On a routine medical examination, a 19-year-old man is found to have a mid systolic click followed by a heart murmur. His height is 78 in, and weight is 157 lb. Physical examination shows arms that are disproportionately long compared with his trunk (arm span of 81 in), thumbs that can be extended to the wrist, pectus excavatum, and laxity of ligaments. Ocular examination demonstrates dislocation of one lens. Family history is positive for sudden death of his father at the age of 41 due to heart problems.

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  With an estimated prevalence of 1 in 3000 to1 in 5000 individuals, Marfan syndrome (MFS) represents the most common autosomal dominant multisystem disorder of the connective tissue with primary predilection of the skeletal, cardiovascular, and ocular system with consequent bone overgrowth, aortic root dilation, and/or aortic dissection and ectopia lentis, respectively.

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  The underlying pathophysiology responsible for the development and progression of MFS is the mutation of the fibrillin-1 (FBN1) gene located on chromosome 15q12. FBN1 regulates expression of the protein fibrillin-1 (composed of 2871 amino acids).¹ There have been more than 1200 identified mutations that affect the FBN1 gene, the majority of which are missense mutations with high affinity for highly conserved cysteine residues. Other mutation types include nonsense small deletions and duplications, splice-site alterations, and mutations involving calcium-binding residues.

  
  
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  Fibrillin is the major protein component of the 10 nm microfibrils of the extracellular matrix that forms the scaffold for the deposition of elastin in tissues of the heart valves, aorta, lens suspensory ligaments, and other ligamentous structures.² In addition, data from numer-ous genetic studies show that fibrillin has an important function in nonelastic tissues, such as ciliary zonules of the eye, tendons, and periosteum of the bone.

Clinical Features

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  The clinical features of MFS, including tall stature and slender digits, were first described by the French pediatrician Dr. Antoine Marfan in 1896 in a 5-year-old female patient. Today, initial diagnosis is usually made clinically utilizing the Ghent criteria, an international diagnostic algorithm based largely on clinical findings in the various earlier-mentioned organ systems, as well as on family history. Given that MFS demonstrates a wide phenotypic variety, in which mildly affected patients may be overlooked, the Ghent criteria underwent a revision in 2010 to decrease the risk of misdiagnosis³ (Table 37-1). The authors of the 2010 revision placed more emphasis on aortic root aneurysm and/or dissection and ectopia lentis and removed some of the less specific manifestations from the diagnostic algorithm. The Ghent criteria are best applied by a geneticist.

  
  
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  A high index of suspicion for MFS should be raised in patients with the presence of the following clinical features: characteristic tall and thin body habitus with long extremities, long fingers (arachnodactyly), pectus excavatum, protuberant frontal eminence, laxity of joints, and/or scoliosis (and other degenerative changes of the spine). Cardiovascular and ocular manifestations include proximal aortic dilatation resulting in aortic insufficiency, mitral valve prolapse (hence, the mid systolic click), and aortic dissection, as well as ectopia lentis (Figures 37-1 and 37-2). Other less specific clinical findings include pes planus, camptodactyly, high-arched palate, skin striae, protrusion of the medial wall of the acetabulum into the pelvic cavity, and recurrent hernias and/or pneumothorax.

  
  
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  Disproportionate overgrowth can be assessed by an arm span length greater than 1.05 times height or a reduced upper-to-lower body segment ratio. On physical examination arachnodactyly is assessed with testing for wrist and thumb signs: The wrist sign is positive when the thumb of one hand overlaps the distal phalanx of the small finger when grasping the contralateral wrist (Figure 37-3). The thumb sign is positive when the entire thumb nail protrudes beyond the ulnar border of the hand when the thumb is clenched without assistance (Figure 37-4).

  
  
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  Scoliosis is present in approximately 60% of MFS patients. Compared to idiopathic scoliosis, MFS scoliosis is characterized by higher prevalence of double thoracic and triple major curves. Up to 40% of patients have kyphosis greater than 50. Another common clinical finding in patients with MFS is dural ectasia (an enlargement of the outer layer of the dural sac and nerve root sleeves), which most commonly affects the L5-S2 lumbosacral spine region. Data from several magnetic resonance imaging (MRI) studies demonstrate that dural ectasia is present in as many as 95% of MFS patients. Most frequently dural ectasia causes lower back pain, followed by leg, abdominal, and/or perineal pain.

  
  
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  Degenerative changes occasionally affect the cervical spine of patients with MFS. In a review of 104 consecutive MFS patients, Hobbs et al. documented that 16% and 54% of patients had focal cervical kyphosis and increased atlantoaxial translation, respectively.⁴ Data from this study also showed that patients with MFS have an increased radiographic prevalence of basilar impression (36%) and increased odontoid height.

  
  
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  The protrusion of the medial wall of the acetabulum into the pelvic cavity is seen in 27% of MFS patients. Pectus excavatum is found in approximately two-thirds of pediatric patients with MFS, which can negatively affect respiratory function in the most severe cases. Spontaneous pneumothorax occurs in approximately 4.4% of patients with MFS. Recurrence rates of pneumothorax are high.

  
  
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  Aortic dissection is the most severe, and potentially life threatening, cardiovascular complication of MFS. The underlying pathology that can lead to this potentially catastrophic complication is related to cystic medial degeneration of the aortic wall, which is characterized by fragmented elastic fibers, a decrease in the amount of smooth muscle cells, and the deposition of collagen and mucopolysaccharides between cells of the aortic tunica media. Elastic fiber fragmentation leads to decreased aortic compliance, which results in aortic root dilatation and, in the most severe cases, aortic dissection. Diameter of the sinus of Valsalva greater than 5 cm, dilatation rate of more than 1.5 mm/y, and a positive family history are the most common risk factors for aortic dissection. These patients require lifelong monitoring of the progression of the aortic dilata-tion (Figure 37-5). In a significant number of patients, pathology of the aortic wall results in aortic valve insufficiency. Laxity of the mitral valve is frequently seen in MFS, resulting in mitral valve prolapse in approximately 50% to 80% of cases. Other cardiovascular manifestations associated with MFS include left ventricular dilatation and dilatation of the pulmonary and iliac arteries (Figure 37-6).

  
  
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  Ectopia lentis (Figures 37-1 and 37-2) is the most common ocular abnormality associated with MFS. It develops in utero and can be clinically apparent at the first ophthalmologic visit. Pathophysiologically, ectopia lentis is characterized by the displacement of the lens(es). Most frequently there is a bilateral displacement of the lenses upward. It is estimated that ectopia lentis is present in approximately 60% of MFS patients. On transmission electron microscopy the ciliary zonular filaments appear stretched or interpositioned by disrupted microfibril bundles. It has to be emphasized that ectopia lentis is not pathognomonic for MFS since it is associated with other disorders, which include Ehlers-Danlos syndrome, Weill-Marchesani syndrome, congenital contractural arachnodactyly, sulfite oxidase deficiency, and homocystinuria. Other less specific ocular disorders associated with MFS include myopia, glaucoma, cataracts, and retinal detachment.

  
  
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  Lastly, patients with MFS have a high incidence of pain: Grahame et al. demonstrated that as many as 70% to 96% of patients report pain in at least one location in the body. The underlying etiology of the pain is idiopathic and remains to be elucidated.