Marfan Syndrome Workup
Initial Diagnostic Evaluation
The workup for suspected Marfan syndrome requires transthoracic echocardiography (TTE) to assess aortic root dimensions at multiple levels, complete imaging of the entire aorta and peripheral vasculature by CMR or CCT, dilated ophthalmologic examination for ectopia lentis, and application of the Ghent nosology criteria which prioritize the two cardinal features: aortic root aneurysm/dissection and ectopia lentis. 1
Cardiovascular Assessment
Echocardiographic evaluation is mandatory and must include:
- Measurements at the aortic annulus, sinuses of Valsalva, sinotubular junction, and proximal ascending aorta—not just maximum diameter 1
- Assessment of left ventricular function 1
- Evaluation for aortic regurgitation 1
- Detection of mitral valve prolapse and/or mitral regurgitation 1
- Assessment for tricuspid valve prolapse and regurgitation 1
Complete vascular imaging with CMR or CCT from head to pelvis is required at initial evaluation to visualize the entire aorta beyond the root and assess peripheral vasculature, as Marfan syndrome affects the entire arterial tree 1. This imaging should be repeated every 3-5 years if stable in patients without previous aortic surgery 1.
For pre-operative coronary assessment, CT coronary angiography is preferred over invasive catheterization because catheter manipulation carries risk of dissection in the weakened aortic wall 1.
Holter monitoring should be performed in symptomatic patients to detect ventricular arrhythmias, conduction disturbances, and assess sudden cardiac death risk 1.
Ophthalmologic Assessment
A dilated eye examination by an ophthalmologist is essential to definitively identify or exclude ectopia lentis, which is one of the two cardinal features of Marfan syndrome 1, 2. The absence of both aortic root dilatation and ectopia lentis makes Marfan syndrome unlikely 2.
Musculoskeletal and Systemic Assessment
Physical examination must document:
- Skeletal features including arm span-to-height ratio, upper-to-lower segment ratio 3, 4
- Presence of pectus deformities (carinatum or excavatum) 3
- Scoliosis 3
- Joint hypermobility using the Beighton score (≥5/9 points indicates hypermobility) 2
- Arachnodactyly (thumb and wrist signs) 3
- Striae distensae 2
- Skin texture and extensibility 2
Imaging for dural ectasia may be considered, though its correlation with back pain is uncertain 3.
Genetic Testing
Molecular genetic testing for FBN1 mutations should be considered when clinical criteria are equivocal, particularly in children where age-dependent penetrance makes clinical diagnosis challenging 1, 3, 5. However, approximately 10% of patients with definite Marfan syndrome will not have an identifiable FBN1 mutation 1.
If clinical features suggest alternative diagnoses, consider testing for:
- TGFBR1 and TGFBR2 mutations (Loeys-Dietz syndrome) 1
- ACTA2, MYH11, SMAD3 mutations (other heritable thoracic aortic disease) 1
Family History
Document detailed three-generation family history for autosomal dominant inheritance patterns, aortic dissection, sudden cardiac death, and characteristic features in relatives 1, 2, 3.
Diagnostic Criteria Application
The Ghent nosology definitively diagnoses or excludes Marfan syndrome in 86% of cases and requires major manifestations in two different organ systems plus involvement of a third organ system 1, 3. The revised nosology gives greater weight to aortic root aneurysm/dissection and ectopia lentis as the cardinal features 1.
Critical caveat: The Ghent nosology must be used with caution in children due to age-dependent penetrance of features; molecular testing is particularly helpful in pediatric cases 3, 5.
Differential Diagnosis Considerations
Many patients referred for "Marfan-like" features do not have Marfan syndrome. In one prospective study of 279 consecutive patients with suspected Marfan syndrome, only 49% were confirmed to have the condition, while 25% had other connective tissue diseases and 26% had no distinct disease 4.
Alternative diagnoses to consider include:
- Loeys-Dietz syndrome (facial features, arterial tortuosity, bifid uvula, dissection at smaller aortic diameters) 1
- Hypermobile Ehlers-Danlos syndrome (joint hypermobility, soft/velvety skin, easy bruising, GI symptoms) 2
- Bicuspid aortic valve with aortopathy 1
- Familial thoracic aortic aneurysm syndromes (ACTA2, MYH11, SMAD3 mutations) 1
- MASS phenotype 1
- Congenital contractural arachnodactyly (Beals syndrome) 1
No single clinical criterion has sufficient positive and negative likelihood ratios to confirm or rule out Marfan syndrome independently 4.
Multidisciplinary Team Requirement
The diagnosis and management requires coordination between cardiology, ophthalmology, genetics, orthopedics, and other specialists given the multisystem nature and phenotypic variability of the condition 1, 3.