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CME: Inherited Disorders

A review of Ehlers-Danlos syndrome

Miller, Erin PA-C; Grosel, John M. MD

Author Information
Journal of the American Academy of Physician Assistants: April 2020 - Volume 33 - Issue 4 - p 23-28
doi: 10.1097/01.JAA.0000657160.48246.91
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Abstract

CASE

Figure
Figure
Box 1
Box 1

A 12-year-old girl presented to her primary care provider to discuss several complaints, including worsening joint pain that had started when she was age 5 years. She participated in numerous athletic activities throughout her childhood, but had begun to limit her physical activity as her joint pain made it increasingly difficult.

History

At birth, the patient was found to have a congenital dislocation of her right hip, which was treated conservatively, and a right-sided pneumothorax that improved without intervention.

When the patient was age 11 months, her mother noted an unusual head posture and took her to a pediatrician. Radiographs of her spine revealed a 24-degree right thoracolumbar curvature, or dextroscoliosis. Due to these radiographic findings, the patient was referred to a pediatric orthopedic clinic, where MRI revealed a C4 hemivertebra and radiographs showed a significant subluxation of C3 on C4 with flexion. To protect the spinal cord, the patient underwent an anterior and posterior fusion of C3 through C5 at age 18 months and was placed in a halo and cast vest for 6 weeks.

At age 5 years, the patient began having bilateral chronic knee joint pain. Physical examination at that time revealed excessive patellar movement at both knee joints, and the patient was diagnosed with patellar tracking syndrome.

When she was age 7 years, flexion and extension radiographs of the patient's cervical spine showed anterolisthesis of C2 on C3 with neck flexion (Figure 1). She also was found to have a right-sided inguinal hernia and underwent surgical repair.

FIGURE 1
FIGURE 1:
Flexion (A) and extension (B) radiographs of the case patient demonstrating anterolisthesis of the C2 vertebrae on C3 on flexion view, which resolves on extension view. Also note postoperative changes of the patient's C3-C5 vertebrae from her spinal fusion surgery.
Box 2
Box 2

The patient's knee joint pain continued to progress until she was age 9 years, also spreading to the hip and shoulder joints. When she began seeing an orthodontist at age 11 years, her orthodontist noted an abnormally high palate.

At a pediatrician visit shortly after the patient turned age 12 years, a review of systems was positive for chronic fatigue, easy bruising, and delayed wound healing. Physical examination revealed joint hypermobility and a cardiac murmur. Her pediatrician also noted the hyperextensibility and velvety texture of her skin. At this appointment, the patient demonstrated her “party trick,” in which she was able to externally rotate her arm 360 degrees while keeping her shoulder in a neutral position (see video on www.jaapa.com). An echocardiogram revealed aortic valve insufficiency and mild aortic root dilation.

Over the years, the patient and her mother had been told by several healthcare providers that her multiple medical problems were unrelated. However, with the new diagnostic findings and a thorough review of the patient's full medical history, clinicians had a high degree of suspicion for Ehlers-Danlos syndrome (EDS); therefore, she was referred to a pediatric geneticist. She was later diagnosed with EDS type II, now known as classical EDS (cEDS). Genotyping showed a heterozygous mutation of the COL52A gene, confirming the diagnosis.

In the years following her diagnosis, the patient continued to receive medical monitoring and developed many medical conditions known to be related to EDS, including migraines, postural orthostatic tachycardia syndrome, a grade V patent foramen ovale, and delta granule storage pool deficiency. In addition, she had to stop playing sports due to debilitating joint pain shortly after her 15th birthday.

Outcome

At ages 16 and 17 years, the patient underwent surgery on her left and right feet, respectively, for repair of hammertoes of all five digits bilaterally. Continued imaging of her cervical spine revealed further instability of her C2 on C3 vertebrae (Figure 2). To treat and monitor her various symptoms, the patient regularly sees several specialists, including cardiology, orthopedics, internal medicine, neurology, and EDS specialists. She also routinely receives physical therapy.

FIGURE 2
FIGURE 2:
Radiographs of the case patient's right foot before (A) and after (B) surgery on all five digits for correction of hammertoes.

UNDERSTANDING EDS

EDS is a broad term that describes a group of heritable connective tissue disorders that are classified together due to shared phenotypic and genotypic features.1,2 The phenotypic hallmarks are tissue fragility, joint hypermobility, and skin hyperextensibility.1-3 These shared features vary in degree in all subtypes, which helps to differentiate EDS from other joint hypermobility disorders.2,4 Genetically, EDS results from defects in genes involved in collagen biosynthesis or structure.2 The syndrome is estimated to affect about 1 in 5,000 people worldwide.4,6-8

Since the discovery of EDS, five different classification systems have been used by clinicians.1,2,4 The Villefranche Nosology, which was the most recent nosology used until 2017, recognized six EDS subtypes according to major and minor clinical criteria.1,2 Since the introduction of the Villefranche Nosology, research on EDS has expanded and new subtypes were discovered. Therefore, an updated classification system for EDS was proposed.1

The International Consortium on EDS, formed in 2012, devised the 2017 International Classification of the Ehlers-Danlos Syndromes, which delineated 13 clinical subtypes of EDS according to their clinical manifestations.1,2 Major clinical criteria were proposed for each subtype, which provide high specificity for diagnosis. Minor criteria were developed with less specificity; they can be used to support a clinical diagnosis of suspected EDS.2 Each subtype was given a name that describes its characteristic phenotypic manifestations.2

EDS once was considered to be a relatively rare condition, but as scientific knowledge of EDS increases, clinicians around the world have agreed that it is underdiagnosed.5,6 The abnormal collagen can affect virtually every body system.5 The presentation and severity of EDS range from undetectable or very mild symptoms to severe or even life-threatening disease.6 This heterogeneity in presentation can make diagnosing EDS a clinical challenge.7

CLINICAL SUBTYPES

The 13 clinical subtypes of EDS according to the 2017 International Classification of the Ehlers-Danlos Syndromes are:

  • Classical EDS (cEDS)
  • Vascular EDS (vEDS)
  • Kyphoscoliotic EDS (kEDS)
  • Arthrochalasia EDS (aEDS)
  • Dermatosparaxis EDS (dEDS)
  • Brittle cornea syndrome (BCS)
  • Classical-like EDS (clEDS)
  • Spondylodysplastic EDS (spEDS)
  • Musculocontractural EDS (mcEDS)
  • Myopathic EDS (mEDS)
  • Periodontal EDS (pEDS)
  • Cardiac-valvular EDS (cvEDS)
  • Hypermobile EDS (hEDS).2

Each subtype has a set of major and minor criteria to guide clinicians evaluating patients with suspected EDS.2 If a patient meets the criteria for a subtype of EDS, further workup is needed. The suspected clinical diagnosis should be confirmed with the appropriate molecular testing.

GENETIC AND PATHOGENETIC MECHANISMS

In addition to the updated clinical classification system, the 2017 International Classification of the Ehlers-Danlos Syndromes also proposed a genetic classification system. This system organizes the clinical subtypes into six groups, A through F, according to their underlying pathogenetic mechanisms. Grouping the subtypes in this manner is beneficial for both the development of treatment options and for guiding future EDS research.2

Group A (cEDS, vEDS, aEDS, dEDS, cvEDS): Disorders of collagen processing and disorders of the primary structure of collagen

Group B (kEDS): A disorder of collagen folding or crosslinking

Group C (clEDS and mEDS): Disorders of the structure and function of the myomatrix

Group D (spEDS [B3GALT6 and B4GALT7 subtypes] and mcEDS): Disorders of glycosaminoglycan biosynthesis

Group E (pEDS): A disorder of the complement pathway

Group F (spEDS [SLC39A13 subtype] and BCS): These are believed to be disorders of intracellular processes; however, the pathogenetic mechanisms of these subtypes are not well understood.

Because the genetic mechanism of hEDS is unknown, it is not included in these groups.2

INHERITANCE PATTERNS

All subtypes of EDS except hEDS have a known genetic basis. EDS can be inherited in an autosomal dominant or recessive manner, or can occur as a novel genetic mutation.2 For example, mEDS can be inherited by either dominant or recessive pattern; cEDS, vEDS, hEDS, aEDS, and pEDS all are autosomal dominant. The remaining subtypes are inherited in an autosomal recessive pattern.2 Therefore, family history and genetic counseling are important when evaluating a patient with suspected EDS.6 Genetic counseling will be further discussed in the diagnosis section.

PHYSICAL EXAMINATION OF HALLMARK SYMPTOMS

The extensive number of ways in which EDS manifests can cause many abnormal physical examination findings; therefore, recognizing the underlying pathology can prove difficult.5 The recognition and evaluation of the hallmark symptoms of EDS (tissue fragility, joint hypermobility, and skin hyperextensibility) are important first steps in the diagnosis and workup of these patients.2,5

Tissue fragility

Symptoms of tissue fragility are common among patients with EDS and can manifest in many ways. Minor manifestations of tissue fragility may include poor wound healing, dystrophic scars, and easy bruising.3 More severe and even life-threatening manifestations of tissue fragility can cause gastrointestinal bleeding, cerebrovascular or intracranial bleeding, and aneurysm formation and rupture.8

Joint hypermobility

This descriptive term is used to describe a joint that has an increased range of motion compared with a normal joint. Generalized joint hypermobility may indicate a larger underlying pathology. In patients with generalized joint hypermobility, affected joints are typically present in the four limbs and axial skeleton. When considering a diagnosis of EDS, clinicians must differentiate between a single hypermobile joint and generalized joint hypermobility.2,9 Several methods can be used to assess generalized joint hypermobility; the most common method involves calculating the Beighton score (Table 1).9-12

TABLE 1
TABLE 1:
The Beighton scoring system for evaluation of generalized joint hypermobility. For each symptom present the patient gets one point. A score of 5 or greater is indicative of generalized joint hypermobility.

Under the Beighton scoring system, patients are given a numeric score on a scale of 0 to 9; a score of 5 or greater indicates generalized joint hypermobility. The updated EDS classification system proposes that clinicians using the Beighton score to assess patients with suspected hEDS must take patient age into account because joint range of motion decreases with age. Therefore, when evaluating prepubertal patients with suspected hEDS, a score of 6 or greater is considered positive. For patients of pubertal age up to age 50 years, a score of 5 or greater is considered positive, and for patients older than age 50 years, a score of 4 or greater is considered positive.2

Skin hyperextensibility

Evaluate skin extensibility by pulling the cutaneous and subcutaneous skin layers until resistance is felt. The skin should stretch easily, and upon release should snap back into place. Testing should be performed in areas that are less likely to undergo mechanical trauma or scarring.2,3

Skin should be considered hyperextensible if it can be stretched excessively in at least three of these locations: distal forearms, dorsum of the hands, neck, elbows, or knees.2 If the skin of the distal forearms and dorsum of the hands can be stretched at least 1.5 cm, or skin of the neck, elbow, and knees stretched at least 3 cm, it is considered hyperextensible (Figure 3).2

FIGURE 3
FIGURE 3:
The case patient demonstrating hyperextensibility of her skin at her elbow (A) and knee (B).

DIAGNOSIS

Diagnosing EDS is considered complex for several reasons.5,13,14 Medical professionals' training often does not include a comprehensive education on the diagnosis and management of EDS.15 Furthermore, many signs and symptoms may be subtle, and thus may not readily alert clinicians to the possibility of an underlying pathology.13 Features of EDS often overlap with symptoms of other connective tissue disorders, such as joint hypermobility syndrome, Marfan syndrome, or osteogenesis imperfecta.7,11,14 Clinical differentiation among the EDS subtypes also can be difficult because of overlapping clinical findings.2

Once the clinician has a clinical suspicion of EDS in a patient, referral to a geneticist for genetic testing is needed to confirm the diagnosis.2 However, hEDS is the only subtype that does not have a confirmatory genetic test. Therefore, the diagnosis of this condition must remain clinical.2

Prompt recognition of EDS often is not achieved, and diagnosis typically occurs late.16 Some patients may be diagnosed during their childhood; others may not be diagnosed until adulthood.17 Conclusive research about the average length of time until EDS is diagnosed is lacking; however, a study published by Hamonet and colleagues in 2018 reported an average of 22 years from symptom onset to diagnosis.7

Patients may be seen by many healthcare providers before receiving a diagnosis of EDS. Early recognition and diagnosis of EDS are associated with better clinical outcomes and can reduce unnecessary use of medical resources and testing.16 An early diagnosis also can help reduce symptom severity, prevent complications, and improve patient quality of life.11,16

GENETIC COUNSELING

Consider genetic counseling and testing for immediate family members of patients with EDS.6 Referring the parents of a patient with EDS for evaluation is appropriate even if they are asymptomatic. If a parent is found to be affected, or if the parent's status cannot be determined, refer siblings for genetic evaluation as well. Patients with EDS who wish to conceive should receive genetic counseling to discuss the risk of their children inheriting the disorder.18

Genetic counseling provides patients and their families with important information about the inheritance pattern and implications of the disorder. This, along with genetic testing, lets patients and their families make more informed medical and personal decisions.13,18

MANAGEMENT

Patients with EDS are managed symptomatically because the condition has no known cure.17 However, no guidelines have been established for managing patients with EDS and treatment varies significantly among patients.1 Document the patient's symptoms through a comprehensive history and physical examination, then make referrals to the appropriate specialists. Because EDS typically involves several organ systems, management often entails collaborative efforts among healthcare providers from several specialties.5,16,17

Patient education is an important component of disease management, and may involve ways to prevent unwanted joint events, such as dislocation.17 A healthful lifestyle can help patients strengthen joints, prevent joint injury, and can help prevent increased joint pain later in life. In addition, physical therapy and occupational therapy may be beneficial.19

Several studies have shown an association among EDS, psychological distress, and reduced quality of life.5,20 Many patients are susceptible to anxiety, depression, disability, and social isolation.15,17 Patients diagnosed with EDS may need psychological support, and early intervention may lead to better clinical outcomes.16

Surgery and other procedures

Patients with EDS may have complications during routine medical procedures, surgery, and the perioperative period. For example, one study showed that patients with vEDS are highly susceptible to surgical complications such as severe bleeding and complications of anesthesia. Patients with EDS should obtain preoperative clearance before undergoing surgery. Clinicians may consider sending these patients to a specialized preoperative evaluation center for clearance.6

Obstetric considerations

Consider referral to an obstetrician who handles high-risk pregnancies for all pregnant patients with EDS, because complications such as premature rupture of membranes, uterine hemorrhage, or uterine rupture can occur during pregnancy and delivery.13,18

Cardiovascular problems

EDS is associated with an increased incidence of cardiovascular abnormalities, such as mitral valve prolapse and aortic dissection.13 Although standardized guidelines are lacking for evaluating cardiovascular abnormalities in patients with EDS, baseline echocardiograms often are obtained at the time of diagnosis.13 Aortic diameter measurement also is recommended, and may require additional evaluation with CT or MRI angiography if visibility on echocardiogram is limited.7,13 Referral to a cardiologist often is warranted for patients with EDS.16,19

Chronic pain

This is one of the most common complaints in patients with EDS, and can impair patients' school and work lives, personal relationships, and psychological well-being. Treating pain in patients with EDS can be challenging and may require referral to a pain specialist.21-23 Management typically involves a multimodal approach, using such methods as physical, occupational and cognitive behavioral therapies, pharmacologic agents, splinting of unstable joints, compression garments, shoe inserts, and specialized exercise programs.22,23

Opioids may be useful in these patients, but should be used with caution. One study found that, compared with age-matched controls, patients with EDS are prescribed opioids more frequently and at higher doses than patients who do not have EDS. Chronic opioid use can lead to tolerance and an increased risk for dependence.21

CONCLUSION

EDS is a complex disease caused by mutations in genes involved in the structure and biosynthesis of collagen. The newest EDS classification system can serve as a diagnostic framework for clinical evaluation of patients with suspected EDS. The diagnosis should be confirmed with the appropriate genetic testing. Prompt recognition, diagnosis, and initiation of treatment in patients with EDS are associated with better clinical outcomes and quality of life. Although an updated system for diagnosing the subtypes of EDS has been established, no standard criteria exist for managing the syndrome; referral to multiple medical specialists typically is required.

REFERENCES

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Keywords:

Ehlers-Danlos syndrome; connective tissue disease; joint hypermobility; tissue fragility; skin hyperextensibility; heritable disease

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