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 Table of Contents    
ORIGINAL ARTICLE
Year : 2020  |  Volume : 13  |  Issue : 2  |  Page : 70-75  

Rare stromal corneal dystrophic diseases in Oman: A clinical and histopathological analysis for accurate diagnosis


1 Department of Ophthalmology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission17-Dec-2019
Date of Decision20-Jan-2020
Date of Acceptance27-Mar-2020
Date of Web Publication28-May-2020

Correspondence Address:
Ahmed Mohamed Reda
Lecturer of Ophthalmology, Faculty of Medicine, Ain Shams University, Abbassia Square, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ojo.OJO_283_2019

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   Abstract 


INTRODUCTION: Corneal dystrophy (CD) encirclements a heterogeneous group of genetically determined corneal diseases. Many features still remain unknown.
AIM: The purpose of this study was to highlight the clinical and the histopathological aspects of rare stromal CDs and to assess the clinical and the histopathological roles in their diagnosis.
PATIENTS AND METHODS: This study incorporated 10 eyes of six patients, clinically diagnosed as follows: four patients with bilateral lattice stromal CD (8 eyes) and two patients, each one eye, one with macular and the other with granular-type CD. Histopathological examination with applications of many special stains was done in four eyes (4 patients) after penetrating keratoplasty.
RESULTS: The histopathological examination was in concordance with the clinical diagnosis of three examined corneas and revealed first eye with lattice dystrophy, second eye with macular dystrophy, and third eye with granular dystrophy. The fourth examined cornea was not that in concordance with the clinical diagnosis of lattice CD as it showed mixed stromal CD patterns of granular, macular, and lattice types.
CONCLUSION: Histopathological assessment of corneal dystrophy cases, subjected to keratoplasty is recommended to avoid missing cases with mixed stromal corneal dystrophy. Also, using low magnification slit lamp alone in the clinical assessment of the corneal opacity appeared to be limited mode and thus, the imaging corneal methods such confocal microscopy and high-definition optical coherence tomography are recommended for future cases especially in cases with unclassic query diagnosis.

Keywords: Corneal dystrophy, granular, histopathology, lattice, macular


How to cite this article:
Reda AM, Saad El-Din SA. Rare stromal corneal dystrophic diseases in Oman: A clinical and histopathological analysis for accurate diagnosis. Oman J Ophthalmol 2020;13:70-5

How to cite this URL:
Reda AM, Saad El-Din SA. Rare stromal corneal dystrophic diseases in Oman: A clinical and histopathological analysis for accurate diagnosis. Oman J Ophthalmol [serial online] 2020 [cited 2020 Sep 28];13:70-5. Available from: http://www.ojoonline.org/text.asp?2020/13/2/70/285299




   Introduction Top


Stromal corneal dystrophies (CDs) are genetic disorders characterized by bilateral, symmetrical, or asymmetrical corneal opacity. The corneal opacities are triggered by progressive accumulation of deposits, disturbing transparency or the refractive power of the cornea.[1] They are primary corneal lesions which are not accompanying with previous inflammation or trauma.

The usual onset is around the first decade of life, and the condition slowly progresses throughout life.[2] Clinically, they can be classified to stromal CD group, including lattice CD (LCD), granular CD type I (GCD1), macular CD (MCD),[3] Schnyder CD, fleck CD, congenital stromal CD, and posterior amorphous CD.[4] The diagnosis of these disorders is built on the association between history and clinical findings and then verification by the identification of the genes responsible for these diseases. Histopathological examination with the application of special stains can further support such diagnosis.[5]

LCD is one of the most common forms of CD, characterized by stromal amyloid depositions that usually present bilaterally and symmetrically.[6] Some author consider LCD1 to be an epithelial–stromal entity, because both epithelial cells and keratocytes are involved, the classic form also known as Biber-Haab-Dimmer, has autosomal dominant inheritance involving the gene transforming growth factor-beta 1 (TGFB1) in the locus 5q31 with no systemic manifestations. LCD1 usually develops in both eyes toward the end of the first decade of life, but infrequently, it begins in the middle life and seldom in infancy.[7] A network of delicate interdigitating branching filamentous opacities collects mostly within the central corneal stroma, with the preservation of the peripheral cornea relatively transparent. Corneal sensation is often reduced, and the interwoven linear opacities have some similarity to nerves. Recurrent corneal erosions may precede the corneal opacities and even appear in individuals with normal stromal appearance.[3]

LCD2, also known as Meretoja's syndrome, is associated with systemic amyloidosis that affects cornea, skin, and cranial nerves.[8] This type has also autosomal dominant inheritance, and the mutation is located in the gelsolin gene, at 9q chromosome.[6] In this type, both corneas contain randomly dispersed short fine glassy lines, which are fewer, more delicate, and more radially oriented than those in LCD1. The peripheral cornea is chiefly affected, and the central cornea is almost spared. Corneal sensitivity is reduced. The cornea has fewer amorphous deposits than LCD1, and the epithelial erosions are not a feature. The condition first becomes apparent after 20 years of age. Vision does not usually become significantly impaired before the age of 65 years. LCD2 can be mistaken for LCD1 both clinically and histopathologically.[3],[9] The stroma show dense deposits, which can be stained with Congo red that gives apple green birefringence under polarized light, and fluorescence occurs with thioflavin-T.[7]

In LCD3, the amyloid marker, Congo red, will show material deposition under Bowman's layer and sometimes at the endothelial Descemet membrane (EBM) level.[8] Histopathologically, amyloid deposits of LCD3 are located in the middle and superficial stroma beneath the Bowman's membrane.[7],[10]

GCD1 (classic GCD, CD Groenouw type I) is an autosomal dominant disease related to the TGFB-induced protein gene at 5q31 gene locus. Biomicroscopically, multiple small white separate irregular-shaped, sharply delineated spots that look-like bread crumbs or snowflakes become apparent beneath Bowman's zone in the superficial central corneal stroma.[3] They initially appear within the first decade of life and may be evident by 3 years of age; however, rarely, visual acuity is impaired before older age.[7] The opaque granules are frequently arranged in lines and gradually by time enlarge and become more abundant sparing the peripheral 2–3 mm of the cornea. In children, the external corneal surface is smooth, while in adults, it often becomes irregular.[3] Early symptoms include glare and photophobia. As the condition advances and the granules become more confluent, decrease in vision and recurrent erosions with pain may occur. On histopathology, it appears as multiple stromal deposits that may extend from deep epithelium to Descemet membrane. The hyaline opacities stain positively red with Masson trichrome. Transmission microscopy can show rod-shaped bodies similar to the ones found at Reis-Bucklers dystrophy. That is why some authors speculate that the latter might be a superficial variant of granular dystrophy.[6]

Avellino dystrophy, also known as GCD2 or combined granular-lattice dystrophy, was first described in patients from Avellino, Italy.[11] The classical manifestations of GCD2 combine the characteristics of GCD and LCD with discrete granular and lattice opacities. The granular opacities appear earlier and more commonly than the lattice opacities.

The opacities could lead to the disruption of visual acuity, but their location and severity determine the final outcomes.[12] The onset seems to be earlier in homozygote than in heterozygote patients.[13] GCD2 is related to TGFB1 gene mutation, is mapped to chromosome 5q, and has an autosomal dominant pattern.[12] Histologically, GCD2 patients have both superficial hyaline granular deposits and deep amyloid lattice deposits. The hyaline granules and amyloid lattice lines are stained with Masson's trichrome and Congo red, respectively.[13] Depending on the shapes, GCD2 lesions can be divided into three types: (1) type 1, diffuse hazy deposits superficially found in an irregular pattern; (2) type 2, granular deposits are subdivided into superficial round granular deposits (type 2a) and superficial round spiculated ones (type 2b). In GCD2 linear (lattice) deposits, the branches radiated out from the main trunks are well below the Bowman's layer and appear dense and white; (3) some deposits have short-side branches (type 3a, <trunk width), while others have long-side branches (type 3b, >trunk width).[12]

In most of GCD cases, visual acuity remains good until late in the progression of the disease. After a penetrating keratoplasty (PKP), the graft frequently remains free of relapse for at least 30 months, but the opacities may reappear in the grafts within a year, usually superficial to the donor tissue, even with lamellar grafts, or at the host–graft interface.[14]

LASIK, LASEK and other forms of refractive surgery are contraindicated in individuals with GCD as recurrence is still a common complication.[15]

MCD (CD Groenouw type II, Fehr CD) is a very rare CD, is dissimilar most of the CDs, and is inherited in an autosomal recessive fashion, involving the gene CHST6 in the 16q22 locus.[7] Corneal findings appear early in life and vision can be severely impaired between 10 and 30 years of age, although it is a gradually progressive disease.[3]

First, in the disease, biomicroscopy shows a diffuse stromal haze extending to the limbus, with disease progression, superficial, central, elevated, and irregular whitish opacities (macules) being developed. Posterior stromal involvement could occur. There are no clear areas between the opacities, and the cornea is usually thinner than normal. The endothelium can be involved later, and decrease in its functions can lead to corneal thickening.[16] MCD is associated with the mutations on the CHST6 gene, which encodes corneal N-acetylglucosamine 6-O-sulfotransferase (C-GlcNAc6ST), an enzyme that transfers sulfate to the unsulfated keratin chains on lumican. Lumican helps sustain the vital size and construction. It also influences corneal hydration and so maintains corneal transparency.[17] MCD can be classified into subtypes I and II, according to the absence or presence of sulfated keratin sulfate in the serum.[18] Histologically, the cornea in MCD is characterized by the accumulation of extracellular deposits in the stroma and descemet's membrane (DM) as well as intracellular storage of similar material in the keratocytes and corneal endothelium. The deposits stain with Alcian blue and other histochemical methods for glycosaminoglycans.[19]

Study design

This study incorporated 10 eyes of six patients; four patients with bilateral stromal CD (8 eyes) and two patients, each one with one eye as they had PKP done before to the other affected eye. The clinical diagnosis for the cases was eight eyes (4 patients) with LCD and two eyes of one with granular dystrophy and the other one with macular dystrophy. PKP was done for 4 eyes/4 patients for visual reduction cause.

The corneas of these four patients were immediately received and preserved in 10% formalin. Corneal specimens were cut at the center and submitted on its edge. All specimens were processed and paraffin blocks were prepared. Five-micron tissue sections were cut for hematoxylin and eosin (H and E), Alcian blue, and Masson's trichrome stains, and thicker sections (10 μ) were cut for Congo red stain followed by polarizing light examination, in all received cases whatever their clinical diagnosis (to assess the deposits of the different types of stromal CDs).

Written informed consent was obtained from all participants before surgery.


   Results Top


Clinical findings

Ten eyes of six patients were incorporated in this study. Four patients had bilateral CD diagnosed clinically as lattice type as they showed a network of delicate interdigitating branching filamentous opacities collected mostly within the central corneal stroma, with the preservation of the peripheral cornea relatively transparent on slit lamp examination [Figure 1]. Three of them were male, with age range from 15 to 40 years. They were presented with pain and photophobia. The corrected visual acuity varies from 0.10 to 0.9 in all the patients, and two patients of them complained of marked drop of vision in one eye to whom PKP was done and sent for histopathology evaluation.
Figure 1: Clinical case diagnosed as lattice corneal dystrophy showing linear and granular whitish opacities in the cornea by slit lamp examination

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The two remaining patients presented by one eye affection as they had PKP in the other eye with no recurrence. One of them was a male aged 35 years and diagnosed clinically as MCD in his right eye. As regards visual acuity, counting finger 3 m is found and slit lamp examination revealed a diffuse stromal haze, extending to the limbus, superficial, central, elevated, and irregular whitish opacities (macules) with neither recurrent corneal erosions nor decrease corneal sensation [Figure 2]. The other patient is a female aged 39 years and diagnosed clinically as GCD in her left eye, as slit lamp examination revealed white, well-defined granules with a snowflake appearance become apparent beneath Bowman's membrane in the superficial central corneal stroma [Figure 3]. This patient had recurrent corneal erosions and decrease corneal sensation. Her vision was 0.1 in the affected eye. Both patients with MCD and GCD underwent keratectomy due to marked visual reduction that sent for histopathology evaluation. Recurrent corneal erosions were found. As well as reduction of corneal sensation, in all cases except MCD case.
Figure 2: Clinical case diagnosed as advanced macular corneal dystrophy showing corneal haze and fluffy irregular whitish corneal deposits

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Figure 3: Clinical case diagnosed as granular corneal dystrophy showing granular whitish opacities in the cornea

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[Table 1] summarizes all demographic and clinical findings and final diagnosis.
Table 1: Summary of the demographic, clinical, and histopathological findings

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Histopathological findings

H and E-stained sections of the first case revealed scattered amorphous to globular eosinophilic material all over the corneal stromal thickness. This material gives orange red color with Congo red stain and apple green birefringence when examined by polarizing light; thus, the amyloid nature of the material was confirmed and the histopathological examination was in concordance with the clinical diagnosis of LCD.

The second case revealed myxoid-like superficial corneal stromal areas just beneath the epithelium that stained blue with Alcian blue stain and thus confirmed the mucopolysaccharide nature of these deposits that are seen in MCD; thus, the histopathological diagnosis was in concordance with clinical diagnosis of MCD.

The third case showed large amorphous looking hyaline material, just beneath the epithelium that in foci leads to atrophic and elevated epithelium and scattered hyaline areas all over the corneal stroma. Masson's trichrome stain revealed mottled corneal stroma with pale bluish green areas and intense dark red areas of hyaline degeneration that seen in GCD; thus, the histopathological diagnosis was in concordance with clinical diagnosis of GCD.

The fourth case showed different materials in the cornea including scattered amorphous to globular eosinophilic material all over the corneal stromal thickness that gives orange red color with Congo red stain and apple green birefringence when examined by polarizing light so confirmed to be the amyloid deposits of the LCD. Meanwhile, it showed myxoid-like superficial corneal stromal areas just beneath the epithelium that stained blue with Alcian blue stain and thus confirmed to be the mucopolysaccharide deposits that are seen in MCD. Finally, it showed large amorphous looking hyaline material, just beneath the epithelium and scattered all over the corneal stroma that appeared mottled with pale bluish green areas and intense dark red areas with Masson's trichrome stain and thus confirmed to be the hyaline degeneration that seen in the GCD [Figure 4]a, [Figure 4]b, [Figure 4]c

, [Figure 4]d, [Figure 4]e, [Figure 4]f. Thus, the final diagnosis of this case was not in concordance with the clinical diagnosis of just LCD; instead, it was mixed stromal CD of lattice, macular, and granular type.
Figure 4: (a and b) A case of mixed corneal dystrophy of macular, granular, and lattice types. (a) The superficial corneal stroma showed myxoid and eosinophilic hyaline material, focally elevate the corneal epithelium (H and E, ×100). (c) The bluish mucopolysaccharide material at the superficial corneal stroma denoting macular corneal dystrophy (Alcian blue, ×100). (d) Mottled dark red (positive deposits) and pale bluish-to-greenish corneal stroma denoting hyaline corneal degeneration of granular corneal dystrophy (Masson's trichrome, ×100). (e) The orange red color of amyloid material in deep corneal stroma (Congo red, ×100). (f) The section was examined by the polarizing light and showed the characteristic apple green birefringence of amyloid deposits seen in lattice corneal dystrophy (Congo red ×100)

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   Discussion Top


CDs are group of heterogeneous diseases that are genetically determined associated with no signs of inflammation and showed progressive bilateral symmetrical or asymmetrical corneal opacity. Most of them have an autosomal dominant pattern of inheritance, starting at the first decades of life, with a steady gradually advanced course.[20]

CDs comprise many subtypes. They are different in causes, clinical manifestations, development, treatments, and diagnosis.[1]

The most common symptom may be visual loss. It appears in many types of CDs, such as GCD and MCD. However, the severity of each type may be different, for example, MCD patients may suffer blindness with aging, which requires keratoplasty. Besides visual loss, foreign body sensation, recurrent erosions, lacrimation, and photophobia are also commonly seen in these patients.[21]

Although histopathological examination by H and E and special stains can show the abnormal deposits in the CD cases,[22],[23] it is mostly not done for the initial diagnosis of such cases as earlier presentation does not need PKP and thus no available tissue for examination.

This study include 10 eyes of six patients; four of them submitted to PKP as a management to severe central corneal opacity with deterioration of the visual acuity not responding to medical treatment. These four eyes were diagnosed clinically as lattice (2 eyes), granular (one eye), and macular (one eye).

We relay in the clinical diagnosis of the cases incorporated in this study on the history, vision, complaints, and slit lamp examination, which showed the characteristic shape of opacity for each type, but it was also showing haze in some cases and we did not use optical coherence tomography (OCT) or high-magnification slit lamp which was not available during the study.

Then, the cases that were subjected to PKP were sent for further histopathological evaluation.

After histopathological examination, it was found that one case with the clinical diagnosis of LCD was finally diagnosed as mixed stromal CD of lattice, granular, and macular types. This case was showing haze in addition to the branching filamentous corneal opacities on slit lamp examination. This case was not further examined by the OCT (was not available) which help a lot in determining the opacities level as well as the density and the corneal thickness and thus can give us guide to the possibility of mixed types of dystrophy.

After this study, they found the possibility of missing the mixed form of CD if slit lamp examination only applied in these cases. The study recommends further examination of these cases by the OCT.

This study is the first study (up to our knowledge) that found mixed stromal CD of three types in one case (granular, lattice, and macular) in Omani patient as previous studies described only mixed GCD and LCD (Avellino dystrophy) that was first described in patients from Avellino, Italy.

This study not applied genetic examination for incorporated cases, although it is recommended to do genetic studied, not only because they are genetic mediated diseases but also to identify the subtype of each type. Moreover, future treatment may depend on gene type mutation or its protein product.


   Conclusion Top


Systematic histopathological approach and evaluation, including special stains in all stromal corneal dystrophies subjected to penetrating keratoplastyis essential to assess the abnormal corneal deposits especially if slit lamp examination showing corneal haze. Also, this study suggests that slit lamp examination alone may not be enough to assess stromal corneal dystrophy and additional methods for corneal imaging such as confocal microscopy and high-definition optical coherence tomography are recommended for future cases especially in cases with unclassic query diagnosis on slit lamp examination and where further histopathological examination will not be done.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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