manifests in the first year of life which is similar to PACD. However, while patients with SCD will see a typical progression in corneal opacification, individuals with PACD are typically non-progressive or slowly progressive.[8]

Congenital Stromal Corneal Dystrophy  

Congenital Stromal Corneal Dystrophy (CSCD) is a rare stromal dystrophy which is caused by mutation of the Decorin gene (DCN) on 12q21.33 which presents with symmetric corneal clouding with white flaky stromal opacities shortly after birth.[17] These changes can be severe enough to cause significant vision loss. This condition presents similarly to PACD because it also involves the DCN gene on 12q21.33 and can present as early within the first decade of life. However, unlike PACD, individuals with CSCD typically have an increase in corneal thickness whereas individuals with PACD typically present with corneal flattening and thinning.  

Lattice Corneal Dystrophy Type 1 (LCD)  

Lattice Corneal Dystrophy Type 1 (Type 1 LCD) is a condition that has a mutation in the TGFBI gene on the 5q31 locus. Similar to PACD, it is also known to have an autosomal dominant pattern of inheritance and can present in the first or second decade of life. However, in Type 1 LCD, the lesions are described as glass-like filamentous lesions that show deposition of amyloid and abnormal corneal lamellar structure in the stroma. The deposits can create linear, “lattice-like” opacities arising primarily in the central cornea that can cause eventual loss of vision without treatment. Type 1 LCD can also show focal thinning or loss of Bowman’s layer, which is different from PACD where it shows a total decrease in corneal thickness or corneal flattening.[18]

Management

General treatment

PACD does not typically progress, therefore treatment is not required. However, some cases of PACD can progress and extend completely through the entire corneal stroma and lead to visual acuity loss. Penetrating keratoplasty is warranted if visual impairment becomes significant. [9] Otherwise, if donor tissue is not available, ablation of the superficial cornea can be done as a temporary measure and symptoms can be managed with observation.[9]

Additional Resources

https://disorders.eyes.arizona.edu/disorders/corneal-dystrophy-posterior-amorphous

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98971

References

  1. 1.0 1.1 Moshegov, Con N., Wilbert K. Hoe, Steven J. Wiffen, and Sheraz M. Daya. "Posterior amorphous corneal dystrophy: a new pedigree with phenotypic variation." Ophthalmology 103, no. 3 (1996): 474-478.
  2. 2.0 2.1 Moshirfar, Majid, Phillip Bennett, and Yasmyne Ronquillo. "Corneal Dystrophy." (2020).
  3. Aldave, Anthony J., George OD Rosenwasser, Vivek S. Yellore, Jeanette C. Papp, Eric M. Sobel, Michele N. Pham, Michael C. Chen et al. "Linkage of posterior amorphous corneal dystrophy to chromosome 12q21. 33 and exclusion of coding region mutations in KERA, LUM, DCN, and EPYC." Investigative Ophthalmology & Visual Science 51, no. 8 (2010): 4006-4012.
  4. 4.0 4.1 Odent, S., Ingele Casteels, C. Cassiman, M. Dieltiëns, M-T. Hua, and Koenraad Devriendt. "Posterior amorphous corneal dystrophy caused by a de novo deletion." Ophthalmic Genetics 38, no. 2 (2017): 167-170.
  5. 5.0 5.1 Kim, Michelle J., Ricardo F. Frausto, George OD Rosenwasser, Tina Bui, Derek J. Le, Edwin M. Stone, and Anthony J. Aldave. "Posterior amorphous corneal dystrophy is associated with a deletion of small leucine-rich proteoglycans on chromosome 12." PloS one 9, no. 4 (2014): e95037.
  6. Carpel, Emmett F., Robert J. Sigelman, and Donald J. Doughman. "Posterior amorphous corneal dystrophy." American Journal of Ophthalmology 83, no. 5 (1977): 629-632.
  7. 7.0 7.1 Johnson, A. Tim, Robert Folberg, Michael P. Vrabec, George J. Florakis, Edwin M. Stone, and Jay H. Krachmer. "The pathology of posterior amorphous corneal dystrophy." Ophthalmology 97, no. 1 (1990): 104-109.
  8. 8.0 8.1 Weiss, Jayne S., H. U. Møller, Walter Lisch, Shigeru Kinoshita, Anthony J. Aldave, Michael W. Belin, Tero Kivelä et al. "The IC3D classification of the corneal dystrophies." Cornea 27, no. Suppl 2 (2008): S1-83.
  9. 9.0 9.1 9.2 9.3 Klintworth, Gordon K. "Corneal dystrophies." Orphanet journal of rare diseases 4 (2009): 1-38.
  10. Dunn, Steven P., Jay H. Krachmer, and Steven ST Ching. "New findings in posterior amorphous corneal dystrophy." Archives of Ophthalmology 102, no. 2 (1984): 236-239.
  11. Erdem, Uzeyir, Orkun Muftuoglu, and Volkan Hurmeric. "In vivo confocal microscopy findings in a patient with posterior amorphous corneal dystrophy." Clinical & experimental ophthalmology 35, no. 1 (2007): 99-102.
  12. Aggarwal, Shruti, Travis Peck, Jeffrey Golen, and Zeynel A. Karcioglu. "Macular corneal dystrophy: A review." Survey of ophthalmology 63, no. 5 (2018): 609-617.
  13. Li, Shouling, Leila Tiab, Xiaodong Jiao, Francis L. Munier, Leonidas Zografos, Béatrice E. Frueh, Yuri Sergeev et al. "Mutations in PIP5K3 are associated with Francois-Neetens mouchetee fleck corneal dystrophy." The American Journal of Human Genetics 77, no. 1 (2005): 54-63.
  14. Patten, J. T., R. A. Hyndiuk, D. D. Donaldson, S. J. Herman, and H. B. Ostler. "Fleck (Mouchetee) dystrophy of the cornea." Annals of ophthalmology 8, no. 1 (1976): 25-32.
  15. Can, Ertuğrul, Emrah Kan, and Halil İbrahim Akgün. "Clinical features and in-vivo confocal microscopic imaging of fleck corneal dystrophy." In Seminars in Ophthalmology, vol. 28, no. 4, pp. 239-241. Taylor & Francis, 2013.
  16. Weiss, Jayne S., Howard S. Kruth, Helena Kuivaniemi, Gerard Tromp, Peter S. White, R. Scott Winters, Walter Lisch et al. "Mutations in the UBIAD1 gene on chromosome short arm 1, region 36, cause Schnyder crystalline corneal dystrophy." Investigative ophthalmology & visual science 48, no. 11 (2007): 5007-5012.
  17. Bredrup, Cecilie, Per M. Knappskog, Jacek Majewski, Eyvind Rødahl, and Helge Boman. "Congenital stromal dystrophy of the cornea caused by a mutation in the decorin gene." Investigative ophthalmology & visual science 46, no. 2 (2005): 420-426.
  18. Moshirfar, Majid, William West, and Yasmyne Ronquillo. "Lattice Corneal Dystrophy." (2020).
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