Connective Tissue Diseases and Rheumatologic Problems in Athletes

Connective Tissue Disorders

Marfan Syndrome

  • Overview: Inheritable autosomal-dominant genetic condition that affects the processing of fibrillin; it is caused by >1800 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. Reported incidence is 1 in 3000–5000 individuals; an estimated 200,000 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 have the following characteristics ( Fig. 41.1 ):

    • Tall (≥97th percentile) and thin

    • Long thin arms, legs, hands, and feet

      • Arm span–to–height ratio is increased: (1:1.05)

    • Aortic root disease, leading possibly to dilatation, regurgitation, and dissection

    • Mitral valve prolapse (40%–54% in two series of Marfan syndrome patients)

    • Joint laxity (including subluxations and dislocations)

    • Reduced joint mobility, particularly in the elbows

    • Joint pain

    • Sixty percent have spinal curvature >20 degrees

    • Pectus (chest wall) deformity (carinatum > excavatum)

    • Visual problems (flat cornea/myopia)

    • Dental crowding (high arched palate)

    • Sports participation where tall, slender build is an advantage. An example would be Flo Hyman (United States Olympic Committee [USOC] volleyball)

    • Arachnodactyly with (+) thumb and wrist signs

    • Hindfoot valgus

    • Vibration of the iris with eye movement—cardinal sign for ectopia lentis

    • Increased risk for spontaneous pneumothorax

    • Skin striae located in uncommon locations like upper arm, axillary region, or thigh

    Figure 41.1, Characteristics of Marfan syndrome.

  • Physical examination: See Fig. 41.1

  • Diagnostics:

    • American College of Cardiology (ACC), American Heart Association (AHA), and American Association for Thoracic Surgery (AATS) as of 2010 recommend echocardiogram to assess for aortic root dilation, aortic dissection, and valvular issues (e.g., mitral valve prolapse [MVP])

    • Annual ophthalmologic evaluation is recommended

    • Imaging of chest and abdomen: computed tomography (CT) scan with intravenous (IV) contrast, magnetic resonance imaging (MRI) with IV contrast, or ultrasound

    • Genetic testing: Blood or tissue samples for FBN1 mutation

      • First-degree relatives of patients with a gene mutation associated with aortic aneurysms/dissection should consider testing.

    • Using diagnostic criteria ( Table 41.1 )

      • The Revised 2010 Ghent Nosology emphasizes 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
      Family History? Criteria Systemic Symptoms
      Yes (need at least 1 criterion for diagnosis) Ectopia lentis
      Systemic score ≥7 points a
      Aortic criterion (aortic diameter Z ≥2 when age ≥20 years, Z ≥3 when age <20 years, or aortic root dissection) a
      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 a
      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.

      a 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 open surgical replacement of the aorta. Use of a beta-blocker has been correlated with increased survival. The dose should be adjusted to maintain the heart rate after submaximal exercise to <100 beats per minute (bpm) in adults and <110 bpm in children. 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. Avoid calcium channel blockers. Valve replacement surgery is also an option, but it is not without severe risks for those with aortic valve insufficiency and ascending aorta dilation. The 2010 ACC/AHA/AATS guidelines recommend elective replacement of aortic valve at an external diameter ≥50 mm to avoid acute dissection or rupture. The 2015 Professional Advisory Statement from the Marfan Foundation stated that there is insufficient evidence for alternative approaches that reinforce rather than replace an aortic aneurysm.

    • 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 . It is not considered acceptable for children with Marfan syndrome to routinely observe exercise by their peers. This will promote stigmatization.

    • 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. Nontraditional treatments like hypnosis, acupuncture, homeopathy, etc., may be effective.

  • 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.

      • Avoid exercising to exhaustion.

      • 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 and Valsalva maneuver (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.

Ehlers–Danlos Syndrome

  • 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 95% 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. The 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 2017, the Ehlers–Danlos Society published the new nosology, diagnostic criteria, treatment, and associated conditions in relation to EDS in the American Journal of Medical Genetics, March 17, 2017 edition. These can be accessed at .

  • 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. The incidence of hEDS is thought to be 1 in 5000 live births, and the frequency of MVP has been reported as 6%.

    • Classical: Second most common type in North America with a prevalence estimated to be around 1 in 20,000; 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% lifetime risk of developing aortic root dilatation; 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 or can have spontaneous pneumothorax or uterine rupture in third trimester). 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). The incidence of vascular EDS is at least 1 in 100,000. This leads to a shortened lifespan with a median age of death of 48 years.

    • 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. Incidence is estimated to be around 1 in 100,000.

    • Dermatosparaxis: Very rare; autosomal recessive, mutations in the ADAMTS2 gene: doughy, redundant skin; diagnosis via skin biopsy. Incidence is unknown.

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

    • Other subtypes of EDS: Be advised there are eight other recognized subtypes of EDS, but they are very rare. Visit for more information.

  • Physical examination: See Fig. 41.2

    • Beighton Scale (score: ≥5/9)

    • Excessive subtalar motion

    • Pes planus

    • Pinchable skin in the relaxed palmar aspect of hand

    • Pectus deformity: excavatum more common than carinatum

    • Touch tip of tongue to nose

    • Skin hyperextensible to >3 cm at the mandibular angle or over olecranon

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

    • Piezogenic papules (often found near sole of feet)

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

    • Joint pain (acute or chronic, episodic)

    • Joint laxity or hypermobility affecting multiple joints

    • Joint subluxations and dislocations

    • Family history

    • Early osteoarthritis

    • Postural orthostatic tachycardia syndrome (POTS) or dysautonomia

    • Chiari malformation

    • Mast cell activation

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

    • MVP

    • Dental malalignment/gingival issues

    • Sudden death (from vascular or bowel rupture)

    Figure 41.2, Characteristics of Ehlers–Danlos syndrome.

  • 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), 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. The management strategies required in patients with EDS differ to some degree between EDS types and should be individualized depending on the severity of the disease.

    • 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). Obtain baseline screening echocardiography in all patients, both children and adults. For classical and hypermobility types, follow-up examinations are performed every 2–5 years if initial screening studies are normal. No further testing is often needed beyond age 25 if the baseline and follow-up examination are normal. Regular ophthalmologic examinations should be performed in all patients with EDS.

    • 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 Society website at .

    • 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 because of 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. The lifespan for patients with classical and hypermobility types is not decreased. In vascular EDS, 80% of individuals experience a major event by age 40 years, and there is a shortened lifespan with a median age of death of 48 years.

  • Return to sport: Once orthopedic or integument 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. 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.

      • Underweight: Not enough muscle mass to stabilize loose joints

      • 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 intraabdominal pressure and blood pressure because of the existing risk of aortic dilatation or colonic rupture.

Osteogenesis Imperfecta

  • Overview: Also known as brittle bone syndrome , osteogenesis imperfecta (OI) is an inheritable genetic disorder that affects collagen (type 1) ( Fig. 41.3 ). OI is classified into a number of major subtypes based on genetic, radiographic, and clinical characteristics. The genetic defect (the COL1A gene) affects type 1 collagen, which is primarily found in the bone. A total of 16 subtypes of OI have been documented. 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. The type II dominant form has more severe manifestations, including long bone fractures and shortening and severe chest wall deformity.

    Figure 41.3, Characteristics of osteogenesis imperfecta.

  • Incidence: An estimated 20,000–50,000 individuals in the United States have OI.

  • Presentation:

    • Long bones fracture easily. Most fractures occur before puberty. Often there may be “bowing” of long bone with or without fractures and excessive periosteal reaction.

    • Normal or near-normal stature

    • Loose joints and muscle weakness

    • Sclera usually have blue, purple, or gray tint

    • Triangular face

    • Tendency toward spinal curvature

    • Bone deformity absent or minimal

    • Brittle teeth possible

    • Hearing loss possible, often beginning in early 20s or 30s

    • May die in utero (type II)

    • Severe chest wall deformity (type II)

    • Often nonambulatory in wheelchair (type II)

  • Physical examination (see Fig. 41.3 ):

    • Dentinogenesis imperfecta (poorly formed teeth)

    • Blue sclera

    • Bone fragility

    • Basilar skull deformity

    • Pathogenic bowing of long bones and multiplicity of fractures

    • Adult-onset hearing loss

    • Osteoporosis

    • Joint hyperextensibility

    • Short stature/limb shortening or deformity in severe forms

  • Diagnostics : Laboratory findings may show elevated alkaline phosphatase and hypercalciuria. Radiographs may show bowing deformities and multiple fractures/callus formation. Bone scan may show multiple areas of increased uptake as a result of multiple areas of occult or stress fractures. Dual energy x-ray absorptiometry (DEXA) scan may show premature decrease in bone density consistent with osteopenia or osteoporosis. Of skin punch biopsy tests, both the collagen biopsy test and the DNA test are thought to detect almost 90% of all type I collagen ( COL1A1 or COL1A2 ) mutations. A negative type I collagen study does not rule out OI. When a type I collagen mutation is not found, other DNA tests to check for recessive forms are available.

  • Treatment:

    • General: Healthy lifestyle, including exercise and diet. The goals of therapy for patients with OI are to reduce fracture rates, prevent long bone deformities and scoliosis, minimize chronic pain, and maximize mobility and other functional capabilities.

    • Prevention: Protection or avoidance of contact or collision sports is paramount. Medic-alert bracelet/necklace stating condition and severity is recommended. Periodic evaluation of hearing, annual eye examination, bone mineral density with DEXA scan, and spirometry to monitor for restrictive lung defects every 2 years (secondary to rib and vertebral fractures). Bisphosphonates are the mainstay of pharmacologic fracture-prevention therapy. However, women of reproductive age should abstain or prevent conception because of the teratogenicity of bisphosphonates.

    • Orthopedic: Mild strength training to stabilize joint laxity; physical therapy may help (particularly after fractures) with pain control and improvement in function after prolonged immobilization. Often because of the nature of the fracture, open-reduction internal fixation is needed (see Fig. 41.3 ). Unweighted exercises may be beneficial (e.g., pool therapy, harnesses, and total gym). “Off-label” use of bisphosphonates has been advocated by some for between 2 and 5 years. A list of orthopedic clinics specializing in OI is available at .

    • Psychology: Provide empathy and psychological support as per individual’s and family’s needs. Realize parents may have been suspected of child abuse in cases where the diagnosis is delayed, leading to feelings of guilt, frustration, and anxiety. Genetic counseling is always strongly advised, as is putting patient in contact with knowledgeable medical professionals and local/national support groups. Have athletes visit the Osteogenesis Imperfecta Foundation website at .

    • Pain control: Oral, injectable, transdermal, and topical medications, including acetaminophen, NSAIDs, opioids, tramadol, TENS units, bracing, ring splints, ambulation-assist devices, and lastly surgery. Nontraditional treatments, including hypnosis, acupuncture, and homeopathy may help.

  • Prognosis: Depends on the type of OI. In general, patients have a full life expectancy, but morbidity seems to be directly correlated to the number of fractures. Type II has a significant higher morbidity, and patients are often wheelchair-bound if they survive the perinatal period.

  • Return to sport: Absolutely avoid contact/collision sports. Certain high-impact sports may be contraindicated, depending on severity of the condition. Joint and bone protection is crucial both in activities of daily life and in selection of athletic and recreational activities. No cardiovascular limitation noted by the 46th Bethesda Guidelines. Allowed once fracture(s) have both clinically and radiographically healed and matured.

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