Marfan Syndrome and Ocular Complications

Key points at a glance

Key points 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 individuals.
• Ophthalmologically, ectopia lentis is observed in about 60% of cases, with characteristic upward and superotemporal displacement.
• High myopia (axial), retinal detachment (often rhegmatogenous with lattice degeneration), glaucoma (lifetime incidence 30–35%), and cataracts are frequently associated.
• Diagnosis uses the revised Ghent criteria (2010), with a combination of aortic root dilation and ectopia lentis confirming the diagnosis.
• Since ectopia lentis may be missed under miosis, slit-lamp examination under mydriasis is essential.
• The most critical complication is aortic dissection, and multidisciplinary collaboration with cardiology determines prognosis.
• Lens extraction is indicated when ectopia lentis involves the visual axis or when anterior chamber dislocation causes elevated intraocular pressure.

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. The FBN1 gene is located on the long arm of chromosome 15 (15q21.1) and encodes microfibrils, a major component of the extracellular matrix.

The prevalence is estimated at 1 in 3,000 to 5,000 individuals, with a worldwide incidence of approximately 20 per 100,000 people²⁾. Although it is autosomal dominant, about 25% of cases result from de novo mutations and should not be overlooked even in the absence of a family history¹⁾.

Extracellular matrix fragility leads to multisystem involvement including the cardiovascular system (aortic aneurysm, aortic dissection), skeletal system (tall stature, arachnodactyly, scoliosis), and ocular system (ectopia lentis, myopia, retinal detachment, glaucoma). The most critical complication affecting life prognosis is aortic dissection, and close collaboration with cardiology is essential.

Q What kind of disease is Marfan syndrome?

A

An autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene, occurring in 1 in 3,000 to 5,000 individuals ¹⁾. In addition to systemic features such as aortic aneurysm/dissection, tall stature, and arachnodactyly, approximately 60% develop ectopia lentis, with high risks of high myopia, retinal detachment, glaucoma, and cataract. About 25% of cases result from de novo mutations ¹⁾.

2. Main Symptoms and Clinical Findings

Ocular Findings

Ectopia Lentis

Frequency: Approximately 60%. Most important ocular feature of MFS.

Direction of dislocation: Often upward or upward-temporal. Useful for differentiation from homocystinuria (downward dislocation).

Difficult to detect under miosis. Slit-lamp examination under mydriasis is essential.

May be accompanied by lens shape abnormalities (spherophakia). The degree varies from subluxation to complete dislocation (into the anterior chamber); dislocation into the anterior chamber is associated with corneal opacity and elevated intraocular pressure.

Myopia

Axial myopia: Many cases present with high myopia.

Fibrillin-1 abnormality causes scleral thinning and dilation, leading to axial elongation⁸⁾.

92% are managed with spectacle correction⁴⁾.

Retinal Diseases

Lattice degeneration: Frequently occurs in the peripheral retina.

Rhegmatogenous retinal detachment (RRD): Develops in 8–38% of patients with lens dislocation¹⁾.

Bilateral retinal detachment is not uncommon¹⁾. Long-term follow-up is necessary.

Other Ocular Complications

Glaucoma: Develops in 30–35% of patients over a lifetime¹⁾. Types include open-angle, pigmentary, and lens-induced.

Cataracts: Tend to develop 10–20 years earlier than in the general population. Some cases occur before age 40¹⁾.

Strabismus: Observed in about 19% of cases, higher than the general population (3–5%)⁷⁾.

Coloboma and megalocornea are also occasionally associated¹⁾.

Systemic Findings

Organ System	Main Findings
Skeletal system	Tall stature, arachnodactyly, scoliosis, high-arched palate
Cardiovascular system	Aortic aneurysm/aortic dissection (most important complication), mitral valve prolapse
Respiratory system	Spontaneous pneumothorax
Skin	Striae distensae

As for sex differences, aortic root dilation (92.1%) is prominent in males, while mitral valve prolapse (65.0%), arachnodactyly (54.2%), and scoliosis (60.4%) are more noticeable in females ¹⁾.

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

A

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

3. Causes and Risk Factors

FBN1 gene and pathology

The causative gene is FBN1 (15q21.1), which encodes fibrillin-1, a major structural protein of microfibrils. Fibrillin-1 is essential for maintaining the structure of the Zinn zonule (ciliary zonule), and FBN1 mutations weaken the zonule, leading to lens dislocation.

Mutant fibrillin inhibits the multimer formation of normal fibrillin (dominant negative effect). Furthermore, FBN1 mutations are also involved in the enhancement of TGF-β signaling ³⁾, causing abnormal remodeling of connective tissues throughout the body.

Inheritance pattern

It is an autosomal dominant disorder, with a 50% probability of transmission to offspring. Approximately 25% of cases are due to de novo mutations, so the condition can occur even without a family history ¹⁾. There is variable expressivity within the same family, meaning severity can differ. Neonatal Marfan syndrome (neonatal MFS) is the most severe form, with rapid progression in multiple organs.

About genetic counseling

Because it is an autosomal dominant disorder, the probability of passing it to a child is 50%. Approximately 25% of cases are due to de novo mutations and occur without a family history, so it is important to consider this condition even in young patients without a family history. Appropriate information provision to families through genetic counseling and genetic testing when indicated are recommended.

4. Diagnosis and Testing Methods

Revised Ghent Criteria (2010)

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

• Aortic root dilation (Z-score ≥2) and ectopia lentis combination → definitive diagnosis
• FBN1 mutation confirmed: diagnosis possible with aortic root dilation alone
• Systemic score ≥7 points indicates systemic involvement (scoring arachnodactyly, scoliosis, high palate, pneumothorax, dural ectasia, etc.)

Ophthalmic Examination

• Slit-lamp examination under mydriasis: Check lens position, zonular status, and iridodonesis. Most important examination.
• Fundus examination: Check for lattice degeneration, retinal tears, and retinal detachment.
• Intraocular pressure measurement: Check for glaucoma.
• Axial length measurement: Assess axial myopia⁸⁾
• Refraction test: Evaluation of high myopia and irregular astigmatism

Differential Diagnosis

Disease	Body type	Direction of lens dislocation	Inheritance pattern	Notes
Marfan syndrome	Tall stature, arachnodactyly	Superior, superotemporal	AD (FBN1)	Aortic aneurysm
Homocystinuria	Tall stature	Inferior, 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, slit-lamp examination under mydriasis evaluates lens position and zonular fibers. FBN1 genetic testing is also useful and aids in family screening.

5. Standard Treatment

Basic Principles

Regular dilated eye examinations should be performed from childhood throughout life.

Refractive correction: Prescribe glasses or contact lenses for high myopia and irregular astigmatism. 92% of cases can be managed with glasses⁴⁾. In children, early correction is important to prevent amblyopia.

Treatment of Lens Dislocation

• Mild dislocation: Conservative management (refractive correction) is the standard. Keep in mind the risk of permanent functional amblyopia ⁴⁾
• Severe dislocation (involving the visual axis): Lens extraction is required
• Surgical method: Pars plana lensectomy with anterior vitrectomy is standard ¹⁾. IOL insertion is performed with scleral-fixated IOL. Capsular stabilization using a capsular tension ring (CTR) is also useful
• Surgical outcomes: Multiple reports have achieved BCVA of 20/30 to 20/40 after PPV with lensectomy ¹⁾

Treatment of Glaucoma

• Drug therapy: Eye drops such as beta-blockers (timolol, betaxolol), carbonic anhydrase inhibitors, and brimonidine
• Caution: Pilocarpine (miotic) may cause zonular relaxation, so use with caution ¹⁾
• Neonatal period: Severe intraocular pressure elevation is managed with beta-blocker eye drops ¹⁾
• Surgery: Trabeculectomy or tube shunt surgery for cases with poor control on eye drops

Treatment of Retinal Detachment

• Vitrectomy (PPV): Combined with silicone oil tamponade and endolaser photocoagulation ¹⁾
• Scleral buckling: Selected for cases with clear lens and anterior retinal tears
• Surgical success rate: Reported success in 86% of cases¹⁾
• Difficult surgical factors: Thin sclera, tendency for miosis, multiple tears¹⁾
• Prophylactic laser photocoagulation: Consider indication for prophylactic coagulation for lattice degeneration

Caution

Aortic dissection is the most important life-threatening complication. Prophylaxis of aortic dilation with beta-blockers (e.g., atenolol) or ARBs (e.g., losartan) is performed. Exercise restrictions such as avoiding contact sports are also necessary. Evaluation by a cardiologist is mandatory before surgery. During pregnancy and childbirth, the risk of aortic dissection increases, so pregnancy management at a specialized facility is required.

Q When is surgery performed for lens dislocation?

A

Surgery is indicated when lens displacement 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 (such as pupil capture) are high, so careful judgment is required. The standard procedure is pars plana lensectomy, with expected postoperative BCVA of 20/30 to 20/40 ¹⁾.

6. Pathophysiology and Detailed Mechanism

FBN1 mutations cause abnormalities in fibrillin-1 protein, leading to disruption of microfibril structure.

Zonules of Zinn → Lens Displacement

Fibrillin-1 is a major component of the zonules of Zinn (ciliary zonules). FBN1 mutations weaken microfibrils, causing zonular rupture. The lens shifts upward and superotemporally, progressing from subluxation to complete dislocation.

Mutant fibrillin inhibits multimer formation of normal fibrillin (dominant negative effect).

Sclera and Axial Length → Myopia and Retinal Detachment

Fibrillin-1 is also distributed in the sclera, and FBN1 mutations cause thinning and dilation of the sclera ⁸⁾. The axial length of the eye increases, leading to axial myopia, and the retina is stretched. Lattice degeneration forms in the peripheral retina, becoming a starting point for rhegmatogenous retinal detachment (RRD).

Enhanced TGF-β signaling: FBN1 mutations reduce the sequestration capacity of TGF-β, leading to enhanced TGF-β signaling ³⁾. This promotes abnormal connective tissue remodeling, contributing to weakening of the aortic wall and skeletal abnormalities.

Mechanism of glaucoma: Abnormalities in the angle structure and changes in aqueous humor dynamics increase the risk of glaucoma. In pigmentary glaucoma, pigment dispersion associated with iridodonesis is thought to obstruct the trabecular meshwork.

7. Latest Research and Future Perspectives

For Patients: Please Read Carefully

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

Long-term Follow-up Study of Ocular Complications

A 10-year follow-up study of Marfan syndrome patients by Sandvik et al. (2019) reported long-term progression patterns of lens dislocation and retinal detachment ⁵⁾, highlighting the importance of regular ophthalmic management starting from childhood.

Advances in Lens Surgery

Fan et al. (2014) reported risk factors for complications after lensectomy-vitrectomy (age, IOL insertion status) ⁶⁾. Application of femtosecond laser-assisted cataract surgery in cases with zonular weakness has also been reported, with some achieving postoperative BCVA of 20/20 to 20/25 ¹⁾.

TGF-β Signaling Regulation

Since TGF-β signaling enhancement is central to the pathology, clinical trials of losartan (ARB) for suppressing aortic dilation are ongoing³⁾. Basic research on treatments targeting TGF-β-related pathways is also being conducted for application in ophthalmology.

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.