Gelatinous drop-like corneal dystrophy

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Disease Entity

Gelatinous drop-like corneal dystrophy (subepithelial amyloidosis, primary familial amyloidosis) [ICD 10: H18.5 - Hereditary corneal dystrophy]

Disease

Gelatinous drop-like corneal dystrophy (GDLD) is a rare corneal disorder characterized by amyloid deposition in the subepithelial tissue and stroma resulting in impaired visual acuity. The onset of GDLD occurs during the first decade of life and with nodules forming in the corneal subepithelial layer. These deposits can progress, and patients experience significant vision loss, along with irritation, tearing, and severe photophobia.[1]

Etiology

GDLD is inherited in an autosomal recessive fashion and associated with mutations in the tumor-associated calcium signal transducer 2 (TACSTD2) gene. There are more than 20 mutations that have been reported in patients with GDLD with the Q118X mutation being the most commonly detected.[1] However, there are genetic and phenotypic variations in these mutations and some affected patients lack the TACSTD2 mutation, suggesting genetic heterogeneity.[2][3][4] Furthermore, not all individuals with the inherited gene manifest the signs and symptoms of GDLD given a low degree of penetrance.[5]

Risk Factors

Similar to other corneal dystrophies, a positive family history increases the risk of GDLD. GDLD is most commonly seen in individuals of Japanese descent.[6] A homozygous for Q118X mutation in the M1S1 gene is most often seen in patients with GDLD, suggesting this may be a risk factor.[7]

General Pathology

GDLD is caused by a mutation in the TACSTD2 gene responsible for the proper functioning of the tight junctions in the corneal epithelium.[6] This dysfunction leads to the permeation of tear fluid, containing lactoferrin, through the loosened epithelial barrier causing amyloid depositions.[8]  The amyloid deposition contains lactoferrin, but GDLD is not linked to the lactoferrin gene.[9] Clinical manifestations of GDLD typically begin with the subepithelial deposition of yellow-white nodules in the central cornea.[8] These nodules then coalesce and cause the typical manifestations of GDLD. As the disease advances, superficial stroma neovascularization can occur.[10]


GDLD can be classified into distinct subtypes that exist on a spectrum of disease progression. The subtypes include the band keratopathy type, stromal opacity type, mulberry type, and kumquat-like type.[8] The band keratopathy type and mulberry type can be seen early in the disease process and are characterized by amyloid deposition in the subepithelial space. The mulberry type has this characteristic milky-white gelatinous deposits resembling the appearance of the mulberry plants. As the disease progresses, the corneal stroma can become involved, resulting in the stromal opacity type and the kumquat-like type manifestations. The kumquat-like type GDLD is characterized by diffuse yellow-white deposits with superficial neovascularization and resembles the kumquat fruit.  

Primary prevention

There are no preventative measures for GDLD currently as it is an inherited corneal dystrophy.

Diagnosis

History

Patients classically presented in their first or second decade reporting severe light sensitivity and deteriorating visual acuity.[5] Corneal involvement will be seen in both eyes and visual acuity can vary depending on the age of presentation.  

Physical examination

Slit-lamp examination will reveal partially thinned epithelium, destruction of Bowman layer, and subepithelial amyloid deposits with nodular or string like features. The cornea may be compressed and edematous.[11] A major clinical feature of this disease is multiple, small subepithelial, gelatinous protrusions giving the corneal surface a mulberry-like appearance.[1] The epithelial and subepithelial nodules are mainly concentrated in the central cornea and spare the periphery.[12] Fluorescent permeation test will reveal immediate permeation of dye into corneal tissues.[13] Overtime, the cornea becomes vascularized and leads to worse vision.[14]

Signs and Symptoms

Severe progressive vision loss is the most concerning symptom. Continuous deposition of the subepithelial nodular lesion leads to a decline in visual acuity. Since GDLD is present within the first decade of life, amblyopia is a concern and can limit visual potential even with the appropriate surgical intervention.[15] Subepithelial involvement can lead to ocular surface symptoms such as irritation, foreign body sensation, photophobia, and epiphora.[1]

Clinical diagnosis

GDLD can be diagnosed via slit-lamp biomicroscopy and family history. Additional testing and imaging can aid in the diagnosis. Patients may be present with any of the subtypes of GDLD during their initial presentation. Deeper stromal involvement is seen later in the disease process.  Anterior segment optical coherence tomography can reveal amyloid deposition throughout the subepithelial layer and corneal stroma.[6]

Diagnostic procedures

Laboratory test

Histopathology reveals epithelial amyloid fibrils below the epithelial regions and multiple areas in the stroma.[1] Parts of the epithelium are edematous and degenerated while other parts are thin due to the accumulation of amyloid deposits. On hematoxylin and eosin stain, amorphous deposits can be appreciated in the subepithelial plane.[1] With the Congo red stain, apple-green dichroism of the subepithelial and stroma deposits can be seen under polarized light.[1] Electron microscopy reveals the replacement of tight junctions in epithelium with electron-lucent spaces.[16] These deposits may also be found in the lamellae causing degeneration of collagen fibrils and proteoglycans.[17]

Differential diagnosis

Spheroidal degeneration

Characterized by the appearance of spherical deposits in the anterior stroma with possible involvement of Bowman layer.[18] These deposits appear translucent and have a golden-brown appearance. Deposits are composed of proteinaceous hyaline material. The conjunctival can be affected[19] which differentiates it from GDLD.  

Salzmann nodular degeneration  

Idiopathic noninflammatory condition characterized by subepithelial elevated nodules located in the central or paracentral cornea.[20] These nodules have a gray-blue-white coloration which may resemble the mulberry-shaped nodules in GDLD. Salzmann’s nodular degeneration typically occurs in middle-aged and older women and has an association with corneal exposure and keratitis. On histology, these nodules are composed of hyaline and fibrillar material located in Bowman layer.[21]

Meesmann epithelial corneal dystrophy (MECD)

An inherited autosomal dominant condition characterized by small intraepithelial vesicles that extend from limbus to limbus. This condition is caused by a mutation in either KRT3 or KRT12 that encodes for the cytokeratin component of the corneal epithelium.[1] Like GDLD, MECD manifests within the first decade and is associated with irritation and photophobia. MECD can be differentiated from GDLD based on the location of the intraepithelial vesicles which stain positively with PAS.[1]

Band keratopathy

Characterized by the degeneration of the superficial corneal resulting in the deposition of calcium or urate in Bowman layer.[22] Deposits typically begin in the periphery at 3 and 9 o’clock and then migrate centrally in the interpalpebral zone. Possible etiologies for band keratopathy are extensive and range from ocular to systemic conditions. Band keratopathy can be differentiated from GDLD based on the location of the deposits and the composition of the deposits.  

Lattice corneal dystrophies (LCD)

Autosomal dominant corneal dystrophy characterized by branching filamentous opacities in the cornea stroma. LCD type I and its variants are associated with the TGFB1 mutation and do not have systemic manifestations.[1] LCD type II is associated with GSN mutation and is associated with systemic manifestations such as a characteristic “mask-like” facial expression and xerosis.[1] LCD is similar to GDLD due to amyloid deposition in the cornea. However, the fine-glassy filaments seen in LCD on slit-lamp biomicroscopy allow its differentiation from GDLD.  

Management

Medical therapy

Medical therapy for GDLD is limited and is mainly geared towards symptom management and delaying surgical intervention. Artificial lubrication can be used to treat symptoms associated with surface irritation. Soft contact lenses have been shown to decrease the need for surgical intervention.[23] However soft contact lenses do not prevent the progression of corneal opacities and neovascularization associated with GDLD and improvement in visual acuity.[23]  

Surgery

Superficial Keratectomy (SK)

SK can be used to debulk the subepithelial nodules to improve vision. Furthermore, the addition of an amniotic membrane to facilitate corneal cell proliferation and migration may assist temporarily in relieving clinical and visual symptoms.[6] However, the results are temporary due to recurrence and patients often needs multiple repeat SK.[24]

Penetrating Keratoplasty (PKP)

PKP is frequently used to treat GDLD. PKP can be difficult to accomplish due to the fragility of the corneal tissue. However, recurrence is a major complication of PKP and patients often require multiple transplantations.[11] This is caused by the replacement of recipient epithelial cells with donor epithelial cells.  Studies have shown a 97% recurrence rate of GDLD within four years with PKP.[6]

Deep Anterior Lamellar Keratoplasty (DALK)

DALK may be preferred over PKP due to the extremely high rates of recurrence with penetrating keratoplasties.[6] Amyloid deposition in GDLD is limited to the epithelium and stroma with sparing of the endothelium. Therefore, DALK can be considered and may help delay amyloid recurrence.[6] However, GDLD can still recur with DALK procedures.[25]

Limbal Stem Cell Transplantation (LSCT)

Due to the persistent recurrence of GDLD following corneal transplantation, the host corneal epithelial cells may be responsible for the amyloid deposition. LSCT from cadaver eyes following PKP has been shown to prevent recurrence and maintain improvements in visual acuity.[26] However, intensive postoperative management and immunosuppression are required to prevent rejection.  

Keratoprosthesis (Kpro)

Kpros have been proposed as a treatment for GDLD given the high rates of early recurrence following corneal transplantation. One case of a Boston type I keratoprosthesis had promising results with BCVA remaining 20/20 fourteen months after the procedure and with no clinical evidence of amyloid redeposition.[24] Postoperative complications of Kpros varied from retroprosthetic membranes treatable with YAG capsulotomy to severe infections.[27][28]

Prognosis and Complications

Surgical follow-up for GDLD is imperative due to the high rate of recurrence and complexity of the surgical treatments. Many of the surgical procedures mentioned above require immunosuppression and monitoring intraocular pressure is key for long-term maintenance of a clear graft.[26] The addition of soft contact lenses has been proposed to delay recurrence as it decreases epithelial turnover.[29] However, recurrence of GDLD remains a major complication, and recurrence within a year is a major concern which often leads to multiple repeated surgeries.[6]

Additional Resources

https://disorders.eyes.arizona.edu/disorders/corneal-dystrophy-gelatinous-drop

https://www.aao.org/Assets/22044689-08d4-4f11-b61a-6bb76096ca93/637151444257870000/k41-pdf?inline=1

References

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  2. Ren, Z., et al. "Mutations of the M1S1 gene on chromosome 1P in autosomal recessive gelatinous drop-like corneal dystrophy." Proc Internat Soc Eye Res 71 (2000): S108P.
  3. Alavi, Afagh, et al. "Four mutations (three novel, one founder) in TACSTD2 among Iranian GDLD patients." Investigative ophthalmology & visual science 48.10 (2007): 4490-4497.
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  23. 23.0 23.1 Maeno, Sayo, et al. "Efficacy of therapeutic soft contact lens in the management of gelatinous drop-like corneal dystrophy." British Journal of Ophthalmology 104.2 (2020): 241-246.
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