Ophthalmology – Reis-Bücklers Corneal Dystrophy

Basics

Description

Reis-Bücklers corneal dystrophy (RBCD) is a rare, bilateral, autosomal dominant TGFBI-associated anterior corneal dystrophy characterized by:

• Recurrent painful corneal erosions beginning in childhood
• Progressive replacement/disruption of Bowman layer
• Superficial stromal fibrosis and opacification
• Increasing corneal irregularity
• Progressive reduction in visual acuity

It was historically called:

• Corneal dystrophy of Bowman layer type 1 (CDB1)
• Granular corneal dystrophy type III

The modern preferred term is:

Reis-Bücklers corneal dystrophy

Key Clinical Pattern

The classic sequence is:

Childhood recurrent erosions → honeycomb/geographic anterior corneal opacities → progressive superficial scarring and irregular astigmatism

Pain from erosions may become less prominent with age while visual loss from:

• Scar
• Surface irregularity
• Anterior stromal deposits

becomes increasingly important.

Epidemiology

RBCD is:

• Rare
• Usually familial
• Bilateral
• Often symmetric early but potentially asymmetric in severity

Exact prevalence is unknown.

Genetics

RBCD is caused by pathogenic variants in:

TGFBI

located on:

Chromosome 5q31

The older gene name:

BIGH3

has largely been replaced by TGFBI.

Classic Mutation

The mutation most strongly associated with classic RBCD is:

TGFBI p.Arg124Leu (R124L)

Inheritance is:

Autosomal dominant

with variable expressivity.

TGFBI Protein

TGFBI encodes:

Transforming growth factor beta-induced protein (TGFBIp)

also known as:

Keratoepithelin

Mutant TGFBIp accumulates extracellularly in the cornea and produces several distinct corneal dystrophies depending on the specific variant.

Other TGFBI Corneal Dystrophies

TGFBI mutations are also associated with:

• Thiel-Behnke corneal dystrophy
• Granular corneal dystrophy type 1
• Granular corneal dystrophy type 2
• Lattice corneal dystrophy type 1

Phenotype–genotype correlation is therefore clinically useful.

RBCD vs Thiel-Behnke Genetics

A classic exam distinction:

Reis-Bücklers

Usually:

TGFBI p.Arg124Leu

Thiel-Behnke

Usually:

TGFBI p.Arg555Gln

This is more useful today than older classifications based solely on electron microscopy.

Pathophysiology

Mutant TGFBI protein accumulates in the:

• Subepithelial region
• Bowman layer
• Superficial anterior stroma

Bowman layer becomes:

• Fragmented
• Replaced
• Irregular

This disrupts epithelial adhesion and produces:

Recurrent corneal erosions

Repeated erosions and abnormal wound healing cause:

• Subepithelial fibrosis
• Superficial stromal scarring
• Irregular anterior corneal surface

Histopathology

Typical findings include:

• Disruption or absence of Bowman layer
• Fibrocellular tissue replacing Bowman layer
• Anterior stromal deposition
• Irregular epithelium

With light microscopy, deposits may stain:

Red with Masson trichrome

Electron Microscopy

RBCD classically demonstrates:

Rod-shaped or granular electron-dense deposits

within the superficial cornea.

This contrasts with Thiel-Behnke dystrophy, which characteristically demonstrates:

Curly fibers

on electron microscopy.

Electron microscopy is now rarely required because:

• Clinical phenotype
• Genetic testing

can usually establish the diagnosis.

Onset

Symptoms usually begin during:

The first decade of life

often around preschool or early school age.

Children may present with:

• Photophobia
• Tearing
• Eye rubbing
• Recurrent painful red eye
• Blepharospasm

Clinical Presentation

Early symptoms result primarily from:

Recurrent corneal epithelial erosions

Typical episodes include:

• Severe ocular pain
• Foreign-body sensation
• Photophobia
• Tearing
• Conjunctival injection
• Temporary blurred vision

Episodes may last:

• Hours
• Days
• Occasionally longer

Disease Evolution

With increasing age:

• Erosions may become less frequent
• Superficial opacification increases
• Corneal surface becomes more irregular
• Best-corrected vision declines

By adolescence or adulthood, visual symptoms may be dominated by:

• Haze
• Irregular astigmatism
• Scar

rather than recurrent pain.

Slit-Lamp Findings

Early disease shows:

Bilateral central and paracentral subepithelial/anterior stromal opacities

that may become:

• Reticular
• Geographic
• Honeycomb-like

Honeycomb Appearance

A classic finding is:

Irregular gray-white honeycomb or reticular opacification of the anterior central cornea

These lesions primarily involve:

• Bowman layer
• Very anterior stroma

and tend to become more confluent with age.

Advanced Disease

Later findings include:

• Dense gray-white superficial opacity
• Irregular anterior corneal surface
• Loss of normal Bowman layer
• Superficial stromal fibrosis
• Irregular astigmatism

The old description of:

“Curdled milk”

may be encountered in historical literature but is not essential diagnostically.

Corneal Erosions

During an active erosion, examination may show:

• Epithelial defect
• Loose surrounding epithelium
• Fluorescein staining
• Mild stromal edema

The underlying dystrophy remains visible between episodes.

Visual Loss

Vision declines because of:

• Central superficial opacity
• Irregular astigmatism
• Corneal surface distortion
• Progressive fibrosis

Early disease may still have relatively good corrected acuity.

Diagnosis

Diagnosis is usually based on:

• Early age of onset
• Recurrent erosions
• Bilateral honeycomb anterior corneal opacities
• Family history
• Characteristic superficial location

Genetic testing can confirm:

TGFBI-related disease

and distinguish overlapping phenotypes.

Genetic Testing

Testing is particularly useful when:

• Phenotype overlaps with Thiel-Behnke dystrophy
• Family counseling is desired
• Surgical planning is being considered
• Diagnosis is uncertain

Identification of a:

TGFBI p.Arg124Leu variant

strongly supports classic RBCD.

Family Examination

Because inheritance is autosomal dominant:

First-degree relatives should be offered slit-lamp examination

when clinically appropriate.

Genetic counseling may be useful for affected families.

Anterior Segment OCT

AS-OCT may demonstrate:

• Hyperreflective subepithelial deposits
• Bowman layer disruption
• Depth of anterior stromal involvement

This is particularly useful before:

PTK

to estimate treatment depth.

In Vivo Confocal Microscopy

Confocal microscopy may show:

• Highly reflective extracellular material
• Abnormal basal epithelium
• Disturbed Bowman layer
• Superficial stromal deposits

It is usually supportive rather than necessary for diagnosis.

Corneal Topography / Tomography

Useful when evaluating:

• Irregular astigmatism
• Progressive visual decline
• Surgical planning

It may show increasingly irregular corneal optics as fibrosis advances.

Differential Diagnosis

Important differentials include:

• Thiel-Behnke corneal dystrophy
• Epithelial basement membrane dystrophy
• Granular corneal dystrophy
• Lattice corneal dystrophy
• Meesmann corneal dystrophy
• Salzmann nodular degeneration
• Superficial corneal scarring
• Herpes simplex keratitis

Reis-Bücklers vs Thiel-Behnke

These are the most important overlapping conditions.

Reis-Bücklers

• Usually earlier onset
• More severe recurrent erosions
• Honeycomb/geographic anterior opacity
• More rapid progression
• TGFBI p.Arg124Leu
• Rod-like deposits on EM

Thiel-Behnke

• Often somewhat later onset
• Honeycomb superficial opacity can look similar
• Usually slower progression
• TGFBI p.Arg555Gln
• Curly fibers on EM

Genetic testing is the most definitive modern distinction.

Reis-Bücklers vs EBMD

RBCD

• Childhood onset
• Autosomal dominant
• Progressive superficial scarring
• Honeycomb opacities
• Significant visual decline with age

EBMD

• Usually later onset
• Map-dot-fingerprint epithelial findings
• Often much milder
• Does not typically cause the characteristic dense Bowman/anterior stromal honeycomb scar pattern

Reis-Bücklers vs Granular Corneal Dystrophy

Granular dystrophy typically produces:

• Discrete white stromal deposits
• Relatively clear spaces between deposits initially

RBCD is much more:

• Superficial
• Diffuse
• Honeycomb-like

with prominent recurrent erosions early in life.

Reis-Bücklers vs Lattice Dystrophy

Lattice dystrophy typically demonstrates:

• Branching refractile stromal lines
• Amyloid deposition

rather than the superficial honeycomb pattern of RBCD.

Both can produce recurrent erosions.

Treatment Principles

Treatment has two goals:

1. Control recurrent epithelial erosions
2. Restore vision when superficial opacity and irregularity become significant

There is no therapy that corrects the underlying TGFBI mutation.

Treatment of Recurrent Erosions

Initial conservative therapy includes:

• Preservative-free artificial tears
• Lubricating ointment at bedtime
• Hypertonic sodium chloride ointment in selected cases

These reduce friction and epithelial trauma.

Acute Erosion

During a significant epithelial defect, treatment may include:

• Lubrication
• Short-term topical antibiotic prophylaxis
• Oral analgesics
• Cycloplegic when photophobia is significant

Bandage Contact Lens

A bandage contact lens can be used for:

• Large painful erosion
• Persistent epithelial defect
• Recurrent episodes despite lubrication

It provides:

• Mechanical protection
• Pain relief
• Epithelial stabilization

Close follow-up is required because of:

Microbial keratitis risk.

Topical Antibiotic

Antibiotic prophylaxis may be appropriate while:

• A significant epithelial defect is open
• A bandage contact lens is being used

It does not treat the dystrophy itself.

Topical Corticosteroids

Routine topical corticosteroid use solely to:

“Prevent corneal scarring”

during uncomplicated erosions is not standard modern treatment.

Steroids may:

• Delay epithelial healing
• Increase infection risk

They should be reserved for selected inflammatory indications under ophthalmic supervision.

Persistent/Recurrent Surface Disease

For recurrent erosions not controlled conservatively, options include:

• Epithelial debridement
• Superficial keratectomy
• Diamond-burr polishing in selected cases
• Phototherapeutic keratectomy

Because RBCD involves abnormal Bowman layer itself, definitive superficial treatment often needs to address more than loose epithelium alone.

Phototherapeutic Keratectomy

PTK is the preferred surgical treatment for visually significant superficial RBCD when disease depth is suitable.

Excimer laser ablation removes:

• Abnormal superficial tissue
• Fibrotic Bowman-layer material
• Irregular anterior stroma

This can:

• Improve visual acuity
• Regularize the surface
• Reduce recurrent erosions

PTK Indications

Consider PTK for:

• Visually significant superficial opacity
• Irregular astigmatism
• Frequent recurrent erosions
• Superficial scarring

especially when disease remains predominantly anterior.

PTK Advantages

Compared with corneal transplantation, PTK:

• Preserves native cornea
• Avoids intraocular surgery
• Has faster rehabilitation
• Can be repeated in selected cases

PTK Limitations

The main limitation is:

Recurrence

because genetically abnormal keratocytes and TGFBI protein production remain.

Deposits may recur over:

• Years
• Sometimes sooner

Refractive Effect of PTK

Because tissue is removed from the central cornea, PTK may produce:

Hyperopic shift

particularly with deeper ablation.

This should be considered during planning.

Mitomycin C With PTK

Mitomycin C has been used adjunctively in an attempt to reduce:

• Haze
• Recurrence

However:

Evidence that MMC reliably prevents recurrent TGFBI deposition is limited, and it is not a universally required component of PTK.

Use is individualized.

Superficial Keratectomy

When excimer PTK is unavailable, superficial keratectomy may remove:

• Abnormal epithelium
• Fibrotic superficial tissue

It can improve:

• Surface regularity
• Erosion frequency

but recurrence remains possible.

Keratoplasty

Corneal transplantation is reserved for:

• Deep or extensive anterior stromal scarring
• Severe visual loss not amenable to PTK
• Multiple failed superficial procedures

Options include:

• Anterior lamellar keratoplasty
• Deep anterior lamellar keratoplasty in selected cases
• Penetrating keratoplasty

Lamellar vs Penetrating Keratoplasty

Because disease is primarily anterior:

Lamellar approaches are attractive when the deeper stroma and endothelium are healthy.

Advantages include:

• Preservation of endothelium
• Lower rejection risk

PK may be necessary when opacity extends too deeply or lamellar surgery is unsuitable.

Recurrence After Keratoplasty

A major clinical feature of RBCD is:

Recurrence in the graft

because host-derived abnormal TGFBI protein can redeposit in transplanted tissue.

Recurrence may occur after:

• Lamellar keratoplasty
• Penetrating keratoplasty

Therefore transplantation is:

Not curative at the molecular level.

Postoperative Monitoring

After PTK or keratoplasty, monitor for:

• Epithelial healing
• Infection
• Haze
• Refractive change
• Recurrence of deposits
• Recurrent erosions

Pediatric Considerations

Children may have:

• Painful recurrent erosions
• Photophobia
• Eye rubbing
• Reduced visual function

Assess:

• Visual acuity
• Refraction
• Corneal clarity

Significant asymmetric visual loss can theoretically contribute to:

Amblyopia

and should be addressed during visual development.

Prevention

There is:

No known method to prevent development of RBCD

in a genetically affected individual.

General ocular surface protection includes:

• Avoiding unnecessary trauma
• Treating dry eye
• Using lubrication during recurrent erosion-prone periods

Prognosis

RBCD is:

Slowly progressive but recurrent

The natural history commonly includes:

• Painful erosions in childhood
• Increasing superficial opacity during adolescence
• Progressive visual impairment in adulthood

Visual Prognosis

Vision can often be substantially improved with:

• PTK
• Superficial keratectomy
• Keratoplasty in advanced cases

However:

Recurrence remains the central long-term problem.

Complications

Potential complications include:

• Recurrent corneal erosions
• Microbial keratitis
• Progressive superficial scarring
• Irregular astigmatism
• Reduced BCVA
• Recurrence after PTK
• Recurrence after corneal transplantation

Ophthalmology Pearls

• Reis-Bücklers corneal dystrophy is an autosomal dominant TGFBI-associated anterior corneal dystrophy with recurrent childhood erosions and progressive Bowman/anterior stromal scarring.
• The classic mutation is TGFBI p.Arg124Leu (R124L).
• The older gene name BIGH3 has been replaced by TGFBI.
• Symptoms typically begin during the first decade of life with recurrent painful epithelial erosions.
• Slit lamp shows bilateral central honeycomb/geographic gray-white opacities involving Bowman layer and superficial stroma.
• With age, pain from erosions may become less prominent while visual loss from superficial fibrosis and irregular astigmatism increases.
• The most important differential is Thiel-Behnke dystrophy, usually associated with TGFBI p.Arg555Gln.
• RBCD shows rod-like deposits ultrastructurally, whereas Thiel-Behnke shows characteristic curly fibers.
• Modern genetic testing often distinguishes the two more directly than electron microscopy.
• Conservative treatment of erosions includes preservative-free lubrication, nighttime ointment, and bandage contact lens when necessary.
• Routine topical corticosteroids solely to prevent scarring during epithelial erosions are not standard therapy.
• PTK is the principal surgical treatment for visually significant superficial disease, improving both surface regularity and recurrent erosions.
• PTK may produce a hyperopic shift, and recurrence is common because the underlying genetic defect persists.
• MMC has been used with PTK, but evidence that it prevents TGFBI redeposition is limited.
• Lamellar or penetrating keratoplasty is reserved for advanced scarring, but RBCD can recur in the graft.
• There are no known systemic associations; the disorder is primarily confined to the cornea.