Ophthalmology – Marfan Syndrome

Basics

Description

Marfan syndrome is an autosomal dominant connective tissue disorder that primarily affects the:

• Cardiovascular system
• Musculoskeletal system
• Eyes

It is most commonly caused by pathogenic variants in FBN1, the gene encoding fibrillin-1.

A major ophthalmic hallmark is ectopia lentis, and Marfan syndrome is one of the most important causes of nontraumatic lens dislocation.

Epidemiology

Marfan syndrome affects approximately 4–6 per 10,000 individuals.

It affects males and females equally.

Approximately 25% of cases arise from a new mutation without a prior family history.

Risk Factors

Important risk factors include:

• Family history of Marfan syndrome
• Known pathogenic FBN1 mutation

Because inheritance is autosomal dominant, an affected individual has approximately a 50% chance of transmitting the disorder with each pregnancy.

Genetics

Marfan syndrome is most commonly associated with mutations in:

• FBN1 on chromosome 15q21

Fibrillin-1 is an important component of extracellular matrix microfibrils.

The disorder has:

• High penetrance
• Marked variability in clinical severity

Some phenotypically related connective-tissue disorders involve abnormalities in the TGF-β signaling pathway.

Pathophysiology

Fibrillin is essential for normal microfibril formation and extracellular matrix integrity.

Within the eye, fibrillin is found in structures including:

• Ciliary zonules
• Lens capsule
• Schlemm canal region
• Sclera
• Choroid
• Bruch membrane
• Lamina cribrosa
• Corneal tissues

Abnormal fibrillin helps explain the tendency toward:

• Ectopia lentis
• Axial myopia
• Retinal detachment
• Glaucoma
• Corneal abnormalities

Commonly Associated Conditions

Cardiovascular

Cardiovascular involvement is a major determinant of morbidity and mortality.

Important manifestations include:

• Aortic root dilatation
• Aortic aneurysm
• Aortic dissection
• Mitral valve prolapse
• Mitral regurgitation

Musculoskeletal

Typical features include:

• Tall stature
• Long extremities
• Arachnodactyly
• Scoliosis or kyphoscoliosis
• Pectus excavatum or pectus carinatum
• Joint laxity or hypermobility

Pulmonary

Possible manifestations include:

• Apical pulmonary blebs
• Spontaneous pneumothorax

Neurologic

A characteristic association is:

• Dural ectasia

Diagnosis

Diagnosis is based on the overall clinical picture, family history, cardiovascular findings, ocular findings, and genetic evaluation when appropriate.

Modern diagnosis uses the revised Ghent criteria rather than relying on a single physical feature.

History

Important history includes:

• Family history of Marfan syndrome
• Sudden cardiovascular death in relatives
• Known aortic disease
• Previous retinal detachment
• Progressive myopia
• Lens instability
• Musculoskeletal abnormalities
• Pneumothorax
• Back or neurologic symptoms that may suggest dural ectasia

Ophthalmic Examination

A complete eye examination should include:

• Visual acuity
• Refraction
• Slit-lamp examination
• Pupil dilation
• Lens position
• IOP
• Dilated peripheral retinal examination

Ectopia Lentis

Ectopia lentis is one of the most characteristic ocular findings.

It occurs in a substantial proportion of patients.

The classic displacement is superotemporal, although displacement can occur in other directions.

The zonules are structurally weak because fibrillin is a major component of the suspensory apparatus of the lens.

Visual Effects of Ectopia Lentis

Lens displacement can cause:

• High astigmatism
• Myopia
• Irregular refractive error
• Monocular diplopia
• Reduced best-corrected vision
• Amblyopia in children

Severe displacement can eventually require surgery.

Iris and Pupil

Patients may have:

• Poor pupillary dilation
• Iris or ciliary muscle hypoplasia

Poor dilation may make both examination and intraocular surgery more difficult.

Refractive Error

Axial myopia is common.

Patients may develop significant refractive error even in the absence of severe lens displacement.

Cataract

Cataract may occur earlier than expected for age.

Nuclear sclerosis may develop earlier than in the general population.

Vitreous Changes

Vitreous abnormalities may include:

• Early central vitreous liquefaction
• Posterior vitreous degeneration

These changes may contribute to retinal complications.

Retinal Detachment

Marfan syndrome is associated with a significantly increased risk of rhegmatogenous retinal detachment.

Risk is increased by:

• Axial myopia
• Abnormal vitreous
• Lens instability
• Prior lens surgery

Retinal detachment may occur at a younger age than in the general population.

Bilateral involvement is an important concern.

Diagnostic Tests

Genetic Testing

Molecular testing for FBN1 can support the diagnosis.

However, diagnosis remains clinical and multidisciplinary because genetic findings must be interpreted in the context of phenotype and family history.

Cardiovascular Imaging

Regular cardiovascular surveillance is essential.

Important studies include:

• Echocardiography
• CT angiography when needed
• MR angiography when needed

The key parameter is often the size and rate of growth of the aortic root.

Ophthalmic Imaging

If the fundus cannot be visualized adequately, especially with severe lens displacement or poor pupillary dilation, B-scan ultrasonography may help evaluate for retinal detachment.

Differential Diagnosis

The differential diagnosis of ectopia lentis includes:

• Trauma
• Homocystinuria
• Weill-Marchesani syndrome
• Familial isolated ectopia lentis
• Ectopia lentis et pupillae
• Aniridia
• Buphthalmos
• Sulfite oxidase deficiency
• Molybdenum cofactor deficiency
• Other metabolic or connective-tissue disorders

Marfan Syndrome vs Homocystinuria

This is an important clinical distinction.

Marfan Syndrome

Lens displacement is classically:

• Superotemporal

Patients often have:

• Tall habitus
• Aortic root disease
• Joint laxity

Homocystinuria

Lens displacement may occur in various directions and is classically described as inferonasal.

Patients may additionally have:

• Developmental or intellectual impairment
• Osteoporosis
• Thromboembolic disease

Treatment

Management is multidisciplinary.

The major goals are:

• Prevent aortic complications
• Optimize vision
• Treat lens instability
• Detect retinal detachment early
• Manage associated systemic disease

Cardiovascular Medical Therapy

Medical therapy is directed toward reducing stress on the aortic wall.

Common approaches include:

• Beta-blockers
• Angiotensin receptor blockers

The exact regimen should be determined by cardiology according to current Marfan and aortopathy guidelines.

Ophthalmic Management

Refractive Correction

Mild-to-moderate ectopia lentis may be managed with:

• Spectacles
• Contact lenses

Children must be monitored carefully for amblyopia.

Amblyopia

In children, asymmetric refractive error or lens displacement can cause amblyopia.

Treatment may include:

• Full optical correction
• Patching
• Other standard amblyopia therapy

Early intervention is important.

Lens Surgery

Lens removal may be considered when there is:

• Severe lens displacement
• Inadequate visual correction
• Cataract
• Secondary glaucoma
• Progressive visual disability
• Lens-related complications

Surgery can be technically challenging because of weak zonules.

Surgical Approach

Modern surgical technique depends on:

• Age
• Degree of lens displacement
• Capsular support
• Retinal status
• Surgeon experience

Pars plana or limbal approaches may be considered depending on the anatomy.

Because retinal detachment risk is increased, careful preoperative and postoperative retinal assessment is important.

Retinal Detachment Treatment

Retinal detachment should be managed promptly by a vitreoretinal surgeon.

Possible procedures include:

• Scleral buckle
• Pars plana vitrectomy
• Combined buckle and vitrectomy

The choice depends on:

• Lens position
• Break configuration
• Extent of detachment
• Vitreous anatomy

The fellow eye should also be examined carefully because bilateral retinal disease is more common than in the general population.

Referral

Patients commonly require coordinated care involving:

• Cardiology
• Ophthalmology
• Retina specialist
• Medical genetics
• Orthopedics
• Pulmonology
• Neurosurgery when dural ectasia is significant

Pregnancy Considerations

Pregnancy increases cardiovascular stress and can increase the risk of aortic enlargement and dissection in women with Marfan syndrome.

Risk is especially important when significant aortic root enlargement is already present.

Management should involve a multidisciplinary team including:

• Cardiology
• Maternal-fetal medicine
• Cardiothoracic surgery when indicated
• Genetics

Serial aortic imaging during pregnancy may be required.

Delivery planning depends largely on:

• Aortic diameter
• Rate of aortic enlargement
• Prior aortic surgery
• Overall cardiovascular status

Because recommendations are highly dependent on current aortopathy guidelines, fixed historical diameter thresholds should not be used without specialist assessment.

Fetal Considerations

Because Marfan syndrome is autosomal dominant:

• Each pregnancy has approximately a 50% chance of inheritance

Severity is highly variable.

A mildly affected parent can have a more severely affected child.

Genetic counseling is strongly recommended.

Follow-Up

Long-term monitoring should include:

• Regular echocardiography or other aortic imaging
• Periodic ophthalmic examinations
• Refraction
• Lens position assessment
• IOP
• Dilated retinal examination

Follow-up frequency depends on disease severity.

Lifestyle

Patients are generally advised to avoid activities that produce extreme cardiovascular stress.

This may include:

• Heavy isometric exercise
• Very heavy weightlifting
• High-intensity contact sports in selected patients

Exercise recommendations should be individualized by cardiology.

Patient Education

Patients should understand the symptoms of retinal detachment:

• New flashes
• Sudden increase in floaters
• Curtain or shadow across the vision
• Sudden peripheral visual field loss

These symptoms require urgent retinal evaluation.

Patients should also understand warning symptoms of aortic emergencies, such as sudden severe chest, back, or abdominal pain, and seek emergency care immediately.

Prognosis

Modern cardiovascular surveillance and treatment have greatly improved life expectancy.

Visual prognosis depends on:

• Severity of ectopia lentis
• Degree of myopia
• Presence of amblyopia
• Cataract
• Glaucoma
• Retinal detachment

Many patients maintain good useful vision with appropriate ophthalmic management.

Complications

Major ocular complications include:

• Ectopia lentis
• High myopia
• Amblyopia
• Cataract
• Glaucoma
• Retinal detachment
• Permanent visual loss

Major systemic complications include:

• Aortic aneurysm
• Aortic dissection
• Valvular disease
• Pneumothorax
• Dural ectasia

Key Clinical Pearls

• Marfan syndrome is an autosomal dominant fibrillin-1 connective-tissue disorder.
• Ectopia lentis is a major ophthalmic hallmark and is classically superotemporal.
• Marfan syndrome is an important cause of nontraumatic ectopia lentis.
• Patients commonly have axial myopia and increased retinal detachment risk.
• Always examine the peripheral retina carefully, particularly before and after lens surgery.
• The most life-threatening manifestation is aortic root disease, so ophthalmic findings can provide an important clue to a systemic diagnosis requiring cardiology evaluation.