Marfan Syndrome and Ocular Complications

Key Points at a Glance

Highlights of This Disease

• Marfan syndrome (MFS) is an autosomal dominant systemic connective tissue disorder caused by mutations in the FBN1 gene, with a prevalence of 1 in 3,000 to 5,000 people.
• Approximately 60% of patients develop ectopia lentis. The direction of dislocation is often upward or upward-temporal, which is important for differentiation from homocystinuria (downward dislocation).
• Ectopia lentis is easily missed under miosis; slit-lamp examination under mydriasis is essential.
• High rates of axial myopia (high myopia), rhegmatogenous retinal detachment (8–38%), glaucoma (30–35%), and cataract (10–20 years earlier than general population) are associated.
• The most critical complication affecting life prognosis is aortic dissection, and collaboration with cardiology is indispensable.
• Treatment involves a multidisciplinary approach combining refractive correction, lens extraction, vitrectomy, and anti-glaucoma therapy.
• Early regular examinations under mydriasis and refractive correction from childhood to prevent amblyopia determine visual prognosis.

1. What is Marfan Syndrome?

Marfan syndrome (MFS) is an autosomal dominant systemic connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene. Due to extracellular matrix fragility, it causes multi-organ disorders in the cardiovascular system (aortic aneurysm/dissection), skeletal system (tall stature, arachnodactyly, scoliosis), and ophthalmic system (ectopia lentis, myopia, retinal detachment, glaucoma).

The prevalence is estimated at 1 in 3,000 to 5,000 people, ¹⁾ and globally about 20 per 100,000. ²⁾ Regional differences exist: 1.5 per 100,000 in Northern Ireland (1958), 6.8 per 100,000 in Scotland, and 4.6 per 100,000 in Denmark (1997). ²⁾

Although it is autosomal dominant, about 25% of cases result from de novo mutations and can occur without a family history. ¹⁾ Variable expressivity within the same family is characteristic.

Ophthalmologically, about 60% of cases develop ectopia lentis, with high risks of high myopia, retinal detachment, glaucoma, and cataract. The most critical complication affecting life prognosis is aortic dissection, and collaboration with cardiology is indispensable.

Q What is Marfan syndrome?

A

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene, with an incidence of 1 in 3,000 to 5,000 people. ¹⁾ In addition to systemic symptoms such as aortic aneurysm/dissection, tall stature, and arachnodactyly, about 60% of patients develop ectopia lentis, and there is a high risk of myopia, retinal detachment, glaucoma, and cataracts. About 25% of cases are due to de novo mutations.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

• Decreased vision: Caused by high myopia or refractive changes and irregular astigmatism due to ectopia lentis.
• Floaters: May appear as a precursor to lattice degeneration or retinal detachment.
• Photopsia: Occurs with retinal traction or tear formation.
• Sudden visual field defect: Appears at the onset of retinal detachment.
• Eye pain/headache: Caused by increased intraocular pressure due to anterior dislocation of the lens, or during acute glaucoma attack.

Clinical Findings

Ectopia Lentis

Frequency: Present in about 60% of patients. It is the most important ocular finding in Marfan syndrome.

Direction of displacement: Most commonly upward or upward-temporal (in contrast to the downward displacement in homocystinuria).

Subluxation: Partial rupture of the zonules. May be accompanied by iridodonesis.

Complete dislocation: The lens moves into the vitreous cavity or anterior chamber. Anterior chamber dislocation can cause corneal opacity and increased intraocular pressure.

Note: Since dislocation may be missed under miosis, slit-lamp examination under mydriasis is essential. Lens shape abnormalities may include spherophakia.

Myopia and Retinal Disease

Axial myopia: Often presents with high myopia. One report indicates that 92% have myopia less than 10 D. ⁴⁾

Lattice degeneration: Tends to occur in the peripheral retina and predisposes to rhegmatogenous retinal detachment (RRD).

Rhegmatogenous retinal detachment: Incidence in patients with lens dislocation is 8–38%. ¹⁾ Bilateral occurrence has also been reported. ¹⁾

Age of onset: Many cases occur near adulthood, and long-term follow-up is necessary.

Glaucoma

Frequency: Approximately 30–35% of MFS patients develop glaucoma during their lifetime. ¹⁾

Types: Open-angle glaucoma, pigmentary glaucoma, and lens-induced glaucoma.

Neonatal onset has also been reported, and early management with beta-blockers may be necessary. ¹⁾

Other Ocular Complications

Cataract: Tends to develop 10–20 years earlier than in the general population. ¹⁾ May occur before age 40.

Megalocornea: Rarely observed.

Coloboma: Lens coloboma associated with zonular abnormalities has been reported. ¹⁾

Strabismus: Present in approximately 19% of MFS patients (higher than the 3–5% in the general population). ⁷⁾

Systemic Findings

The major systemic findings that ophthalmologists should be aware of are listed below.

System	Major Findings
Skeletal	Tall stature, arachnodactyly, scoliosis, high-arched palate
Cardiovascular	Aortic aneurysm, aortic dissection (affects life prognosis), mitral valve prolapse
Respiratory	Spontaneous pneumothorax
Skin	Striae distensae

Regarding sex differences, it has been reported that males have more pronounced tall stature, weight, and aortic root dilation (92.1%), while females have more pronounced mitral valve prolapse (65.0%), arachnodactyly (54.2%), and scoliosis (60.4%). ¹⁾

Q In Marfan syndrome, in which direction does the lens dislocate?

A

Dislocation is often upward or upward-temporal. This is an important distinguishing point from homocystinuria (often downward dislocation) and Weill-Marchesani syndrome (often downward dislocation). It is difficult to detect under miosis, so slit-lamp examination under mydriasis is essential.

3. Causes and Risk Factors

The causative gene for Marfan syndrome is FBN1 (chromosome 15 long arm 15q21.1), which encodes fibrillin-1. Fibrillin-1 is a major structural protein of microfibrils and is essential for maintaining the structure of the zonules of Zinn (ciliary zonules).

Mutant fibrillin inhibits the multimerization of normal fibrillin (dominant negative effect). Furthermore, FBN1 mutations cause increased TGF-β signaling, leading to abnormal connective tissue remodeling. ³⁾

The inheritance pattern is autosomal dominant, but about 25% of cases are due to de novo mutations. ¹⁾ Due to variable expressivity, the severity can differ even within the same family. Neonatal Marfan syndrome (neonatal MFS) is the most severe form, with rapid progression in multiple organs.

Genetic Counseling

Because of autosomal dominant inheritance, the risk of passing the condition to a child is 50%. It is important to note that about 25% of cases are due to de novo mutations, so the condition can occur even without a family history. Genetic counseling and, if necessary, genetic testing are recommended.

4. Diagnosis and Examination Methods

Revised Ghent Criteria (2010)

The revised Ghent criteria (2010) are used internationally for the clinical diagnosis of Marfan syndrome. ³⁾

• Definitive diagnosis (no family history): Coexistence of aortic root dilation (Z-score ≥2) and ectopia lentis, or confirmed FBN1 mutation plus aortic root dilation
• Definitive diagnosis (with family history): The diagnostic threshold is set lower
• Systemic score: Arachnodactyly (wrist sign, thumb sign), scoliosis, high palate, pneumothorax, dural ectasia, etc. are scored; ≥7 points indicates systemic involvement

If an FBN1 mutation is confirmed, diagnosis is possible with aortic root dilation alone.

Ophthalmic Examination

• Slit-lamp examination under dilation: Confirmation of lens position, zonule status, and iridodonesis. Most important. Since lens dislocation may be missed under miosis, it must be performed under dilation.
• Fundus examination: Evaluate for lattice degeneration, retinal tear, and retinal detachment.
• Intraocular pressure measurement: Check for glaucoma.
• Axial length measurement: Assess axial myopia. Elongated axial length is a characteristic finding of MFS. ⁸⁾
• Refraction test: Evaluate and correct high myopia and irregular astigmatism.

Differential Diagnosis

The main differential diagnoses for lens dislocation are listed below.

Disease	Body habitus	Direction of lens dislocation	Inheritance pattern	Other features
Marfan syndrome	Tall stature, arachnodactyly	Upward, superotemporal	AD (FBN1)	Aortic aneurysm
Homocystinuria	Tall stature	Downward and inferonasal	AR	Intellectual disability, thrombosis, elevated urinary homocystine
Weill-Marchesani syndrome	Short stature, brachydactyly	Downward	AD/AR	Spherophakia, angle-closure glaucoma
Ehlers-Danlos syndrome	Joint hypermobility	Variable	AD/AR	Skin hyperextensibility, vascular fragility

Q How is Marfan syndrome diagnosed?

A

Clinical diagnosis is based on the revised Ghent criteria (2010). ³⁾ The presence of both aortic root dilation (Z-score ≥2) and ectopia lentis confirms the diagnosis. Ophthalmologically, the lens position and Zinn zonules are evaluated by slit-lamp microscopy under mydriasis. FBN1 genetic testing is also useful for definitive diagnosis.

5. Standard Treatment

Basic Principles of Ophthalmic Management

Regular dilated ophthalmic examinations should be performed from childhood throughout life. Refractive correction (glasses or contact lenses) is used for high myopia and irregular astigmatism, and early intervention is important in children to prevent amblyopia. 92% of patients are managed with glasses for refractive correction. ⁴⁾

Treatment of Ectopia Lentis

For mild displacement, conservative management (refractive correction) is performed. However, conservative management alone carries a risk of permanent functional amblyopia. ⁴⁾

Lens extraction is indicated for severe displacement (involving the visual axis) or when anterior chamber dislocation causes corneal opacity or elevated intraocular pressure. In young patients, surgical risk is high, so careful judgment is required.

Main surgical methods:

• Pars plana lensectomy + anterior vitrectomy: Standard procedure. ¹⁾
• Scleral-fixated IOL: In young patients, note that the iris is highly extensible and postoperative pupillary capture is likely.
• CTR (capsular tension ring): Useful for capsular stabilization.
• Femtosecond laser-assisted cataract surgery: Reported for use in cases with fragile Zinn zonules. ¹⁾

Postoperative outcomes: multiple reports have achieved BCVA 20/30 to 20/40 after PPV + lensectomy. ¹⁾

Treatment of Glaucoma

• Pharmacotherapy: Beta-blockers (betaxolol, timolol), carbonic anhydrase inhibitors, brimonidine, etc. In cases with elevated intraocular pressure in the neonatal period, management with the beta-blocker betaxolol is performed (e.g., right 30 mmHg, left 40 mmHg). ¹⁾
• Caution with pilocarpine (miotic): It causes relaxation of the zonules of Zinn, so careful administration is required. ¹⁾
• Surgical treatment: In poorly controlled cases, trabeculectomy, etc., is considered.

Treatment of Retinal Detachment

• Pars plana vitrectomy (PPV): Combined with silicone oil tamponade and endolaser photocoagulation. ¹⁾
• Scleral buckling surgery: Selected in cases with an intact lens and anterior retinal breaks.
• The surgical success rate is reported to be 86%. ¹⁾
• Thin sclera, miotic tendency, and multiple breaks are factors that make surgery difficult. ¹⁾
• Prophylactic laser photocoagulation: Considered for lattice degeneration of the retina.

Treatment Flow for Ophthalmic Management

1. Dilated ophthalmic examination (1–2 times per year, from childhood)
2. Refractive correction (prescription of glasses; contact lenses if needed)
3. Severe lens dislocation → Lens extraction ± scleral fixation of IOL
4. Lattice degeneration of the retina → Consider prophylactic laser photocoagulation
5. Retinal detachment → PPV or scleral buckling
6. Glaucoma → eye drops; surgery if inadequate
7. Referral to cardiology (regular aortic root evaluation)

Importance of systemic management

Aortic dissection is the most important life-threatening complication, and collaboration with cardiology is essential. Beta-blockers (e.g., atenolol) or ARBs are used to prevent aortic dilation. Strenuous activities such as contact sports are recommended to be avoided. Pregnancy and childbirth increase the risk of aortic dissection, requiring special caution.

Q When is surgery indicated for lens dislocation?

A

Surgery is indicated when lens dislocation affects the visual axis causing significant visual impairment, or when anterior chamber dislocation leads to corneal opacity or elevated intraocular pressure. In young patients, surgical risks (e.g., pupil capture) are higher, so careful judgment is needed. The standard procedure is pars plana lensectomy, with expected postoperative BCVA of 20/30 to 20/40. ¹⁾

6. Pathophysiology and detailed mechanisms

The pathophysiology of Marfan syndrome is understood through a multi-step mechanism starting from FBN1 mutation leading to abnormal fibrillin-1 protein.

Fibrillin-1 and microfibril abnormalities

Fibrillin-1 is a major structural protein of microfibrils. Mutant fibrillin inhibits multimerization of normal fibrillin (dominant negative effect). Microfibrils are a major component of the zonules of Zinn (ciliary zonules), so their weakening leads to lens dislocation.

Non-pigmented ciliary epithelium (NPCE) cells are the main producers of fibrillin-1, directly affecting the zonules of Zinn. ³⁾

Enhanced TGF-β signaling

FBN1 mutation reduces the ability to sequester TGF-β, leading to increased signaling. This causes abnormal connective tissue remodeling, resulting in aortic wall weakening, skeletal abnormalities, and ocular tissue abnormalities. ³⁾

Zonules of Zinn → lens dislocation

Pathway: FBN1 mutation → fibrillin-1 abnormality → microfibril fragility → zonule rupture → lens subluxation (often upward and superotemporal) → progression to complete dislocation

Clinical significance: Partial rupture results only in subluxation, but complete rupture causes the lens to move into the vitreous cavity or anterior chamber.

Sclera/Ocular axis → Myopia/Retinal detachment

Pathway: Fibrillin-1 is also distributed in the sclera → scleral thinning and expansion → axial elongation → axial myopia → retinal thinning → lattice degeneration → rhegmatogenous retinal detachment

Clinical significance: The development of high myopia and increased risk of retinal detachment occur together.

Pathogenesis of glaucoma

Multiple mechanisms, including abnormalities of the zonules of Zinn, changes in angle structure, and lens-related mechanisms, contribute to increased glaucoma risk. Fibrillin-1 is also present in the trabecular meshwork of the angle, and its abnormality is thought to cause impaired aqueous humor outflow.

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7. Latest research and future perspectives (research-stage reports)

For patients: Please read

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Long-term follow-up studies of ocular complications

Sandvik et al. (2019) reported detailed long-term progression patterns of lens dislocation and retinal detachment in a 10-year follow-up study of patients with Marfan syndrome. ⁵⁾ The importance of long-term follow-up is demonstrated.

Risk factors for complications in lens surgery

Fan et al. (2014) reported risk factors for complications after lensectomy-vitrectomy (age, presence or absence of IOL insertion, etc.). ⁶⁾ It is shown that the presence or absence of IOL insertion affects the postoperative course.

Reports of new surgical techniques

Simultaneous PPV + silicone oil tamponade + retropupillary iris-claw IOL placement has been reported for the concurrent management of retinal detachment and aphakia. ¹⁾ Additionally, the application of femtosecond laser-assisted cataract surgery in cases with fragile Zinn zonules has been reported, with some cases achieving postoperative BCVA of 20/20 to 20/25. ¹⁾

TGF-β Signal Regulation and Prospects for Gene Therapy

Since TGF-β signal enhancement is central to the pathology, clinical trials of the ARB (angiotensin II receptor blocker) losartan for suppressing aortic dilation are ongoing. ³⁾ Application to the ophthalmic field and development into gene therapy remain future challenges.

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8. References

1. Adji AS, Billah A, Fadila F, et al. A systematic review of case series of Marfan syndrome: ocular findings and complications. 2025.

2. Groth KA, Hove H, Kyhl K, et al. Prevalence, incidence, and age at diagnosis in Marfan syndrome. Orphanet J Rare Dis. 2015;10:36.

3. Milewicz DM, Braverman AC, De Backer J, et al. Marfan syndrome. Nat Rev Dis Primers. 2021;7:24.

4. Esfandiari H, Ansari S, Mohammad-Rabei H, Mets M. Management strategies of ocular abnormalities in patients with Marfan syndrome: current perspective. J Ophthalmic Vis Res. 2019;14(1):36-42.

5. Sandvik GF, Vanem TT, Rand-Hendriksen S, et al. Ten-year reinvestigation of ocular manifestations in Marfan syndrome. Clin Exp Ophthalmol. 2019;47(2):212-218.

6. Fan F, Luo Y, Liu X, et al. Risk factors for postoperative complications in lensectomy-vitrectomy with or without intraocular lens placement in ectopia lentis associated with Marfan syndrome. Br J Ophthalmol. 2014;98(10):1338-1342.

7. Akram H, Aragon-Martin JA, Chandra A. Marfan syndrome and the eye clinic: from diagnosis to management. Ther Adv Rare Dis. 2021;2:26330040211055738.

8. Gehle P, Goergen B, Pilger D, et al. Biometric and structural ocular manifestations of Marfan syndrome. PLoS One. 2017;12(9):e0183370.