Marfan syndrome (MFS) is an inherited connective tissue disorder noteworthy for its worldwide distribution, relatively high prevalence, and clinical variability. This autosomal dominant syndrome has pleiotropic manifestations involving primarily the ocular, cardiovascular, and skeletal systems.[1, 2] Classic MFS (MFS type 1, MFS1) has been considered a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1; however, studies of Marfan mouse models and Marfan-related conditions have expanded our current understanding to a pathogenic model that involves dysregulation of cytokine-transforming growth factor beta (TGFβ) signaling.[3, 4] . Patients who have clinical findings of MFS, as well as genetic variants in the transforming growth factor-beta receptor-1 gene (TGFβR1) and the transforming growth factor-beta receptor-2 gene (TGFβR2), aredesignated as having MFS type 2 (MFS2).[5]
Marfan syndrome (MFS) results from heterozygous mutations in the fibrillin-1 gene (FBN1; OMIM #134797), located on chromosome 15 at band q21.1 (15q21.1), which encodes for the glycoprotein fibrillin. Fibrillin is a major building block of microfibrils, which constitute the structural components of the suspensory ligament of the ocular lens and serve as substrates for elastin in the aorta and other connective tissues. Abnormalities involving microfibrils weaken the aortic wall. Progressive aortic dilatation and eventual aortic dissection occur due to the tension caused by left ventricular ejection impulses. Likewise, deficient fibrillin deposition leads to reduced structural integrity of the lens zonules, ligaments, lung airways, and spinal dura.
Production of abnormal fibrillin-1 monomers from the mutated gene disrupts the multimerization of fibrillin-1 and prevents microfibril formation. This pathogenetic mechanism has been termed dominant-negative because the abnormal fibrillin-1 disrupts microfibril formation (although other fibrillin genes still encode normal fibrillin). Evidence of this mechanism is shown in studies of cultured skin fibroblasts from patients with MFS who produce greatly diminished and abnormal microfibrils.
A study by Benarroch et al suggested that clinical variability in MFS may result from alternative splicing of FBN1.[6]
FBN1 mutations cause several Marfan-like disorders, such as the MASS (myopia, mitral valve prolapse, borderline and nonprogressive aortic enlargement, nonspecific skin and skeletal findings) phenotype and isolated ectopia lentis.
Studies have suggested that abnormalities in the transforming growth factor-beta (TGFβ)-signaling pathway may represent a common pathway for the development of the Marfan phenotype.[7] This gene defect ultimately leads to decreased and disordered incorporation of fibrillin into the connective tissue matrix.
The identification of mutations in TGFβR2 in patients with MFS type 2 (MFS2 mapped at 3p24.2-p25) provided direct evidence of abnormal TGFβ signaling in the pathogenesis of MFS.
Abnormalities in TGFβR1 and TGFβR2 were also reported to cause a new dominant syndrome similar to MFS1; it was associated with aortic aneurysm and congenital anomalies, including Loeys-Dietz syndrome (LDS). LDS is an autosomal dominant aortic aneurysm syndrome with widespread systemic involvement (LDS; OMIM #609192).[7] These results define a new group of Marfan syndrome–related connective tissue disorders, namely, TGFβ signalopathies, and include LDS1 and LDS2 (TGFβR1 and TGFβR2) and the SMAD3 and TGFβ2 disorders, with the latter two being classified as Loeys-Dietz-like (or as LDS3 and LDS4).
Shprintzen-Goldberg syndrome (SGS) has been found to be caused by a pathogenic variant in the SKI gene, which encodes a negative regulator of TGFβ signaling. There is phenotypic overlap with MFS and LDS.
A variant of the fibrillin-2 gene, FBN2, causes congenital contractural arachnodactyly, known as Beals syndrome.[8]
MFS is one of the most common single-gene malformation syndromes. MFS1 affects about 1:5000 to 1:10,000 individuals.[9, 10] Estimates suggest that at least 200,000 people in the United States have MFS or a related connective-tissue disorder.
A study by Behr et al found that in patients presenting with a chief complaint of pectus deformity, the incidence of MFS was 5.3%, with the incidence being 20% in persons with combined type pectus deformity.[11]
International
No geographic predilection is known.
Mortality/Morbidity
Cardiovascular disease (aortic dilatation and dissection) is the major cause of morbidity and mortality in MFS. Without proper medical management, MFS can be lethal in young adulthood, with death occurring at an average age of 30-40 years.
Infant morbidity, as related to cardiovascular disease, is due to progression of mitral valve prolapse to mitral regurgitation and often occurs in conjunction with tricuspid prolapse and regurgitation. Progression to congestive heart failure is a leading cause of cardiovascular morbidity and mortality, as well as the leading indicator for cardiovascular surgery.
Death later in life is usually due to chronic aortic regurgitation and ascending aortic dissection. Dissection generally occurs at the aortic root and is uncommon in childhood and adolescence.
A Norwegian study, by Vanem et al, found that out of 84 adults with Marfan syndrome (MFS) first investigated in 2003-2004, 16 (19.0%) were deceased by 2014-2015 follow-up, including 11 (68.8%) who had died of cardiovascular causes. Standardized mortality ratios were 8.20 for men and 3.85 for women.[12]
Race
Marfan syndrome is panethnic.
Sex
No sex predilection is known.
Age
MFS may be diagnosed prenatally, at birth, in childhood, during adolescence, or in adulthood. Neonatal presentation is associated with a severe clinical course.
Many clinical features are specific to age. Some features may not present until later in life, a situation that may make early diagnosis in childhood difficult.
Classic Marfan syndrome (MFS1) is currently diagnosed using a criteria-based approach that includes an evaluation of family history, molecular data, and six organ systems. Diagnosis cannot be based on molecular analysis alone because molecular diagnosis is not generally available, mutation detection is imperfect, and not all FBN1 mutations are associated with MFS. As cited by the 1988 Berlin criteria, MFS was diagnosed on the basis of involvement of the skeletal system and two other systems, with the requirement of at least one major manifestation (ie, ectopia lentis, aortic dilatation or dissection, or dural ectasia).
In 1996, a group of the world's leading clinicians in MFS proposed a revised diagnostic criteria. The Ghent-1 criteria were intended to serve as an international standard for clinical and molecular studies and for investigations of genetic heterogeneity and genotype-phenotype correlations. The Ghent nosology identified major and minor diagnostic findings, which were based on clinical observation of various organ systems and on family history. A major criterion was defined as one that carried high diagnostic precision, because it was relatively infrequent in other conditions and in the general population. Clinical diagnosis in adults should be made using the Ghent criteria, which are considered not as reliable in children.
Further revision of the nosology was necessary, however, because, while the Berlin criteria did not provide for molecular studies and may have led to incorrect diagnoses in relatives of the proband, the Ghent-1 criteria may have been too stringent and hence have excluded MFS in affected patients. For example, 19% of patients whose disease was diagnosed based on the Berlin criteria did not meet the Ghent-1 criteria. Of those patients who were screened for dural ectasia, 23% were diagnosed with MFS by the Berlin criteria; however, these patients were not diagnosed with MFS when the Ghent-1 criteria were applied.[13]
In 2010, an international expert panel revised the Ghent-1 criteria to the Ghent-2 criteria.[14] Ghent-2 gave greater weight to cardiovascular manifestations (aortic aneurysm/dissection) and to molecular testing of the FBN1 gene, as well as other relevant genes, such as TGFβR1/2, COL3A1, and ACTA2. This new scoring system was designed to address systemic features. In the absence of family history, the presence of aortic root aneurysm and ectopia lentis is sufficient for the unequivocal diagnosis of MFS1. In the absence of either aortic aneurysm or ectopia lentis, the presence of an FBN1 mutation or a combination of systemic manifestations is required.
Application of the Ghent-2 criteria should help and support clinicians who are less knowledgeable of the Marfan phenotype. Indeed, even if the diagnosis of MFS is not reached, regular aortic follow-up is mandatory in every patient with a diagnosis of ectopia lentis syndrome, MASS, or mitral valve prolapse syndrome. Longitudinal studies of patient follow-up with such alternative diagnoses are required to determine the proportion of patients who will meet the criteria for MFS in later life.[15]
Family history and results of molecular studies are part of the major criteria; hence the need to carefully obtain a complete family history and pedigree. Major criteria include the following:
A first-degree relative (parent, child, or sibling) who independently meets the diagnostic criteria.
Presence of an FBN1 mutation known to cause MFS.
Inheritance of an FBN1 haplotype known to be associated with unequivocally diagnosed MFS in the patient's family.
In family members, major involvement in one organ system and involvement in a second organ system.
If the family and genetic histories are noncontributory, major criteria in two different organ systems and involvement of a third organ system are required to make the diagnosis (organ system criteria are described in the Physical section).
Clinical presentations are as follows:
Delayed achievement of gross and fine motor milestones due to ligamentous laxity of the hips, knees, ankles, plantar arches, wrists, and fingers
A decrescendo diastolic murmur from aortic regurgitation
An ejection click at the apex followed by a holosystolic high-pitched murmur due to mitral prolapse and regurgitation
Dysrhythmia (a primary feature)
Abrupt onset of thoracic pain, which occurs in more than 90% of patients with aortic dissection
Other signs of aortic dissection are syncope, shock, pallor, pulselessness, and paresthesia or paralysis in the extremities.
Acute onset of hypotension may indicate aortic rupture.
Low back pain near the tailbone, burning sensation and numbness or weakness in the legs in severe dural ectasia.
Dural ectasia may cause headaches and neurologic deficits.
Dural ectasia is shown in the magnetic resonance imaging (MRI) scan below.
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Dural ectasia in the lumbosacral region.
Joint pain in older patients
Dyspnea, severe palpitations, and substernal pain in significant pectus excavatum
Breathlessness, often associated with chest pain, in spontaneous pneumothorax
Visual problems, such as vision impairment due to lens dislocation or retinal detachment.
Common refractory errors are myopia and amblyopia.
Patients with Marfan syndrome (MFS) are usually taller and thinner than their family members. Their limbs are disproportionately long when compared with the trunk (dolichostenomelia). Arachnodactyly ("spider fingers," abnormally long and slender fingers) is a common feature. See the images below for examples.
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Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.
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Arachnodactyly.
Although most patients are diagnosed before the age of 10 years, few present with the four skeletal criteria, which tend to develop in later life.[16]
Major skeletal criteria include the following:
Pectus excavatum (sunken or funnel chest) or pectus carinatum (keel-shaped or pigeon chest) that requires corrective surgery or intervention (See the image below.)
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Pectus excavatum of moderate severity.
Reduced upper-to-lower body segment ratio (0.85 vs 0.93) or arm span–to-height ratio greater than 1.05 - Arms and legs may be unusually long in proportion to the torso.
Positive wrist (Walker) and thumb (Steinberg) signs - Two simple maneuvers help demonstrate arachnodactyly. A positive wrist sign is identified if, when encircling the opposite wrist, the distal phalanges of the first and fifth digits of one hand overlap. A positive thumb sign is identified if the thumb extends past the ulnar border when completely opposed within the clenched hand. (See the images below.)
Scoliosis greater than 20° - More than 60% of patients have scoliosis. Progression is more likely with a curvature of more than 20° in growing patients (prior to puberty).
Reduced elbow extension (< 170°)
Medial displacement of the medial malleolus, resulting in pes planus (fallen arches or flat feet) - Pes planus is best diagnosed by examining the foot from the back side of the patient. A valgus deviation of the hindfoot indicates pes planus.
Protrusio acetabuli of any degree - This is a deformity of the hip joint in which the medial wall of the acetabulum invades the pelvic cavity with associated medial displacement of the femoral head. Radiography is used to diagnose protrusio acetabuli. Protrusio acetabuli affects 31-100% of patients with MFS to varying degrees.[17] Clinical manifestations are hip joint stiffness and progressive limitation in activity as related to joint pain, a waddling gait, limited range of motion, flexion contracture, a pelvic tilt with a resulting hyperlordosis of the lumbar spine, and eventually osteoarthritic changes.[18] Local progressive protrusion can lead to early hip pain and osteoarthritis.
For the skeletal system to be involved, at least two major criteria or one major criterion plus two minor criteria must be present.
Ocular findings
The major criterion for the ocular system is ectopia lentis (the dislocation or displacement of the eye's natural crystalline lens). About 50% of patients have lens dislocation, with the dislocation position described as superior and temporal. Ectopia lentis may be present at birth or develop in childhood or adolescence.
Minor criteria for the ocular system are as follows:
Flat cornea (as measured by keratometry)
Increased axial length of the globe (as measured by ultrasonography)
Cataract, described as nuclear sclerotic (patients < 50 y)
Hypoplastic iris or hypoplastic ciliary muscle that causes decreased miosis
Nearsightedness (myopia), regardless of whether or not the lens is properly positioned - Myopia is the most common refraction error and is due to an elongated globe and amblyopia ("lazy eye").
Glaucoma (patients < 50 y)
Retinal detachment
At least 2 minor criteria must be present.
Cardiovascular findings
Cardiovascular involvement is the most serious problem associated with MFS.
Major criteria include the following:
Aortic root dilatation at the level of the sinuses of Valsalva - The prevalence of aortic dilatation in MFS is 70-80%. It manifests at an early age and tends to be more common in men than women. A diastolic murmur over the aortic valve may be present.[19]
Aortic dissections that involve the ascending aorta
Minor criteria are listed as follows:
Mitral valve prolapse (MVP) occurs in 55-69% of patients with MFS. Midsystolic clicks may be followed by a high-pitched late-systolic murmur. In severe cases of MVP, a holosystolic murmur is auscultated.
Dilatation of proximal main pulmonary artery, in the absence of peripheral pulmonic stenosis or another understood cause
Calcification of mitral annulus (patients < 40 y)
Dilatation of abdominal or descending thoracic aorta (patients < 50 y)
For the cardiovascular system to be involved, one minor criterion must be present.
Pulmonary findings
For the pulmonary system, only minor criteria are noted. If there is pulmonary system involvement, one minor criterion must be present.
Minor criteria include the following:
Spontaneous pneumothorax (seen in about 5% of patients)
Apical blebs on chest radiography
Integumentary findings
For integument system, only minor criteria are noted. If there is integument system involvement, one minor criterion must be present.
Minor criteria include the following:
Striae atrophicae (stretch marks) in the absence of marked weight changes, pregnancy, or repetitive dermatologic stress - Stretch marks are usually found on the shoulder, midback, and thighs. (See the image below.)
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Stretch marks (striae atrophicae) in the lower back.
Recurrent hernia or an incisional hernia (hernia due to an incompletely healed surgical wound)
Dural findings
For the dura, only one major criterion is defined: Dural ectasia must be present and confirmed using computed tomography (CT) scanning or MRI modalities. The characteristics of dural ectasia are as follows:
Dural ectasia is defined as a ballooning or widening of the dural sac, often associated with herniation of the nerve root sleeves out of the associated foramina.
Dural ectasia occurs most often in the region of the lumbosacral spine.
Dural ectasia is a common feature in patients with MFS, with an estimated prevalence of 65-92%.
Common clinical symptoms are low back pain, headache, weakness, loss of sensation above and below the affected limb, and occasional rectal pain and/or pain in the genital area.[20] These symptoms are aggravated mainly in the supine position and are relieved by lying on the back.[21]
Severity appears to increase with age, hence supporting the hypothesis that a weakened dural sac expands from the cumulative effect of increased intrathecal pressure at the spine base from upright posture. Less than 20% of patients with MFS are diagnosed with serious dural ectasia.
Dural ectasia is also associated with conditions such as Ehlers-Danlos syndrome, neurofibromatosis type 1, ankylosing spondylitis, trauma, scoliosis, and tumors.
Key issues in the assessment of Marfan syndrome
Diagnosis or exclusion of MFS in an individual should be based on the Ghent-2 diagnostic nosology.[22]
Initial assessment should include a personal history, detailed family history, clinical examination and, specifically, an ophthalmologic examination and a transthoracic echocardiogram. For echocardiographic interpretation, the aortic diameter at the sinus of Valsalva should be related to normal values as based on age and body surface area.
The development of scoliosis and protrusio acetabuli is dependent on age, commonly occurring after periods of rapid growth. Radiography is indicated for these features, depending on age. A positive finding aids confirmation of the diagnosis of MFS.
A pelvic MRI scan to detect dural ectasia is indicated. A positive finding would confirm the diagnosis of MFS.
The Ghent-2 nosology cannot exclude MFS in children, because of the age-dependent penetrance of many clinical features. Young patients with a positive family history but with unsuccessful DNA testing and insufficient clinical features to fulfill the diagnostic criteria, and young patients with no family history who miss fulfilling the diagnostic criteria by one system, should have further clinical evaluations up to least age 18 years or until a diagnosis can be made.
Family history of aortic aneurysm may represent a disorder, such as familial thoracic aortic aneurysm, such that the use of the Ghent-2 nosology to assess risk in relatives is inappropriate.
Revised Ghent criteria (Ghent-2) for the diagnosis of MFS and related conditions
Abbreviations are as follows:
Ao - Aortic diameter at the sinuses of Valsalva above indicated Z-score or aortic root dissection
EL - Ectopia lentis
ELS - Ectopia lentis syndrome
FBN1 - Fibrillin-1 mutation
FBN1 not known with Ao - FBN1 mutation that has not previously been associated aortic root aneurysm/dissection
FBN1 with known Ao - FBN1 mutation that has been identified in an individual with aortic aneurysm
According to the 2010 revised Ghent nosology (Ghent-2), the diagnosis of MFS depends on the following seven rules[14, 15] :
In the absence of family history:
Aortic root dilatation Z score ≥ 2 and EL = MFS (Ao [Z ≥ 2] and EL = MFS). The diagnosis of MFS is confirmed when the patient demonstrates aortic root dilatation (Z ≥ 2 when standardized to age and body size) or dissection and ectopia lentis, regardless of whether or not systemic features exist (except in cases in which systemic features indicate the presence of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome).
Aortic root dilatation Z score ≥ 2 and FBN1 = MFS (Ao [Z ≥ 2] and FBN1 = MFS). Even in the absence of ectopia lentis, the diagnosis of MFS can be confirmed by aortic root dilatation (Z ≥ 2) or dissection and the identification of a bona fide FBN1 mutation.
Aortic root dilatation Z score ≥ 2 and systemic score ≥ 7pts = MFS (Ao [Z ≥ 2] and Syst (≥7 points) = MFS. Sufficient systemic findings can confirm the diagnosis of MFS when aortic root dilatation (Z ≥ 2) or dissection is present but ectopia lentis is not and the FBN1 status is either unknown or negative (≥ 7 points, according to a scoring system). However, it is necessary to exclude findings indicative of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome; also, appropriate alternative genetic testing (eg, TGFβR1/2, SMAD3, TGFβ2, TGFβ3, collagen biochemistry, COL3A1) should be carried out.
EL and FBN1 with known aortic root dilatation = MFS (EL and FBN1 with known Ao = MFS). If ectopia lentis is present but aortic root dilatation/dissection is not, the diagnosis of MFS can only be confirmed by the identification of an aortic disease–associated FBN1 mutation.
In the presence of family history (FH):
EL and FH of MFS = MFS (EL and FH of MFS = MFS). MFS can be diagnosed based on the presence of ectopia lentis and a family history of MFS.
A systemic score ≥ 7 points and FH of MFS = MFS (Syst [≥7 points] and FH of MFS = MFS). MFS can be diagnosed based on a systemic score of greater than or equal to 7 points and a family history of MFS. However, it is necessary to exclude findings indicative of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome; also, appropriate alternative genetic testing (eg, TGFβR1/2, SMAD3, TGFβ2, TGFβ3, collagen biochemistry, COL3A1) should be carried out.
Aortic root dilatation (Z score ≥ 2 above age 20 y, ≥ 3 below age 20 y) + FH of MFS = MFS (Ao [Z ≥ 2 above age 20 y, ≥3 below age 20 y] + FH of MFS = MFS). MFS can be diagnosed based on the presence of aortic root dilatation (Z ≥ 2 above age 20 y, ≥ 3 below age 20 y) and a family history of MFS. However, it is necessary to exclude findings indicative of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome; also, appropriate alternative genetic testing (eg, TGFβR1/2, SMAD3, TGFβ2, TGFβ3, collagen biochemistry, COL3A1) should be carried out.
Systemic score list (maximum total = 20 points; score ≥7 indicates systemic involvement)
Wrist (Walker) AND thumb (Steinberg) sign - 3 (wrist OR thumb sign - 1)
Marfan syndrome (MFS) is caused by mutations in the FBN1 gene located on chromosome 15 at band q21.1. Mutations in TGFβR1 or TGFβR2 genes, located on chromosome 9q22.33 and on chromosome 3p24.2-p25, respectively, are typically associated with Loeys-Dietz syndrome, and there is marked phenotypic overlap with MFS. If the patient has ectopia lentis (dislocation of the lens), this is a more specific finding to MFS versus the other syndromes.
More than 500 fibrillin gene mutations have been identified. Almost all of these mutations are unique to an affected individual or family. Different fibrillin mutations are responsible for genetic heterogeneity. Phenotypic variability in the presence of the same fibrillin mutation suggests the importance of other, yet-to-be-identified factors that affect the phenotype.
Despite intensive international efforts, genotype-phenotype correlations have not been made, with the exception of an apparent clustering of mutations in patients diagnosed with neonatal MFS. Neonatal MFS represents the most severe end of the clinical spectrum of the fibrillinopathies and is associated with FBN1 gene mutation on chromosome 15q21.1 in exons 24–32.[23] Affected individuals are generally diagnosed at birth or shortly thereafter. Unique features include joint contractures, "crumpled" external ears, and loose skin. Congestive heart failure associated with mitral and tricuspid regurgitation is the main cause of death. Aortic dissection is uncommon in neonatal MFS, and survival beyond 24 months is rare.[24] A study by Ágg et al suggests that for patients with MFS, there are extracardiac predictors of aortic dissection: elevated TGFβ, increased matrix metalloproteinase 3 (MMP3) gene expression in peripheral blood mononuclear cells, and a greater frequency of striae atrophicae.[25]
Genotype-phenotype correlations in MFS have been complicated by the large number of unique mutations reported, as well as by the degree of clinical heterogeneity among individuals with the same mutation.
Mutations in the FBN1 gene have also been found in patients with other fibrillinopathies. Identifying a given mutation is currently of limited value in establishing a phenotype or providing a prognosis in MFS.
MFS is known as an autosomal dominant connective tissue disorder. However, a family was reported to have homozygosity for an FBN1 missense mutation and demonstrated molecular evidence for recessive MFS.[26] This case report has significant implications for genetic counseling and for interpretation of molecular diagnoses.
Currently, the standard of care in Marfan syndrome (MFS) is to obtain confirmatory molecular diagnostics on these patients 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.[38]
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.[39, 40] 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.[41] 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.
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:
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
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
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.
Ocular care and treatment should be managed by an ophthalmologist with expertise in Marfan syndrome (MFS). Examination should include the following:
Slit lamp examination - Pupils should be dilated and checked for lens subluxation and retinal tears.
Refraction and visual correction - It is important to assess young patients for myopia and amblyopia.
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.
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.
General guidelines for all adults diagnosed with Marfan syndrome (MFS) are as follows[10, 42] :
Restriction of physical activity with avoidance of contact sports, isometric exercise, and activities that can cause joint injury/pain
Avoidance of agents that stimulate the cardiovascular system, such as decongestants and caffeine
Annual ophthalmological examination - LASIK correction of refractive errors is not recommended.
Subacute endocarditis prophylaxis for dental work in the presence of mitral or aortic valve regurgitation
Annual echocardiography to evaluate the ascending aorta in cases of small aortic dimensions and/or a slow aortic dilatation rate - Echocardiography is required with greater frequency when aortic root diameter is over 4.5 cm in adults, if aortic dilatation is greater than 0.5 cm per year, and if significant aortic regurgitation is present.
Beta-blocking treatment to reduce hemodynamic stress on the aortic wall
Key issues in cardiovascular management are as follows [22] :
Beta-blocker therapy should be considered at any age if the aorta is dilated, but prophylactic treatment may be more effective in those patients with an aortic diameter of less than 4 cm.
Risk factors for aortic dissection include an aortic diameter of over 5 cm, aortic dilatation extending beyond the sinus of Valsalva, rapid rate of dilatation (an increase of 45% per year, or 1.5 mm per year in adults), and a family history of aortic dissection.
Annual cardiovascular evaluation should be offered and should include clinical history, examination, and echocardiography.
In children, serial echocardiography at 6- to 12-month intervals is recommended, with the frequency dependent on the aortic diameter (in relation to body surface area) and rate of aortic dilatation.
Prophylactic aortic root surgery should be considered when the aortic diameter at the sinus of Valsalva is over 5 cm.
Counseling for pregnant women diagnosed with MFS is as follows[42] :
MFS is a genetic disorder historically known to be inherited in an autosomal dominant fashion. About 75% of patients with MFS have an affected parent. In this situation, there is a 50% chance to pass the mutation to offspring. About 25% of patients will have MFS due to a de novo event.
Multidisciplinary approach to care is recommended.
Pregnancy is considered high-risk and should be monitored throughout by a high-risk obstetrician and with continued monitoring into the immediate postpartum period.
Concurrent and ongoing cardiovascular care - Aortic root diameter of over 40 mm, previous cardiovascular surgery, or severe heart disease is a source of concern. Consider prepartum aortic root replacement with a diameter of more than 40 mm. Serial echocardiography is recommended until 3 months postpartum.
The importance of beta blockers in medical management is as follows:
Beta-adrenergic receptor antagonists have gained acceptance as potential agents for delaying aortic expansion and for delaying progression to aortic rupture or dissection. The optimal age to initiate beta-blocker therapy has not been determined. Some practitioners begin therapy in infancy, but others wait until the aortic diameter exceeds the 95th percentile or a rapid rate of aortic dilatation is observed. Beta-blocker therapy retards aortic growth in children and adolescents with MFS. The optimal dose of beta blockers to minimize dilatation of the aortic root has not been established. The need for cardiovascular surgical intervention has substantially declined since the start of beta-blocker use.
A study concluded that data are not sufficient to recommend or discourage the use of beta blockers in children with congestive heart failure.[43]
Calcium antagonist therapy also retards aortic growth, but a recommended dose has not been established.
In asymptomatic patients, the elastic properties of the aortic root appear to have a heterogeneous response after long-term treatment with the beta blocker atenolol.
The stiffness index and distensibility are most likely to be useful when the baseline end-diastolic aortic root diameter is over 40 mm.
The importance of angiotensin-converting enzyme (ACE) inhibitors in medical management is as follows[44, 45] :
ACE inhibitors reduce central arterial pressure and conduit arterial stiffness and may be useful in MFS. This approach received support by a short-term, nonrandomized study comparing enalapril with beta blockade in which stiffness and rate of dilatation improved with ACE inhibitors.[46]
Another study of patients with MFS maintained on beta blockade examined the impact of adding an ACE inhibitor, perindopril, when compared with placebo. Over a 24-week period, those receiving the ACE inhibitor had a reduction in aortic stiffness and less absolute change in aortic root dimensions.[47]
The importance of matrix metalloproteinases (MMPs) in medical management is as follows[45, 47] :
Syndromes that resemble MFS, especially with regard to the potential for aortic aneurysm and dissection, were found to be due to mutations in genes encoding TGFβ receptors.[31]
The potential importance of MMPs was investigated in studies of non-MFS abdominal aortic aneurysm in humans and thoracic aortic aneurysm in mice engineered to have MFS. In both case situations, the levels of MMP-2 and MMP-9 were raised.[48, 49]
Long-term treatment with doxycycline in a mouse model of MFS suppressed MMPs (MMP-2 and -9) and improved aortic wall architecture and stiffness. When compared with atenolol, doxycycline was more efficacious in preventing thoracic aortic aneurysm (TAA) in the MFS model, through preservation of elastic fiber integrity, normalization of vasomotor function, and reduction in TGFβ activation.[48]
Other therapeutic interventions are as follows:
Anticoagulant medications, such as warfarin, are needed after artificial heart valve placement.
Intravenous antibiotic therapy is required during cardiac and noncardiac procedures to prevent bacterial endocarditis.
Progesterone and estrogen therapy have been used to induce puberty and reduce the patient's ultimate height if hormonal treatment is begun before puberty. No conclusive data are yet available to show whether this therapy reduces the degree of scoliosis.
Conservative treatment of protrusio acetabuli mostly involves physiotherapy by forcible stretching (stress fractures of the femoral neck due to stretching can occur),[50] weight extension on an abduction frame, local heating, and reeducation concerning daily activities.[18]
Myopia is treatable with refraction correction.
Patients with flat feet may wear shoes with adequate arch support, although custom orthotics may be required. Guidelines for the diagnosis and treatment of pediatric flatfoot have been established.[51]
Psychological counseling is helpful for families coping with feelings of denial, anger, blame, depression, or guilt.
Future therapeutic strategies are as follows[4] :
An angiotensin-II receptor blocker (ARB) regimen is now recommended as first-line treatment and should be emphasized. Some cardiologists who specialize in MFS also continue their patients on beta blockers to cover both arms of the pathway. However, no studies have been published as yet to officially recommend this approach.
The current criterion standard for treatment of aortic aneurysm in MFS is the preventive administration of beta blockers. However, beta blockers do not prevent surgery at a later age.
The discovery that TGFβ antagonism can rescue aortic aneurysm in C1039G/+ mice prompted the idea to test the efficacy of losartan, a widely used angiotensin-II type I receptor (AT1) antagonist, because of its antihypertensive properties and ability to counteract TGFβ in animal models of chronic renal disease and cardiomyopathy.
Thus, TGFβ antagonism is a general strategy against aneurysm progression in patients with MFS and other disorders of the TGFβ-signaling network.
Proof of the above principle was obtained by treating Marfan mice with TGFβ- neutralizing antibody by intraperitoneal injection.[52]
In a preliminary observational study, 17 pediatric MFS patients with progressive aortic enlargement despite optimal medical therapy were given an angiotensin receptor blocker agent and were followed for 12-42 months. Patients had a significant decrease in rate of change of aortic root dimension. This study provided the first evidence for a significant benefit of angiotensin receptor blocker use over current therapies in reducing aortic root dilatation in patients with severe pediatric MFS.[53]
Study results by Pees et al have added insight regarding the beneficial effect of losartan as monotherapy, even in mild to moderate cases, as confirmed by the reported results in severely affected children and adolescents.[54]
A large randomized clinical trial of MFS patients compared the use of atenolol to losartan in a 3-year treatment plan. The study, which included a total of 608 patients, found that the rate of aortic root dilatation did not significantly differ between the two treatment groups, ie, children and young adults with MFS who were randomly divided between losartan and atenolol therapy.[55]
Genetic counseling points for patients and their families include the following[56] :
If neither biological parent is affected, recurrence risk for the patient's siblings is small, although gonadal mosaicism has been reported as the cause of multiple affected offspring being born to unaffected parents. Risk is 50%, if one parent is affected.
Recurrence risk for the patient's offspring is 50% if the spouse is normal. Homozygous MFS was reported in a case of an affected spouse. Compound heterozygosity at the FBN1 locus was confirmed at the molecular level; the child was severely affected and died early in life.
During counseling, the variability of MFS should be emphasized because an affected child may be more or less affected than the affected parent.
Indicators for prophylactic surgery of the aortic root in adults (at least one criterion is needed) include the following[42] :
Aortic root diameter of more than 55 mm or aortic root diameter of greater than 50 mm (45-50 mm according to some authors) in patients with high risk for aortic complications
Family history of aortic dissection
Growth of the aortic root by over 10 mm per year
Dilatation of the aortic sinus involving the ascending aorta
More than mild aortic regurgitation
Severe mitral regurgitation
Before major noncardiovascular surgery
Women planning pregnancy
Aortic ratio of over 1.5.
Diameter ratio of the aortic root to the descending aorta of more than 2.
Indicators for prophylactic surgery of the aortic root in children include the following[42] :
Aortic root diameters with similar thresholds as adult patients.
Aortic root diameters outside the upper confidence interval that increase in percentile on follow-up echocardiograms.
If possible, however, surgery should be delayed until adolescence.
Cardiovascular surgery
Cardiovascular surgery can substantially prolong survival. Prophylactic and emergency cardiovascular surgery is needed for treatment of aortic and mitral regurgitation, aortic aneurysm, and aortic dissection. Emergency surgical replacement of the aortic root is indicated for survivors of acute proximal aortic dissection.
The ascending aorta is usually replaced when the aorta exceeds 55-60 mm in diameter. Composite valve-graft replacement is performed, in which the dilated aortic segment is replaced by a prosthetic valve sewn into a tube graft with reimplantation of the coronary ostia (modified Bentall procedure). Composite valve-graft replacement of the aortic root has low rates of morbidity and mortality, produces excellent long-term results, and is currently the treatment of choice for proximal dissection or clinically significant annuloaortic ectasia in patients with Marfan syndrome (MFS).
An aortic valve–sparing procedure is evolving for patients with an aortic aneurysm and favorable characteristics of the aortic valve and annulus. The advantages of this procedure include the avoidance of anticoagulation and a lowered risk of thromboembolism and endocarditis. The aortic valve–sparing procedure is still controversial because of concerns that it poses a risk of progressive valvular degeneration and annular dilation. Additional long-term data are required before routine use of this procedure can be recommended.
Scoliosis surgery
Severe scoliosis requires surgery. Bracing has a limited role in treating the most severe form of infantile scoliosis. Surgery should not be performed on a child younger than 4 years, because many patients with large curves before this age spontaneously die of cardiac complications. Results of spinal fusion are better in children older than 5 years.
Indications for surgery in adults include pain, neurologic signs, and thoracic curves greater than 45°, which can cause restrictive lung disease.
Protrusio acetabuli surgery
This is directed at arresting progression, relieving pain, and restoring hip function through hip replacement with bone grafting of the medial acetabular cavity in older patients and closure of the triradiate cartilage in a child or adolescent.[18]
Pectus excavatum repair
The shape of the front of the thorax becomes stable and established by midadolescence. Repair of pectus excavatum to improve respiratory mechanics should be delayed until then, to lessen recurrence risk. Pectus carinatum repair is mainly performed for cosmetic reasons
Pneumothorax therapy
A chest tube is an appropriate initial therapy. After one recurrence, a more aggressive approach involving bleb resection and pleurodesis is recommended.
Ocular therapy
Lasers can be used to restore a detached retina. The risk of retinal detachment related to lens extraction is increased; the lens is removed only in the following few instances:
Dislocation of a lens in the anterior chamber, especially when it touches the corneal endothelium
Significant lens opacity
Evidence of lens-induced uveitis and glaucoma
Inadequate visual acuity that is not correctable by refraction and iris manipulation
Patients with Marfan syndrome (MFS) can remain fully active unless they are limited by their symptoms. Patients should be discouraged from participating in demanding sports, because several highly trained athletes with undiagnosed MFS have died suddenly from ruptured aortic aneurysms.
Competitive and contact sports are potentially dangerous because of underlying aortic weakness and dilatation, valvular insufficiency, ocular abnormalities, and skeletal problems. Patients should avoid blows to the head (eg, in boxing or high diving) and should protect themselves against blows to the globe (in racquet sports) by wearing cushioned spectacles.
To protect against pneumothorax, patients should avoid the rapid decompression associated with quick ascents in elevators, scuba diving, and flying in unpressurized aircraft. Playing an instrument that requires breathing against resistance, such as a brass instrument, is not recommended.
Patients should avoid activities involving isometric work such as weightlifting, climbing steep inclines, gymnastics, and performing pull-ups. These exercises cause excessive elevations of systolic blood pressure and can lead to sudden death.
Nonstrenuous activities and sports (eg, golf, walking, fishing) are recommended. Appropriate exercise is physically and emotionally beneficial.
Beta-blocker and calcium antagonist therapy retard the aortic growth rate in children and adolescents with Marfan syndrome (MFS). Atenolol is a beta blocker that is longer acting and more cardioselective than others; it has largely replaced propranolol as the beta blocker of choice. Experience with calcium antagonists is limited.
An ARB regimen is now recommended as first-line treatment and should be emphasized. Some cardiologists who specialize in MFS also have their patients on beta blockers, to cover both arms of the pathway.
These drugs are used to delay aortic expansion and its subsequent progression to dissection or rupture. They inhibit chronotropic, inotropic, and vasodilatory responses to beta-adrenergic stimulation.
Ensure long-term cardiac follow-up, including regular blood pressure measurements and echocardiography. Patients also need lifelong cardiovascular surveillance to detect new or recurrent disease. After aortic surgery, follow-up is necessary to monitor for the possible development of lesions involving different segments and for pseudoaneurysms at the anastomosis site, which cause nearly 40% of late deaths postoperatively.
Provide care for postoperative complications in patients with Marfan syndrome (MFS), including dysrhythmias, thromboembolism, endocarditis, coronary dehiscence, congestive heart failure, renal failure, and respiratory failure. Observe the patient for postoperative hemorrhage and pseudoaneurysm formation.
Patients should avoid strenuous activities and sports, such as basketball, volleyball, football, racquetball, squash, boxing, track, diving, and weightlifting.
Patients should wear eye protection to guard their eyes from injury during work and sports.
In general, athletes should be referred to a cardiologist if physical evidence of Marfan syndrome (MFS) is noted.[57] The following studies are indicated:
Complications that affect the aorta are the primary cause of death in Marfan syndrome (MFS). Aortic dissection can result in lethal hemorrhage, acute aortic valvular insufficiency, mitral insufficiency, pericardial tamponade, or visceral ischemia.
Complications can also include the following:
Mitral valve prolapse - May cause clinically significant mitral regurgitation, the most common cause of death in children with MFS
Bacterial endocarditis - Commonly occurs after procedures and surgeries
Severe pectus excavatum - Can compromise cardiac and pulmonary function
The patient's prognosis depends on the severity of cardiovascular complications and is mainly determined by progressive dilation of the aorta, which potentially leads to aortic dissection and death at a young age.
In the 1970s, the average life expectancy for a patient with MFS was 45 years old. Life expectancy has since increased to about 70 years.[58] Awareness, early and improved detection skills, timely and improved surgical techniques, and the prophylactic use of beta blockers have all contributed to increased survival.
Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Lois J Starr, MD, FAAP, Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Maria Descartes, MD, Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Harold Chen, MD, MS, FAAP, FACMG, Professor, Department of Pediatrics, Louisiana State University Medical Center
Disclosure: Nothing to disclose.
James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago
Lee B, Godfrey M, Vitale E, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature. 1991. 352:337-339.
Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.
Arachnodactyly.
Pectus excavatum of moderate severity.
Positive wrist (Walker) sign.
Positive thumb (Steinberg) sign.
Hypermobility of finger joints.
Stretch marks (striae atrophicae) in the lower back.
Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.
Positive wrist (Walker) sign.
Positive thumb (Steinberg) sign.
Arachnodactyly.
Pectus excavatum of moderate severity.
Hypermobility of finger joints.
Stretch marks (striae atrophicae) in the lower back.
Dural ectasia in the lumbosacral region.
Typical face seen in a girl with Marfan syndrome characterized by dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, and down-slanting palpebral fissures.
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