What is the recommended initial workup for a patient suspected of having Marfan syndrome?

Initial Workup for Suspected Marfan Syndrome

The initial workup for suspected Marfan syndrome must include transthoracic echocardiography to assess aortic root dimensions, a dilated ophthalmologic examination to identify or exclude ectopia lentis, complete vascular imaging with CMR or CCT from head to pelvis, and application of the Ghent nosology criteria to establish diagnosis. 1

Cardiovascular Assessment

Transthoracic echocardiography is mandatory and must measure specific anatomic locations: 1

• Aortic annulus dimensions
• Sinuses of Valsalva (most critical for Marfan diagnosis)
• Sinotubular junction
• Proximal ascending aorta
• Left ventricular function assessment
• Evaluation for aortic regurgitation
• Detection of mitral valve prolapse and/or mitral regurgitation
• Assessment for tricuspid valve prolapse and regurgitation

Complete vascular imaging with cardiac MRI or cardiac CT is required at initial evaluation to visualize the entire aorta beyond the root and assess peripheral vasculature from head to pelvis, as aortic involvement can occur anywhere along the vessel. 1

Holter monitoring should be performed if the patient is symptomatic to detect ventricular arrhythmias, conduction disturbances, and assess sudden cardiac death risk. 1

Ophthalmologic Evaluation

A dilated eye examination by an ophthalmologist is essential and non-negotiable to definitively identify or exclude ectopia lentis, which is one of the two cardinal features of Marfan syndrome. 1, 2 This finding is pathognomonic for Marfan syndrome and essentially rules out Ehlers-Danlos syndrome, making it a critical differentiating feature. 2

The examination must also assess for refractive errors, which are common in Marfan syndrome. 3

Physical Examination Findings

Focus on high-yield physical features that have the strongest diagnostic value: 4

• Craniofacial characteristics (dolichocephaly, malar hypoplasia, enophthalmos, downslanting palpebral fissures)
• Thumb and wrist signs (Steinberg and Walker-Murdoch signs) - highly specific features
• High-arched palate
• Pectus excavatum or carinatum requiring surgery or causing functional impairment
• Severe hindfoot valgus
• Scoliosis (>20 degrees or spondylolisthesis)
• Arm span-to-height ratio >1.05
• Reduced upper-to-lower segment ratio or increased lower extremity-to-body ratio

Patients with three to four physically evident features, or two highly specific features (thumb and wrist signs, craniofacial features, dural ectasia, or protrusio acetabuli) warrant immediate comprehensive workup. 4

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, 5 The penetrance of some features is age dependent, so the Ghent nosology must be used with caution in pediatric patients. 3

Testing for TGFBR1 and TGFBR2 mutations (Loeys-Dietz syndrome), ACTA2, MYH11, and SMAD3 mutations should be considered if clinical features suggest alternative diagnoses or familial thoracic aortic disease. 1

Application of Ghent Nosology

The Ghent nosology will unequivocally diagnose or exclude Marfan syndrome in 86% of cases. 3 The diagnosis requires one of the following combinations: 2

• Aortic root dilation AND ectopia lentis
• Aortic root dilation AND FBN1 mutation
• Aortic root dilation AND systemic score ≥7 points

Critical Differential Diagnoses to Exclude

Alternative diagnoses that must be considered include: 1

• Loeys-Dietz syndrome - requires magnetic resonance angiography of head, neck, thorax, abdomen, and pelvis to assess for arterial tortuosity; TGFBR1/TGFBR2 gene sequencing 6
• Hypermobile Ehlers-Danlos syndrome - assess Beighton score (≥5/9 indicates hypermobility), skin hyperextensibility (soft, velvety texture), and absence of ectopia lentis 6, 2
• Bicuspid aortic valve with aortopathy
• Familial thoracic aortic aneurysm syndromes
• MASS phenotype (Mitral valve prolapse, Aortic enlargement, Skin and Skeletal findings)
• Congenital contractural arachnodactyly (Beals syndrome) - characterized by flexion contractures, crumpled ear helices, and requires FBN2 testing 6

Common Pitfalls to Avoid

Do not rely solely on skeletal features: 27% of confirmed Marfan patients have major skeletal involvement, while 19% have zero or one skeletal feature, and 83% of non-Marfan patients have at least one skeletal feature. 4

Ectopia lentis is the key differentiator - EDS does not cause lens dislocation, while Marfan syndrome typically presents with this finding. 2 A dilated ophthalmologic examination is mandatory to avoid misdiagnosis.

Aortic root dilation severity differs between conditions: Marfan syndrome presents with significant aortic root dilation (>40-42 mm) and high dissection risk, while EDS hypermobile type shows only mild dilation in one-quarter to one-third of patients with no dissection risk without significant dilation. 2