Clinical Guidance

No genotype-phenotype correlations have emerged to date.

Source: GeneReviews — "Classic Ehlers-Danlos Syndrome"

Penetrance

Penetrance is presumably 100% in both males and females, but in some individuals the condition is very mild, and may be undiagnosed.

Source: GeneReviews — "Classic Ehlers-Danlos Syndrome"

Diagnostic Criteria

There are no consensus clinical diagnostic criteria for classic Ehlers-Danlos syndrome (cEDS); diagnosis requires molecular testing. Suggestive Findings Classic EDS should be suspected in a proband with either of the following: • skin hyperextensibility and atrophic scarring OR • generalized joint hypermobility (GJH) and/or ≥3 Major criteria • Skin hyperextensibility is measured by pinching and lifting the cutaneous and subcutaneous layers of the skin on the volar surface at the middle of the nondominant forearm as described by . Skin is hyperextensible if it can be stretched over a standardized cutoff in three of the following areas: 1.5 cm for the distal part of the forearms and the dorsum of the hands; 3 cm for neck, elbows, and knees. • Atrophic scarring (See .)

• GJH depends on an individual's age, sex, and family and ethnic background. Joint hypermobility in cEDS is usually general, affecting both large and small joints, and is usually noted when a child starts to walk. It should be assessed using the Beighton scale, the most widely accepted grading system for the objective semiquantification of joint hypermobility . A Beighton score of ≥5 is considered positive for the presence of GJH.Table 1. Beighton Criteria for Joint HypermobilityJoint/Finding. Negative. Unilateral. Bilateral. Passive dorsiflexion of the 5th finger 90. 0. 1. 2. Passive flexion of thumbs to the forearm. 0. 1. 2. Hyperextension of the elbows beyond 10. 0. 1. 2. Hyperextension of the knees beyond 10. 0. 1. 2. Forward flexion of the trunk with knees fully extended and palms resting on the floor. 0. 1 Since laxity decreases with age, individuals with a Beighton score of 5 may be considered positive based on historical observations.. —

Source: GeneReviews — "Classic Ehlers-Danlos Syndrome"

Differential Diagnosis

Other forms of Ehlers-Danlos syndrome (EDS) should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation. Clinical overlap with classic EDS (cEDS) is seen with all other forms of EDS, in particular with hypermobile EDS (hEDS) and the EDS types listed in . Hypermobile EDS is generally considered the least severe type of EDS, although significant complications, primarily musculoskeletal, can occur. Similar to cEDS, generalized joint hypermobility, mild atrophic scarring, mild skin hyperextensibility, and soft, velvety skin are seen in hEDS. Unlike cEDS, hEDS is not associated with truly papyraceous and/or hemosiderotic scars. The diagnosis of hEDS is based entirely on clinical evaluation and family history. The gene(s) in which pathogenic variants cause hEDS are unknown. Table 4. Ehlers-Danlos Syndrome-Related Genes of Interest in the Differential Diagnosis of Classic Ehlers-Danlos Syndrome

Management Guidelines

For a detailed review of complications and management of classic Ehlers-Danlos syndrome (cEDS), see . Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with cEDS, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Classic Ehlers-Danlos Syndrome: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "Classic Ehlers-Danlos Syndrome"

Clinical Guidance

Sports with heavy joint strain should be avoided (contact sports, fighting sports, football, running).

Source: GeneReviews — "Classic Ehlers-Danlos Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Classic Ehlers-Danlos Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 7.

Classic Ehlers-Danlos Syndrome: Recommended Surveillance

System/Concern | Evaluation | Frequency

Skin | Assessment for skin fragility | At each visit or as needed

Joints/Pain

| Assessment for joint instability, occupational physical therapy needs, mobility issues, pain

Neurologic

| Eval for hypotonia motor development | At each visit in infants children

Hematologic

| Assessment for easy bruising /or prolonged bleeding | At each visit

Eval of clotting factors (platelet count, aPTT, PT, thrombin time) | If severe easy bruising is present

Cardiovascular

| Echocardiogram | In those w/normal initial echocardiogram:

• Children: frequency of follow up per pediatric cardiologist

• Adults: no follow-up echocardiogram necessary

In those w/abnormal echocardiogram (aortic dilatation, mitral valve prolapse): annually

aPTT = activated partial thromboplastin time; PT = prothrombin time

Source: GeneReviews — "Classic Ehlers-Danlos Syndrome"