Fleck Corneal Dystrophy
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Disease Entity
Fleck corneal dystrophy (ICD-10 #H18.59 - other hereditary corneal dystrophies)
Disease
Fleck corneal dystrophy (FCD), formerly known as Francois-Neetens speckled corneal dystrophy, is a non-progressive, autosomal dominant disease of the corneal stroma characterized by small, discrete, dandruff-like opacities scattered throughout the stroma.
Etiology
The FCD phenotype results from one or more mutations in the gene encoding for the phosphotidylinositol 3-phosphate 5-kinase type III (PIP5K3 or PIKFYVE) enzyme, located on chromosome 2q35[1][2] or 2q34.[3]
Risk Factors
Positive family history.
General Pathology
The characteristic pathology associated with FCD is the appearance of non-progressive stromal opacities. Expressivity is highly variable, and clinical presentation can vary within families. Opacities may appear small, round, semi-circular or ring-like with well-defined margins, or cloud-like or snowflake shaped with poorly defined borders. Opacities can be at any level of the stroma. Outside of the opacities, the stroma appears clear, and the epithelium, Bowman membrane, Descemet membrane and endothelium are unaffected.[3] [4]
Pathophysiology
The action of the PIKFYVE enzyme is twofold: maintenance of endomembrane homeostasis and participation in the formation of endosome carrier vesicles. In patients with FCD, truncation of this enzyme due to a frameshift mutation results in a disruption in endosomal sorting mechanisms.[1] Light microscopy shows swollen keratocytes which accumulate glycosaminoglycans and complex lipids. Keratocytes may show membrane-based inclusions with granular material.[3]
Diagnosis
Diagnosis of FCD is clinical. Additional image modalities such as confocal microscopy and anterior segment optical coherence tomography can aid in diagnosis.
History
The corneal flecks associated with FCD are most often bilateral and symmetrical, but asymmetric or unilateral corneal involvement is possible.[3][5] The onset of FCD occurs within the first years of life, but can be as early as birth.[3][4] The disease is non-progressive and does not affect visual acuity. In addition to a complete ocular history, a detailed family history should also be taken. The patient's relatives can be examined to assess for previously undetected pathologies due to the subtle presentation of the disease.[6]
Physical Examination
A thorough slit-lamp examination of both eyes will demonstrate fleck-like opacities scattered throughout the corneal stroma. Typically, both corneas demonstrate opacities but may differ in distribution and concentration.
Symptoms
Usually asymptomatic, but mild photophobia or reduced corneal sensitivity can occur. No systemic manifestations have been reported.[7]
Clinical Diagnosis
Clinical diagnosis is primarily based on correlating family history with the pathognomonic corneal flecks evident in both slit-lamp biomicroscopy and confocal microscopy.
Diagnostic Procedures
Confocal microscopy and anterior segment optical coherence tomography are imaging modalities that can be used to diagnose FCD.
- Confocal microscopy will demonstrate hyperreflective, dot-like material and enlarged keratocytes with intracytoplasmic glycosaminoglycans and lipids.[3][4]
- Anterior segment optical coherence tomography can demonstrate hyperreflective foci within the stroma.[8]
Laboratory test
On histopathological testing, FCD demonstrates keratocytes containing fibrillogranular material within intracytoplasmic vacuoles or pleomorphic electron-dense and membranous intracytoplasmic inclusions. This intracytoplasmic material is histochemically similar to glycosaminoglycans and lipids and therefore stains with alcian blue, colloidal iron, Sudan black B, and oil red O stains.[4]
Differential diagnosis
Macular corneal dystrophy is an autosomal recessive dystrophy of the corneal stroma resulting from abnormal keratan sulfate. Unlike FCD, the opacities can involve the deep stromal down to Descemet membrane.[3] Furthermore, while FCD patients will remain asymptomatic throughout their life, MCD is a progressive disease, where areas of opacity with poorly-defined borders gradually grow and merge, eventually spreading from limbus to limbus. This causes significant vision impairment by the second or third decade of life in most patients. Corneal thinning also occurs in patients with MCD, compared to FCD, which is not associated with changes in corneal thickness.[4][9]
Schnyder corneal dystrophy (SCD) is characterized by the progressive development of small opacities and diffuse stromal haze. In approximately 50 percent of SCD cases, there is also annular deposition of birefringent cholesterol crystals in Bowman’s membrane and adjacent stroma. SCD begins to manifest in the first year of life, and as the disease progresses, arcus lipoides begin to develop due to cholesterol accumulation at the limbus. In late stage disease, the opacity characteristic of SCD is typically grossly visible without the aid of a slit lamp. Patients with SCD will complain of glare and exhibit progressive photopic vision loss with sparing of scotopic vision. Patients may also have elevated cholesterol.[4][10]
Congenital stromal corneal dystrophy
Congenital stromal corneal dystrophy is an exceedingly rare stromal dystrophy. Patients will present at birth with a limbus-to-limbus haze evenly distributed throughout the cornea. Like FCD, it is non-progressive and spares all other layers of the cornea. Unlike FCD, patients with CSCD typically present with significant vision loss, with preoperative visual acuity ranging from 20/100 to counting fingers. Finally, corneal thickening usually occurs in patients with CSCD due to the separation of stromal lamellae, which is not seen in patients with FCD.[11]
Posterior amorphous corneal dystrophy
Posterior amorphous corneal dystrophy (PACD) is characterized by collections of irregular, sheet-like opacities predominantly in the posterior stroma and Descemet membrane. These opacities are observed very early in life, possibly even in infancy. Unlike the other stromal dystrophies (including FCD), patients with PACD will often present with non-corneal findings in addition to the aforementioned opacities. These manifestations include scleral changes in the corneal periphery, iris coloboma, corectopia, iris atrophy, and iridocorneal adhesions.[4][12]
Pre-Descemet corneal dystrophy
Pre-Descemet corneal dystrophy (PDCD) is the stromal dystrophy most similar in presentation to FCD, but there are a few key characteristics that differentiate these two diagnoses. Both PDCD and FCD are characterized by tiny, pleomorphic stromal opacities. However, they are localized to the posterior stroma and endothelium in patients with PDCD. Although opacities may be more numerous in the posterior stroma in patients with FCD, they can be observed throughout the stroma in most cases. Additionally, the opacities seen in PDCD manifest later in life, around the fourth decade, and are typically more rapidly progressive, unlike the early onset, non-progressive nature of the opacities characteristic of FCD.[13][14]
Management
General treatment
Treatment is not required due to the non-progressive nature of FCD and its minimal impact on vision. In one case of a patient with a history of FCD undergoing penetrating keratoplasty for severe keratoconus, the donor tissue did not exhibit signs of recurrent FCD after a 10-year postoperative follow-up.[15] The asymptomatic nature of this condition can be managed with observation.
Additional Resources
https://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/Fleck-Corneal-Dystrophy/index.htm
References
- ↑ 1.0 1.1 Li, S., Tiab, L., Jiao, X., Munier, F. L., Zografos, L., Frueh, B. E., Sergeev, Y., Smith, J., Rubin, B., Meallet, M. A., Forster, R. K., Hejtmancik, J. F., Schorderet, D. F. Mutations in PIP5K3 are associated with Francois-Neetens mouchetee fleck corneal dystrophy. Am. J. Hum. Genet. 77: 54-63, 2005. PMID 15902656.
- ↑ Jiao, X., Munier, F. L., Schorderet, D. F., Zografos, L., Smith, J., Rubin, B., Hejtmancik, J. F. Genetic linkage of Francois-Neetens fleck (mouchetee) corneal dystrophy to chromosome 2q35. Hum. Genet. 112: 593-599, 2003. PMID 12607114
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Weiss JS, Rapuano CJ, Seitz B, Busin M, Kivelä TT, Bouheraoua N, Bredrup C, Nischal KK, Chawla H, Borderie V, Kenyon KR, Kim EK, Møller HU, Munier FL, Berger T, Lisch W. IC3D Classification of Corneal Dystrophies-Edition 3. Cornea. 2024 Apr 1;43(4):466-527. doi: 10.1097/ICO.0000000000003420. Epub 2024 Feb 12. PMID: 38359414; PMCID: PMC10906208.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Klintworth GK (2009). "Corneal dystrophies". Orphanet J Rare Dis. 4: 7. doi:10.1186/1750-1172-4-7. PMC 2695576. PMID 19236704.
- ↑ Goldberg, M. F., Krimmer, B., Sugar, J., Sewell, J., Wong, P. Variable expression in flecked (speckled) dystrophy of the cornea. Ann. Ophthal. 9: 889-896, 1977. PMID: 302662
- ↑ Kawasaki, S., Yamasaki, K., Nakagawa, H., Shinomiya, K., Nakatsukasa, M., Nakai, Y., Kinoshita, S. A novel mutation (p.Glu2389AspfsX16) of the phosphoinositide kinase, FYVE finger containing gene found in a Japanese patient with fleck corneal dystrophy. Molec. Vis. 18: 2954-2960, 2012. PMID: 23288988
- ↑ Patten JT, Hyndiuk RA, Donaldson DD, Herman SJ, Ostler HB. Fleck (Mouchetée) dystrophy of the cornea. Ann Ophthalmol. 1976 Jan;8(1):25-32. PMID: 1082286.
- ↑ Weiss JS, Møller HU, Aldave AJ, Seitz B, Bredrup C, Kivelä T, Munier FL, Rapuano CJ, Nischal KK, Kim EK, Sutphin J, Busin M, Labbé A, Kenyon KR, Kinoshita S, Lisch W. IC3D classification of corneal dystrophies--edition 2. Cornea. 2015 Feb;34(2):117-59. doi: 10.1097/ICO.0000000000000307. Erratum in: Cornea. 2015 Oct;34(10):e32. PMID: 25564336.
- ↑ Aggarwal S, Peck T, Golen J, Karcioglu ZA. Macular corneal dystrophy: A review. Surv Ophthalmol. 2018 Sep-Oct;63(5):609-617. doi: 10.1016/j.survophthal.2018.03.004. Epub 2018 Mar 28. PMID: 29604391.
- ↑ Weiss JS. Schnyder corneal dystrophy. Curr Opin Ophthalmol. 2009 Jul;20(4):292-8. doi: 10.1097/ICU.0b013e32832b753e. PMID: 19398911.
- ↑ Cecilie Bredrup, Per M. Knappskog, Jacek Majewski, Eyvind Rødahl, Helge Boman; Congenital Stromal Dystrophy of the Cornea Caused by a Mutation in the Decorin Gene. Invest. Ophthalmol. Vis. Sci. 2005;46(2):420-426. doi: https://doi.org/10.1167/iovs.04-0804.
- ↑ Kim MJ, Frausto RF, Rosenwasser GO, Bui T, Le DJ, Stone EM, Aldave AJ. Posterior amorphous corneal dystrophy is associated with a deletion of small leucine-rich proteoglycans on chromosome 12. PLoS One. 2014 Apr 23;9(4):e95037. doi: 10.1371/journal.pone.0095037. PMID: 24759697; PMCID: PMC3997350.
- ↑ Robert E. Curran, Kenneth R. Kenvon, W. Richard Green, Pre-Descemet's Membrane Corneal Dystrophy, American Journal of Ophthalmology, Volume 77, Issue 5, 1974, Pages 711-716, ISSN 0002-9394, https://doi.org/10.1016/0002-9394(74)90536-4.
- ↑ Lin ZN, Chen J, Cui HP. Characteristics of corneal dystrophies: a review from clinical, histological and genetic perspectives. Int J Ophthalmol. 2016 Jun 18;9(6):904-13. doi: 10.18240/ijo.2016.06.20. PMID: 27366696; PMCID: PMC4916151.
- ↑ Purcell JJ Jr, Krachmer JH, Weingeist TA. Fleck corneal dystrophy. Arch Ophthalmol. 1977 Mar;95(3):440-4. doi: 10.1001/archopht.1977.04450030082009. PMID: 139144.
