Genetics of Marfan Syndrome Clinical Presentation

Updated: Jun 16, 2023
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
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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. [17]

In 2010, an international expert panel revised the Ghent-1 criteria to the Ghent-2 criteria. [18] 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. [19]

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

      Dural ectasia in the lumbosacral region. 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



Skeletal findings

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.

Adult with Marfan syndrome. Note tall and thin bui Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.
Arachnodactyly. 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. [20]

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.)

    Pectus excavatum of moderate severity. 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.)

  • Positive wrist (Walker) sign. Positive wrist (Walker) sign.
  • Positive thumb (Steinberg) sign. Positive thumb (Steinberg) sign.
  • 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. [21]  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. [22]  Local progressive protrusion can lead to early hip pain and osteoarthritis.

Minor criteria are as follows:

  • Pectus excavatum of moderate severity

  • Scoliosis less than 20°

  • Thoracic lordosis

  • Joint hypermobility (See the image below.)

    Hypermobility of finger joints. Hypermobility of finger joints.
  • High arched palate

  • Dental crowding

  • Facial phenotype - Dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, and down-slanting palpebral fissures

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.

A nationwide Danish study, by Kjeldsen et al, found that out of 407 persons with Marfan syndrome, 226 (56%) had at least one entry of an ophthalmologic diagnosis in Danish health-care registers (the hazard ratio [HR] being 8.0). [23]

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. [24]

  • 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:

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.)


    Stretch marks (striae atrophicae) in the lower bac 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. [25]  These symptoms are aggravated mainly in the supine position and are relieved by lying on the back. [26]
  • 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. [9]

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

  • FH - Family history

  • MASS - Myopia, mitral valve prolapse, borderline (Z< 2) aortic root dilatation, striae, skeletal findings phenotype

  • MFS - Marfan syndrome

  • MVPS - Mitral valve prolapse syndrome

  • Syst - Systemic score

  • Z - Z-score

According to the 2010 revised Ghent nosology (Ghent-2), the diagnosis of MFS depends on the following seven rules [18, 19] :

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 syndromeLoeys-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, TGF β R1/2, SMAD3,  TGF β 2, TGF β 3, 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, TGF β R1/2, SMAD3TGF β 2, TGF β 3, 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, TGF β R1/2, SMAD3, TGF β 2, TGF β 3, 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)

  • Pectus carinatum deformity - 2 (pectus excavatum or chest asymmetry - 1)

  • Hindfoot deformity - 2 (only pes planus - 1)

  • Pneumothorax - 2

  • Dural ectasia - 2

  • Protrusio acetabuli - 2

  • Reduced US/LS AND increased arm/height AND no severe scoliosis - 1

  • Scoliosis or thoracolumbar kyphosis - 1

  • Reduced elbow extension - 1

  • Facial features (3 out of 5; dolichocephaly, enophthalmos, down-slanting palpebral fissures, malar hypoplasia, retrognathia) - 1

  • Skin striae - 1

  • Myopia > 3 diopters - 1

  • Mitral valve prolapse (all types) - 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. [27] 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. [28]  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. [29]

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. [30] This case report has significant implications for genetic counseling and for interpretation of molecular diagnoses.