Laboratory Studies
Currently, the standard of care in Marfan syndrome (MFS) is to obtain confirmatory molecular diagnostics on patients with the syndrome and their family members, due to the variable expression of MFS and the diagnosable "look-alike" conditions.
Molecular studies of the fibrillin-1 (FBN1) gene should be performed in patients in whom MFS is suspected. Mutation analysis can identify the exact mutation in the fibrillin gene, and linkage analysis can be used to track an abnormal fibrillin gene within a family. [6]
The gene structure of FBN1 is large, being greater than 600 kb and containing 65 exons. At least 1000 pathogenic variants in FBN1 that cause MFS and related phenotypes have been described. [42, 43] Most mutations are missense mutations, small in-frame deletions, or insertions that alter a single peptide. All mutations described produce an abnormal fibrillin-1 protein.
Although ordering FBN1 sequencing with del/dup analysis is appropriate if the patient clearly meets the clinical criteria for MFS, the search should not stop there if the results are negative. Many geneticists and cardiologists are utilizing next-generation sequencing panels that include other connective-tissue disorder genes. It is important to include genes described for Loeys-Dietz syndromes, Stickler syndrome, and Ehlers-Danlos syndromes (especially type IV; COL3A1). These additional gene analyses are becoming more cost-effective for patients.
Faivre et al reported a comprehensive clinical and molecular description of a large series of pediatric cases with an FBN1 mutation. [44] Most clinical manifestations of MFS become more apparent with age. This highlights the limited usefulness of international criteria for diagnosis in early infancy and also emphasizes the value of FBN1 mutation screening, which confirms the diagnosis and facilitates determination of prognosis and timely management.
Imaging Studies
Advances in noninvasive diagnostic imaging modalities have had a significant impact on case management. These studies provide accurate detection and quantification of the severity of cardiovascular disease, aiding in the appropriate timing for surgical intervention.
Radiography
Chest radiography should be focused on apical blebs. Chest radiographs may also detect a thoracic aortic dissection by demonstrating enlargement of the aortic and cardiac silhouette. Pelvic radiography may be required if a positive finding of protrusio acetabula is needed for the diagnosis.
Echocardiography
Standard echocardiography is valuable to assess mitral valve prolapse, left ventricular size and function, left atrial size, and tricuspid valve function.
Cross-sectional echocardiography is a common tool used to diagnose and manage aortic root dilatation. The upper limit of normal aortic root size is 1.9 cm/m2 of body surface area and is independent of the patient's sex.
Transesophageal echocardiography depicts the distal ascending and descending aorta and can provide assessment of prosthetic valves. Doppler echocardiography is useful to detect and grade the severity of aortic and mitral regurgitation.
CT scanning and MRI
Magnetic resonance imaging (MRI) is the best choice for assessing chronic dissection of any region of the aorta. It should be performed in any patient at any age who has an aortic root dimension of more than 150% of the mean for their body surface area or a ratio of actual to predicted aortic root dimension of more than 1.5.
CT scanning or MRI of the lumbosacral spine may be needed to detect dural ectasia. The following MRI and CT scan criteria for dural ectasia in adults have been proposed, with the presence of dural ectasia requiring one major criterion or both minor criteria:
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Major criterion - Sagittal width of the dural sac at S1 or below that is greater than the sagittal width of the dural sac above L4
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Minor criteria - Nerve root sleeve at L5 of more than 6.5 mm in diameter or scalloping at S1 of more than 3.5 mm
Other Tests
An ambulatory electrocardiogram (ECG) should be obtained in patients with symptomatic palpitations, syncope, or near syncope. A baseline ECG that indicates a major rhythm or conduction disturbance should prompt immediate attention.
Procedures
Ocular examination
Ocular care and treatment should be managed by an ophthalmologist with expertise in Marfan syndrome (MFS). Examination should include the following:
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Slit lamp examination - Pupils should be dilated and checked for lens subluxation and retinal tears.
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Refraction and visual correction - It is important to assess young patients for myopia and amblyopia.
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Assessment for glaucoma and cataract
Skeletal examination
Evaluation may be required by an orthopedist. Assess for bone overgrowth and ligamentous laxity. This can cause progressive, severe scoliosis requiring surgical intervention for spine stabilization.
Chest wall examination should be performed to assess for the degree of pectus excavatum/pectus carinatum. Surgical correction may be indicated.
Histologic Findings
Immunohistologic evaluation of the skin for abnormal fibrillin has been reported. However, there is an incidence of false-positive results in patients who do have connective-tissue disorders but not Marfan syndrome (MFS).
Electron microscopy of fibrillin from cultured fibroblasts has shown a substantial increase in fraying of microfibrils in patients with MFS. In neonatal MFS, electron microscopy of fibrillin strands reveals beads that are not strung together in the usual necklacelike pattern, resulting in poor elastic tissue strength.
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Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.
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Positive wrist (Walker) sign.
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Positive thumb (Steinberg) sign.
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Arachnodactyly.
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Pectus excavatum of moderate severity.
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Hypermobility of finger joints.
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Stretch marks (striae atrophicae) in the lower back.
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Dural ectasia in the lumbosacral region.
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Typical face seen in a girl with Marfan syndrome characterized by dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, and down-slanting palpebral fissures.
