Subepithelial Mucinous Corneal Dystrophy

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Article initiated by:

Oscar Chen

All contributors:

Jake Lesher, Vatinee Y. Bunya, MD, MSCE, Colleen Halfpenny, M.D., Oscar Chen

Assigned editor:

Vatinee Y. Bunya, MD, MSCE

Review:

Assigned status Up to Date

 by Vatinee Y. Bunya, MD, MSCE on July 23, 2024.

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Disease Entity

Subepithelial Mucinous Corneal Dystrophy (ICD-10 # H18.593, H18.599 - Other hereditary corneal dystrophies)

Disease

Subepithelial mucinous corneal dystrophy (SMCD) is an exceedingly rare autosomal dominant disease of the anterior cornea characterized by the bilateral subepithelial deposition of mucins. Signs and symptoms typically appear within the first decade of life with recurrent corneal erosions. Erosions subsides in adolescence but corneal opacities eventually develop due to the accumulation of the glycosaminoglycans chondroitin-4-sulfate and dermatan sulfate immediately anterior to Bowman’s layer, causing progressively declining visual acuity later in life.

Etiology

Although SMCD is known to have an autosomal dominant inheritance pattern, this disease entity has only been seen in a single three-generation family. No specific gene locus has been identified in SMCD. The only known affected family is of Slovak descent; however, there is no known association between this population and SMCD. Despite the accumulation of glycosaminoglycans within the anterior cornea, patients with SMCD show no evidence of any systemic mucopolysaccharidosis.

Risk Factors

Similar to other corneal dystrophies, a positive family history increases the risk of SMCD. No other risk factors have been identified.

General Pathology

The characteristic ocular pathology associated with SMCD is the appearance of the bilateral subepithelial mucinous deposits. Deposits are dense central and fades as it progresses peripherally to the limbus with focal, irregular extension to the anterior stroma. These opacities may or may not be elevated such that they alter the normal anterior corneal contour. Bowman’s membrane, though largely intact, appears thickened on slit-lamp examination and under light microscopy. Additionally, transmission electron microscopy will reveal areas of decreased electron scattering beginning just below the epithelium and extending to the anterior stroma. The middle and posterior stroma, Descemet’s membrane, and endothelium are unaffected. Immunohistochemical demonstrates the presence of chondroitin-4-sulfate and dermatan sulfate in the regions of abnormal deposition.

Pathophysiology

Although the genetic locus of SMCD has not been identified and thus the exact pathophysiological mechanism of disease progression remains unclear, the deposition of dermatan sulfate and chondroitin-4-sulfate in the subepithelial space results in the clinical findings and symptoms. These subepithelial deposits disrupts the function of the epithelium resulting in recurrent erosions. Furthermore, loss of optical clarity and disruption of the normal refractive curvature of the cornea will result in progressive vision loss observed clinically in documented cases of SMCD.

Primary prevention

There are not preventive strategies and measures studied to date.

Diagnosis

Diagnosis of SMCD is accomplished mainly with slit-lamp biomicroscopy. Should the patient undergo penetrating keratoplasty or superficial keratectomy, immunohistochemical staining and examination of corneal samples under light microscopy can help confirm the diagnosis. Clinical and laboratory findings should be correlated with the patient’s family history.  

History

Patients with SMCD may present in childhood with frequent episodes of painful foreign body sensation due to recurrent corneal erosions. As these patient progress into adulthood, they may experience progressive decline in vision over decades. Age of presentation in available case reports ranges from the 5th to the 9th decade of life; however, the two oldest patients examined (71 and 82 years of age at presentation) had the most significant visual impairment associated with SMCD progression.

Signs

Slit-lamp examination of both eyes will reveal diffuse subepithelial haze most dense centrally and fading towards the limbus. Intervening focal irregular subepithelial opacities may extend to the anterior stroma as well as slightly elevate the anterior corneal surface. Decline in visual acuity can be tracked over decades.

Symptoms

Recurrent episodes of painful foreign body sensation bilaterally during the first decade of life along with progressive decrease in visual acuity. No systemic manifestations have been reported.

Clinical diagnosis

Clinical diagnosis is predicated on a correlation of the patient’s family history -- which should reveal a pattern of similar ocular symptoms consistent with autosomal dominant inheritance -- with findings on slit lamp exam previously described that are consistent with SMCD (see General Pathology section above).  

Diagnostic procedures

Transmission electron microscopy can used to assist in diagnosing SMCD. On electron microscopy, relative translucent bands are seen beneath the epithelium with extension to the anterior stroma.

Laboratory test

Corneal samples collected from patients with SMCD have demonstrated a constellation of immunohistochemical findings. On light microscopy, a layer of uniform eosinophilic deposit just anterior to Bowman’s layer can be seen. This layer is distinct from the epithelial basement membrane. The abnormal layer stains positively with the periodic acid-Schiff stain, reflecting the presence of mucopolysaccharides. It stains a lighter blue than Bowman’s membrane on Masson trichrome stain, reflecting some presence of collagen in this layer. Additionally, this layer stains intensely with Alcian blue at pH 1.4, which disappears following addition of testicular hyaluronidase. Finally, monoclonal antibody stains specific for dermatan sulfate and chondroitin-4-sulfate confirm the distinct biochemical composition of SMCD deposits.  

Differential diagnosis

Epithelial basement membrane dystrophy (EBMD)

EBMD is caused by dysfunctional development of the basement membrane of the corneal epithelium, resulting in a thickened, folded, and redundant appearance associated with epithelial cysts. The basement membrane abnormalities result in distinctive “map”, “dot”, and “fingerprint” lesions not consistent with the presentation of SMCD. Additionally, patients with EBMD only present with corneal erosions in the fourth decade of life, in contrast to those with SMCD who present with erosions in early childhood.

Meesmann corneal dystrophy (MECD)

Meesmann corneal dystrophy (MECD) presents at infancy with bilateral tiny “dew-drop” opacities predominantly in the central corneal epithelium and becoming less dense towards the periphery. This is in contrast to SMCD, in which corneal erosions are observed in the first decade and opacities do not typically appear until adulthood. Additionally, vision is rarely significantly diminished at any point in the progression of MECD.

Lisch corneal dystrophy (LCD)

LCD is a corneal dystrophy affecting the epithelium inherited in an X-linked dominant fashion, although sporadic cases have been reported. Like SMCD, patients with LCD typically present with opacities in adulthood, which can severely limit vision over time. However, the epithelial lesions pathognomonic for LCD occur in feathery, band-shaped, or whorled patterns localized in the corneal epithelium, which is not consistent with the opacities documented in cases of SMCD. Furthermore, unlike SMCD, symptomatic erosions are not associated with LCD.

Gelatinous drop-like corneal dystrophy (GDCD)

GDCD is characterized by bilateral deposition of subepithelial amyloid-rich opacities which may sometimes extend to the stroma. While patients with GDCD and SMCD may both experience foreign body sensation, patients with GDCD may also experience photophobia, and loss of vision occurs much earlier in life. Furthermore, GDCD presents with multiple, small subepithelial, gelatinous protrusions giving the corneal surface a mulberry-like appearance. Additionally, corneal samples from patients with GDCD stain positively with Congo red, given the large amyloid content below the epithelium. Finally, while penetrating keratoplasty (PKP) can be curative for patients with SMCD, cases of GDCD are refractory to PKP and other surgical interventions.

Reis-Bucklers corneal dystrophy

Reis-Bucklers corneal dystrophy is an epithelial-stromal dystrophy associated with a mutation in the TGFB1 gene inherited in an autosomal dominant pattern. Much like SMCD, it initially presents with corneal erosions in early childhood followed by significant visual loss. Although the classic presentation of Reis-Bucklers dystrophy consists of a combination of morphologically characteristic opacities resembling a fishnet, wreath, or ground-glass, it can also atypically present with opacities more morphologically consistent with SMCD. In such cases where differentiation is difficult on slit-lamp examination, genetic testing for TGFB1 may be indicated as well as immunohistochemical staining, as unlike SMCD, Reis-Bucklers corneal dystrophy has no consistent staining pattern.

Management

General treatment

The ideal treatment course for SMCD is not well outlined due to the exceedingly rare nature of this disease. However, manage includes medical treatment of recurrent corneal erosion that presents during the first decade of life. Patient with significantly diminished visual acuity due to corneal opacities and haze may benefit from surgical interventions, including superficial keratectomy (SK), lamellar keratoplasty, phototherapeutic keratectomy (PTK), or penetrating keratoplasty (PKP).

Medical therapy

When patients present in childhood with recurrent erosions, topical lubricate with artifical tears and lubicating ointment can help with the ocular pain and prompt healing. Besides lubrication, topical antibiotic, cycloplegic, and pressure patch can be used as well. Bandage contact lenses may also be beneficial to prevent further erosion.

Medical follow up

There have been no case studies that describe outcomes of medical treatment of early SMCD, so patients should be followed closely to track the response of erosions to the current treatment regimen.  

Surgery

The only previously attempted surgical interventions to improve visual acuity in patients with SMCD are SK and PKP. Disease recurrence may necessitate repeat surgical intervention and theoretically cause graft rejection. No episodes of disease recurrence have been documented following either superficial keratectomy or PKP. Although never previously performed on a patient affected by SMCD, phototherapeutic keratectomy (PTK) with excimer laser or lamellar keratoplasty may be indicated due to the superficial nature of the disease. However, the diagnosis of SMCD cannot be confirmed with histopathological staining following PTK treatment.

Surgical follow up

Although no episodes of disease recurrence have been confirmed following surgical intervention for SMCD, annual or biannual ophthalmologic examinations may be advisable to continually assess for novel corneal opacities or graft rejection following PKP.  Topical steroids should also be used to prevent graft rejection.

Complications

No adverse events following surgery have been reported for the two patients who underwent surgical interventions for SMCD. However, potential complications include those common to any corneal surgery, such as risk of infection, loss of vision, abrasions, perforations, and iatrogenic damage the cornea and other structures.  

Prognosis

In the one patient that underwent SK as well PKP with insertion of PCIOL, visual acuity improved by two lines bilaterally. However, visual acuity assessment was confounded by epiretinal membranes.

Additional Resources

https://disorders.eyes.arizona.edu/disorders/corneal-dystrophy-subepithelial-mucinous