Fleck Corneal Dystrophy
Fleck corneal dystrophy (ICD-10 #H18.59 - other hereditary corneal dystrophies)
Fleck corneal dystrophy (FCD) (also known as Francois-Neetens speckled corneal dystrophy) is a rare autosomal dominant disease of the corneal stroma characterized by the intracytoplasmic accumulation of glycosaminoglycans and complex lipids in swollen keratocytes, which results in numerous dandruff-like opacities of the stroma.
FCD results from the inheritance of one or more mutated copies of the gene encoding for the phosphotidylinositol 3-phosphate 5-kinase type III (also known as PIP5K3 or PIKFYVE) enzyme with a locus at chromosome 2q35.
Positive family history.
The characteristic pathology associated with FCD is the appearance of small, non-progressive opacities within the stromal layer of the cornea. There are two distinct phenotypes of FCD opacities. However, these phenotypes are not mutually exclusive and can occur in the same family or the same patient. The first phenotype includes opacities that are small, oval, round, or semi-circular with well-defined margins, giving the cornea the "flecked" appearance for which the disease is named. The second phenotype of opacities resembles clouds or snowflakes with poorly defined borders. Although flecks are distributed throughout the stroma in both phenotypic cases, patients with the latter phenotype have opacities which are often most numerous in the posterior and central stroma. Areas of the stroma unaffected by the opacities appear grossly normal, and the endothelium, epithelium, Bowman's membrane, and Descemet's membrane are unaffected.
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.
No preventive strategies have been studied to date.
Diagnosis of FCD is accomplished mainly with slit-lamp biomicroscopy. Additional image modalities such as confocal microscopy and anterior segment optical coherence tomography can aid in diagnostic process. Lastly, Histopathological staining can be used to confirm the diagnosis.
The corneal flecks associated with FCD are most often bilateral and symmetrical. Asymmetric or unilateral manifestation is possible but uncommon. The onset of FCD occurs early in life, normally around 2 years of age, but can be as early as birth. 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. Regardless of the prevalence of FCD within the family, the patient’s relatives should still be examined to assess for previously undetected pathologies due to the subtle presentation of the disease.
A thorough slit-lamp examination of both eyes will demonstrate multiple fleck-like opacities in the corneal stroma. These opacities can be located throughout the cornea with intervening section of normal corneal tissue. Both corneas should demonstrate these opacities but may be different in distribution and concentration.
Usually asymptomatic, but mild photophobia or reduced corneal sensitivity can occur. No systemic manifestations have been reported.
Clinical diagnosis is primarily based on correlating family history with the pathognomonic corneal flecks evident in both slit-lamp biomicroscopy and confocal microscopy.
Confocal microscopy and anterior segment optic coherence tomography are imaging modalities that can be used in diagnosing FCD
- Confocal microscopy will demonstrate individual keratocytes enlarged with intracytoplasmic glycosaminoglycans and lipids 
- Anterior segment optical coherence tomography may demonstrate hyperreflective foci within the stroma.
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.
Macular corneal dystrophy
Macular corneal dystrophy is an autosomal recessive dystrophy of the corneal stroma resulting from abnormal keratan sulfate. Unlike FCD, it additionally involves Descemet membrane as well as the corneal endothelium, while sparing the corneal epithelium. 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.
Schnyder corneal dystrophy (SCD) is characterized by the progressive acquisition of small opacities and diffuse haze of the corneal stroma. 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. Late in disease progression, the opacity characteristic of SCD is typically grossly visible without the aid of a slit lamp, in contrast to the more subtle opacities of FCD. Patients with SCD will complain of glare and exhibit progressive photopic vision loss with sparing of scotopic vision. Patients may also present with elevated cholesterol.
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.
Posterior amorphous corneal dystrophy
Posterior amorphous corneal dystrophy (PACD) is characterized by collections of eponymous irregular laminar 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.
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.
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. Therefore, the asymptomatic nature of this condition can be managed with observation.
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