Malady Wise

View Original

Marfan Syndrome

Maladywise

Introduction

  • Marfan’s Syndrome (MFS) is one of the most common inherited disorders of connective tissue

  • Autosomal dominant

  • Broad range of severity from mild to severe

  • Classically involve eyes, heart and muscles but also lungs, skin and central nervous system

  • There is a 50:50 chance of inheriting the mutation from an affected parent, which is independent of sex.

  • Prevalence is about 1 in 10,000.

Genetics

  • Usually a mutation in the FBN1 gene

  • Most people have an affected parent

  • 25% have a de novo (new) mutation

  • 10% of cases have no mutation in FBN1

  • Mutations involving a second gene FBN2 have been linked to a different type of MFS

Pathogenesis

  • Not well understood

    • Mechanisms include the role of microfibrils in coordinating tissue morphogenesis, homeostasis and response to stress

    • Increased bioavailability of transforming growth factors (TGF)-beta

Clinical Manifestations

Aortic Disease

  • Aortic root disease leads to aneurysms is the main cause of mortality and morbidity

  • Can be a poor correlation between skeletal symptoms and cardiac symptoms

  • 60 to 80% of adults with MFS have dilatation of the aortic root often with aortic regurgitation

  • Echo recommended at initial diagnosis and repeated at 6 months to check stability

  • MFS present in 50% of young patients under the age of 40 who have aortic dissection

Cardiac Disease

  • Mitral valve prolapse is frequently identified (40-50%)

  • Tricuspid prolapse may also occur

Skeletal Findings

  • Excess linear growth of the long bones and joint laxity

  • Paradoxically some people with MFS are stiff with reduced joint mobility, mostly elbows and fingers

  • Pain is common

Arachnodactylyl

  • Patients typically have a positive thumb and wrist sign

Pectus Deformity

  • Pectus carinatum is more specific for MFS than pectus excavatum

Hind Foot Valgus

  • Assigned two points. Flat feet (pes planus) is assigned one point.

Abnormal US/LS and arm span / height

  • Disproportionate long arms and legs compared to trunk

  • Lower segment (LS) = top of pubic symphysis to the floor

  • Upper segment (US) = height minus lower segment

Scoliosis and kyphosis

  • Cobbs angle >20 degrees

  • Vertical difference of 1.5cm between ribs of the left and right hemithorax

Protrusio acetabuli

  • Acetabular protrusion on imaging

Facial features

  • Needs 3/5 of the following

    • Dolichocephaly (reduced cephalic index = head width)

    • Enophthalmos (posterior placement of the eye globe)

    • Downslanting palpebral fissures (outsides of eyes slant down)

    • Malar hypoplasia (under developed cheek bones)

    • Retrognathia

Eye abnormalities

  • Ectopia lentis occurs in 50 to 80% (dislocation of lens)

  • Myopia (shortsighted)

Dural ectasia

  • Enlargement of spinal canal due to ectasia of dura seen on imaging

Lung disease

  • Emphysematous changes with lung bullae, can lead to spontaneous pneumothorax

Skin striae

  • Stretch marks

Diagnosis

Using the revised Ghent criteria of 2010. This is based on the presence or absence of a family history of MFS.

If positive family history, the presence of any one of the following is diagnostic

  • Ectopia lentis.

  • Systemic score ≥7 points.*

  • Aortic criterion (aortic diameter Z ≥2 above 20 years old, Z ≥3 below 20 years, or aortic root dissection).*

If no family history, the presence of one of the following is diagnostic

  • Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and ectopia lentis.* (See 'Ocular abnormalities' above.)

  • Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and a causal FBN1 mutation as defined above. (See 'Causal FBN1 mutations' above.)

  • Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and a systemic score ≥7.* (See 'Systemic score' below.)

  • Ectopia lentis and a causal FBN1 mutation as defined above (see 'Causal FBN1 mutations' above) that has been identified in an individual with aortic aneurysm.

Systemic Scoring

Systemic score — The revised Ghent nosology includes the following scoring system for systemic features in patients with a family history.

  • Wrist AND thumb sign: 3 points (wrist OR thumb sign: 1 point).

  • Pectus carinatum deformity: 2 (pectus excavatum or chest asymmetry: 1 point).

  • Hindfoot deformity: 2 points (plain pes planus:1 point).

  • Pneumothorax: 2 points.

  • Dural ectasia: 2 points.

  • Protrusio acetabuli: 2 points.

  • Reduced upper segment/lower segment ratio AND increased arm span/height AND no severe scoliosis: 1 point.

  • Scoliosis or thoracolumbar kyphosis: 1 point.

  • Reduced elbow extension (≤170 degrees with full extension): 1 point.

  • Facial features (at least three of the following five features: dolichocephaly [reduced cephalic index or head width/length ratio], enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia): 1 point.

  • Skin striae: 1 point.

  • Myopia >3 diopters: 1 point.

  • Mitral valve prolapse (all types): 1 point.

A systemic score ≥7 indicates major systemic involvement.

Differential Diagnoses

FBN1 mutation phenotypes

  • Some patients have identifiable mutations and several features of MFS but not enough to meet the criteria

TGFBR1 or 2 mutations: Loeys-Dietz syndrome

  • Characterised by wide-spaced eyes, split uvula, cleft palate, and aortic aneurysms

Mitral Valve Prolapse Syndrome

  • Mitral valve prolapse with systemic features but score < 5 + aortic diameter <2

Others

  • Ehler’s Danlos, Stickler syndrome, Homocystinuria, Mass phenotype

Evaluation

  • After diagnosis, image those at risk for aortic dilatation

  • In individuals under 20 years old with systemic findings, consider yearly echo until after the age of 20

  • First-degree relatives should be screened

Management

Aortic Monitoring

  • At the time of diagnosis

  • Usually CT or MRI initially to ensure echo isn’t underestimating measurements

  • Repeat 6 months later to check progression

  • Repeat cross-sectional imaging every 3 to 5 years (CT or MRI)

  • In adults, if the aortic diameter is documented as stable then annual imaging (each) if diameter <45mm

  • If >45mm then twice yearly

  • For children, annual imaging if aortic dimension is documented as stable

  • In individuals under 20 years of age wit systemic findings suggest of MFS but without heart involvement should have annual echocardiograms

Medication

  • For adults and children with MDS without aortic aneurysm but with one of more risk factors (aortic root enlargement, family history of aortic root enlargement) use a Beta blocker or ARB (Angiotension II Receptor Blocker).

    • Start with Atenolol

    • Goal is to maintain heart rate after submaximal exercise to below 100 bpm

Exercise

  • Recreational (non-competitive) exercises that are of low and moderate intensity that are probably permissible including bowling, golf, skating, snorkeling, brisk walking, stationary bike, modest hiking, doubles tennis.

  • Patients should avoid contact sports, exercising to exhausting and isometric exercises which entail the valsalva manoevre.

  • Activities of intermediate risk include basketball, squash, running, skiing, soccer, motorcycling, lap swimming.

Aortic Root Replacement

  • Elective replacement is an option

Eye abnormalities

  • Annual eye check

  • Vision correction for myopia

Heart valve

  • Mitral valve repair if severe mitral regurgitation

Scoliosis

  • Brace correction if severe

Life Expectancy

  • The lifespan of untreated Marfan’s in 1972 was 32 years

  • Current lifespan as of 1993 was 72 years

Links

References