Marfan Syndrome Diagnostic Criteria
The diagnosis of Marfan syndrome (MFS) requires either aortic root aneurysm plus ectopia lentis, or aortic root aneurysm plus a confirmed FBN1 mutation, or aortic root aneurysm plus a systemic score ≥7 points when there is no family history. 1
Revised Ghent Nosology (2010) - Current Standard
The revised Ghent criteria prioritize cardiovascular and ocular manifestations as the cardinal features, with aortic root aneurysm and ectopia lentis being the two most critical diagnostic elements 1. This represents a significant shift from the 1996 criteria, placing greater emphasis on life-threatening cardiovascular complications that directly impact mortality 1, 2.
Diagnostic Pathways Based on Family History
In patients WITH a family history of MFS:
- Ectopia lentis alone is sufficient for diagnosis 1
- Systemic score ≥7 points alone is sufficient for diagnosis 1
- Aortic root dilation (Z-score ≥2 when above age 20, or ≥3 below age 20) alone is sufficient for diagnosis 1
In patients WITHOUT a family history of MFS:
- Aortic root dilation (Z-score ≥2) PLUS ectopia lentis establishes the diagnosis 1
- Aortic root dilation PLUS confirmed FBN1 mutation establishes the diagnosis 1
- Aortic root dilation PLUS systemic score ≥7 establishes the diagnosis 1
- Ectopia lentis PLUS FBN1 mutation with known aortic disease establishes the diagnosis 1
Systemic Score Calculation
The systemic score assigns points to various skeletal and other manifestations 1:
Skeletal features (maximum 20 points total):
- Wrist AND thumb sign = 3 points 1
- Wrist OR thumb sign = 1 point 1
- Pectus carinatum deformity = 2 points 1
- Pectus excavatum or chest asymmetry = 1 point 1
- Hindfoot deformity = 2 points 1
- Plain pes planus = 1 point 1
- Pneumothorax = 2 points 1
- Dural ectasia = 2 points 1
- Protrusio acetabuli = 2 points 1
- Reduced upper segment/lower segment ratio AND increased arm span/height ratio AND no severe scoliosis = 1 point 1
- Scoliosis or thoracolumbar kyphosis = 1 point 1
- Reduced elbow extension (≤170°) = 1 point 1
- Facial features (3 of 5: dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia) = 1 point 1, 3
- Skin striae = 1 point 1
- Myopia >3 diopters = 1 point 1
- Mitral valve prolapse = 1 point 1
A systemic score of ≥7 points is required for diagnosis in the appropriate clinical context 1.
Key Cardiovascular Criteria
Aortic root dilation is defined as Z-score ≥2 above age 20 years, or Z-score ≥3 below age 20 years 1. The aortic root diameter should not exceed 40-42 mm even in tall individuals 4. Aortic dissection is a major criterion and life-threatening complication that drives the emphasis on cardiovascular surveillance 1, 5.
Molecular Genetic Testing
FBN1 mutations are found in approximately 66% of patients who meet full clinical criteria for MFS, but only 12% of those who do not meet criteria 6. The presence of a confirmed FBN1 mutation carries substantial diagnostic weight in the revised nosology, though testing is not mandatory 1. Patients with ectopia lentis have a significantly higher likelihood of having an FBN1 mutation (P=0.04) 6.
Critical Diagnostic Considerations
The revised Ghent criteria reclassify approximately 15% of patients compared to the 1996 criteria 2. Specifically, 10% of patients previously diagnosed with MFS are reclassified as ectopia lentis syndrome or MASS syndrome when aortic dilation is absent, while 5% are newly classified as MFS when aortic dilation is present 2.
In children and young adults under age 20, the diagnosis may need to be deferred as "potential MFS" since many manifestations are age-dependent 1, 2, 6. The median age at diagnosis is approximately 7.3 years for those with major skeletal involvement 3.
Essential Diagnostic Workup
- Echocardiography to measure aortic root diameter with Z-score calculation 4, 1
- Dilated ophthalmologic examination to assess for ectopia lentis 4
- Comprehensive skeletal examination including wrist and thumb signs, pectus deformities, scoliosis, hindfoot valgus, and craniofacial features 1, 3
- Lumbosacral MRI or CT if dural ectasia assessment would change diagnostic classification 4
- FBN1 genetic testing when diagnosis is uncertain or for family screening 1, 6
Common Diagnostic Pitfalls
Approximately 19% of patients with confirmed MFS have zero or only one skeletal feature, making skeletal manifestations alone unreliable for diagnosis 3. Conversely, 83% of non-MFS patients have at least one skeletal feature, and 13% have two features 3.
The most diagnostically useful physical findings are thumb and wrist signs, craniofacial characteristics, pectus excavatum, and severe hindfoot valgus 3. Patients with 3-4 physically evident features, or two highly specific features (thumb/wrist signs, craniofacial features, dural ectasia, or protrusio acetabuli) warrant echocardiography and genetics consultation 3.
Joint hypermobility (Beighton score ≥5/9) can mimic MFS but is more characteristic of Ehlers-Danlos syndrome hypermobile type, which has different cardiovascular risk profiles 4, 7. While 25-33% of EDS patients develop mild aortic root dilation, dissection risk without significant dilation is minimal 4.