A 14-year-old girl is brought to her pediatrician for a routine health maintenance visit. The pediatrician notes that she is tall for her age, has long, slender fingers, hypermobile joints, and that her arm span is longer than her body span (Figures 223-1 to 223-3). She also has a high arched palate and a systolic murmur. The pediatrician refers the girl to a cardiologist, who performs an echocardiogram, which reveals mitral valve prolapse without regurgitation, and dilatation of the aortic root. The pediatrician and cardiologist suspect that the child has Marfan syndrome and order a test for fibrillin 1 mutation, which confirms the diagnosis. Her pediatrician plans a multidisciplinary team for the girl, including baseline and follow-up ophthalmology examinations, and close follow-up visits with the cardiologist, orthopedist, and geneticist.

Marfan syndrome (MFS) is a heritable disorder of connective tissue resulting from mutations in the gene encoding the extracellular matrix protein fibrillin 1(FBN1). Individuals with MFS manifest variable clinical features, which often involve the skeletal, cardiovascular, and ocular systems.

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  The incidence of this disorder is about 1 per 5,000 to 10,000 births.¹

  
  
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  MFS is inherited in an autosomal dominant manner; thus, there is a 50 percent chance of an offspring inheriting the condition from the affected parent.

  
  
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  Approximately 1/3 of cases are sporadic due to de novo mutations; new mutations are often associated with advanced paternal age.

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  MFS is associated with abnormal biosynthesis of fibrillin-1, which is the major constituent of microfibrils. Mutations in FBN1 are found in about 95 percent of patients who meet the diagnostic criteria for Marfan syndrome.^2,3

  
  
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  The FBN1 locus resides on the long arm of chromosome 15 (15q21) and the gene is composed of 65 exons. More than 1,000 mutations distributed throughout FBN1 have been identified, many being unique to a given family.^4,5

  
  
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  The condition results from a structural deficiency of connective tissues. The decreased fibrillin-1 leads to a primary derangement of elastic fiber deposition, along with elastic fiber fragmentation. The decreased elastin in the aorta, skin, and other connective tissue is responsible for accelerated degeneration of tissue resulting in the clinical manifestations.

  
  
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  Mutations in FBN1 are associated with a wide phenotypic spectrum ranging from severe rapidly progressing neonatal manifestations, manifestations that present in childhood and early adulthood, to isolated features such as ectopia lentis or skeletal manifestations.

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  The diagnosis of MFS is based on well-defined clinical criteria. Genetic testing of FBN1 should be reserved for those patients in whom there is strong suspicion of the diagnosis, or for patients who are suspected of having the disorder but who may not meet full clinical criteria.⁶

  
  
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  The revised Ghent diagnostic criteria⁷ outlines a definitive diagnosis of MFS when any of the following are present:

  
  
  
  
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    Aortic root dilation (≥2 z score) and ectopia lentis (z score is a standard measure of aortic root diameter at the sinus of Valsalva based on body surface area).

    
    
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    Aortic root dilation (≥2 z score) and FBN1 mutation.

    
    
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    Aortic root dilation (≥2 z score) and systemic score ≥7 (see the following for scoring system).

    
    
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    Ectopia lentis and FBN1 mutation known to be associated with Marfan syndrome.

    
    
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    Positive family history of Marfan syndrome and ectopia lentis.

    
    
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    Positive family history of Marfan syndrome and systemic score ≥7.

    
    
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    Positive family history of Marfan syndrome and aortic root dilation (≥3 z score) in those <20 y of age or ≥2 z score in those >20 y of age.

  
  
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  A potential diagnosis is made when there is an FBN1 mutation with aortic root dilation with a z score <3 in those <20 years of age.

  
  
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  The systemic scoring system used for the diagnosis of MFS includes:

  
  
  
  
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    Wrist and thumb sign (3 points; Figures 223-4 and 223-5).

    
    
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    Wrist or thumb sign (1 point).

    
    
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    Pectus carinatum (2 points; Figure 223-6).

    
    
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    Pectus excavatum (1 point; Figure 223-6).

    
    
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    Hindfoot deformity (2 points).

    
    
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    Pes planus (1 point; Figure 223-7).

    
    
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    Pneumothorax (2 points).

    
    
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    Dural ectasia (2 points).

    
    
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    Protrusio acetabulae (2 points).

    
    
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    Reduced upper to lower segment ratio and increased arm-span-to-height ratio (1 point; Figure 223-1).

    
    
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    Scoliosis or thoracolumbar kyphosis (1 point; Figure 223-8).

    
    
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    Reduced elbow extension (1 point).

    
    
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    Craniofacial features such as dolichoencephaly, downward-slanting palpebral fissures, endophthalmos, retrognathia, and malar hypoplasia (1 point if at least 3 of these are present).

    
    
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    Skin striae (1 point; Figure 223-9).

    
    
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    Myopia (1 point).

    
    
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    Mitral valve prolapse (1 point).

Clinical Features

The skeletal system

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  Excessive growth of long bones is common, typically resulting in tall stature.

  
  
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  Disproportionate growth of skeletal systems results in an arm span >1.05 times the height, or a reduced upper to lower segment ratio (in the absence of severe scoliosis; Figure 223-1).

  
  
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  Arachnodactyly (long spider like fingers) is generally a subjective finding (Figure 223-2). The combination of long fingers and loose joints leads to the characteristic:

  
  
  
  
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    Walker-Murdoch or “Wrist” sign—Full overlap of the distal phalanges of the thumb and fifth finger when wrapped around the contralateral wrist (Figure 223-4).

    
    
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    The Steinberg or “Thumb” sign—Distal phalanx of the thumb fully extends beyond the ulnar border of the hand when folded across the palm, with or without active assistance by the patient or examiner (Figure 223-5).

  
  
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  Patients may have overgrowth of the ribs, pushing the sternum anteriorly (pectus carinatum) or posteriorly (pectus excavatum; Figure 223-6).

  
  
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  Thoracolumbar scoliosis is present in about half of individuals with MFS and can range from mild to severe and can be progressive (Figure 223-8).

  
  
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  Pes planus (flat feet) is commonly present and varies from mild and asymptomatic to severe deformity (Figure 223-7).