Marfan Syndrome
Overview
Plain-Language Overview
Marfan syndrome is a genetic disorder that affects the body's connective tissue, which provides support to many parts of the body. People with this condition often have long arms, legs, and fingers, and may be taller than average. The syndrome can also affect the heart, especially the aorta, which may become enlarged and weak, leading to serious complications. The eyes are commonly involved, with a risk of lens dislocation and vision problems. Marfan syndrome varies in severity, and symptoms can range from mild to life-threatening.
Clinical Definition
Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene, which encodes fibrillin-1, a critical component of the extracellular matrix. This leads to defective microfibril formation and abnormal transforming growth factor-beta (TGF-β) signaling. The syndrome is characterized by systemic manifestations involving the skeletal system, such as arachnodactyly, pectus deformities, scoliosis, and joint hypermobility. Cardiovascular involvement includes dilation of the ascending aorta, aortic aneurysm, and risk of dissection or rupture. Ocular features include ectopia lentis and myopia. Diagnosis relies on clinical criteria supported by genetic testing. The disorder exhibits variable expressivity and penetrance. Management focuses on surveillance and prevention of cardiovascular complications. Life expectancy has improved with early diagnosis and treatment.
Inciting Event
- none
Latency Period
- none
Diagnostic Delay
- Variable and subtle early symptoms can lead to delayed recognition of Marfan syndrome.
- Overlap of features with other connective tissue disorders may complicate diagnosis.
Clinical Presentation
Signs & Symptoms
- Tall stature with long limbs and fingers (arachnodactyly).
- Chest wall deformities such as pectus excavatum or carinatum.
- Joint hypermobility causing joint pain or frequent dislocations.
- Visual disturbances due to ectopia lentis.
- Cardiovascular symptoms from aortic root dilation including chest pain or dyspnea.
- Scoliosis or spinal curvature abnormalities.
History of Present Illness
- Patients often report tall stature with disproportionately long limbs and fingers (arachnodactyly).
- Complaints of joint hypermobility and frequent joint dislocations are common.
- Visual problems such as lens dislocation (ectopia lentis) or myopia may be present.
- Symptoms related to cardiovascular complications like chest pain or shortness of breath may occur due to aortic dilation.
Past Medical History
- History of skeletal abnormalities such as scoliosis or pectus excavatum.
- Previous ocular issues including lens dislocation or early cataracts.
- Prior cardiovascular events such as aortic aneurysm or mitral valve prolapse.
Family History
- Autosomal dominant inheritance pattern with affected first-degree relatives.
- Family members may have a history of aortic aneurysm, sudden cardiac death, or lens dislocation.
Physical Exam Findings
- Tall stature with disproportionately long limbs and fingers (arachnodactyly) is a classic physical finding.
- Pectus excavatum or pectus carinatum deformities of the chest wall are commonly observed.
- Positive wrist and thumb signs indicate joint hypermobility.
- Scoliosis or kyphosis may be present on spinal examination.
- Ectopia lentis manifests as lens dislocation visible on slit-lamp eye exam.
- Aortic root dilation may be suggested by a murmur of aortic regurgitation.
Diagnostic Workup
Diagnostic Criteria
The diagnosis of Marfan syndrome is based on the revised Ghent criteria, which emphasize aortic root dilation or dissection and ectopia lentis as major features. A confirmed FBN1 mutation or a positive family history supports diagnosis. Additional systemic features include skeletal abnormalities such as pectus excavatum, scoliosis, and arachnodactyly, as well as dural ectasia. A systemic score quantifies these features to aid diagnosis. The presence of aortic root enlargement combined with ectopia lentis or a pathogenic FBN1 mutation confirms the diagnosis. In the absence of family history, multiple systemic features are required to establish the diagnosis.
Pathophysiology
Key Mechanisms
- Marfan syndrome is caused by mutations in the FBN1 gene, leading to defective fibrillin-1 protein and abnormal connective tissue.
- Defective fibrillin-1 results in weakened elastic fibers in the extracellular matrix, affecting multiple organ systems.
- Increased activity of transforming growth factor-beta (TGF-β) contributes to the pathogenesis by promoting tissue remodeling and damage.
| Involvement | Details |
|---|---|
| Organs | Heart is affected by mitral valve prolapse and aortic root dilation leading to cardiovascular complications. |
| Eyes commonly show lens dislocation (ectopia lentis) due to weakened zonular fibers. | |
| Skeleton exhibits features such as long limbs, arachnodactyly, and scoliosis due to connective tissue defects. | |
| Tissues | Connective tissue is structurally compromised due to defective fibrillin-1, leading to systemic manifestations. |
| Aortic media shows cystic medial necrosis weakening the vessel wall and predisposing to aneurysm. | |
| Cells | Fibroblasts produce defective fibrillin-1 protein leading to weakened connective tissue. |
| Smooth muscle cells in the aortic media are affected by abnormal extracellular matrix causing vessel wall weakness. | |
| Chemical Mediators | Transforming growth factor-beta (TGF-β) is overactive due to defective fibrillin-1, contributing to abnormal connective tissue remodeling. |
| Matrix metalloproteinases (MMPs) degrade extracellular matrix components, promoting aortic wall weakening. |
Treatment
Pharmacological Treatments
Beta-blockers
- Mechanism: reduce heart rate and aortic wall stress by decreasing myocardial contractility and blood pressure
- Side effects: fatigue, bradycardia, hypotension
Angiotensin II receptor blockers (ARBs)
- Mechanism: inhibit TGF-β signaling, reducing aortic root dilation
- Side effects: hyperkalemia, hypotension, renal impairment
Non-pharmacological Treatments
- Regular echocardiographic monitoring to assess aortic root size and progression of dilation.
- Restriction of intense physical activities and contact sports to reduce risk of aortic dissection.
- Elective aortic root surgery when dilation exceeds threshold size to prevent rupture.
Prevention
Pharmacological Prevention
- Beta-blockers reduce aortic wall stress and slow aortic root dilation.
- Angiotensin receptor blockers (ARBs) like losartan may decrease TGF-beta signaling and aortic dilation.
- Regular use of cardiovascular medications to manage hypertension and reduce complication risk.
Non-pharmacological Prevention
- Avoidance of strenuous physical activity and contact sports to reduce aortic rupture risk.
- Regular cardiovascular monitoring with echocardiography to detect aortic dilation early.
- Genetic counseling for affected families.
- Elective surgical repair of the aortic root before critical dilation occurs.
Outcome & Complications
Complications
- Aortic root aneurysm leading to aortic dissection or rupture.
- Severe mitral valve regurgitation causing heart failure.
- Lens dislocation resulting in visual impairment.
- Spontaneous pneumothorax from lung blebs.
- Neurological deficits from dural ectasia.
| Short-term Sequelae | Long-term Sequelae |
|---|---|
|
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Differential Diagnoses
Marfan Syndrome versus Ehlers-Danlos Syndrome
| Marfan Syndrome | Ehlers-Danlos Syndrome |
|---|---|
| Tall stature with disproportionately long limbs (arachnodactyly) | Hyperextensible skin and fragile tissues with easy bruising |
| Aortic root dilation leading to aneurysm or dissection | Joint hypermobility with frequent dislocations but without tall stature |
| Ectopia lentis (dislocation of the ocular lens) | Absence of aortic root dilation or ectopia lentis |
Marfan Syndrome versus Homocystinuria
| Marfan Syndrome | Homocystinuria |
|---|---|
| Normal cognitive function without intellectual disability | Intellectual disability and developmental delay |
| Risk of aortic root dilation and dissection | Thromboembolic events due to hypercoagulability |
| Upward lens dislocation (superotemporal ectopia lentis) | Downward lens dislocation (inferonasal ectopia lentis) |
Marfan Syndrome versus Loeys-Dietz Syndrome
| Marfan Syndrome | Loeys-Dietz Syndrome |
|---|---|
| Normal facial features without hypertelorism or bifid uvula | Hypertelorism (widely spaced eyes) and bifid uvula or cleft palate |
| Primarily aortic root dilation without widespread arterial aneurysms | More aggressive arterial aneurysms involving multiple vessels |
| Ectopia lentis present in many cases | Absence of ectopia lentis |