> Table of Contents > Marfan Syndrome
Marfan Syndrome
Rayna Goldstein, MD
Michele Roberts, MD, PhD
image BASICS
DESCRIPTION
  • Marfan syndrome (MFS) is an inherited disorder of connective tissue.
  • Because many features of MFS appear in the general population, specific diagnostic criteria (Ghent nosology) were established and revised, recognizing a constellation of features with major and minor criteria for establishing the diagnosis (1,2).
  • System(s) affected: musculoskeletal, cardiovascular, ocular, pulmonary, skin/integument, connective tissue (dura)
Pediatric Considerations
Careful monitoring, as described. Early surgical intervention may reduce the degree of scoliosis.
Pregnancy Considerations
  • Manage pregnancy in MFS as high risk, with a cardiologist; prepregnancy evaluation: screening transthoracic echocardiogram for aortic root dilation
  • Consider &bgr;-blockers in all pregnancies to minimize 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.
  • Avoid spinal anesthesia due to risk of dural ectasia.
EPIDEMIOLOGY
  • 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
Prevalence
1/5,000 to 1/10,000
ETIOLOGY AND PATHOPHYSIOLOGY
Genetic abnormality; mutations of the FBN1 (fibrillin) gene. Fibrillin is an extracellular matrix protein widely distributed in elastic and nonelastic connective tissue.
Genetics
  • Mutations of the fibrillin-1 (FBN1) gene on chromosome 15q21.1 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 MFS 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.
COMMONLY ASSOCIATED CONDITIONS
  • High prevalence of obstructive sleep apnea in MFS; may be a risk factor for aortic root dilatation
  • Increased prevalence of migraine in MFS
image DIAGNOSIS
  • In the revised Ghent nosology:
    • Cardiovascular 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, when 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: http://www.marfan.org/
  • 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 when 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 of ≥7 points using 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 Exam”):
    • Wrist and thumb sign + 3 (thumb protrudes from clenched fist); wrist or thumb sign + 1 (encircles wrist with little finger and thumb of opposite hand)
    • 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, “nonspecific connective tissue disorder” is diagnosed; close follow-up is recommended.
  • In the presence of a relevant FBN1 mutation, “potential MFS” is diagnosed and close follow-up is recommended.
  • In adults who have suggestive findings but who do not meet Ghent criteria, consider alternative diagnoses: ectopia lentis syndrome, mitral valve prolapse syndrome, MASS (Mitral valve prolapse, Aortic dilation, Skin, and Skeletal) phenotype.
PHYSICAL EXAM
  • Facial features: dolichocephaly (head length longer than expected compared with width), enophthalmos, down-slanting palpebral fissures, malar hypoplasia, micrognathia
  • High-arched, narrow palate
  • 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; distinguish from pes planus
  • Height may be normal or may be ≥3.3 SD >mean.
  • Reduced upper segment-to-lower segment (US/LS) ratio: 0.93 in unaffected individuals versus ≤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 midpubic bone; LS from the top of the pubic bone to the sole of the foot. In children, abnormal US/LS: US/LS <1, age 0 to 5 years; US/LS <0.95, 6 to 7 years; US/LS <0.9, 8 to 9 years; <0.85, age ≥10 years.
  • Increased arm span to height ratio >1.05
  • Scoliosis or thoracolumbar kyphosis is diagnosed if, on 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 ≤170 degrees on full extension
  • Skin: Striae atrophicae are significant if not associated with significant weight changes (or pregnancy) and if located on midback, lumbar region, upper arm, axilla, or thigh.
  • Because of lack of specificity, joint hypermobility, high-arched palate, and recurrent or incisional herniae were removed from diagnostic criteria (1).
DIFFERENTIAL DIAGNOSIS
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 usually nonprogressive; some risk for more severe vascular involvement.
  • Shprintzen-Goldberg, Loeys-Dietz, Ehlers-Danlos, Stickler syndromes; congenital contractural arachnodactyly; Weill-Marchesani syndrome, multiple endocrine neoplasia type 2B, fragile X
  • Homocystinuria: Marfanoid habitus, thrombosis, mental retardation; urine amino acid analysis is diagnostic; lens dislocates downward.
  • Familial thoracic aortic aneurysm
  • Aortopathy NGS panel likely to play a more prominent role, especially as VUS are classified (3)
DIAGNOSTIC TESTS & INTERPRETATION
  • Sequencing of FBN1 is the preferred method for molecular diagnosis. Mutations can be found in 95% of patients meeting diagnostic criteria for MFS.
  • Specific criteria have been established (1) for FBN1 mutations causative of MFS. FBN1 mutation is a valuable marker for risk or aortic dissection (4).
  • Echocardiography: Measure aortic root at the level of sinuses of Valsalva; check for mitral valve prolapse. The Marfan Foundation has nomograms to calculate aortic root Z-score in children (http://www.marfan.org/).
  • P.633

  • In patients whose physical exam is suggestive of MFS, measure urinary homocystine to rule out homocystinuria, an inborn error of metabolism.
  • Anteroposterior (AP) radiograph: protrusio acetabuli
  • Scoliosis: Cobb angle ≥20 degrees 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
  • MRI or CT to evaluate for dural ectasia and if symptomatic, symptoms highly variable, nonspecific, and include lower back pain
Diagnostic Procedures/Other
  • Ectopia lentis is diagnosed on slit-lamp examination after maximal dilatation of the pupil (60%); lens dislocation is most often upward and temporal.
  • Myopia: Common in the general population; myopia >3 diopters contributes to MFS systemic score.
  • Elongated globe, keratoconus, increased risk of vitreous or retinal detachment, glaucoma, and early cataract formation
Test Interpretation
  • Cystic medial necrosis of the aorta: descriptive, not pathognomonic
  • Myxomatous degeneration of cardiac valves
image TREATMENT
MEDICATION
  • Prevention of aortic complications: &bgr;-adrenergic blockers. Dosage adjusted to target heart rate (resting rate 60 bpm, increase to ≤110 bpm after moderate exertion or <100 bpm after submaximal exercise) (1)[C]
  • If &bgr;-blockers are contraindicated: Calcium channel blockers, ACE inhibitors, and ARBs may retard aortic dilation in children and adolescents (5)[B].
  • Consider antibiotic prophylaxis for dental procedures in presence of mitral or aortic regurgitation (http://www.marfan.org/resource/fact-sheet/endocarditis-prophylaxis-people-marfan-syndrome#.VhMqKvlViko).
  • Recent studies support losartan plus &bgr;-blockers to prevent progressive aortic root dilatation (6)[B].
ISSUES FOR REFERRAL
Genetics, cardiology, orthopedics, ophthalmology
SURGERY/OTHER PROCEDURES
  • When cardiac symptoms develop or aortic root diameter is ≥5 cm, consider surgical intervention (7). 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 cm, rate of change approaches 1 cm/year, and with progressive aortic regurgitation (3); other risk factors: family history, other cardiac pathology, pregnancy.
    • Dissection of descending thoracic aorta (type B): Surgical indications include intractable pain, limb or organ ischemia, and aortic diameter >5.5 cm (or rapidly increasing) (1).
  • Mitral valve repair: for severe mitral valve regurgitation or progressive LV dilatation or dysfunction, or in patients undergoing valve-sparing root replacement (1)
  • 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 for opacity, impending complete luxation, lensinduced glaucoma or uveitis, or anisometropia or refractive error not amenable to optical correction (1)
  • Severe pectus excavatum may interfere with pulmonary or cardiac function and require surgery.
  • Scoliosis: bracing for curves 20 to 40 degrees until growth is complete or surgery if >40 degrees
  • Surgery for only most severe cases of dural ectasia
  • Hip replacement in middle age or later if protrusio acetabuli has led to severe arthritic change
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Avoid sports that can increase aortic root enlargement or pneumothorax; in general, avoid contact sports, Valsalva, breathing against resistance, and exhaustion (8)[C].
  • Exercise restrictions: Follow recommendation from the National Marfan Foundation (http://www.marfan.org/) and guidelines from the American Heart Association/American College of Cardiology Task Forces.
Patient Monitoring
Exams at least twice/year while patient is growing, with attention to the cardiovascular system and to scoliosis.
  • Cognitive ability is usually normal, but visual and medical difficulties may interfere with learning (8)[C].
  • Cardiac
    • Aortic root dilatation in MFS is usually progressive, warrants vigilance even when not seen on initial examination; age <20 years, yearly echocardiogram; adults with repeatedly normal aortic root measurements, echo every 2 to 3 years (1)[C].
    • Yearly echocardiograms (initially), more frequent if aortic diameter is increasing rapidly (≥5 cm/year) or is approaching surgical threshold (≥4.5 cm in adults)
    • Regular imaging after surgical repair of aorta
  • Musculoskeletal
    • Excessive linear growth of long bones, extremities disproportionately long, paucity of muscle mass, peak growth velocity 2 years early. Growth curves for MFS are available (8)[C].
    • Clinical evaluation for scoliosis earlier than in general population; plain radiographs of spine during growth years
    • Evaluate for scoliosis, joint laxity, and pectus deformity every visit to age 1 year, annually age 1 to 5 years, semiannually age 6 to 18 years, and yearly thereafter.
    • Bone age in preadolescence: Consider hormonal therapy if with large discrepancy (8)[C].
    • Scoliosis or pectus deformity may progress more rapidly than in those without MFS.
    • Excellent prognosis for scoliosis curves <30 degrees; bracing may be effective for curves <35 degrees; rapid progression likely if curve >50 degrees (8)[C]
  • Annual ophthalmologic evaluation: ectopia lentis, myopia, cataract, glaucoma, and retinal detachment; myopia is very common in MFS with early onset, rapid progression, and high degree of severity; early monitoring, aggressive refraction to prevent amblyopia (1)[C]
  • Respiratory: pulmonary function tests (PFTs) for pulmonary complaints; obstructive sleep apnea
  • Review diagnosis, examine family members, offer support group information at diagnosis and PRN.
  • Provide genetic counseling at diagnosis, discuss pregnancy risks in adolescence, discuss activity restrictions starting age 6 years, transition planning in early adolescence. Review symptoms of potential catastrophic events: aortic dissection, vision changes, and pneumothorax starting age 6 years.
PATIENT EDUCATION
  • National Marfan Foundation, http://www.marfan.org/
  • NLM Genetics Home Reference: Marfan syndrome http://ghr.nlm.nih.gov/condition/marfan-syndrome
PROGNOSIS
Life-threatening complications involve cardiovascular dysfunctions. In 1972, lifespan was 32 years. Currently, lifespan is nearly normal.
REFERENCES
1. Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47(7):476-485.
2. 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(5):854-860.
3. Wooderchak-Donahue W, VanSant-Webb C, Tvrdik T, et al. Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. Am J Med Genet A. 2015;167A(8):1747-1757.
4. 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(6):384-390.
5. Williams A, Davies S, Stuart AG, et al. Medical treatment of Marfan syndrome: a time for change. Heart. 2008;94(4):414-421.
6. Groenink M, den Hartog AW, Franken R, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J. 2013;34(45):3491-3500.
7. Benedetto U, Melina G, Takkenberg JJ, et al. Surgical management of aortic root disease in Marfan syndrome: a systematic review and meta-analysis. Heart. 2011;97(12):955-958.
8. Tinkle BT, Saal HM. Health supervision for children with Marfan syndrome. Pediatrics. 2013;132(4):e1059-e1072.
Codes
&NA;
ICD10
  • Q87.40 Marfan's syndrome, unspecified
  • Q87.43 Marfan's syndrome with skeletal manifestation
  • Q87.418 Marfan's syndrome with other cardiovascular manifestations
Clinical Pearls
&NA;
  • 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.
  • Screen very tall athletes for aortic root dilatation.
  • Early diagnosis of homocystinuria is important because clinical complications can be minimized with appropriate diet and medication.
  • Ectopia lentis and aortic root dilatation are best discrimination features, but height ≥3.3 SD above the mean is a simple discriminant in primary care.