Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene. It is the second most common inherited connective tissue disorder after osteogenesis imperfecta, with an estimated worldwide incidence of about 1 in 5,000 people.
There is no gender difference, and it occurs in all ethnic groups. About 75% of patients inherit the mutated gene from a parent, while about 25% are due to sporadic (de novo) mutations. Because of autosomal dominant inheritance, the probability of a patient passing the mutation to a child is 50%.
The FBN1 gene is located on chromosome 15 (15q21.1) and encodes the fibrillin-1 protein. Fibrillin-1 is a major component of microfibrils, which are distributed in connective tissues throughout the body, including the zonular fibers, aorta, skin, and skeletal system. Mutations lead to structural fragility of the connective tissue.
The disease was first formally reported by Antoine Marfan at the Paris Medical Society in 1896, and it is designated as an intractable disease.
About 25% of cases are due to sporadic mutations, so it can occur even without a family history. If it occurs, the chance of passing it to a child is 50%. Regular genetic counseling is recommended.
Marfan syndrome is a multisystem disorder affecting the skeletal, cardiovascular, and ocular systems. The main ocular subjective symptoms are as follows:
Systemic symptoms include tall stature, arachnodactyly (spider fingers), scoliosis, pectus excavatum, joint hypermobility, and aortic dilation/dissection.
Ocular abnormalities occur in about 80% of patients with Marfan syndrome. The most common finding is ectopia lentis, which is present in 50–80% of patients.
Lens Displacement
Direction of displacement: Upward and outward (superotemporal) displacement is most common. Theoretically, displacement can occur in any direction.
Zonular findings: The zonules are often stretched but remain intact without rupture. Slit-lamp examination reveals iridodonesis and phacodonesis.
Spherophakia: The lens may be abnormally shaped (spherical).
Caution with miosis: Displacement is difficult to detect when the pupil is constricted; recheck after dilation.
Other Ocular Findings
High myopia and astigmatism: Primarily axial myopia due to increased axial length. The Ghent criteria include myopia ≥3D as a diagnostic score.
Poor dilation and small pupil: Due to hypoplasia of the pupillary dilator muscle.
Flat cornea: Decreased corneal curvature.
Scleral thinning: Due to connective tissue fragility.
Retinal detachment: Based on axial elongation, vitreous liquefaction, and peripheral retinal degeneration. In cases of ectopia lentis, retinal detachment occurs in 8–38% of patients1).
Complete dislocation of the lens into the pupil or anterior chamber can cause pupillary block glaucoma. Cataracts are common in Marfan syndrome patients, but the incidence is not higher than in the general population; however, onset is typically 10–20 years earlier1). Cases of cataract onset before age 40 have also been reported1).
Mild subluxation often causes few subjective symptoms. When displacement progresses to the point where the lens edge crosses the pupil, diplopia occurs. Regular ophthalmic examinations are important for Marfan syndrome patients to monitor lens position.
The main cause of Marfan syndrome is mutation of the FBN1 gene, leading to dysfunction of fibrillin-1 and generalized connective tissue fragility1). Fibrillin-1 is a major component of the zonules (fibers supporting the lens), and its deficiency results in ectopia lentis and axial elongation1).
Furthermore, FBN1 mutations cause overactivation of TGF-β (transforming growth factor beta) signaling, leading to abnormal remodeling of the extracellular matrix. This TGF-β hyperactivity is thought to contribute to weakening of the aortic wall and abnormal elongation of the ocular axis1).
Additionally, abnormal extracellular matrix remodeling disrupts aqueous humor dynamics, increasing the risk of elevated intraocular pressure and glaucoma1).
The diagnosis of Marfan syndrome is based on the Revised Ghent Nosology. Major diagnostic criteria include the following.
If ectopia lentis is present and there is a positive family history of Marfan syndrome, or an aortic diameter Z-score ≥ 2, a definitive diagnosis is made.
| Disease | Direction of Lens Dislocation | Main Differentiating Points |
|---|---|---|
| Marfan syndrome | Superotemporal | FBN1 mutation, aortic disease |
| Homocystinuria | Inferonasal | Intellectual disability, thrombotic tendency |
| Weill-Marchesani syndrome | Anterior (microspherophakia) | Brachydactyly, short stature |
Even if an FBN1 gene mutation is not confirmed, a clinical diagnosis of Marfan syndrome can be made if clinical findings meet the revised Ghent criteria. However, genetic testing is useful for definitive diagnosis, genetic counseling for families, and differential diagnosis (e.g., B3GAT3-related disorders).
Management of Ectopia Lentis: For mild subluxation with preserved vision, observation with refractive correction using glasses or contact lenses is recommended. Determine whether the phakic or aphakic portion is used under natural pupil and provide appropriate optical correction.
Indications for lens extraction are as follows (Nemet et al. criteria):
Cataract Surgery: Cataract surgery is the main surgical intervention for Marfan syndrome 1). Due to zonular weakness, it is more challenging than standard cataract surgery 1). Femtosecond laser-assisted cataract surgery enables precise capsulotomy and nuclear fragmentation, and has been reported as a promising approach for Marfan syndrome patients 1). Surgery combined with zonular support devices (e.g., capsular tension ring, scleral suture fixation) is also performed 1).
Glaucoma Management:
Management of Retinal Detachment: For retinal detachment, surgical treatment combining scleral buckling, vitrectomy, and silicone oil tamponade is performed 1). Prophylactic laser treatment to the fellow eye may be considered.
Management of Pediatric Patients: To prevent amblyopia, refractive errors and anisometropia due to lens subluxation should be corrected early. Prioritize treatment that promotes visual development within the sensitive period.
If lens subluxation is mild and zonules are preserved, IOL insertion is possible. However, if zonules are severely fragile, only lens removal may be performed. Special IOL fixation methods such as scleral-sutured IOL may be selected. Detailed preoperative examination and thorough consultation with the physician are necessary.
Fibrillin-1 is a major structural protein of microfibrils and forms the scaffold of elastic fibers. In the eye, fibrillin-1 supports the lens as a component of the zonules 1).
FBN1 mutations lead to ocular and systemic pathology through the following pathways:
In the case of B3GAT3-related disease reported by Li et al. (2022), the patient presented with arachnodactyly and aortic root dilation from the neonatal period, suggesting Marfan syndrome, but whole-exome sequencing did not detect FBN1 mutations and identified a B3GAT3 mutation instead2). Since other diseases clinically similar to Marfan syndrome exist, molecular diagnosis is important for definitive diagnosis.
The location of mutations in Marfan syndrome varies widely within the FBN1 gene, and the site and type of mutation are thought to influence the severity of ocular and systemic symptoms. Neonatal Marfan syndrome is associated with mutations in exons 24–32 (neonatal region) of the FBN1 gene, follows a particularly severe course, and has a high mortality rate before 2 years of age2).
Research on drug therapy targeting TGF-β overactivation, the fundamental pathology of Marfan syndrome, is progressing. In animal models, losartan (an angiotensin II receptor blocker) has been reported to suppress TGF-β signaling and reduce aortic dilation. Clinical trials in humans have also been conducted, but the current standard treatment is beta-blockers.
The application of femtosecond laser cataract surgery for patients with Marfan syndrome and fragile zonules is being actively studied1). Several cases have reported good visual outcomes when combined with a capsular tension ring1). However, establishing a standardized protocol remains a future challenge.
Basic research on gene therapy aimed at fundamentally correcting the FBN1 gene is underway, but it has not yet reached clinical application.
