Marfan Syndrome– Causes, Symptoms, Diagnosis, Treatment and Ongoing care



  • Marfan syndrome (MFS) is an inherited disorder of connective tissue.
  • System(s) affected: Musculoskeletal; Cardiovascular; Ocular; Pulmonary; Skin/Integument; Connective Tissue (Dura)
  • Because many features of MFS appear in the general population, specific diagnostic criteria (Ghent nosology) were established, recognizing a constellation of features, with major and minor criteria for establishing the diagnosis (1).
  • The nosology was revised (23) because the previous criteria were not sufficiently validated, were not consistently applicable in children, or necessitated expensive and specialized tests.

Pediatric Considerations

Early surgical intervention may reduce the degree of scoliosis.

Pregnancy Considerations

  • Manage pregnancy in MFS as high-risk, preferably with a cardiologist. Pre-pregnancy evaluation should include a screening transthoracic echocardiogram for aortic root dilation.
  • Beta-blockers should be considered in all pregnancies to minimize the risk of aortic dilation throughout the pregnancy.
  • 1% complication rate if aortic root diameter <40 mm; 10% if >40 mm. Consider elective surgery before pregnancy if >47 mm.


  • Congenital. Although clinical manifestations may be apparent in infancy, affected individuals may not present until adolescence or young adulthood.
  • No gender, ethnic, or racial predilection. With advanced paternal age, a slightly increased risk of de novo mutation resulting in MFS in offspring.



Risk Factors


  • Mutations of the fibrillin-1 (FBN1) gene on chromosome 15q21.1 are responsible for Marfan syndrome, OMIM #154700.
  • MFS is an autosomal-dominant condition with complete penetrance and variable expressivity. Apparent nonpenetrance may be due to lack of recognition of MFS in a mildly affected individual.
  • Each child of an affected parent has a 50% chance of inheriting the disorder, and may be more or less severely affected. 25% of cases result from de novo mutation.

General Prevention

  • Prenatal diagnosis is possible in families with a known mutation.
  • Antibiotic prophylaxis against endocarditis for dental and other procedures is no longer routinely recommended by the ADA/AHA.
  • Athletes who are especially tall should be screened for aortic root dilation.


Genetic abnormality; mutations of the FBN1 (fibrillin) gene. Fibrillin is an extracellular matrix protein widely distributed in elastic and nonelastic connective tissue.

Commonly Associated Conditions

  • High prevalence of obstructive sleep apnea in MFS; may be a risk factor for aortic root dilatation (4).
  • Increased prevalence of migraine in MFS.

Connective tissue, tissue system, echocardiogram, dilation, young adulthood,


  • In the revised Ghent nosology:
    • CV manifestations (aortic root aneurysm/dissection) and ectopia lentis have more weight.
    • Molecular genetic testing for FBN1 plays a more prominent diagnostic role but is not required.
    • Less-specific manifestations were removed or made less influential, thus avoiding obligate thresholds that were not evidence-based. Careful follow-up diminishes risk of missed diagnosis.
    • New criteria explicitly allow for alternative diagnoses, where additional features warrant: Shprintzen-Goldberg syndrome (SGS), Loeys-Dietz syndrome (LDS), or vascular type Ehlers-Danlos syndrome (vEDS).
    • Z-score calculator for aortic root enlargement:
  • In the absence of a family history of MFS:
    • Aortic root dilatation or dissection (Z≥2) (Ao) and ectopia lentis (EL): Unequivocal diagnosis of MFS, irrespective of systemic features, except were they are diagnostic of SGS, LDS, or vEDS
    • Ao and a bona fide FBN1 mutation: Diagnostic of MFS, even in the absence of EL
    • Where Ao is present, but EL is absent and the FBN1 status is negative (or unknown), diagnosis of MFS requires systemic findings score ≥7 points using a new scoring system (see below), and exclusion of SGS, LDS, and vEDS.
    • With EL but without Ao, FBN1 mutation previously associated with Ao is required for diagnosis of MFS.
  • Systemic features, scoring system (see Physical Examination):
    • Wrist and thumb sign +3; wrist or thumb sign +1
    • Pectus carinatum deformity +2; pectus excavatum or chest asymmetry +1
    • Hindfoot deformity +2; pes planus +1
    • Pneumothorax +2
    • Dural ectasia +2
    • Protrusio acetabuli +2 by X-ray, CT, or MRI
    • Reduced Upper-to-Lower segment ratio (US/LS) and increased arm/height and no severe scoliosis +1
    • Scoliosis or thoracolumbar kyphosis +1
    • Reduced elbow extension +1
    • Facial features (3/5) +1
    • Skin striae +1
    • Myopia >3 diopters +1
    • Mitral valve prolapse (all types) +1
  • Maximum: 20 points; score ≥7 indicates systemic involvement
  • Positive family history requires a family member independently diagnosed using above criteria.
  • With a positive family history, MFS can be diagnosed with ectopia lentis, or systemic score ≥7, or aortic root dilatation with Z ≥2 in persons >20 years old, or Z ≥3 in persons <20 years old.
  • In persons <20 years old who have negative family history and suggestive findings, but who do not meet Ghent criteria, “non-specific connective tissue disorder” is diagnosed, and close clinical follow-up is recommended.
  • In the presence of a relevant FBN1 mutation, “potential MFS” is diagnosed, and close follow-up recommended.
  • In adults who have suggestive findings but who do not meet Ghent criteria, consider alternative diagnoses: Ectopia lentis syndrome (ELS), mitral valve prolapse syndrome (MVPS), MASS phenotype.

Physical Exam

  • Facial features: Dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia
  • Thumb sign: Distal phalanx of thumb protrudes from clenched fist. Wrist sign: Thumb and 5th digit overlap when circling wrist.
  • Pectus carinatum deformity: Pectus excavatum or chest asymmetry beyond normal variation
  • Hindfoot valgus with forefoot abduction and lowering of the midfoot; should be distinguished from pes planus
  • Reduced US/LS: 0.93 in unaffected individuals vs ≤0.85 in affected white adults, ≤0.78 in affected black adults. US is measured from the top of the head to the top of the mid pubic bone; LS is measured from the top of the pubic bone to the sole of the foot. In children, abnormal US/LS: US/LS <1, age 0–5 years; US/LS <0.95, 6–7 years; US/LS <0.9, 8–9 years; <0.85, age ≥ 10 years.
  • Increased arm span to height ratio >1.05
  • Scoliosis or thoracolumbar kyphosis diagnosed if upon bending forward, there is a vertical difference ≥1.5 cm between the ribs of the left and right hemithorax.
  • Reduced elbow extension if angle between upper and lower arm measures ≤170º upon full extension.
  • Skin: Striae atrophicae are significant if not associated with significant weight changes (or pregnancy) and if located on mid-back, lumbar region, upper arm, axilla, or thigh.
  • Because of lack of specificity, the following criteria were removed from the current nosology: Joint hypermobility, high arched palate, and recurrent or incisional herniae (2).

Diagnostic Tests & Interpretation


  • Other than FBN1 mutation, no specific laboratory abnormalities are associated with MFS.
  • Specific criteria have been established (2) for FBN1 mutations causative of MFS, including those found in families with MFS. FBN1 mutation is a valuable marker for risk or aortic dissection (5). In a small subset of patients with unequivocal MFS, no known FBN1 mutation is found.
  • In patients whose physical examination is suggestive of MFS, urinary homocystine should be measured to rule out homocystinuria, an inborn error of methionine metabolism.


  • Anteroposterior (AP) radiograph: Diagnosis of protrusio acetabuli. Results from deepening of hip sockets during growth; does not cause problems during childhood
  • Scoliosis: Cobb’s angle ≥20º on radiographs. Imaging for MFS diagnosis, or as per clinical exam.
  • Hindfoot valgus with forefoot abduction and lowering of the midfoot: Anterior and posterior views if clinically indicated
  • Echocardiography: Measure aortic root at the level of sinuses of Valsalva; check for mitral valve prolapse.
  • MRI or CT to evaluate for dural ectasia for diagnosis, and if symptomatic. Symptoms highly variable, nonspecific, and include lower back pain.

Diagnostic Procedures/Surgery

  • Ectopia lentis is diagnosed on slit lamp examination after maximal dilatation of the pupil. Lens dislocation is most often upward and temporal.
  • Myopia: Common in the general population; myopia >3 diopters contributes to MFS systemic score.

Pathological Findings

  • Cystic medial necrosis of the aorta
  • Myxomatous degeneration of cardiac valves

Differential Diagnosis

Several conditions present clinical manifestations overlapping with MFS in cardiovascular, ocular, and skeletal systems.

  • Ectopia lentis syndrome—no aortic root dilatation
  • Mitral valve prolapse syndrome—MVP, limited systemic features may include pectus excavatum, scoliosis, mild arachnodactyly; aortic enlargement and ectopia lentis preclude this diagnosis.
  • MASS phenotype—(Mitral valve prolapse; myopia; borderline, nonprogressive Aortic enlargement (Z <2); and nonspecific Skeletal and Skin involvement). Aortic involvement in MASS is usually nonprogressive; some risk for more severe vascular involvement.
  • Shprintzen-Goldberg syndrome; Loeys-Dietz syndrome; Ehlers-Danlos syndrome
  • Homocystinuria—Marfanoid habitus, thrombosis, mental retardation; urine amino acid analysis is diagnostic; lens dislocates downward.
  • Familial thoracic aortic aneurysm
  • Stickler syndrome; congenital contractural arachnodactyly; Weill-Marchsesani syndrome; multiple endocrine neoplasia, type 2B



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  • Prevention of aortic complications: Labetalol or other β-adrenergic blockers. Dosage adjusted to target heart rate (resting rate 60 beats/min, increase to ≤110 beats/min after moderate exertion; or <100 beats/min after submaximal exercise) (2)[C].
  • Other agents used if β-blockers contraindicated. Calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers also retard aortic dilation in children and adolescents (6)[B].

Additional Treatment

Issues for Referral

Genetics, Cardiology, Orthopedics, Ophthalmology

Surgery/Other Procedures

  • When cardiac symptoms develop or aortic root diameter is ≥5.0 cm, consider surgical intervention. Many MFS patients will ultimately require reconstructive cardiovascular surgery.
    • Dissection of ascending aorta (type A) is a surgical emergency. Consider prophylactic surgery when diameter of sinus of Valsalva approaches 5.0 cm (2). Other considerations include family history, rate of change, other cardiac pathology, pregnancy.
    • Dissection of descending thoracic aorta (type B) surgical indications include intractable pain, limb or organ ischemia, aortic diameter >5.5 cm (or rapidly increasing) (2).
  • Mitral valve repair: For severe mitral valve regurgitation or progressive LV dilatation or dysfunction, or in patients undergoing valve-sparing root replacement (2).
  • Lens subluxation: Incidence of glaucoma is high, so surgery is performed only if the condition cannot be treated with corrective lenses. Surgical removal of lens in lens opacity, impending complete luxation, lens-induced glaucoma or uveitis, or anisometropia or refractive error not amenable to optical correction (2).
  • Severe pectus excavatum may require surgery.
  • Scoliosis: Bracing for curves 20–40º until growth is complete, or surgery if >40º.
  • Surgery only for most severe cases of dural ectasia.
  • Hip replacement in middle age or later if protrusio acetabulae has led to severe arthritic change.

Ongoing Care

Follow-Up Recommendations

  • Avoid sports that can increase aortic root enlargement or pneumothorax, including weightlifting and acceleration/deceleration sports. Low-risk sports include bowling, golf, skating (but not ice hockey), snorkeling, brisk walking, treadmill walking or stationary biking, modest hiking (7)[C].
  • Exercise restrictions based on individual circumstances (7). Recommendation from the National Marfan Foundation ( and guidelines from the American Heart Association/American College of Cardiology task forces. In general, avoid contact sports, Valsalva, and exhaustion.

Patient Monitoring

Frequent examinations (at least twice per year) while patient is still growing, with particular attention to cardiovascular system and to scoliosis.

  • Yearly echocardiograms (initially), more frequent if aortic diameter is increasing rapidly (≥5 cm/year) or is approaching the surgical threshold (≥4.5 cm in adults).
  • Aortic root dilatation in MFS is usually progressive, warrants vigilance even when not seen on initial examination. Age <20, yearly echocardiogram. Adults with repeatedly normal aortic root measurements, echocardiogram every 2–3 years (2).
  • Regular imaging after surgical repair of aorta.
  • Scoliosis or pectus deformity: standard orthopedic management. Clinical evaluation for scoliosis earlier than in general population. Plain radiographs of spine during growth years to detect and measure scoliosis.
  • Annual ophthalmologic evaluation for detection of ectopia lentis, myopia, cataract, glaucoma, and retinal detachment. Myopia is very common in MFS and may have early onset, rapid progression, and high degree of severity. Early monitoring, aggressive refraction to prevent amblyopia (2).

Patient Education

  • National Marfan Foundation, 382 Main St., Port Washington, NY 11959; 800-8MARFAN,
  • American Heart Association at


Life-threatening complications involve cardiovascular dysfunction. In 1972, life span was 32 years. Currently, life span is nearly normal.


Bacterial endocarditis, aortic dissection, aortic or mitral valve insufficiency, dilated cardiomyopathy, retinal detachment, glaucoma, pneumothorax.


1. De Paepe A, Devereux RB, Dietz HC, et al. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet. 1996;62:417–26.

2. Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476–85.

3. Faivre L, Collod-Beroud G, Callewaert B, et al. Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion. Am J Med Genet A. 2009;149A:854–60.

4. Kohler M, Blair E, Risby P, et al. The prevalence of obstructive sleep apnoea and its association with aortic dilatation in Marfan’s syndrome. Thorax. 2008.

5. Faivre L, Collod-Beroud G, Child A, et al. Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands. J Med Genet. 2008;45:384–90.

6. Williams A, Davies S, Stuart AG, et al. Medical treatment of Marfan syndrome: a time for change. Heart. 2008;94:414–21.

7. Maron BJ, Chaitman BR, Ackerman MJ, et al. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation.2004;109:2807–16.



759.82 Marfan syndrome


19346006 Marfan syndrome (disorder)

Clinical Pearls

  • Because many features of MFS appear in the general population, diagnostic criteria have been established. Molecular diagnostic testing for FBN1 mutations will play an increasing role.
  • Not all individuals with MFS are tall.
  • Early diagnosis of homocystinuria is important because clinical complications, which include a high risk of vascular thrombosis, can be minimized with appropriate diet and medication.

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