Overview: Inheritable autosomal-dominant genetic condition that affects the processing of fibrillin; it is caused by >400 mutations in the gene encoding fibrillin-1 (FBN-1), located on chromosome 15 at the q21 loci. Approximately 10% of patients with Marfan phenotype have no identifiable mutation in the FBN1 gene; mutations in TGF-beta receptor 2 and TGF-beta receptor 1 genes have been linked to these patients. Incidence is 1 in 3000–10,000 live births; an estimated 2,00,000 Americans have Marfan syndrome. Fibrillin, which is a major component of microfibrils, is found in large amounts in the aortic root > aorta > lens > joints > other connective tissues.

Presentation: Athletes with Marfan syndrome may ( Fig. 41.1 ):

• •
  

  Be tall (≥97th percentile) and thin

  
  
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  Have long thin arms, legs, hands, and feet

  
  
• •
  

  Present with sudden death (aortic root dissection)

  
  
• •
  

  Complain of joint laxity (including joint subluxations and dislocations)

  
  
• •
  

  Have paradoxical reduction in joint mobility, particularly in the elbow and digits

  
  
• •
  

  Have joint pain

  
  
• •
  

  Have scoliosis (60% have curvature >20 degrees)

  
  
• •
  

  Have a pectus (chest wall) deformity (carinatum > excavatum)

  
  
• •
  

  Have visual problems

  
  
• •
  

  Have dental crowding

  
  
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  Be drawn to sports where tall, slender build is an advantage (e.g., basketball, volleyball, rowing, and track)

  
  
• •
  

  Famous athletes with Marfan syndrome include Flo Hyman (the United States [US] 1984 Olympic Silver Medalist in Volleyball—died of aortic dissection)

Characteristics of Marfan syndrome.

Physical examination: See Fig. 41.1

Diagnostics:

• •
  

  Echocardiogram: aortic root dilation, aortic dissection, and valvular issues (e.g., mitral valve prolapse [MVP])

  
  
• •
  

  Slit-lamp examination or ocular ultrasound: look for lens abnormalities

  
  
• •
  

  Imaging of chest and abdomen: CT scan with IV contrast, MRI with IV contrast, and ultrasound

  
  
• •
  

  Genetic testing: via blood or tissue samples for FBN-1 mutation; may be helpful if family members are tested

  
  
• •
  

  Using diagnostic criteria (see Table 41.1 )

  
  
  
  
  • •
    

    The Revised 2010 Ghent Nosology emphasizes more on cardinal clinical features of Marfan syndrome (aortic root dilatation/dissection and ectopia lentis) and on testing for mutations in the FBN1 gene.

    
    
  • •
    

    Application of diagnostic criteria to individuals aged <20 years requires special care because additional clinical features may present/develop later.

  
  
  
  

  TABLE 41.1

  
  

  GHENT NOSOLOGY

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Family History?	Criteria	Systemic Symptoms
  Yes (need at least 1 criterion for diagnosis)	Ectopia lentis Systemic score ≥7 points * Aortic criterion (aortic diameter Z ≥2 when age ≥20 years, Z ≥3 when age <20 years, or aortic root dissection) *	Wrist AND thumb sign: 3 points (wrist OR thumb sign: 1 point) Pectus carinatum deformity: 2 points (pectus excavatum or chest asymmetry: 1 point) Hindfoot valgus: 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 with full extension): 1 point Facial features (at least 3 of the following 5 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 prolapsed (all types): 1 point
  No (need at least 1 criterion for diagnosis)	Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and ectopia lentis * Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and a causal FBN1 mutation Aortic criterion (aortic diameter Z ≥2 or aortic root dissection) and a systemic score ≥7 Ectopia lentis and a causal FBN1 mutation that has been identified in an individual with aortic aneurysm

   
  

  Aortic Root Z score determined by height, weight, age, and aortic root (in cm) at sinuses of Valsalva.

  
  

  * Diagnosis of Marfan syndrome can be made only in the absence of discriminating features of Shprintzen–Goldberg syndrome, Loeys–Dietz syndrome, or vascular Ehlers–Danlos syndrome and after TGFBR1/2, collagen biochemistry, or COL3A1 testing, if indicated.

  
  

Treatment:

• •
  

  General : Healthy lifestyle, including exercise and diet to control lipids and systemic blood pressure; Medic-alert bracelet/necklace stating the condition

  
  
• •
  

  Prevention : Annual evaluation of eyes (ectopic lentis or lens dislocation), heart (valvular issues, aortic root dilatation, or dissection), and imaging of chest and abdomen (identifying/following aortic dissections, aneurysms, or dilatation)

  
  
• •
  

  Vascular: Echocardiogram should be performed at the time of diagnosis and 6 months later to determine the rate of enlargement of the aortic root and ascending aorta. If stable over time, monitor annually for any changes in the aorta. Avoid strenuous activities that will increase intrathoracic pressure (e.g., powerlifting). If aortic pathology worsens, consider intraluminal prosthetic device versus elective open surgical replacement of the aorta. Use of a beta-blocker has been correlated with increased survival. The age at which beta-blockers should be initiated is still debated. Therapy targeting the renin–angiotensin system, such as losartan, may reduce aortic root dilatation rate in adults. Valve replacement surgery is also an option, but it is not without severe risks for those with aortic valve insufficiency and ascending aorta dilation.

  
  
• •
  

  Orthopedic: Mild strength training to stabilize severe joint laxity; physical therapy (particularly joint and core strengthening, proprioceptive training modalities, and strengthening)

  
  
• •
  

  Psychology: Provide empathy and psychological support as per the individual’s and family’s needs; genetic counseling is always strongly advised, as is putting the patient in contact with knowledgeable medical professionals and local/national support groups such as the National Marfan Foundation at www.marfan.org

  
  
• •
  

  Pain control: Encourage smoking cessation. Control pain with oral, injectable, transdermal, and topical medications including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, tramadol, transcutaneous electrical nerve stimulation (TENS) units, bracing, ring splints, and lastly, surgery.

Prognosis: In 1972, the mean age of death was 32 (range, 16–48) years. By 1995, the median cumulative probability of survival was 72 years.

Return to play:

• •
  

  46th Bethesda American College of Cardiology recommendations (2015):

  
  
  
  
  • •
    

    May participate in low and moderate static/low-dynamic competitive sports if they do not have one of the following: aortic root dilation, moderate-to-severe mitral valve regurgitation, or family history of aortic dissection at an aortic diameter of <50 mm.

    
    
  • •
    

    Athletes with aortic root dilation may only participate in low-intensity competitive sports.

    
    
  • •
    

    Avoid sports with bodily collision.

    
    
  • •
    

    Same recommendation for aortic valve regurgitation

    
    
  • •
    

    Prefer nonstrenuous, low-static, low-dynamic sports (e.g., golf, walking, billiards, riflery, and bowling).

  
  
  
  
• •
  

  Encourage an active lifestyle.

  
  
  
  
  • •
    

    Favor noncompetitive, isokinetic exercise performed at a nonstrenuous aerobic pace.

    
    
  • •
    

    Avoid activities that involve high levels of isometric workloads (e.g., Olympic weightlifting, gymnastics, etc.).

    
    
  • •
    

    Mild strength training (nonbreath-holding) if joint laxity is present; prefer multiple repetitions at lower resistance rather than maximal repetitions at higher resistance

    
    
  • •
    

    Be careful in environments with rapid atmospheric pressure changes (scuba diving or flying in an unpressurized cabin) or rapid decelerations (car racing or skydiving).

    
    
  • •
    

    Control lipid levels, blood pressure, and blood sugar to decrease long-term injury to the vascular endothelium.

    
    
  • •
    

    Educate the patient regarding the risks of participation.

    
    
  • •
    

    Use protective eyewear whenever appropriate.

  
  
  
  
• •
  

  Once orthopedic or ocular injury has healed and the injured area is adequately protected, the athlete may return to play. Support the patient with reasonable adaptive measures in order to participate.

Overview: Group of inheritable genetic conditions that affect connective tissue, particularly collagen in joints, vessels, skin, and internal organs; variable severity seen within each type and within the same family of pedigree; there are six types of Ehlers–Danlos syndrome (EDS), of which, 90% seem to fall into the first three categories (hypermobility, classical, and vascular). Incidence is approximately 1 in 5000 live births. The term generalized or benign joint hypermobility syndrome (GJHS or BJHS) was first used by Kirk, Ansell, and Bywaters in 1967. EDS hypermobility type was first described as a condition in 1946 and noted to be genetically based in 1970. The description of BJHS also uses the Beighton Scale and the same diagnostic criteria as EDS hypermobility type. Essentially, they are the same entity with only varying degrees of expressivity. A literature review seems to reveal no significant difference in the nosology between BJHS and aspects of EDS hypermobility type. BJHS seems to be a term preferred by those outside genetic circles (e.g., rheumatology, orthopedics, etc.) and EDS hypermobility type and Marfan syndrome are preferred by general medical and genetic groups. As of 2016, just after this chapter went to print, an international group, Ehlers–Danlos Society, published the NEW nosology, diagnostic criteria, treatment, and associated conditions in relation to EDS. The results will be available at www.ednf.org .

Presentation:

• •
  

  Hypermobility: Most common type in North America; autosomal dominant inheritance with unknown underlying genetic abnormality: mild to severe joint laxity, most often involving multiple joints subluxating or dislocating, mild skin involvement, chronic joint pain with often normal imaging studies, Beighton Scale score of ≥5/9, and 22% risk of developing aortic root dilatation in lifetime; 12% of pediatric patients with EDS show aortic root dilatation on their first echocardiogram.

  
  
• •
  

  Classical: Second most common type in North America; autosomal dominant inheritance, mutations found within the collagen genes COL5A1 and COL5A2, interact with type 1 collagen molecules during fibrillogenesis. Skin hyperextensibility, wide atrophic scarring (“cigarette paper scar tissue”), and joint hypermobility are the major criteria. Minor criteria include easy bruising; soft, doughy skin; tissue friability; molluscoid pseudotumors; piezogenic papules; hernia; epicanthal folds around eyes, and first-degree family member with EDS. Diagnosis must have one major and two minor criteria or three minor criteria. There is a 33% risk of developing aortic root dilatation in lifetime; 6% of pediatric patients with EDS show aortic root dilatation on their first echocardiogram; early osteoarthritis particularly in smaller joints.

  
  
• •
  

  Vascular: Third most common type in North America; autosomal dominant inheritance, mutations in the COL3A1 gene; life-threatening (sudden death often from aortic/vascular or bowel rupture). Particular facial features include delicate nose, wide-set eyes, thin cheekbones, thin, translucent skin, very prominent veins on extremities and chest, skin friability, and mild to moderate joint laxity; a very significant risk (90% by the age of 40) of developing aortic pathology (e.g., root dilatation, aneurysm, and dissection).

  
  
• •
  

  Kyphoscoliotic: Very rare; autosomal recessive inheritance, mutations in the PLOD1 gene: severe congenital hypotonia, progressive scoliosis, risk of ocular rupture, marfanoid body habitus, and diagnosis via urine test available

  
  
• •
  

  Dermatosparaxis: Very rare; autosomal recessive, mutations in the ADAMTS2 gene: doughy, redundant skin, autosomal recessive, diagnosis via skin biopsy

  
  
• •
  

  Arthrochalasia: Very rare; autosomal dominant inheritance, mutations in COL1A1 or COL1A2: congenital hip dislocation, atrophic scars, joint hypermobility, and diagnosis via skin biopsy

Physical examination: See Fig. 41.2

• •
  

  Beighton scale (score: ≥5/9)

  
  
• •
  

  Excessive subtalar motion

  
  
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  Pes planus

  
  
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  Pinchable skin in the relaxed palmer aspect of hand

  
  
• •
  

  Pectus deformity: excavatum more common than carinatum

  
  
• •
  

  Touch tip of tongue to nose

  
  
• •
  

  Skin hyperextensibile to >3 cm at the mandibular angle

  
  
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  Widened, atrophic scars (known as “cigarette paper scar tissue”) (see Fig. 41.2 )

  
  
• •
  

  Piezogenic papules (often found near sole of feet)

  
  
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  Subcutaneous spheroids (subcutaneous, firm, small, and mobile)

  
  
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  Joint pain (acute or chronic, episodic)

  
  
• •
  

  Joint laxity or hypermobility affecting multiple joints

  
  
• •
  

  Joint subluxations and dislocations

  
  
• •
  

  Family history

  
  
• •
  

  Early osteoarthritis

  
  
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  Postural orthostatic tachycardia syndrome (POTS)

  
  
• •
  

  Chiari malformation

  
  
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  Mast cell activation

  
  
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  Hernias (e.g., ventral, umbilical, and inguinal)

  
  
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  MVP

  
  
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  Dental malalignment/gingival issues

  
  
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  Sudden death (due to vascular or bowel rupture)

Characteristics of Ehlers–Danlos syndrome.

(Photograph from Goldman L, Ausiello D, Arend W, et al., eds: Cecil Textbook of Medicine , 23 ^rd ed. Philadelphia: Elsevier, 2007.)

Diagnostics: Genetic testing, echocardiogram periodically, CT scan of chest and abdomen with IV contrast or ultrasound periodically, skin punch biopsy (4 mm) or blood serum put into a live medium for EDS and TGF-beta (e.g., Chlamydia culture) (currently only for classical and vascular types), and radiographs, and other imaging of affected joints

Treatment:

• •
  

  General: Healthy lifestyle that includes exercise and diet to control lipids and systemic blood pressure; Medic-alert bracelet/necklace stating condition

  
  
• •
  

  Prevention: Periodic evaluation of heart (e.g., valvular issues), chest/abdomen (e.g., identifying/following aortic dissections, aneurysms, or dilatation), and eyes (e.g., annual ophthalmologic evaluations in kyphoscoliotic type)

  
  
• •
  

  Vascular: Monitor any changes in the aorta and avoid strenuous activities that will increase intrathoracic pressure (e.g., powerlifting); if aortic pathology worsens, consider intraluminal prosthetic device versus elective open surgical replacement of aorta; encourage smoking cessation.

  
  
• •
  

  Orthopedic: Mild strength training to stabilize severe joint laxity; physical therapy, particularly joint and core strengthening, proprioceptive training modalities, strengthening, and unweighted exercise (e.g., pool therapy, harnesses, and total gym)

  
  
• •
  

  Psychology: Provide empathy and psychological support as per individual’s and family’s needs. Genetic counseling is always strongly advised, as is putting patient in contact with knowledgeable medical professionals and local/national support groups. Have the athlete visit the Ehlers Danlos National Foundation website at www.ednf.org .

  
  
• •
  

  Pain control: Oral, injectable, transdermal, and topical medications including acetaminophen, NSAIDs, tramadol, TENS units, bracing, ring splints, ambulation-assist devices, and lastly surgery; use opioids only for acute trauma or as intermittent rescue medication owing to the risk of dependence from chronic use.

Prognosis: Proportion of patients with EDS who will develop pathology within their aortic root or aorta: 90% vascular type, 33% classical type, and 22% hypermobility type

Return to sport: Once orthopedic or integument injury has healed and the injured area adequately protected, the athlete may return to play. Support the patient with reasonable adaptive measures in order to participate. According to the 46th Bethesda recommendations (2015):

• •
  

  Individuals with vascular type EDS may participate in low-static, low-dynamic sports if they do not have any of the following: aortic enlargement or dissection (or branch vessel enlargement), moderate to severe mitral regurgitation, or extracardiac organ system involvement that makes participation hazardous.

  
  
• •
  

  Keep normal weight.

  
  
  
  
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    Underweight: Not enough muscle mass to stabilize loose joints

    
    
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    Overweight: Promotes early osteoarthritis

  
  
  
  
• •
  

  Encourage an active lifestyle.

  
  
• •
  

  Control lipids, blood pressure, and blood sugar to decrease long-term injury to vascular endothelium.

  
  
• •
  

  Mild to moderate strength training is often helpful in joint stabilization.

  
  
• •
  

  Encourage noncontact nontraumatic sports, particularly for those with skin fragility (i.e., classical type) and severe joint laxity (i.e., hypermobility type).

  
  
• •
  

  Do not recommend high-dynamic sports that could increase intra-abdominal pressure and blood pressure owing to the existing risk of aortic dilatation or colonic rupture.

Overview: Also known as brittle bone syndrome , osteogenesis imperfecta (OI) is an inheritable genetic disorder that affects collagen (type 1) ( Fig. 41.3 ). A classification system is commonly used to describe how severely a person is affected by OI. The genetic defect (the COL1A gene) affects type 1 collagen, which is primarily found in the bone. A total of nine types of OI have been documented (most autosomal dominant; four types have autosomal recessive expressivity). There are two major forms of OI: Type I and Type II. In the Type I dominant (classical) form, the patient has extremely little or a poor quality of type 1 collagen. Type II dominant form has more severe manifestations, including long bone fractures and shortening and severe chest wall deformity.

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