[Antoine Bernard-Jean Marfan (1858–1942), Chef de clinique medicale de l'Université de Paris and Hôpital des Enfants Malades]

= ARACHNODACTYLY

= autosomal dominant (in 75%) multisystemic connective tissue disorder with high penetrance but extremely variable expression; new sporadic mutations in 25–30%

Genetics:>135 mutations in fibrillin-1 gene (FBN1) on chromosome 15 which encodes a large glycoprotein (= component of extracellular microfibrils → connects elastic lamina to adjacent endothelial cells + smooth muscle cells for structural integrity and coordination of contractile + elastic tension of vessel walls

Prevalence: 2–3÷10,000; M÷F = 1÷1

Path: disintegration and elastolysis of connective tissue with abnormal cross-linking of collagen fibers → aneurysm formation and dissection

Most common cause of death: aortic dissection, CHF, cardiac valvular disease

1. MUSCULOSKELETAL MANIFESTATIONS
   • tall thin stature with long limbs, arm span greater than height (commonly basketball + volleyball players)
   • muscular hypoplasia + hypotonicity
   • scarcity of subcutaneous fat (= emaciated look)
   • generalized osteopenia
   • Skull
     • elongated face
     • dolichocephaly
     • prominent jaw
     • high arched palate
   • Hand
     • arachnodactyly = elongation of phalanges + metacarpals:
       • Steinberg sign = protrusion of thumb beyond confines of clenched fist (found in 1.1% of normal population)
       • metacarpal index (averaging the 4 ratios of length of 2^nd–5^th metacarpals divided by their respective middiaphyseal width) >8.8 (male) or 9.4 (female)
     • flexion deformity of 5^th finger
   • Foot
     • pes planus (25%) / planovalgus ← increased ligamentous laxity
     • clubfoot
     • hallux valgus
     • hammer toes
     • disproportionate elongation of 1^st digit of foot
   • Chest wall deformity (66%)
     Cause: longitudinal overgrowth of ribs during periods of rapid growth (adolescence)
     • reduction in lung capacity + forced vital capacity + forced expiratory volume in 1 second
     • pectus excavatum = retraction of lower sternum:
       • displacement of heart + lungs + diaphragm
         Rx: surgery (Ravitch / Nuss procedure) for pectus index >3.25 (dividing width of chest wall at its widest point by distance between posterior surface of sternum and anterior surface of spine) after maturation of skeleton
     • pectus carinatum = anterior protrusion of upper portion of sternum
       Rx: surgery for cosmetic reasons
   • Spine
     • ratio of measurements between symphysis and floor + crown and floor >0.45
     • severe rigid progressive scoliosis (45–62%) / kyphosis (16%) / kyphoscoliosis
       ◊ Most frequent + potentially severe manifestation of Marfan syndrome → restriction of lung volume
       Age: young patient; M÷F = 1÷1
       Rx: bracing for curvature <25°; surgical correction for curvature >40°
     • atlantoaxial translation (54%)
     • increased incidence of Schmorl nodes (Scheuermann disease) and spondylolisthesis
     • straight back syndrome
     • winged scapulae
     • dural ectasia (56–65%) of lumbosacral spine:
       = ballooning / widening of dural sac ± nerve root sleeves
       • usually asymptomatic
       • occasionally back pain, headache, neurologic deficit
       
       Location: lumbosacral spine
       May be associated with: bone erosion, meningocele, arachnoid cyst
       • widening of interpediculate distance
       • posterior scalloping of vertebral body
       • dilatation of nerve root sleeve
       • expansion of sacral spinal canal
       • presacral + lateral sacral meningoceles
       • enlargement of sacral foramina
   • Joints
     • ligamentous laxity + hypermobility + instability
     • premature osteoarthritis
     • patella alta
     • genu recurvatum
     • recurrent dislocations of patella, hip, clavicle, mandible
     • slipped capital femoral epiphysis
     • progressive protrusio acetabuli (16–27%) = invasion of acetabulum + femoral head into pelvic cavity
       Location: bilateral >unilateral; F >M
       • limited internal rotation + abduction of hip
       • increased center-edge angle of Wiberg >40°
       • “teardrop” crossed by ilioischial line / obscured by femoral head
2. OCULAR MANIFESTATIONS
   • bilateral ectopia lentis, usually upward + outward ← poor zonular attachments
   • glaucoma, macrophthalmia
   • hypoplasia of iris + ciliary body
   • miosis (= contracted pupils) ← absence of dilatory effect of hypoplastic ciliary muscle
   • myopia (= increased axial length of globe)
   • retinal detachment
   • strabismus, ptosis
   • blue sclera
   • megalocornea = flat thickened cornea
3. CARDIOVASCULAR MANIFESTATIONS (60–98%)
   affecting mitral valve, ascending aorta, pulmonary artery, splenic + mesenteric arteries (occasionally)
   • Dominant cause of death in 93%!
   • chest pain, palpitations, shortness of breath, fatigue
   • mid-to-late systolic murmur + one / more clicks
   
   In ⅓ associated with: congenital heart defect (ASD, incomplete coarctation)
   • Aorta (cause of death in 55%)
     Histo: degeneration of elastic tissue in aortic media + cystic medial necrosis of smooth muscle cells
     1. Annuloaortic ectasia (in 60–80% of adults
        = uniform dilatation of all 3 sinuses of Valsalva with distal progression to sinotubular junction (= obliteration of normal sinotubular ridge) and aortic annulus
        Histo: cystic medial necrosis
        • leading cause of aortic valve insufficiency
        • “tulip bulb aorta” = symmetrical dilatation of aortic sinuses of Valsalva slightly extending into ascending aorta (58%)
        • triangular coaptation defect of valve cusps (during middiastolic closure at 70% of R-R interval of gated CT) = radiographic sign of aortic insufficiency
        • tethered valve cusps at midsystolic opening (= at 10% of R-R interval of a gated CT) ← dilatation of the sinus of Valsalva
        
        Cx: aortic regurgitation (in 81% if root diameter >5 cm; in 100% if root diameter >6 cm), aortic root dissection, aortic root rupture
        Prognosis: average age of death at 35 (75) years in untreated (treated) patients
        Rx: prophylactic surgery at a sinus diameter of 55 mm in adulthood + 45–50 mm in childhood / aneurysm expansion of >0.5–1 mm per year
        The classic phenotypic appearance of the aorta in Marfan syndrome is annuloaortic ectasia with dilatation of aortic annulus and sinuses of Valsalva, and effacement of the sinotubular junction, resulting in a tulip-shaped configuration of the aortic root.
     2. Aortic aneurysm (without annuloaortic ectasia)
        • fusiform dilatation of ascending aorta, rarely beyond innominate artery (rapid enlargement, young patient)
        • more rapid enlargement than atherosclerotic aneurysm
        • rarely intimal calcifications of the aortic wall
        
        DDx: atherosclerotic aneurysm (older patient, less rapid enlargement, frequent thrombosis, intimal calcifications common)
   • Aortic dissection
     CXR:
     • progressive aortic enlargement at serial imaging
     • enlarged aortic arch
     • double contour of aortic arch
     • displacement of intimal calcifications >6 mm
     • new pericardial / pleural effusion
     
     CT:
     • intimal flap + false lumen (in 70%) PATHOGNOMONIC
     • increased attenuation of thrombosed false lumen
     • internal displacement of intimal calcification
     • mediastinal / pericardial hematoma
     • infarction of organs supplied by branch vessels from the false lumen
     
     Prognosis: recurrence common
     Rx: composite graft to replace aortic root (Bentall procedure); antihypertensive medication
   • Mitral valve
     Histo: myxomatous degeneration of valve leads to redundancy + laxness
     • mid-to-late systolic murmur + one / more clicks
     • “floppy valve syndrome” (95%) = redundant chordae tendineae with mitral valve prolapse + regurgitation
     
     Cx:
     1. Mitral regurgitation
     2. Rupture of chordae tendineae (rare)
   • Coarctation (mostly not severe)
   • Pulmonary artery aneurysm and dilatation of pulmonary artery:
     • >35 mm at root (in 43%) and >28 mm at bifurcation
   • Cor pulmonale ← chest deformity
   
   

   Criteria for Diagnosis of Marfan Syndrome (Ghent Classification)

   System Affected Major Criteria Minor Criteria Cardio-vascular √dilatation of ascending aorta ± aortic regurgitation involving >1 sinus of Valsalva √dissection of descending aorta √dilatation / dissection of descending aorta <50 years of age Musculo-skeletal √scoliosis with curvature >20° / spondylolisthesis √pectus excavatum of moderate severity √pectus carinatum √joint hypermobility √pectus excavatum requiring surgery √highly arched palate with crowding of teeth √acetabular protrusion √reduced upper-to-lower segment ratio / arm span-to-height ratio >1.05 √wrist and thumb signs √reduced extension of elbow <170° √abnormal facial appearance (dolichocephaly, malar hypoplasia, enophthalmos, retrognathism, downslanting palpebral fissures) √medial displacement of medial malleolus causing pes planus CNS √lumbosacral dural ectasia Lung √spontaneous pneumothorax √apical blebs Eye √ectopia lentis √abnormal flat cornea √increased axial length of globe √hypoplastic iris / ciliary muscle causing decreased miosis Skin √striae atrophicae √recurrent / incisional hernia

4. PULMONARY MANIFESTATIONS (rare)
   • lung cysts, bullae, blebs + diffuse apical bullous emphysema
   • congenital malformation of bronchus + bronchiectasis
   • recurrent spontaneous pneumothoraces (4–15%; 10 x times more common than in general population)
   • interstitial parenchymal disease ± honeycombing
5. ABDOMINAL MANIFESTATION
   • recurrent biliary obstruction
6. INTEGUMENTUM
   • striae atrophicae
   • recurrent incisional hernia

Prognosis: life expectancy close to normal; death (in 90% from aortic dissection, CHF, valvular disease)

DDx:

1. Homocystinuria (osteoporosis)
2. Ehlers-Danlos syndrome
3. Congenital contractural arachnodactyly (ear deformities, NO ocular / cardiac abnormalities)
4. MEN 3 (medullary thyroid carcinoma, mucosal neuromas, pheochromocytoma, marfanoid habitus)