|Year : 2022 | Volume
| Issue : 2 | Page : 371-375
Recurrence in Reis Bücklers corneal dystrophy: Clinicopathological correlation
Murugesan Vanathi1, Alisha Kishore1, Yogita Gupta1, Prithvi Bheemanna Setty1, Seema Sen2, Tapas C Nag3, Ranjan Gupta3, Arundati Sharma3, Radhika Tandon1
1 Cornea Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, New Delhi, India
2 Ocular Pathology Services, Dr Rajendra Prasad Centre for Ophthalmic Sciences, New Delhi, India
3 Department of Anatomy and Genetics, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||15-Sep-2021|
|Date of Acceptance||25-Oct-2021|
|Date of Web Publication||13-Apr-2022|
Department of Cornea and Ocular Surface, Cataract and Refractive Services, Dr R P Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
We report a case series highlighting clinical correlation of recurrence of Reis–Bucklers corneal dystrophy (RBCD) with histopathology (HPE), genetic analysis, and electron microscopy (EM). This was an interventional case series of three cases in three generations of one family. The index case was a 23-year-old male with bilateral recurrent RBCD following OD PTK and OS ALTK done 6 years earlier. His father had undergone OU PK. His 35-year-old sister and 9-year-old niece were also affected who underwent OU ALTK. Clinical examination, histopathological examination (HPE), and electron microscopy (EM) evaluation were done. The recurrence of RBCD was noted in one of the three members of the same family. Corneal examination showed a dense reticulate pattern of epithelial-stromal involvement. On HPE, disrupted Bowman's membrane and underlying abnormal subepithelial collagen staining positive with PAS and Masson's trichrome were noted. On EM, degenerated stroma with dense collagen fibrils in aggregates, dispersed among regular collagen fibrils, were noted. All four members showed TGFß1 mutation (chromosome 5q31) with Arg124Leu mutation. A trend toward more advanced presentation with increasing age of cases was noted. The clinical and pathological correlation was performed. Clinical correlation with HPE, EM with genetic analysis of RBCD is interesting with presentation severity varying in different generations.
Keywords: Corneal dystrophy, dystrophy recurrence, RBCD, recurrence, Reis–Bücklers, stromal dystrophy
|How to cite this article:|
Vanathi M, Kishore A, Gupta Y, Setty PB, Sen S, Nag TC, Gupta R, Sharma A, Tandon R. Recurrence in Reis Bücklers corneal dystrophy: Clinicopathological correlation. Indian J Ophthalmol Case Rep 2022;2:371-5
|How to cite this URL:|
Vanathi M, Kishore A, Gupta Y, Setty PB, Sen S, Nag TC, Gupta R, Sharma A, Tandon R. Recurrence in Reis Bücklers corneal dystrophy: Clinicopathological correlation. Indian J Ophthalmol Case Rep [serial online] 2022 [cited 2022 May 27];2:371-5. Available from: https://www.ijoreports.in/text.asp?2022/2/2/371/342955
Reis–Bucklers corneal dystrophy (RBCD) is a bilateral and autosomal dominant inherited disease that primarily affects the Bowman's layer and superficial stroma. It was first described by Reis in 1917 as an annular dystrophy and was later reexamined by Bucklers in 1949. Since then, the clinical, histologic, and ultrastructural aspects and genetic disorders of RBCD have been widely elaborated., There is a gradually progressive deterioration of vision as the Bowman's layer gets replaced by sheet-like granular Masson trichrome red deposits. RBCD is associated with the transforming growth factor (TGFB1) gene located on chromosome 5q31.,,
Corneal surgery is required in RBCD when the disease is in the advanced stage for visual rehabilitation. Surgical treatment involves a minimally invasive procedure such as superficial keratectomy, including excimer laser phototherapeutic keratectomy (PTK), anterior lamellar therapeutic keratoplasty (ALTK), and hemi-automated lamellar keratoplasty (HALK). In the advanced stage, when the opacity reaches deeper stroma, full-thickness penetrating keratoplasty may be required. Recurrences have been noted within several months postoperatively. Clinically significant recurrence has been reported to occur in 47% of RBCD eyes in an average of 21.6 months after PTK.
| Case Series|| |
This was an interventional case series of three cases in three generations of one family. Consent to participate in the study was obtained. A 23-year-old male (index case) of RBCD with a history of RBCD in his father was studied. His father had undergone OU PK 20 years ago at our center. Our patient reported 6 years after bilateral keratoplasty [OD-phototherapeutic keratectomy (PTK) and OS anterior lamellar therapeutic keratoplasty (ALTK)], with recurrence in both eyes [Figure 1]. He underwent OD-ALTK and OS-hemi-automated lamellar keratoplasty (HALK). His 35-year-old elder female sibling and 9-year-old niece with RBCD also underwent OU ALTK [Figure 2] and [Figure 3]. Clinical, histopathological (HPE), and electron microscopy (EM) evaluations were done. Visual acuity and complete slit-lamp biomicroscopy for corneal evaluation (corneal diameter, depth of opacity, and vascularization) were noted. Anterior segment optical coherence tomography (AS-OCT) (ZEISS Visante OCT Model 1000; Carl Zeiss Meditec, Dublin, California, USA) imaging documented the depth of corneal involvement [Figure 4]. Histopathological examination with periodic acid-Schiff stain and Masson's trichrome stain and electron microscopy to evaluate the epithelial cells, Bowman's layer, and the collagen fibrils arrangement in the stroma, respectively, were done. Further, 2 ml of blood was collected from the willing members of the family for genetic analysis.
|Figure 1: Clinical picture on diffuse slit lamp of the index case showing irregular gray-white opacities in the subepithelial layer due to recurrence in both corneas - OD (a) and OS (b) and post HALK - OS (c)|
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|Figure 2: Clinical picture (from surgical video) of index case's elder sibling showing irregular gray-white opacities in the subepithelial layer OD with the preoperative and intraoperative OCT picture confirming the same (a, b) and OS preoperative (c) and slit-lamp photograph post ALTK with glue and well-attached graft (d)|
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|Figure 3: Slit-lamp photograph of index case's niece showing irregular gray-white opacities in the subepithelial layer pre operatively – OD (a) and OS (b)|
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|Figure 4: AS-OCT image showing involvement of the subepithelial and anterior stroma preoperatively (a, c, and e) and clear cornea with the attachment of the graft post operatively (b, d, and f) in the index case (a, b), index case' elder sibling (c, d) and index case's niece (e, f)|
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| Results|| |
Twenty members of the three generations of the involved family were screened, of which eight had RBCD. The family pedigree [Figure 5] suggested an autosomal dominant inheritance pattern. Of these, the index case (case 19), elder female sibling (case 13), and niece (case 21) were the available members for detailed ocular evaluation and genetic testing. Case 19 presented with RBCD recurrence in the third decade of life, while cases 13 and 21 were primary presentation in the first and fourth decade of life, respectively.
|Figure 5: The pedigree of the family with Reis–Bucklers corneal dystrophy (Circle: Male; square: Female; filled circle/square: Affected individual; arrow: Index case; slash through symbol: Death)|
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The visual acuity of the index case (19) was 2/60 (OD) and 4/60 (OS) preoperatively, which improved to 6/12 (OU) postoperatively. The visual acuity of the elder sister (case 13) was 5/60 (OU) preoperatively and 6/18 (OU) postoperatively, while that of the niece (case 19) was 4/60 (OD) and 6/60 (OS) preoperatively and 6/12 (OU) postoperatively. The case with recurrence (case 19) and primary presentation (cases 13 and 21), all had anterior corneal opacities forming reticulate patterns [Figure 1],[Figure 2],[Figure 3] and distributed in anterior stroma and subepithelial layer. Intervening stroma was also hazy. The lesions were denser in the center than at the periphery of cornea.
A trend toward deeper stromal involvement was noted as dystrophy cases were arranged according to their duration of pathology. The depth of corneal opacities as noted preoperatively using anterior segment optical coherence tomography (AS-OCT) (ZEISS Visante OCT Model 1000; Carl Zeiss Meditec, Dublin, California, USA) was 180, 140, and 100 μm in the right eye and 160, 136, and 110 μm in the left eye in cases 21, 19, and 13, respectively. The pachymetry was 651, 663 and 661 μm in the right eye and 660, 670, and 652 μm in the left eye, respectively, in cases 21, 19, and 13, respectively.
The corneal button obtained after keratoplasty surgeries were studied for HPE [Figure 6]. Light microscopy of index case (case 19), who was a recurrence of RBCD in his third decade of life, showed thickened epithelium, thickened Bowman's membrane, and abnormal subepithelial collagen with an orange hue. The case presenting in the first decade of life (case 21) showed only mild changes: disruption of Bowman's membrane and abnormal subepithelial collagen with relatively normal stroma. The case presenting in the fourth decade of life (case 13) showed an advanced disease with complete anterior stromal involvement with nodule-like structures in stroma, single layer epithelial lining, and destroyed Bowman's membrane. The abnormal collagen in the subepithelial layer was positive for Masson's trichrome (MT) and periodic acid-Schiff (PAS) stain.
|Figure 6: Histopathology examination under 200 × magnification by using light microscopy showing advanced stage of the disease (index case's elder sibling: a), intermediate stage of the disease (index case: b), and early stage of the disease (index case's niece: c)|
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Electron microscopy [Figure 7] showed mildly disarrayed stromal collagen fibrils in case 13, necrotic epithelial cells and more disorganization of stromal collagen lamellae in case 19, and totally disorganized stroma with irregularly aligned, degenerated collagen lamellae in case 21.
|Figure 7: Electron microscopy images of the case having intermediate disease, showing few intact stromal collagen lamellae (a, star), but disorganized in other parts (b, arrowhead) and necrotic epithelial cells (c)|
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On genetic analysis, Arg124Leu mutation of the transforming growth factor-induced (TGFβ1) gene on chromosome 5q32 was detected in the three affected family members.
| Discussion|| |
Corneal dystrophies refer to a group of inherited disorders that are usually bilateral, symmetric, slowly progressive, and not related to environmental or systemic factors. The newer updated corneal dystrophy classification includes histopathological, electron microscopy, and confocal microscopy findings. All the patients in our case series presented with progressive vision loss which had an early onset in life. On examination, reticular pattern subepithelial corneal opacities with relative sparing of the periphery with anterior corneal haze characteristic of anterior corneal dystrophy was seen in all three cases. Anterior corneal dystrophy includes epithelial-stromal corneal dystrophy or epithelial–subepithelial corneal dystrophy. Reis–Bucklers corneal dystrophy (RBCD) is an autosomal dominant disease associated with the TGFB1 gene located on chromosome 5q31 (Arg124Leu mutation). It presents with recurrent corneal erosions in early childhood. Early and marked visual loss occurs from corneal scarring. On slit-lamp examination, geographic or reticulate, irregular, gray-white opacities are present in the Bowman's layer and superficial stroma which are initially discrete but progress with age to involve the limbus and deeper stroma. The same can be correlated with AS-OCT imaging, which delineates the deeper involvement of the stroma as the disease progresses. On histopathological examination, RBCD shows disrupted Bowman's membrane and abnormal subepithelial collagen in the early stage. Thickened epithelium, thickened Bowman's membrane, abnormal subepithelial collagen (orange hue), and distorted Bowman's membrane are seen in the intermediate stage. The advanced stage of the disease shows a single layer of epithelium; Bowman's membrane is destroyed with nodule-like structures seen in the anterior stroma. PAS stain shows abnormal collagen, PAS-positive deposits, and subepithelial bullae. Masson trichrome stain shows granular red deposits in the subepithelial layer.,
Ultrastructural studies in RBCD reveal degenerative changes in the epithelial cells with replacement of the Bowman membrane with disoriented collagen fibrils. In the early stage of the disease, EM shows intact stromal collagen lamellae but collagen fibrils are not present. Stromal collagen stains intensely and is randomly oriented while the collagen fibrils are aggregated.,, In the intermediate stage, necrotic epithelial cells are present. Stromal collagen may be disorganized in some parts. In the more advanced disease, there is totally disorganized stroma with irregularly aligned, degenerated collagen lamellae taking intense stain. Bowman's layer and the subepithelial collagen are disarrayed. All these findings were consistent with our patients in this case series. Biopsy of the bulbar conjunctiva has shown reduplication of the basement membrane.
RBCD should be differentiated from Thiel–Behnke corneal dystrophy (TBCD). TBCD generally presents as honeycomb-like fleck-shaped corneal opacities in the subepithelial layer., RBCD and TBCD have been described as distinct corneal dystrophy – Bowman (CDB) disorders. Comparative histological analysis of these two dystrophies describes RBCD as CDB type I, and TBCD as CDB type II. On EM evaluation, TBCD is characterized by the presence of “curly” fibers in the Bowman and subepithelial layers, while TBCD has band-shaped granular Masson-positive subepithelial deposits and “rod-shaped bodies” resembling granular dystrophy. Visual loss has been described to be of higher magnitude with RBCD as compared to TBCD.
Both RBCD and TBCD are caused by missense mutations in the TGFBI gene on chromosome 5 (5q31). The mutation in RBCD results in a p.Arg124Leu amino acid substitution while in TBCD it results in a p. Arg555Gln substitution. Both disorders are inherited in an autosomal dominant pattern.
Recurrence in RBCD was first reported in 1978 by Olson et al. Recurrence of RBCD has been noted to occur as late as 15 years after PK. Recurrence rate among stromal corneal dystrophies has been reported to be the highest for dystrophies of the Bowman's layer (RBCD and TBCD), followed by granular corneal dystrophies and lattice corneal dystrophies. Recurrence lesions have a fine granular pattern in peripheral cornea and denser opacification in central cornea, with more irregular pattern than primary lesions., RBCD recurrence has been reported to be more common after PTK. Recurrence was noted in two out of four members in our case series.
Asymptomatic patients or those with mild corneal erosions can be treated with lubricants and observed. If the opacity is present superficially (involving 100 μm with residual bed thickness being more than 300 μm), then phototherapeutic keratectomy (PTK) may be preferred. The disadvantage of PTK includes corneal haze, glare, and recurrence of the pathology. Custom component lamellar keratoplasty to selectively replace the involved anterior layers of the cornea include superficial anterior lamellar keratoplasty (SALK), automated lamellar therapeutic keratoplasty (ALTK), and hemi-automated lamellar keratoplasty (HALK). Automated lamellar keratoplasty results in smooth interface, thereby resulting in less interface scarring, better contrast, and glare acuity with better epithelization. HALK is performed when manual dissection of the host bed is required, as in small size of palpebral fissure which precludes optimal fit of the automated microkeratome suction ring, or in cases where the host corneal thickness does not permit a safe automated microkeratome passage. We did OD HALK and OS ALTK in the index case. OU ALTK was done in both eyes of the index case's elder sister and OD HALK, and OS ALTK was done in index case's niece with good postoperative visual gain.
| Conclusion|| |
This case series elaborates the clinical correlation of RBCD with HPE and of EM with genetic analysis. It is interesting to observe the presentation severity varying in the different generations of this affected family. The severity of stromal involvement tends to increase with increasing age.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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