Ophthalmology – Weill-Marchesani Syndrome

What the Disorder Represents

Weill-Marchesani syndrome (WMS) is a rare inherited connective-tissue disorder characterized by the combination of:

• Microspherophakia
• Ectopia lentis
• High lenticular myopia
• Secondary glaucoma
• Short stature
• Brachydactyly
• Joint stiffness

The most vision-threatening ophthalmic complication is:

Pupillary-block angle-closure glaucoma caused by the small, spherical, anteriorly displaced lens.

The Characteristic Body Habitus

The systemic phenotype contrasts strongly with Marfan syndrome.

Typical findings include:

• Short stature
• Broad, short fingers and toes
• Brachydactyly
• Reduced joint mobility
• Muscular or stocky body habitus

Not every patient demonstrates every systemic feature to the same degree.

The Genetic Basis

Both:

• Autosomal recessive
• Autosomal dominant

forms occur.

Important genes include:

• ADAMTS10 – classically autosomal recessive WMS
• FBN1 – autosomal dominant WMS
• LTBP2 – associated with recessive WMS phenotypes in some families

Related disorders involving genes such as ADAMTS17 may produce a Weill-Marchesani-like phenotype.

Why FBN1 Can Cause Both Marfan and Weill-Marchesani Phenotypes

Fibrillin-1, encoded by FBN1, is a major extracellular matrix component.

Different pathogenic variants can produce very different phenotypes.

Thus:

• Some FBN1 variants cause Marfan syndrome
• Other variants can produce autosomal dominant Weill-Marchesani syndrome

despite their almost opposite skeletal appearances.

How the Lens Becomes Abnormal

The zonular apparatus and extracellular matrix develop abnormally.

The crystalline lens becomes:

• Smaller in equatorial diameter
• Thicker anteroposteriorly
• More spherical

This is termed:

Microspherophakia.

The abnormal zonules also predispose to:

• Lens subluxation
• Lens dislocation

Why Microspherophakia Causes Myopia

A spherical lens has:

Greater refractive power

than a normal flatter crystalline lens.

Patients therefore frequently develop substantial:

Lenticular myopia.

The refractive error may change as the lens becomes more mobile or shifts position.

Why the Anterior Chamber Becomes Shallow

The thick spherical lens can sit relatively far forward.

This produces:

• Shallow anterior chamber
• Increased iris-lens contact
• Narrow iridocorneal angle

The result is a strong predisposition to:

Pupillary block.

Mechanism of Angle-Closure Glaucoma

Aqueous cannot move normally from the posterior to anterior chamber because of excessive iris-lens contact.

Pressure builds behind the iris, producing:

Iris bombé → peripheral angle closure → elevated IOP.

Repeated episodes may eventually create:

Peripheral anterior synechiae and chronic angle closure.

Lens Subluxation

Abnormal zonular support permits the microspherophakic lens to move.

It may become:

• Mildly decentered
• Markedly subluxated
• Completely dislocated

Unlike the classic superotemporal displacement in Marfan syndrome, WMS lens displacement can be:

Variable in direction.

Anterior Lens Dislocation

The lens can rarely dislocate into the anterior chamber.

This may cause:

• Acute pupillary block
• Severe angle closure
• Corneal endothelial damage
• Markedly elevated IOP

This is an:

Urgent surgical problem.

When the Syndrome Becomes Apparent

Systemic characteristics may be recognized during childhood.

Ocular complications may appear later and include:

• Progressive myopia
• Lens subluxation
• Angle narrowing
• Glaucoma

Therefore lifelong ophthalmic surveillance is important.

Typical Ocular Findings

Important examination findings include:

• Microspherophakia
• High lenticular myopia
• Shallow anterior chamber
• Iridodonesis
• Phacodonesis
• Ectopia lentis
• Narrow angles
• Secondary glaucoma

The lens equator may become visible after dilation if zonular loss is substantial.

Recognizing Microspherophakia at the Slit Lamp

Features include:

• Small lens diameter
• Increased lens thickness
• More spherical contour
• Abnormally deep curvature

With zonular weakness, the lens may also show:

Phacodonesis.

Gonioscopy

Gonioscopy is important for assessing:

• Angle width
• Peripheral anterior synechiae
• Chronic angle closure

It should be performed carefully because the lens position can change with:

• Accommodation
• Medications
• Body position

Anterior Segment Imaging

Useful modalities include:

• Anterior segment OCT
• Ultrasound biomicroscopy

These can document:

• Lens position
• Anterior chamber depth
• Iris configuration
• Angle closure
• Zonular abnormalities

UBM is particularly useful when the lens-iris relationship is difficult to visualize.

Refractive Assessment

Refraction may reveal:

High myopia caused predominantly by the lens rather than axial elongation.

This distinction matters because lens extraction can produce a major refractive change.

Glaucoma Evaluation

Patients should undergo:

• IOP measurement
• Gonioscopy
• Optic nerve examination
• RNFL OCT
• Visual field testing when age and cooperation permit

Glaucoma may develop gradually even without dramatic acute attacks.

Important Differential Diagnoses

The major differential for ectopia lentis includes:

• Marfan syndrome
• Homocystinuria
• Familial isolated ectopia lentis
• Ectopia lentis et pupillae
• Sulfite oxidase deficiency
• Molybdenum cofactor deficiency
• Trauma
• Aniridia
• Congenital glaucoma

Microspherophakia narrows the differential considerably.

Weill-Marchesani vs Marfan Syndrome

Weill-Marchesani Syndrome

• Short stature
• Brachydactyly
• Joint stiffness
• Microspherophakia
• High lenticular myopia
• Pupillary-block glaucoma

Marfan Syndrome

• Tall stature
• Arachnodactyly
• Joint laxity
• Ectopia lentis without typical microspherophakia
• Aortic root disease

The body habitus is almost the mirror image.

Weill-Marchesani vs Homocystinuria

Homocystinuria may cause:

• Ectopia lentis
• Developmental delay
• Thromboembolic disease
• Marfanoid habitus

Lens dislocation is often classically inferonasal, although direction is not absolute.

Microspherophakia and the typical short, brachydactylic phenotype favor:

Weill-Marchesani syndrome.

Molecular Diagnosis

Modern genetic testing can identify pathogenic variants in genes associated with WMS.

Testing is useful for:

• Confirming the diagnosis
• Determining inheritance pattern
• Testing relatives
• Reproductive counseling

A negative test does not completely exclude the diagnosis because not every causative variant is necessarily detected.

Systemic Evaluation

Evaluation should include attention to:

• Height
• Hands and feet
• Joint mobility
• Cardiovascular system

Possible cardiovascular abnormalities have been reported, including:

• Valvular abnormalities
• Patent ductus arteriosus
• Aortic abnormalities in selected genotypes

Cardiology evaluation is reasonable when clinically indicated.

Genetic Counseling

Inheritance risk depends on the molecular subtype.

Autosomal Dominant WMS

An affected individual typically has approximately a:

50% chance of transmitting the pathogenic variant to each child.

Autosomal Recessive WMS

Parents are typically carriers, with each pregnancy having:

• 25% affected
• 50% carrier
• 25% unaffected/noncarrier

when both parents carry the same pathogenic variant.

Managing the Refractive Error

Early disease may be managed with:

• Spectacles
• Contact lenses

particularly when myopia is the main visual problem.

Children require assessment for:

• Amblyopia
• Strabismus

because uncorrected lenticular myopia can interfere with visual development.

Treating Elevated IOP

Medical therapy generally begins with:

Aqueous suppressants, such as:

• Beta-blocker
• Topical carbonic anhydrase inhibitor
• Alpha-2 agonist when age appropriate

Prostaglandin analogues may also be used for chronic pressure control.

Pediatric Medication Caution

Brimonidine should be avoided in infants and very young children, particularly under approximately 2 years, because it can cause:

• CNS depression
• Somnolence
• Apnea
• Hypotension

Medication choice must therefore be age appropriate.

Why Miotics Are Usually Avoided

Miotics such as pilocarpine can worsen the lens-iris relationship by:

• Relaxing zonular tension
• Allowing the lens to move anteriorly
• Increasing pupillary block

Therefore they are generally:

Avoided in microspherophakia-associated angle closure.

Why Mydriasis Can Also Be Risky

Mydriatic agents may precipitate angle closure in an already crowded anterior segment.

However, dilation is sometimes necessary for diagnosis.

Therefore pharmacologic dilation should be undertaken:

With awareness of the angle anatomy and IOP risk.

Acute Angle Closure

Acute attacks may present with:

• Severe ocular pain
• Headache
• Blurred vision
• Halos
• Red eye
• Nausea or vomiting
• Markedly elevated IOP

This requires urgent pressure lowering and correction of the underlying pupillary block.

Initial Management of Acute Angle Closure

Treatment may include:

• Topical aqueous suppressants
• Systemic acetazolamide when appropriate
• Hyperosmotic therapy in severe cases

Miotics are generally avoided because of the abnormal zonular-lenticular anatomy.

Definitive management often requires:

Laser iridotomy and/or lens extraction.

Laser Peripheral Iridotomy

LPI can bypass pupillary block by allowing aqueous to move directly from the posterior to anterior chamber.

It can be useful when:

Pupillary block is the dominant mechanism.

Important Modern Correction About Prophylactic Iridotomy

Older sources sometimes recommended routine prophylactic peripheral iridotomy for virtually all patients.

A more individualized approach is appropriate.

LPI is particularly considered when there is:

• Narrow/occludable angle
• Previous pupillary-block episode
• Progressive anterior chamber shallowing
• High risk of acute closure

It does not correct the underlying:

Large, mobile microspherophakic lens.

Why Iridotomy May Not Be Enough

Even after a patent iridotomy, the spherical lens can continue to cause:

• Anterior chamber crowding
• Chronic angle narrowing
• Lens instability

Therefore some patients continue to develop:

Angle-closure glaucoma despite LPI.

When Lens Extraction Becomes Definitive Therapy

Lens removal should be considered for:

• Recurrent or uncontrolled pupillary block
• Progressive angle closure
• Glaucoma inadequately controlled medically
• Significant lens subluxation
• Anterior lens dislocation
• Severe lenticular myopia causing functional impairment

Removing the bulky spherical lens:

Deepens the anterior chamber and removes the principal source of pupillary block.

Surgical Challenges

Lens surgery can be technically difficult because of:

• Weak or abnormal zonules
• Lens mobility
• Small capsular bag
• Vitreous prolapse
• Poor capsular support

Surgery should ideally be performed by an anterior segment surgeon experienced in:

Ectopia lentis and complex lens surgery.

Surgical Options

Depending on age and anatomy, options include:

• Lensectomy
• Pars plana or limbal lens removal
• Anterior vitrectomy when required
• Aphakia
• Secondary IOL implantation

The exact approach depends on:

• Zonular support
• Capsular integrity
• Patient age
• Glaucoma status

Intraocular Lens Decisions

Stable in-the-bag IOL implantation may not be possible when zonular support is poor.

Alternative approaches include:

• Scleral-fixated IOL
• Iris-fixated IOL
• Leaving the patient aphakic with optical rehabilitation

IOL choice must be individualized rather than assumed at the time of lensectomy.

Glaucoma After Lens Removal

Lens extraction often improves angle anatomy, but longstanding disease may leave:

• Peripheral anterior synechiae
• Trabecular damage
• Established optic neuropathy

Some patients therefore continue to require:

• Glaucoma medications
• Glaucoma surgery

after lens removal.

Role of Glaucoma Surgery

If IOP remains uncontrolled despite correction of the lens-related mechanism, options may include:

• Trabeculectomy
• Glaucoma drainage device
• Selected angle surgery

The choice depends on:

• Degree of synechial closure
• Age
• Previous surgery
• Remaining visual potential

Why Supine Positioning Is Not Definitive Therapy

Historical descriptions suggested lying supine or using ocular massage to encourage posterior movement of a dislocated lens.

These measures are:

Temporary at best and not definitive treatment.

An anteriorly dislocated lens with pupillary block or corneal compromise requires urgent ophthalmic surgical management.

Long-Term Surveillance

Patients with an intact lens should undergo lifelong monitoring for:

• Increasing myopia
• Progressive ectopia lentis
• Angle narrowing
• Elevated IOP
• Glaucomatous optic nerve damage

Follow-up frequency depends on:

• Age
• Lens position
• Angle anatomy
• IOP

What Patients Should Know

Patients and families should recognize symptoms of acute angle closure:

• Eye pain
• Redness
• Sudden blurred vision
• Halos
• Headache
• Nausea

They should seek urgent eye care if these occur.

Expected Long-Term Course

Visual prognosis depends largely on:

• Timing of glaucoma recognition
• Degree of lens instability
• Success of surgical correction
• Presence of amblyopia in children

With appropriate surveillance and intervention:

Useful vision can often be preserved.

Major Ocular Complications

Potential complications include:

• Acute angle-closure glaucoma
• Chronic synechial angle closure
• Glaucomatous optic neuropathy
• Lens dislocation
• Corneal endothelial damage
• High refractive error
• Amblyopia

Severe untreated glaucoma can cause irreversible blindness.

High-Yield Takeaways

• Weill-Marchesani syndrome is a rare inherited connective-tissue disorder characterized by microspherophakia, ectopia lentis, lenticular myopia, short stature, brachydactyly, and joint stiffness.
• Both autosomal recessive and autosomal dominant forms occur.
• Important genes include ADAMTS10, FBN1, and LTBP2, with related ADAMTS17-associated phenotypes.
• The hallmark ocular abnormality is microspherophakia: a small-diameter, unusually spherical and thick crystalline lens.
• Microspherophakia causes high lenticular myopia and predisposes strongly to pupillary-block angle closure.
• Angle closure occurs because the spherical lens moves anteriorly, increasing iris-lens contact and producing iris bombé.
• Lens subluxation or complete dislocation can occur because of abnormal zonular support.
• The syndrome contrasts with Marfan disease: WMS causes short stature and brachydactyly, whereas Marfan syndrome causes tall stature and arachnodactyly.
• Gonioscopy and anterior segment imaging help document angle narrowing and the lens-iris relationship.
• Medical glaucoma therapy generally begins with aqueous suppressants.
• Miotics are usually avoided because they may allow further anterior lens movement and worsen pupillary block.
• Mydriasis can also precipitate angle closure in a markedly crowded eye and should be used cautiously.
• Laser peripheral iridotomy can relieve pupillary block, but it does not remove the underlying microspherophakic lens.
• Routine prophylactic iridotomy for every patient is too absolute; it is most appropriate when there is occludable angle anatomy or evidence of pupillary-block risk.
• Lens extraction is definitive therapy for recurrent or uncontrolled angle closure, severe ectopia lentis, anterior lens dislocation, or visually significant lenticular myopia.
• Lens surgery can be difficult because of zonular weakness and capsular instability, and IOL fixation must be individualized.
• Chronic glaucoma may persist even after lens removal because of peripheral anterior synechiae and permanent trabecular damage.
• Children require attention to refractive correction and amblyopia prevention in addition to glaucoma surveillance.
• Lifelong follow-up is essential because both lens instability and glaucoma can progress over time.

High-Yield Takeaways