Is genetic testing recommended for diagnosing hypermobile Ehlers-Danlos Syndrome (hEDS)?

Genetic Testing for Hypermobile Ehlers-Danlos Syndrome (hEDS)

Genetic testing is not currently recommended for diagnosing hypermobile Ehlers-Danlos Syndrome (hEDS) as no specific genetic mutation has been identified for this condition. 1

Diagnostic Approach for hEDS

• The diagnosis of hEDS is based primarily on clinical evaluation and family history, not genetic testing 1
• The 2017 diagnostic criteria for hEDS requires fulfillment of three major criteria:
  1. Generalized joint hypermobility (using the 9-point Beighton scale) 1
  2. Presence of systemic manifestations consistent with connective tissue disorder 1
  3. Exclusion of alternative diagnoses 2

Role of Genetic Testing in hEDS Evaluation

• While a small subset of individuals with hypermobile EDS have insertions or deletions in the TNXB gene, this is not common enough to warrant routine genetic testing 1
• Genetic testing is valuable primarily to rule out other EDS subtypes and related connective tissue disorders that may present with similar features 2, 3
• Recent research shows that genetic testing identified alternative or additional diagnoses in 26.4% of patients clinically diagnosed with hEDS, highlighting its importance in the exclusion process 2

When Genetic Testing Should Be Considered

• When clinical features suggest a different EDS subtype (other than hypermobile) 4, 5
• When there are features that overlap with other heritable connective tissue disorders 3
• When there is a strong family history suggesting a monogenic disorder 5
• For patients with aortic root/ascending aneurysms or thoracic aortic dissection with risk factors for heritable thoracic aortic disease 1

Diagnostic Evaluation Algorithm for hEDS

1. Comprehensive clinical assessment using the 2017 diagnostic criteria 1, 6:

   • Joint hypermobility assessment (Beighton score ≥5)
   • Evaluation of skin characteristics (soft/velvety with normal or slightly increased extensibility)
   • Assessment for absence of skin/soft tissue fragility

2. Evaluation for systemic manifestations and minor diagnostic criteria 1:

   • Recurrent joint dislocations or subluxations
   • Chronic joint or limb pain
   • Easy bruising
   • Functional bowel disorders
   • Neurally mediated hypotension or POTS
   • Dental and palate abnormalities

3. Family history assessment (three generations) 1

4. Exclusion of other conditions through:

   • Echocardiogram to evaluate for aortic root dilatation 1
   • Dilated eye exam to exclude Marfan syndrome 1
   • Consideration of genetic testing only to rule out other EDS subtypes or related disorders 3, 5

Important Clinical Considerations

• Hypermobile EDS may present with extra-articular manifestations including anxiety disorders, chronic pain, fatigue, orthostatic intolerance, and gastrointestinal disorders 6
• Testing for POTS should be considered in patients with orthostatic intolerance symptoms 1
• Evaluation for mast cell activation syndrome (MCAS) may be warranted in patients with episodic symptoms affecting multiple physiological systems 1
• Regular cardiovascular surveillance is recommended due to the risk of aortic root dilation in 25-33% of individuals with hEDS 1

Pitfalls and Caveats

• Relying solely on genetic testing for hEDS diagnosis will lead to false negatives as no specific genetic mutation has been identified 5
• Failure to exclude other EDS subtypes or related disorders may lead to inappropriate management 2
• Hypermobility may represent a shared phenotype across multiple disorders, including inflammatory diseases and chromosomal abnormalities 2
• Genetic testing in children with suspected EDS should be guided by the 2017 clinical diagnostic criteria, as molecular diagnosis was confirmed in only 28% of children who did not fully meet clinical criteria 4