Marfan syndrome

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Marfan syndrome is a genetic disorder of the connective tissue, inherited and transmitted as an autosomal dominant trait, carried by the gene FBN1. The incidence is approximately 1:5000–10,000; about 26% of cases have no family history and their syndrome is the result of sporadic mutation[1]

Contents

Clinical presentation and diagnosis

  • Marfan syndrome affects mainly the cardiovascular system, the sckeletal aparatus, and the eyes.
  • The Ghent criteria [3] specified characteristics of the phenotype and genotype.


Ghent Criteria for Marfan Syndrome Diagnosis
Organ System Major Criteria Minor Criteria
Family history
Primary relative with Marfan criteria;
FBN1 mutation present
Haplotype around FBN1 with unequivocally diagnosed Marfan syndrome in family
None
Skeletal

Four of the following:

Pectus carinatum;
Pectus excavatum, needing surgery;
Reduced upper segment–to–lower segment ratio or arm span–to-height ratio >1.05;
Wrist and thumb signs;
Scoliosis >20°;
<170° extension of elbows;
Pes planus (medial displacement of medial malleolus);
Protrusio acetabuli.
Pectus excavatum (moderate severity);
Joint hypermobility;
Arched palate;
Facial features (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures)
Ocular
Ectopic lentis
Flat cornea;
Increased axial length of globe;
Hypoplastic iris.
Cardiovascular
Dilatation of the ascending aorta;
Ascending aortic dissection;
Mitral valve prolapse;
Pulmonary artery dilatation;
Mitral annular calcification (<40 y);
Dilatation or dissection of the descending thoracic aorta or abdominal aorta (<50 y);
Pulmonary
None
Spontaneous pneumothorax;
Apical blebs.
Skin/integument
None
Striae atrophicae without weight gain, pregnancy, or stress;
Recurrent incisional herniae.
Dura
Lumbosacral dural ectasia.
None


  • Diagnostic criteria have been published pointing to the need for the application of strict rules, especially for relatives, in order to avoid over-diagnosis.


Genetic basis

Marfan syndrome presents with highly variable expression, but complete non-penetrance (silent gene carriers) has not been definitively documented. The genetic basis of Marfan syndrome is mutations in the gene encoding fibrillin-1 (FBN1) at chromosomal locus 15q21.1.[4] Fibrillin is a major building block of microfibrils, which constitute the structural components of the suspensory ligament of the lens and serve as substrates for elastin in the aorta and other connective tissues.


Cardiovascular features and echocardiographic assessment

Life expectancy is primarily determined by the severity of cardiovascular involvement.

  • Echocardiography plays an important role in:
♦ detection and evaluation of the cardiovascular features;
♦ following up patients with Marfan syndrome;
♦ timing of prophylactic surgical intervention.
  • Cardiovascular features in Marfan syndrome:
♦ mitral valve prolapse;
♦ mitral annular calcification (below age 40);
♦ proximal ascending aortic dilatation;
♦ ascending aortic dissection;
♦ dilatation or dissection of the descending thoracic aorta or abdominal aorta;
♦ aortic regurgitation;
dilated cardiomyopathy in the absence of severe valvular dysfunction (rarely);
♦ cardiac failure and pulmonary artery dilatation (below age 40).

Mitral valve prolapse

¤ the most common cardiac abnormality (figure 1 C,D);
¤ typically, the leaflets are diffusely thickened and redundant;
¤ the leaflets have characteristic buckling or prolapse behind the plane of the mitral anulus;
¤ because of the myxomatous degeneration, there is a greater incidence of spontaneous chordal rupture and secondary mitral regurgitation.

Vascular abnormalities

→ the most frequent cause of morbidity and mortality;
→ caused by cystic medial necrosis, a degeneration of the medial layer of the aorta;
→ patients are at risk of aneurysm formation, dissection, and rupture at any point along the course of the aorta;
→ the most prominent areas of dilation frequently are in the proximal aorta and may be confined to the aortic sinuses (figure 1 A);
→ diameters must be related to normal values for age and body surface area;
→ whereas the normal aorta gradually dilates and stiffens with age in Marfan, those changes are more pronounced at any age and can be detected by echocardiography;
→ echocardiographic measurements should be made at the level of the anulus, sinuses, sinotubular junction, and proximal ascending aorta in parasternal long-axis view (figure 2);
Figure 1: A, Two-dimensional echo image in the parasternal long axis demonstrates dilation of the aortic root in a Marfan syndrome patient. B, Color Doppler echo shows mild regurgitation through an otherwise normal aortic valve, which results from the dilatation of the root. C, Marfan Syndrome patient with moderate mitral valve prolapse, demonstrated in 2-dimensional echo images. D, Classic M-mode demonstration of prolapse of the posterior mitral valve leaflet (arrow). Source: Keane M G , Pyeritz R E Circulation 2008;117:2802-2813
→ management of patients with Marfan syndrome involves serial imaging to evaluate aortic size and progression of dilation; surgery is indicated, whatever the severity of AR, in patients with Marfan syndrome who have aortic root disease with maximal ascending aortic diametere ≥50 mm (lower thresholds can be used for combining surgery on the ascending aorta for patients who have an indication for surgery on the aortic valve) and it should be considered in patients with Marfan syndrome who have aortic root disease with maximal ascending aortic diameter ≥45 mm and risk factors: family history of aortic dissection and/or aortic size increase >2 mm/year (on repeated measurements using the same imaging technique, measured at the same aorta level with side-by-side comparison and confirmed by another technique), severe AR or mitral regurgitation, desire of pregnancy[5];
→ after replacement of the ascending aorta in a patient with Marfan syndrome, follow-up may require transesophageal echocardiography, computed tomography, or magnetic resonance imaging because additional disease will typically not be in the range of view of transthoracic echocardiography;
→ cystic medial necrosis can also involve proximal coronary arteries;
→ spontaneous coronary dissection may occur in association with pregnancy or in the postpartum period; so, identification of a regional wall motion abnormality in a patient with Marfan syndrome should heighten the awareness of spontaneous coronary dissection.

Aortic insufficiency

* the aortic cusps actually insert at the level of the sinotubular junction, and effacement or frank dilation of the sinotubular junction will result in malcoaptation and subsequent aortic regurgitation (figure 1B);
* dilation of the true anulus is uncommon;
* may result in left ventricular dilation, which may mask underlying mitral valve prolapse.
Figure 2: Diagram of the normal aortic root as seen at echocardiography. The aortic diameter may be measured at the aortic annulus (1), the sinuses of Valsalva (2), the supra-aortic ridge (3), and the proximal ascending aorta (4). Source: Dean J C S Heart 2002;88:9



Further reading and external links

Feigenbaum H., Armstrong W. F., Ryan T. Feigenbaum's Echocardiography, 6th Edition; 22: 741-743


References

  1. Dean J. „Management of Marfan syndrome”. Heart 2002;88:97-103
  2. Keane M G , Pyeritz R E.”Medical Management of Marfan Syndrome”. Circulation 2008;117:2802-2813
  3. De Paepe A, Devereux RB, Dietz HC, et al. „Revised diagnostic criteria for the Marfan syndrome”. Am J Med Genet 1996;62:417–26
  4. Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, et. „Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene”. Nature. 1991; 352: 337–339
  5. Vahanian A., Alfieri O., Andreotti A. et al. "Guidelines on the management of valvular heart disease (version 2012)".Eur Heart J 2012; 33: 2451–2496
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