Ehlers-Danlos Syndromes (EDS): Diagnosis, Clinical Criteria, and Genetic Testing

How to Diagnose EDS?

Diagnosing Ehlers-Danlos Syndromes (EDS) is a complex process primarily based on clinical criteria, patient history, and physical examination, often supported by genetic testing for specific subtypes, and requires a multidisciplinary approach.

Understanding Ehlers-Danlos Syndromes (EDS)

Ehlers-Danlos Syndromes (EDS) are a group of heritable connective tissue disorders characterized by defects in collagen synthesis or processing. Collagen is the most abundant protein in the body, providing strength and elasticity to skin, joints, blood vessels, and other tissues. Due to these defects, individuals with EDS can experience a wide range of symptoms affecting various body systems, including joint hypermobility, skin hyperextensibility, tissue fragility, chronic pain, and autonomic dysfunction. There are 13 recognized types of EDS, each with distinct genetic causes and clinical manifestations, though Hypermobile EDS (hEDS) is the most common and often the most challenging to diagnose genetically.

The Diagnostic Journey: A Multi-faceted Approach

Diagnosing EDS is not achieved through a single test but rather through a comprehensive evaluation that integrates several key components. This journey typically involves a thorough clinical assessment, detailed patient and family history, a specific physical examination to assess joint hypermobility, and, for many types, confirmatory genetic testing. The process is often iterative, requiring collaboration among various medical specialists.

Initial Clinical Assessment and Patient History

The diagnostic process typically begins with a detailed clinical assessment by a knowledgeable physician, often a geneticist, rheumatologist, or medical specialist familiar with connective tissue disorders.

• Detailed Medical History: The clinician will inquire about a wide array of symptoms, including:
  • Joint-related issues: Frequent dislocations or subluxations, chronic joint pain, early-onset osteoarthritis.
  • Skin characteristics: Soft, velvety skin, easy bruising, poor wound healing, atrophic scars.
  • Systemic symptoms: Chronic fatigue, gastrointestinal problems (e.g., dysmotility, reflux), autonomic dysfunction (e.g., postural orthostatic tachycardia syndrome - POTS), bladder dysfunction, dental issues, eye problems.
  • Pain profile: Nature, location, and severity of chronic pain.
• Family History: A comprehensive family history is critical, as EDS is a genetic condition. The clinician will look for patterns of similar symptoms or diagnosed conditions among first-degree relatives, which can provide crucial clues about the inheritance pattern and potential type of EDS.

The Beighton Score: Assessing Joint Hypermobility

A key component of the physical examination for EDS, particularly hEDS, is the assessment of generalized joint hypermobility using the Beighton Score. This is a 9-point system that evaluates the range of motion in specific joints:

• Passive dorsiflexion of the 5th metacarpophalangeal joint to 90 degrees or more (1 point for each hand).
• Passive apposition of the thumb to the forearm (1 point for each hand).
• Elbow hyperextension beyond 10 degrees (1 point for each arm).
• Knee hyperextension beyond 10 degrees (1 point for each leg).
• Forward flexion of the trunk with palms resting flat on the floor with knees fully extended (1 point).

A score of 4 or more (or lower thresholds depending on age and ethnicity) typically indicates generalized joint hypermobility. It is important to note that while the Beighton Score is a fundamental tool, it only assesses hypermobility and is not, by itself, diagnostic of EDS. Many individuals can be hypermobile without having EDS.

The 2017 International Classification Criteria

The diagnostic criteria for EDS were revised in 2017 by an international consortium of experts, providing more precise guidelines for each of the 13 types. These criteria are particularly significant for diagnosing Hypermobile EDS (hEDS), which often lacks a definitive genetic marker.

For Hypermobile EDS (hEDS), diagnosis relies entirely on clinical criteria, categorized into three main areas, all of which must be met:

1. Generalized Joint Hypermobility (GJH): Confirmed by a Beighton Score of ≥5/9 (prepubertal children and adolescents <50 years) or ≥4/9 (adults ≥50 years).
2. Systemic Manifestations of a Generalized Connective Tissue Disorder: Presence of at least two of the following:
   • Skin involvement (soft, velvety texture, mild hyperextensibility, abnormal scarring).
   • Musculoskeletal complications (recurrent dislocations, chronic pain, early osteoarthritis).
   • Pelvic floor, rectal, or uterine prolapse.
   • Hernia.
   • Dental crowding or high narrow palate.
   • Gastrointestinal functional disorders (e.g., gastroparesis, functional dyspepsia).
   • Autonomic dysfunction (e.g., POTS, orthostatic intolerance).
   • Anxiety disorder.
   • Positive family history.
3. Exclusion of Other Diagnoses: It is crucial to rule out other connective tissue disorders (e.g., Marfan syndrome, Loeys-Dietz syndrome) and other conditions that could explain the symptoms. If another EDS type is confirmed genetically, then hEDS is excluded.

For other EDS types (e.g., Classical EDS, Vascular EDS, Kyphoscoliotic EDS), the diagnostic criteria include specific clinical features, often combined with confirmatory genetic testing that identifies a pathogenic variant in a specific gene known to cause that type of EDS.

Genetic Testing: Confirming Specific EDS Types

Genetic testing plays a crucial role in diagnosing most types of EDS, but it is not typically used to confirm hEDS.

• Purpose: Genetic testing identifies specific mutations in genes associated with different EDS types. For example, mutations in COL5A1 or COL5A2 are linked to Classical EDS, while mutations in COL3A1 are characteristic of Vascular EDS.
• When it's Used: Genetic testing is usually pursued when the clinical presentation strongly suggests a specific, rarer type of EDS, or when a definitive diagnosis is needed for prognosis, family planning, or specific management protocols (e.g., monitoring for vascular complications in vEDS).
• Genetic Counseling: Genetic counselors are integral to this process, helping patients understand the implications of genetic testing, interpret results, and discuss inheritance patterns and family risks.

Differential Diagnosis and Exclusion of Other Conditions

A critical step in diagnosing EDS is performing a differential diagnosis to rule out other conditions that present with similar symptoms. These can include:

• Other Heritable Connective Tissue Disorders: Such as Marfan syndrome, Loeys-Dietz syndrome, Stickler syndrome, or Osteogenesis Imperfecta.
• Autoimmune or Rheumatic Conditions: Like rheumatoid arthritis or lupus, which can cause joint pain and fatigue.
• Neurological Conditions: That might mimic autonomic dysfunction.
• Musculoskeletal Conditions: That explain localized hypermobility or pain.

This exclusionary process ensures that the most accurate diagnosis is reached, leading to appropriate management.

The Role of a Multidisciplinary Team

Given the systemic nature of EDS, a diagnosis often leads to the involvement of a multidisciplinary team of specialists to manage the various symptoms and complications. This team may include:

• Geneticists: For initial diagnosis and genetic counseling.
• Rheumatologists: For joint pain and hypermobility management.
• Cardiologists: To monitor for cardiac involvement (e.g., aortic root dilation in vEDS).
• Physical and Occupational Therapists: For strengthening, stability, pain management, and adaptive strategies.
• Pain Specialists: For chronic pain management.
• Gastroenterologists: For digestive issues.
• Neurologists: For autonomic dysfunction or neurological symptoms.
• Psychologists/Psychiatrists: For mental health support, including anxiety and chronic illness coping.

Post-Diagnosis: Management and Support

Receiving an EDS diagnosis is often a significant turning point for individuals who have experienced unexplained symptoms for years. While there is no cure for EDS, an accurate diagnosis allows for targeted management strategies aimed at symptom control, prevention of complications, and improvement of quality of life. This includes tailored physical therapy, pain management, lifestyle adjustments, and regular monitoring by the appropriate specialists. Ongoing support from healthcare providers and patient advocacy groups is crucial for navigating life with EDS.