How do you investigate for Marfan syndrome?

Investigation for Marfan Syndrome

The investigation for Marfan syndrome requires echocardiography to measure aortic root dimensions, dilated slit-lamp ophthalmologic examination to assess for ectopia lentis, detailed family history with physical examination of first-degree relatives, and systematic assessment of skeletal features using the revised Ghent criteria. 1

Diagnostic Framework

The diagnosis of Marfan syndrome is fundamentally clinical and requires meeting specific criteria from the revised Ghent nosology, which prioritizes aortic root dilatation and ectopia lentis as the two cardinal features. 1, 2 Genetic testing for FBN1 mutations detects abnormalities in only 90-95% of unequivocal cases, so molecular testing has a circumscribed role and cannot replace clinical diagnosis. 1, 3

Essential Cardiovascular Evaluation

Echocardiography is mandatory and must include specific measurements at the aortic annulus, sinuses of Valsalva, sinotubular junction, and distal ascending aorta, indexed to body surface area with Z-scores calculated. 1, 2 A Z-score ≥+2 (≥2 standard deviations above the mean for age, sex, and body surface area) defines aortic root dilatation. 1 The echocardiogram must also assess:

• Left ventricular function 2
• Aortic valve morphology and function 2
• Mitral valve prolapse and regurgitation 2
• Tricuspid valve abnormalities 2

If aortic root dimensions are normal, the risk of aortic dissection is very low in most conditions except Loeys-Dietz syndrome, where dissection can occur without significant dilatation. 1 This is a critical pitfall—normal echocardiography does not completely exclude risk in all Marfan-like syndromes. 1

Advanced imaging with cardiac MRI or CT angiography should be performed to visualize the entire aorta from root to bifurcation, as dilatation can occur beyond the root. 2

Ophthalmologic Assessment

A dilated slit-lamp examination by an ophthalmologist experienced with Marfan syndrome features is essential to definitively exclude ectopia lentis. 1, 4 This cannot be adequately performed without full pupillary dilation. 1 Ectopia lentis is a major diagnostic criterion and, when combined with aortic root dilatation, establishes the diagnosis even without other features. 1

Skeletal System Evaluation

Assess for at least four of the following eight skeletal manifestations to meet major skeletal criteria: 1

• Pectus carinatum or pectus excavatum requiring surgery
• Wrist and thumb signs (Walker-Murdoch wrist sign and Steinberg thumb sign)
• Reduced upper-to-lower segment ratio or arm span-to-height ratio >1.05
• Scoliosis >20° or spondylolisthesis
• Reduced elbow extension (<170°)
• Pes planus with medial displacement of the medial malleolus
• Protrusio acetabuli
• Facial features (dolichocephaly, malar hypoplasia, enophthalmos, downslanting palpebral fissures, retrognathia)

Family History and Examination

Obtaining detailed family history with medical and autopsy records is crucial, but personally examining siblings and parents is equally important because many diagnostic features are clinically silent. 1 Features like scoliosis, striae atrophicae, disproportionate stature, mitral valve prolapse, and aortic root dilatation may not be apparent to relatives. 1

Document any family history of:

• Aortic dissection or aneurysm (specify location and age at occurrence) 1
• Sudden cardiac death 1
• Ectopia lentis 1
• Skeletal features consistent with Marfan syndrome 1

Additional Investigations When Diagnosis is Equivocal

Lumbosacral MRI or CT to assess for dural ectasia should only be performed when the diagnosis hinges on this finding, as it involves radiation exposure (if CT) and expense. 1 Dural ectasia occurs rarely outside of Marfan and Loeys-Dietz syndromes, making it diagnostically valuable when present, but its absence does not exclude the diagnosis. 1

FBN1 genetic testing is most useful when:

• Clinical features are present but insufficient to meet Ghent criteria 1
• The patient is young and age-dependent features have not yet manifested 1
• Differentiating between Marfan syndrome and related fibrillinopathies 1

However, a negative genetic test does not exclude Marfan syndrome given the 5-10% false-negative rate in clinically definite cases. 1

Diagnostic Criteria for Patients Without Family History

In the absence of family history, Marfan syndrome is diagnosed by any of the following: 1

1. Aortic root dilatation (Z-score ≥+2) AND ectopia lentis
2. Aortic root dilatation AND FBN1 mutation
3. Aortic root dilatation AND systemic score ≥7 points (from skeletal, skin, and dural features)
4. Ectopia lentis AND FBN1 mutation known to cause aortic disease

Critical Differential Diagnoses to Exclude

The investigation must systematically exclude conditions with overlapping features: 1

• Loeys-Dietz syndrome (look for hypertelorism, bifid uvula, arterial tortuosity, and consider TGFBR1/TGFBR2 testing) 1
• Ehlers-Danlos syndrome, hypermobile type (assess skin hyperextensibility, tissue fragility, and Beighton hypermobility score) 1, 4
• Familial thoracic aortic aneurysm (isolated aortic disease without systemic features) 1
• MASS phenotype (mitral valve prolapse, aortic borderline dilatation, striae, skeletal features—but does not meet full Marfan criteria) 1

Common Pitfalls

Do not diagnose Marfan syndrome based solely on tall stature and joint hypermobility—these features are common in the general population and have polygenic inheritance patterns. 1 Conversely, short stature does not exclude Marfan syndrome, as rare cases with significant aortic disease have been documented despite atypical height. 5

Do not rely on historical diagnoses of "cystic medial necrosis" from autopsy reports of deceased relatives—this finding was historically overattributed to Marfan syndrome even when other diagnostic features were absent. 1

Do not assume a normal echocardiogram provides complete reassurance—serial surveillance is necessary because aortic dilatation is age-dependent and progressive. 1, 4 For patients with some features but normal aortic dimensions, repeat echocardiography every 2-3 years until adult height is reached, then only if symptoms develop or major physical activity changes are planned. 4