Corneal dystrophies, according to the IC3D classification system are categorized into epithelial and subepithelial, epithelial–stromal TGFBI, and stromal and endothelial dystrophies . The overall classification includes 22 different types of corneal dystrophies, frequently further divided into subcategories. The differential diagnosis of corneal dystrophies is challenging and includes infectious corneal diseases, mostly of the viral form, corneal degenerations, such as mosaic (crocodile shagreen) degeneration, cornea farinata or peripheral hypertrophy, subepithelial corneal degeneration, vernal keratoconjunctivitis, and keratopathies related to dry eye disease, such as keratoconjunctivitis sicca or keratopathies related to blepharitis. Additionally, corneal diseases of unknown origin, such as Thygeson’s superficial punctate keratitis (TSPK), or of various systemic causes, including several skin diseases, monoclonal gammopathy, enzyme-related deficiencies (tyrosinemia, lecithin-cholesterol-acyltransferase deficiency, mucopolysaccharidoses), systemic lysosomal storage diseases or cystinosis, should be incorporated into the differential diagnosis.
After the initial interview and slit lamp examination of our patient, which revealed multiple, diffuse, grayish, indistinct, superficial corneal opacities extending from limbus to limbus, accompanied by subepithelial haze (Fig. 1), the most likely differential diagnoses included epithelial, subepithelial or stromal corneal dystrophy, multiple subepithelial corneal infiltrates caused by epidemic keratoconjunctivitis or Thygeson’s superficial punctate keratitis (TSPK). The majority of epithelial and epithelial–stromal TGFBI corneal dystrophies are autosomal dominant, but the patient could have been the first affected member of the family. Moreover, the early signs of stromal dystrophies include epithelial and subepithelial corneal abnormalities, subsequently followed by stromal involvement; therefore, stromal dystrophies could not be ruled out only because slit lamp examination did not reveal stromal involvement and due to the young age of the patient.
Multiple subepithelial corneal infiltrates may be caused by epidemic keratoconjunctivitis, they usually occur during the subacute and chronic phases and may persist for months to years. In the slit lamp examination, the probability of central corneal involvement, namely, involvement of the pupillary zone, is higher than that of peripheral corneal involvement. This was not consistent with our patient’s results, since the corneal changes were diffuse rather than centralized. On confocal microscopy, MSIs are visible as distinct round hyperreflective plaques, accompanied by increased anterior stromal hyperreflectivity and hyperreflective foci and inflammatory cells within the basal epithelium [23, 24].
Based on the corneal appearance on slit lamp examination, TSPK should also be considered in the differential diagnosis. TSPK is a bilateral corneal disease of unknown origin in which factors such as viral infection or the immune reaction to viral infection and allergic reactions have been proposed to play a pathogenic role. Slit lamp examination reveals numerous punctate opacities involving the epithelium and underlining superficial corneal stroma. Confocal microscopy changes are characteristic and include highly reflective deposits with a starburst-like appearance in the superficial and basal epithelial cell layers, an increased number of dendritic cells in the epithelial basal cell layer and the subepithelial nerve plexus, and highly reflective, tiny, needle-shaped material in the anterior corneal stroma [25, 26].
In contrast to MSIs and TSPK features, confocal microscopy analysis for our patient revealed significant stromal involvement. Starting at the level of Bowman’s layer, multiple, differently oriented dark striae were visible. The keratocytes and the intercellular space had a granular, hyperreflective appearance throughout the whole stroma (Fig. 4). These findings are consistent with previous reports describing confocal corneal changes in MCD. In contrast to those at advanced stages, the epithelium layers of our patient were of normal morphology, while in advanced forms, numerous hyperreflective basal epithelial cells among cells of normal morphology were reported [19, 20]. Despite the lack of visible stromal involvement on slit lamp examination, the cornea presented changes involving the deep stromal layers, confirming the high utility of confocal microscopy in the differential diagnosis of corneal dystrophies.
Clinical examination of our patient also showed regular corneal astigmatism and diffuse corneal thinning, which are characteristic features of MCD, confirmed by previous histopathological, Scheimpflug imaging, ultrasound biomicroscopy and OCT studies [5, 20, 27,28,29,30]. The diffuse corneal thinning is believed to be a result of the dysregulation of keratan sulfate proteoglycan synthesis or catabolism, which directly influences corneal structure . The above observation leads us to conclude that generalized corneal thinning precedes the progressive loss of corneal transparency. A high-definition corneal scan of our patient revealed very discrete, diffuse hyperreflective opacities with no clearly distinguishable borders and various shapes located in the subepithelial regions. As the disease progresses, OCT scans show hyperreflective stromal corneal deposits with associated thinning of the epithelium over the deposits and characteristic pre-Descemetic peripheral deposits. In some patients, thickening of the Descemet membrane may be noted. In advanced stages of the dystrophy, dense stromal deposits cause an optical shadow in the posterior part of the cornea. Additionally, the progression of deposits in the endothelial cell layer can eventually lead to endothelial decompensation and increased corneal thickness [1, 4, 5, 20,21,22, 28].
It has been described that the visual function of patients with corneal dystrophies is not only compromised by scattering induced by the corneal opacity but also associated and correlated with higher-order aberrations (HOAs). HOAs of the total cornea and anterior and posterior surfaces were reported to be larger in subjects with stromal corneal dystrophies than in normal control subjects [32, 33]. The analysis of the Fourier indices for our patient revealed abnormalities regarding two parameters: regular astigmatism on the anterior and posterior surfaces and asymmetry on the anterior surface. The results of the 6 mm keratometric and real higher order index analyses were borderline in both eyes, while the results of the 3 mm and 6 mm posterior higher-order index analyses were within the normal range. Yagi-Yaguchi Y. et al. reported that HOAs were increased at the late stage of MCD. Their study group compromised 13 eyes of seven patients with advanced MCD without genetic confirmation; the mean age of the patients was 49.9 ± 5.8 years, and the visual acuity was logMAR 0.48 ± 0.62 . The results cannot be compared directly to our results because of the significant difference in age and visual acuity (our patient’s age was 8 years, and VA was logMAR 0.0). Age has been reported to be strongly correlated with visual function, refraction, astigmatism and HOAs . The borderline results of the 6 mm higher-order keratometric index in our patient may be directly connected to the anterior subepithelial abnormalities revealed by HD OCT scans and may indicate that Fourier index abnormalities occur early in the disease course. On the other hand, such subtle changes on the anterior surface of the cornea are not specific, and the result may be influenced by several factors, such as disturbances of the tear film, patient cooperation during the examination or internal/indoor environmental factors [35, 36]. Therefore, the influence of MCD on Fourier index results should be studied in a larger sample size, and one case report cannot be representative of the population.
There are few case reports on the cooccurrence of keratoconus and MCD [37, 38]. In the study of Dudakova et al., the authors observed anterior, paracentral steepening of the corneal surface, which was graded as keratoconus by Scheimflug integrated software, but without a coexisting ectasia pattern on the posterior corneal surface . The anterior and posterior Ectasia Screening Index (ESI), which is a parameter used in the detection of corneas with ectasia patterns implemented in the SS OCT software, was 0 % in both eyes of our patient. Thus, our findings may serve as evidence of diffuse corneal thinning not associated with an ectasia pattern.
According to the American Society of Ophthalmology guidelines, genetic testing should be offered to patients with clinical findings suggestive of a Mendelian disorder, whose causative gene(s) have been identified [39, 40]. The known, previously described homozygous pathogenic variant, c.1 A > T, with alteration of the start codon (p.M1?) was found following CHST6 gene sequencing in our patient, thus confirming a diagnosis of MCD. Alterations of the first codon have also been reported in Polish, Czech, German and Turkish populations [20, 41,42,43]. It is wort mentioning, that in case of MCD, not only missense mutations are pathogenic, but also deletions, insertions or indels, which account for approximately 30 % of MCD cases. In our case, the upstream region of the CHST6 gene was not covered by the gene sequencing, which could be regarded as a study limitation. Genetic testing provides future prospects for implementing gene therapy. Moreover, MCD with precisely identified genetic defects fulfils the prerequisites for attempting clinical gene therapy . Currently, we are faced with new possibilities in future methods of gene therapy, such as clustered regularly interspaced short palindromic DNA repeat (CRISPR) and CRISPR-associated gene (cas) systems of gene editing. Such an approach was already employed in Meesman corneal dystrophy [44,45,46].
The main importance of this case report is in defining the early characteristic features of MCD, despite the absence of characteristic corneal abnormalities on slit lamp examination. The main limitations are the difficulties in performing high-quality slit lamp and confocal microscopy scans in an 8-year-old patient. Additionally, the influence of environmental factors and tear film disturbances could interfere with the OCT Fourier indices results.
To conclude, the initial signs and symptoms of different epithelial and stromal corneal dystrophies are not specific; therefore, it is very important to establish early characteristic corneal features that could guide the diagnostic process. The clinical examination should be complemented with corneal imaging techniques, such as confocal microscopy and optical coherence tomography. Early corneal characteristic features of MCD, established according to the findings of the case report, include corneal astigmatism (not specific), diffuse corneal thinning without a pattern of corneal ectasia (specific), and those obtained on confocal microscopy (specific), including multiple, dark, oriented striae at different corneal depths. In patients suspected of corneal dystrophy, genetic testing plays an important role in establishing the final diagnosis and may provide encouraging results for future gene therapy.