What is the appropriate workup for an 18-year-old patient suspected of having Marfan syndrome?

Workup for Suspected Marfan Syndrome in an 18-Year-Old

Order a transthoracic echocardiogram immediately to measure the aortic root at the sinuses of Valsalva, sinotubular junction, and ascending aorta with Z-score calculation, and arrange a dilated ophthalmologic examination to assess for ectopia lentis—these two cardinal features, along with systemic scoring and family history, form the foundation of the revised Ghent diagnostic criteria. 1

Immediate Cardiovascular Assessment

• Obtain transthoracic echocardiography (TTE) without delay, measuring the aortic annulus, sinuses of Valsalva (the most critical segment), sinotubular junction, and ascending aorta 1, 2
• Calculate Z-scores to determine if aortic root diameter exceeds 2 standard deviations above the mean for age, sex, and body surface area 1
• If TTE does not adequately visualize the entire thoracic aorta, obtain cardiac-gated CT or MRI of the complete thoracic aorta 1, 2
• In adults, consider CT or MRI after the initial TTE to confirm aortic dimensions and assess the remainder of the thoracic aorta 1, 2

Ophthalmologic Evaluation

• Perform a dilated slit-lamp examination by an ophthalmologist to detect ectopia lentis (lens dislocation), which is a cardinal diagnostic feature 1, 2
• The presence of ectopia lentis together with aortic root dilation (Z-score >2) establishes the diagnosis even without other features 1, 2
• Also assess for myopia >3 diopters, which contributes 1 point to the systemic score 1, 2

Systemic Feature Assessment and Scoring

Apply the revised Ghent systemic scoring system by examining for the following features 1, 2:

Feature	Points
Wrist AND thumb sign (both positive)	3 points
Wrist OR thumb sign (only one positive)	1 point
Pectus carinatum deformity	2 points
Pectus excavatum or chest asymmetry	1 point
Hindfoot deformity (severe valgus)	2 points
Plain pes planus (flat feet)	1 point
Pneumothorax (history or current)	2 points
Dural ectasia (on imaging)	2 points
Protrusio acetabuli (on imaging)	2 points
Scoliosis or thoracolumbar kyphosis	1 point
Reduced elbow extension (<170°)	1 point
Facial features (≥3 of 5: dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia)	1 point
Skin striae	1 point
Myopia >3 diopters	1 point
Mitral valve prolapse	1 point

• A systemic score ≥7 points indicates "multiple systemic features" and, when combined with aortic root dilation (Z-score >2), confirms Marfan syndrome in the absence of a family history 1, 2

Detailed Family History

• Obtain a three-generation pedigree focusing on sudden death, aortic dissection, aortic aneurysm, ectopia lentis, and skeletal features 1, 3
• If a first-degree relative has independently confirmed Marfan syndrome, the diagnostic threshold is lower: the patient qualifies with ectopia lentis alone, multiple systemic features (≥7 points) alone, or aortic root Z-score >3 (if under 20 years) or >2 (if over 20 years) 1
• Screen all first-degree relatives with TTE regardless of genetic testing results 2, 4

Diagnostic Criteria Summary (Revised Ghent Nosology)

Without a Family History of Marfan Syndrome:

The diagnosis is established by any one of the following 1, 2:

1. Aortic root dilation (Z-score ≥2) AND ectopia lentis
2. Aortic root dilation (Z-score ≥2) AND a pathogenic FBN1 mutation
3. Aortic root dilation (Z-score ≥2) AND systemic score ≥7
4. Ectopia lentis AND an FBN1 mutation previously associated with aortic disease

With a Positive Family History:

The diagnosis is established by any one of the following 1:

1. Ectopia lentis
2. Systemic score ≥7
3. Aortic root Z-score >2 (if age >20 years) or >3 (if age <20 years)

Genetic Testing

• FBN1 gene sequencing is reserved for equivocal cases where clinical criteria are not fully met 1, 2
• Current molecular testing detects mutations in only 90–95% of unequivocal Marfan syndrome cases, so Marfan syndrome remains primarily a clinical diagnosis 1, 2
• Consider comprehensive gene panel testing (FBN1, TGFBR1, TGFBR2, COL3A1, ACTA2, MYH11) if the clinical picture suggests an alternative connective tissue disorder such as Loeys-Dietz syndrome or vascular Ehlers-Danlos syndrome 4
• A pathogenic FBN1 mutation, when combined with aortic root dilation or ectopia lentis, confirms the diagnosis and mandates immediate cardiovascular management 2

Additional Imaging for Specific Indications

• Lumbar spine MRI to assess for dural ectasia (contributes 2 points to systemic score) if back pain or neurologic symptoms are present 1, 2
• Pelvic radiograph or CT to evaluate for protrusio acetabuli (contributes 2 points) if hip pain or limited range of motion is noted 1
• Chest radiograph to document pneumothorax history (contributes 2 points) 1

Differential Diagnosis Considerations

Evaluate for alternative or overlapping diagnoses that share features with Marfan syndrome 1:

• Loeys-Dietz syndrome (TGFBR1/2 mutations): Look for bifid uvula, cleft palate, craniosynostosis, hypertelorism, and arterial tortuosity; these patients have a much higher dissection risk at smaller aortic diameters (≥4.0–4.5 cm) 1, 4
• Ehlers-Danlos syndrome (hypermobile type): Assess for joint hypermobility (Beighton score ≥5/9), skin hyperextensibility, easy bruising, and chronic pain; mild aortic root dilation may occur but dissection risk without significant dilation is low 1
• Familial thoracic aortic aneurysm and dissection (FTAAD): Consider if there is isolated aortic disease without major skeletal or ocular features; exclude bicuspid aortic valve on TTE 1
• Bicuspid aortic valve sequence: Carefully assess valve morphology on TTE, as 20–84% of individuals with bicuspid aortic valve develop aortic dilation 5

Common Pitfalls to Avoid

• Do not dismiss the diagnosis based on a negative FBN1 test alone; 5–10% of patients meeting clinical criteria have no detectable mutation 1, 2
• Do not rely solely on absolute aortic diameter measurements; always calculate Z-scores indexed to body surface area and height, especially in tall patients, to avoid underestimating dissection risk 1, 5
• Do not overlook ectopia lentis; it is present in approximately 60% of Marfan patients and is a cardinal diagnostic feature that requires specialized ophthalmologic examination 1, 3
• Do not delay cardiovascular imaging if skeletal features are prominent; aortic dissection can occur even in young patients with normal-appearing aortic dimensions on initial screening 1
• Do not confuse joint hypermobility in Ehlers-Danlos syndrome with Marfan syndrome; use the Beighton scale (≥5/9 points) to distinguish hypermobile EDS, which has a different natural history and lower cardiovascular risk 1

Immediate Management if Diagnosis is Confirmed

• Initiate beta-blocker therapy immediately (regardless of aortic size) to slow aortic dilation and reduce dissection risk; titrate to a resting heart rate of 60–70 bpm 1, 2
• Establish a surveillance imaging protocol: annual TTE if aortic root <4.5 cm and growth <0.5 cm/year; TTE every 6 months if aortic root ≥4.5 cm or growth ≥0.5 cm/year 1, 2
• Refer to cardiology and cardiovascular surgery for co-management and surgical planning; prophylactic aortic root replacement is indicated at ≥4.5 cm in Marfan syndrome 1, 2
• Restrict high-intensity isometric exercise and competitive contact sports due to sudden blood-pressure spikes that increase dissection risk; encourage moderate aerobic activity 2, 5
• Arrange genetic counseling for the patient and family members, as Marfan syndrome follows autosomal dominant inheritance with 50% transmission risk 2, 4