Review Gelatinous drop-like : a review Hrishikesh Kaza,1 Manas R Barik,2 Mamatha M Reddy,2 Ruchi Mittal,3 Sujata Das1

1Cornea and Anterior Segment ABSTRACT life.11 Clinically, this disease is characterised by mul- Service, LV Prasad Eye Gelatinous drop-like corneal dystrophy (GDLD) is a rare tiple, small subepithelial, gelatinous excrescences, Institute, Bhubaneswar, Odisha, India autosomal recessive form of corneal dystrophy which may give the corneal surface a mulberry-like 2Molecular and Cell Biology characterised by subepithelial and stromal amyloid appearance in typical cases (figure 1A, B). It may also Laboratory, LV Prasad Eye deposits. It is relatively common in Japan. It usually be characterised by recurrent corneal epithelial ero- Institute, Bhubaneswar, presents in the first two decades of life with sions.4 The deposits or lesions have different appear- Odisha, India subepithelial nodular lesions that later coalesce to form ances depending on the type of illumination used in 3Dalmia Ophthalmic Pathology Service, LV Prasad Eye mulberry-like opacities. Although various surgical the -opaque with direct illumination and Institute, Bhubaneswar, modalities have been attempted, recurrence remains a translucent on retro illumination, in contrast to the Odisha, India major challenge. multiple white or grey-white elevated lesions of Salzmann’s nodular degeneration.712The corneal Correspondence to fl Dr Sujata Das, and epithelium also shows increased uorescein perme- Anterior Segment Service, L V INTRODUCTION ation in GDLD. Disease progression leads to superfi- Prasad Eye Institute, Gelatinous drop-like corneal dystrophy (GDLD) is cial and deep corneal vascularisation in the areas of Bhubaneswar, Odisha 751024, an autosomal recessive disease characterised by the opacity with further deposition of amyloid in – India; [email protected] corneal subepithelial and stromal deposits of gelat- deeper layers causing severe visual loss.13 16 Amyloid Received 24 August 2016 inous amyloid material, insidious in onset and pre- deposit has also been reported to arise from perilim- 10 17 Revised 3 November 2016 sents usually in the first two decades of life. It was bal conjunctival stroma in patients with GDLD. Accepted 9 November 2016 first described by Nakaizumi1 in 1914 and named In case of recurrence of GDLD after keratoplasty, it as gelatinous drop-like dystrophy, prior to which, it has been shown to recur along the sutures.18 An early was known as primary familial amyloidosis or sube- sign of recurrence is glass-like subepithelial haze. pithelial amyloidosis. It is bilaterally symmetric, has Ide et al13 described four clinical phenotypic low degree of penetrance and manifests commonly varieties—, stromal opacity, between 8 and 18 years of age.23 kumquat-like and typical mulberry. Of these, the two GDLD is a monogenic disease caused due to a predominant clinical forms are the mulberry type homozygous biallelic loss-of-functional mutation of and the band keratopathy type. It is unclear if the the tumour-associated calcium signal transducer 2 four different phenotypes might change from one to (TACSTD2) gene, located on the short-arm of the other in a single person. However, Akiya et al19 chromosome 1.4 This gene encodes for TACSTD2 reportedacaseofoneeyewithmulberrytypeand protein which is implicated in the disease the other eye with the band keratopathy type. The pathogenesis. mulberry and the band keratopathy types tend to occur in the early to intermediate stage, while the EPIDEMIOLOGY kumquat-like type tends to occur in the very late 9 It is significantly more common in Japan with the stage. There are no directly associated systemic dis- highest reported prevalence of 1 in 33 000 but is a orders associated with gelatinous drop-like dys- – rarity in other parts of the world.4 7 It is noted to trophy; thus, it was previously named as primary occur in India and China, with a few cases scattered corneal amyloidosis and later classified as corneal in Europe. It has also been found in Vietnamese, dystrophy, category-1. Tunisian, Turkish and Iranian families.8 Parents of affected individuals have a markedly higher fre- DIFFERENTIAL DIAGNOSES quency of consanguineous marriages than the Spheroidal degeneration general population.9 The autosomal recessive inher- Spheroidal degeneration of the cornea or climatic itance accounts for its rarity. In a study conducted droplet keratopathy may present in a similar at a tertiary eye care centre in India, Pandrowala manner with the above-mentioned complaints and et al5 evaluated 181 corneal buttons of 144 is also typically bilateral. Exposure to ultraviolet patients with corneal dystrophies who underwent rays seems to be a risk factor. The lesions are clas- penetrating keratoplasty (PK) and found GDLD in sically elevated and golden yellow in colour.20 eight buttons only, thus accounting for about 4.4% Simultaneous occurrences of GDLD and spheroidal of the total cases of corneal dystrophies seen by degeneration has been reported in literature; them. Elsewhere, Santo et al10 evaluated 80 however, the authors feel that it is purely an inci- patients with corneal dystrophies and found 15 dental observation since spheroidal degeneration is patients with GDLD (18.8%). a degenerative disorder and can be associated with any other corneal disease.19 21 CLINICAL FEATURES ’ ’ To cite: Kaza H, Barik MR, Patients symptoms include severe , lacri- Salzmann s nodular degeneration Reddy MM, et al. Br J mation, foreign body sensation, blepharospasm and a Salzmann’s nodular degeneration of the cornea, ini- Ophthalmol 2017;101:10– relatively later onset of progressively deteriorating tially classified as a dystrophy, is a degenerative 15. vision, with manifestation in the first two decades of corneal disease, insidious in onset and consists of

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Figure 1 (A) Slit-lamp photograph (case 1: 25 years/male, no history of parental consanguinity, presented with diminution of vision, intermittent redness and watering, both eyes) showing multiple nodular lesions on the corneal surface giving a mulberry-like appearance. (B) Slit-lamp photograph (case 2: 23 years/female, no history of parental consanguinity, post-deep anterior lamellar keratoplasty (DALK) recurrence) showing the recurrence of deposits around sutures and the graft including the central part. She underwent DALK for a primary mulberry pattern gelatinous drop-like corneal dystrophy. (C) Photomicrograph (case 2) showing discontinuous corneal epithelium; epithelial and subepithelial tissue lies partially separated from the stroma in the central cornea. There is presence of amorphous eosinophilic band-like and nodular deposits in the subepithelium and anterior stroma (H&E; original magnification: ×100). (D) High magnification photomicrograph (case 1) showing irregularly thinned corneal epithelium. Bowman’s layer cannot be appreciated and there are dense eosinophilic thick band-like deposits (H&E; original magnification: ×400). (E) Eosinophilic deposits are seen exhibiting distinctive brick red stain on Congo red stain (case 1; original magnification: ×400). (F) Characteristic apple green birefringence can be appreciated under polarised light (case 1; original magnification: ×400). multiple blue-white subepithelial nodules arranged circularly in moon crater-like endothelial changes visible with retroillumina- the central part of the cornea.22 Unlike GDLD, Salzmann’s tion and a dilated .12 nodular degeneration presents commonly in middle to older age groups. Secondary corneal amyloidosis—GDLD type Secondary corneal amyloidosis is known to occur after chronic ocular irritation/inflammatory/infective disorders like , Lattice corneal dystrophy , and so forth. It has been classified into Lattice corneal dystrophy, a corneal stromal dystrophy, asso- three subtypes according to their clinical appearance. The ciated with amyloid protein deposits mainly within the corneal GDLD type secondary corneal amyloidosis resembles GDLD stroma is clinically characterised by branching stromal lattice lesions morphologically, having milky white soft masses on the lines. In addition, there is presence of subepithelial opacities corneal surface. Correlation with clinical history is of para- which can be band-like, thus making differentiation from mount importance for its differentiation from primary corneal GDLD difficult in some cases. Nakamura et al23 have described amyloidosis. The deposits seem to be confined to the site of few patients of GDLD with clinical features that may resemble inflammation or chronic irritation. These patients have an lattice dystrophy type-1. earlier age at presentation as compared with the other secondary corneal amyloidosis types but were still considerably higher than Band-shaped keratopathy patients with GDLD.25 It is characterised by the appearance of a band across the central cornea. Primary band-shaped keratopathy, when bilateral, may INTERNATIONAL CLASSIFICATION clinically mimic GDLD. Bilateral primary band-shaped keratopa- According to International Committee for Classification of thy has been reported to progress to GDLD over years; Corneal Dystrophies Classification of corneal dystrophies, it is however, authors feel that this could have been primarily a case classified as an epithelial and subepithelial dystrophy, of GDLD.24 The primary GDLD band keratopathy shows no category-1.17 It is an autosomal recessive disease and individuals endothelial changes, whereas secondary band keratopathy is may be compound heterozygotes or homozygotes for disease seen as a clinical sign in different endothelial dystrophies as a manifestations to occur.

Kaza H, et al. Br J Ophthalmol 2017;101:10–15. doi:10.1136/bjophthalmol-2016-309555 11 Review

GENETICS OF THE DISEASE an ability to regulate binding to other molecules or the plasma TACSTD2 gene (also termed as TROP-2, EGP-2, GA 733-1) is membrane. The mutations may lead to loss of the PIP2 binding an intron-less gene, consisting of only a single exon, located in site, thereby leading to loss of the various cell adhesion func- chromosome 1 (1p 32).26 The TACSTD2 gene encodes a tions.35 To summarise, TACSTD2 is an important component of human glycoprotein consisting of an additional transmembrane desmosomes and zonulae occludentes and is central to disease domain and acts as cell surface receptor. In 1998, Tsujikawa pathogenesis in GDLD. The mutations may cause an abnormal et al26 mapped the locus for GDLD at the short-arm of chromo- functioning or loss of function of the gene, which leads to an some 1, thus excluding association of serum amyloid P gene27 increase in corneal epithelial permeability and affect cell adhe- and the transforming growth factor β-induced gene as the pos- sion functions. sible candidate gene/s for GDLD.28 At the same time, sequence analysis of DNA isolated from patients with GDLD also showed DNA sequence analysis absence of mutations in the entire coding region of big-h3 For this study, blood sample was collected after obtaining 28 et al29 fi gene. Further in 1999, Tsujikawa identi ed the approval from the Institutional Review Board and written 30 TACSTD2 gene as the possible candidate for GDLD harbour- informed consent from the patient. Genomic DNA was isolated fi ing four deleterious mutations. The mutations identi ed were p. using QIAamp DNA Mini Kit as per the manufacturer’s instruc- Gln118Ter (Q118X), c.632delA, p.Gln207Ter (Q207X) and p. tions. TACSTD2 gene was amplified by PCR as described previ- Ser170Ter (S170X), of which p.Gln118Ter (Q118X) was found ously.21 The entire coding region of the gene was sequenced. 29 to be the most commonly observed mutation. Interestingly, The obtained genomic DNA sequence showed a transversion of their group also demonstrated absence of genetic variability in thymidine to guanine at nucleotide position 614 (c.614). This Japanese patients who presented with phenotypic variations and homozygous single base substitution predicted an amino acid were clinically initially diagnosed as atypical bilateral amyloid- change from leucine to arginine at position 205 of the protein 31 → osis. The p.Gln118Ter (Q118X) mutation consists of a C T sequence (L205R) (figure 2). TACSTD2 gene is known to transition at nt352, replacing the nucleotide sequence codon harbour mutations throughout the coding sequence. L205R is in encoding for glutamine at position 118 with a stop codon, very close proximity to another key mutation Q207X that was which in turn truncates the protein sequence at that point. This shown to be deleterious in GDLD. Both leucine at 205 and glu- results in abnormal functioning or loss of function of the gene. tamine at 207 are conserved residues across different species. — A novel compound heterozygous mutation p.Gln118Ter Substitution of non-polar amino acid leucine by basic polar (Q118X) with p.Tyr184Cys (Y184C) was found in a Chinese amino acid arginine is expected to change the structure and 32 et al33 patient with GDLD. Jing reported in-frame mutation function of the protein. of TACSTD2, c526_576del 51 in two Chinese brothers. However, Alavi et al34 concluded that there was evidence for the existence of at least one other gene locus for GDLD as the PATHOGENESIS disease in their pedigree was probably not caused by a mutation TACSTD2 gene is explained to be responsible for proper main- tenance of corneal epithelial barrier function by binding to in TACSTD2 gene. This is important as it has led to an 36 increased appreciation of previously presumed benign claudin 1 and 7 tight junction-related proteins. The abnormal mutations. increase in the permeability of the corneal epithelium in 37 fl TACSTD2 also transduces intracellular calcium signals. The GDLD has been demonstrated by diffusion of uorescein into fi gene mutation and the disturbed localisation of cell-to-cell adhe- the corneal stroma. This supports the nding observed in sion molecules cause an abnormal increase in corneal epithelial GDLD that the tight junctions are disturbed due to the muta- permeability.35 In addition, the phosphatidylinositol tions and the disease process. The corneal epithelium in these patients shows abnormal gaps. The superficial layer of cornea 4,5-bisphosphonate (PIP2) binding site, presumed to be located at the C-terminal intracellular domain of TACSTD2 gene, has showed abnormal basal epithelium with disordered desmosomes between them.38 Uhlig et al39 concluded that corneal vascular- isation and mechanical stress promoted the development of gel- atinous deposits in GDLD.

HISTOPATHOLOGY Sections from corneal tissue show morphological changes, pre- dominantly in the central cornea. Epithelium is of varying thick- ness, with or without intercellular oedema, and may lie separated from the stroma. There is destruction of epithelial basement membrane, with interruptions and/or absence of Bowman’s layer (figure 1C, D). Homogenous, acellular eosino- philic deposits are seen in the subepithelial, intraepithelial and anterior stromal location. The deposits may appear band- shaped, nodular and/or like small linear strands. The nodular subepithelial and/or intraepithelial deposits raise the basement membrane/epithelium, causing their destruction/interruptions, giving a mulberry-like appearance. The deposits are positive for periodic acid Schiff’s stain; however, they stain with less inten- ’ Figure 2 Sequence analysis (case 2: 23 years/female, no history of sity as compared with the Descemet s membrane. They display parental consanguinity) of TACSTD2 gene identified a novel congophilia (brick red stain) when subjected to Congo red stain homozygous missense mutation c.614 resulting in an amino acid and demonstrate characteristic apple green birefringence under substitution (L205R). Arrowhead indicates the transversion of T>G. polarised light (figure 1E, F). Mondino et al16 reported that the

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amyloid found in of patients with GDLD is of serum numerous long processes protruding into the amyloid amyloid protein type. substance.45 On immunohistochemistry, these deposits stain for lactoferrin. In addition, lactoferrin expression has been observed in the OTHER INVESTIGATIONS nuclei of the overlying corneal epithelium; however, the muta- Anterior segment optical coherence tomography tion associated with GDLD is not linked with lactoferrin Fourier-domain optical coherence tomography (OCT) shows gene.40 Amyloid typing in a single case of GDLD performed by high reflectivity in the area of amyloid deposition. A recent using shotgun liquid chromatography/tandem mass spectrometry study done by Magalhães et al46 on anterior segment OCT has also suggested lactoferrin as the precursor protein.41 It has (ASOCT) in GDLD showed that the treatment modality could been postulated that increased permeability of corneal epithe- have been changed if the ASOCT had been done earlier as their lium is responsible for lactoferrin expression and thus patient showed involvement of superficial corneal layers only. lactoferrin-related amyloid formation, it being a component of Thus, it may be important in early diagnosis and in establishing the human tear film. Nishida et al42 has demonstrated localisa- the best possible treatment option in them. tion of apolipoproteins J as well as E, in patients with GDLD, which they hypothesise could be involved in the pathogenesis or Confocal microscopy may be an additional protein in these corneas with increased Laser scanning confocal microscopy has revealed that the epi- epithelial permeability. Yoshida et al43 reported expression of thelial cells were irregular in shape and often elongated in con- vitronectin, an extracellular matrix adhesion molecule in cornea trast to polygonal shape of normal epithelium. Mild of patients with GDLD and suggested its role in corneal neovas- disorganisation of epithelial cells and large accumulation of cularisation occurring in patients with GDLD in advanced cases. brightly reflective amyloid materials were noted beneath the epi- Electron microscopy study of a case of GDLD showed abnor- thelium and anterior stroma.33 mally thickened epithelium with increased intercellular spaces and intact desmosomes. Similar observations have also been MANAGEMENT reported by Kinoshita et al.37 They explained presence of Medical management amyloid deposits in the stromal collagen fibrils, which led to Medical treatment is usually inadequate for this disorder. But in some stromal disorganisation. The amyloid deposits were non- the initial stages of the disease, it can be started with lubricating branching, irregularly arranged fibrils, often in the form of eye drops and bandage contact lenses for symptomatic relief to spheres and ranged from tens of nanometres to several microns the patient. in diameter.44 Ohnishi et al reported intact basal lamina and Bowman’s layer in early cases. However, in severe cases, the Surgical management basal lamina of the basal cells was discontinuous and there were The various surgical treatment options include superficial kera- tectomy, penetrating keratoplasty, lamellar keratoplasty, limbal stem cell transplant (LSCT) (either a living-related allogenic transplant or a cadaveric allogenic transplant) and keratoprosth- Table 1 Modality of treatment for GDLD with outcome esis (K-Pro) (table 1). No. of eyes/ Modality of Authors cases treatment Outcome Superficial keratectomy Superficial keratectomy can be done to debulk a lesion initially, Shimazaki 9 eyes (7 cases) Keratoplasty No recurrence noted et al48 (lamellar or after a mean improving the vision to some extent. The effects of this are penetrating) +LSCT follow-up of 4 years in short-lived, as the deposits are invariably known to recur. A (allograft— 8 of 9 eyes phototherapeutic keratectomy (PTK) may be performed to cadaver) smoothen the corneal surface and to provide symptomatic relief. Shimazaki 35 keratoplasties Keratoplasty alone Recurrence noted in In one of the latest articles published, Alex et al47 have per- et al18 in 7 patients in (lamellar or 34 of 35 keratoplasties formed amniotic membrane graft (AMG) overlay to promote the study penetrating) within 4 years et al47 corneal cell migration and proliferation in addition to PTK. Alex 1 case PTK+AMG Recurrence noted at fi 6 months, but patient They have hypothesised that the additional anti- brotic and was symptom-free for anti-inflammatory properties present in an AMG reduces post- 22 months operative fibrosis. Although it reoccurred earlier, the patient Movahedan 3 eyes Allograft LSCT Recurrence-free during remained comfortable for a much longer duration (up to et al15 +penetrating follow-up in all 3, 22 months). Thus, this could be a promising modality of treat- keratoplasty or mean follow-up of superficial 23 months ment in patients where the primary aim of surgery is not visual keratectomy rehabilitation. Omoto 2 cases LSCT+DALK No recurrence for up et al51 to 2 years Penetrating keratoplasty Fadlallah 1 case Boston type 1 Good PK is an option commonly used to treat GDLD; however, the 56 et al K-Pro in a case of noted at last follow-up surgery may be complicated because of fragility of corneal recurrent graft (at 12 months after tissues. Recurrence even after keratoplasty is a problem, with failure Yag capsulotomy) reported recurrence rates as high as 50%–70%.1 Therefore, Cortina 1 case Boston type 1 BCVA of 20/20 was et al55 K-Pro as primary maintained for repeat keratoplasty is almost always needed. This leaves room treatment option >14 months for possible secondary complications such as , AMG, amniotic membrane graft; BCVA, best-corrected visual acuity; DALK, deep and infections. An early sign of recurrence is the development anterior lamellar keratoplasty; GDLD, gelatinous drop-like corneal dystrophy; K-Pro, of a subepithelial glass-like haziness, which usually occurs 8–12 keratoprosthesis; LSCT, limbal stem cell transplant; PTK, phototherapeutic months after a PK.48 According to few studies, subepithelial keratectomy. haze has been seen to develop as early as 1 month

Kaza H, et al. Br J Ophthalmol 2017;101:10–15. doi:10.1136/bjophthalmol-2016-309555 13 Review postoperatively around suture materials. Post-keratoplasty recur- In case of a recurrence in an eye which has undergone a previ- rence may be reduced by the use of bandage soft contact ous PK, K-Pro may be done to avoid another recurrence and/or wear, which acts by decreasing the epithelial turnover.49 speed up the rehabilitation process of the involved eye.56 Currently, Boston K-Pro is considered to be better if not the best Lamellar keratoplasty modality of treatment, in cases of recurrent graft failure. Lamellar keratoplasty may be done for a good effect considering However, it is important to understand that Boston K-Pro is asso- the inevitable recurrence with a PK as the inner corneal layers ciated with severe complications in a few which may lead to per- are essentially normal. This can reduce the risk of endothelial manent blindness. These include formation of a retroprosthetic 18 membrane, persistent epithelial defect, elevated IOP, corneal rejection reported in a few cases. Deep anterior lamellar kera- 57 toplasty (DALK) can be tried before attempting a PK in these stromal necrosis to name a few. A complication that needs cases. Femtosecond-assisted anterior lamellar keratoplasty is also mention in K-Pro is recurrent epithelial defect(s) around the an option where the involvement is limited to anterior corneal optical cylinder, which can be the entry way for with stroma. Femtosecond-assisted surgery has the advantage of a further spread of infection. GDLD being primarily an epithelial more precise and a regular incision through the anterior stroma. disease, it is very important to keep these patients on a close watch to make sure the epithelium stays intact. The use of bandage contact lens in K-Pro has been shown to decrease Limbal stem cell transplant complications. Shimazaki et al48 50 reported that LSCT when done along with a PK decreases the chances for recurrence. Simultaneous kerato- plasty with allogenic LSCT has been shown to maintain corneal CONCLUSION clarity and useful vision for up to 2 years after surgery in GDLD, an uncommon autosomal recessive disease, is charac- patients with GDLD.15 In a study by Omoto et al,51 LSCT done terised by bilateral corneal amyloidosis. It can manifest in differ- with DALK had no recurrence up to 2 years postoperatively. ent phenotypical forms. The TACSTD2 gene is implicated in Donor-derived epithelial cells found on the central graft several GDLD. Newer treatment options like limbal stem cell treatment years after LSCT suggests that stem cells on the allograft con- and K-Pro are practiced currently to decrease the risk of recur- tinue to supply corneal epithelial cells preventing abnormal rence and also to offer better visual outcomes for patients. amyloid deposition, thus, helping in maintaining stable visual acuity for a longer period. A well-documented serious complication of LSCT is ocular METHOD OF LITERATURE SEARCH hypertension.52 Hence, a regular check on the intraocular pres- PubMed was queried with combinations not limited to the fol- sure (IOP) and, if possible, early diagnosis and treatment of the lowing search terms: gelatinous drop-like corneal dystrophy, same are needed to maintain visual potential. Inability to genetics, histopathology, investigation and treatment. We examine IOP and disc status preoperatively and removal of included references that we considered to have major contribu- episcleral venous tissue, which drains the aqueous intraopera- tions to the understanding of GDLD. The abstracts of the tively, are the causes of raised IOP,which is further compounded non-English articles were also included. Case reports without by the use of steroid eye drops postoperatively. The limbal area additional value over another report of the same condition were contains numerous Langerhans cells making the risk of immuno- not included. logical reactions more likely than seen with lamellar or PK.53 Contributors All the authors included in this paper fulfil the criteria of authorship. These risks suggest that intensive postoperative management is equally important after any treatment procedure and is respon- Funding Hyderabad Eye Research Foundation, Hyderabad. sible for long-term success. In cases undergoing LSCT, treatment Competing interests None declared. with oral ciclosporin A, mycophenolate mofetil and prednisol- Patient consent Obtained. one has been used for a duration of up to 18 months, with Ethics approval Institutional Ethics Committee of LV Prasad Eye Institute, regular blood cell count monitoring.15 LSCT overall has been Bhubaneswar, Odisha, India. shown to suppress recurrence and maintain corneal clarity for a Provenance and peer review Not commissioned; externally peer reviewed. longer duration. In spite of achieving acceptable vision after LSCT for various indications, a progressive decline in vision and graft survival REFERENCES occurs with time. PK done simultaneously with LSCT may not 1 Nakaizumi GA. A rare case of corneal dystrophy. Acta Soc Ophthalmol Jpn – have the best outcome. A second LSCT has been shown to have 1914;18:949 50. fi 2 Gartry DS, Falcon MG, Cox RW. Primary gelatinous drop-like keratopathy. 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