The 13 Types of Ehlers-Danlos Syndrome

Ehlers-Danlos Syndrome (EDS) is a group of inherited connective tissue disorders that impact the body’s collagen structure and function. Collagen, a vital component of connective tissue, plays a key role in providing strength and elasticity to the skin, joints, blood vessels, and internal organs. Consequently, individuals with EDS often experience symptoms such as joint hypermobility, skin hyperextensibility, and tissue fragility, which can vary significantly in severity and presentation.

Over the decades, the classification of EDS has evolved in response to advancements in genetics and clinical research. From its initial categorization using Roman numerals to the refined Villefranche nosology of 1997, and ultimately to the comprehensive 2017 International Classification, each update has aimed to improve diagnostic accuracy and patient care. The 2017 framework introduced 13 distinct subtypes, integrating molecular insights and clinical criteria to better reflect the diverse presentations of EDS.

This article provides an in-depth look at the history and evolution of EDS classification, from the early Roman numeral system to the current 2017 classification and beyond. It also explores how scientific advancements have enhanced our understanding of EDS, highlighting the ongoing efforts to refine diagnostic tools and develop management strategies, such as the Road to 2026 initiative. By examining the past, present, and future of EDS classification, this article aims to offer a comprehensive resource for clinicians, researchers, and individuals affected by this complex condition.

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The Current Classification of Ehlers-Danlos Syndromes

The 2017 classification represents a significant advancement in the understanding of Ehlers-Danlos Syndromes (EDS). It addressed the limitations of earlier systems, particularly the Villefranche nosology, by incorporating genetic discoveries and clinical research. This comprehensive update categorized EDS into 13 subtypes, offering a more precise and detailed framework for diagnosis and management.

Subtypes of Ehlers-Danlos Syndrome

The 2017 classification includes the following 13 subtypes, each characterized by specific genetic markers and clinical features:

• Classical EDS (cEDS): Associated with COL5A1 and COL5A2 mutations, characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility.
• Classical-like EDS (clEDS): Linked to TNXB mutations, presenting with skin fragility, joint hypermobility, but no atrophic scarring.
• Cardiac-valvular EDS (cvEDS): Caused by COL1A2 mutations, marked by severe cardiac-valvular disease alongside joint and skin manifestations.
• Vascular EDS (vEDS): Associated with COL3A1 mutations, defined by arterial rupture risk, thin translucent skin, and facial characteristics such as a pinched nose.
• Hypermobile EDS (hEDS): The most common subtype, lacking an identified genetic cause and diagnosed clinically based on specific criteria for joint hypermobility and associated features.
• Arthrochalasia EDS (aEDS): Caused by COL1A1 and COL1A2 mutations, characterized by congenital hip dislocation and severe joint hypermobility.
• Dermatosparaxis EDS (dEDS): Linked to ADAMTS2 mutations, presenting with extreme skin fragility, easy bruising, and characteristic facial features such as a sagging appearance.
• Kyphoscoliotic EDS (kEDS): Associated with PLOD1 and FKBP14 mutations, leading to severe congenital scoliosis, hypotonia, and visual impairments.
• Brittle Cornea Syndrome (BCS): Caused by ZNF469 and PRDM5 mutations, marked by corneal thinning and rupture risk, as well as other ocular complications.
• Spondylodysplastic EDS (spEDS): Related to B4GALT7, B3GALT6, and SLC39A13 mutations, presenting with short stature, limb bowing, and generalized joint laxity.
• Musculocontractural EDS (mcEDS): Caused by CHST14 or DSE mutations, characterized by congenital joint contractures, skin fragility, and craniofacial abnormalities.
• Myopathic EDS (mEDS): Linked to COL12A1 mutations, associated with muscle weakness, joint hypermobility, and occasionally proximal contractures.
• Periodontal EDS (pEDS): Caused by mutations in C1R and C1S, presenting with severe periodontal disease, early tooth loss, and a predisposition to gingival fragility.

The emphasis on genetic testing for most subtypes underscores the importance of molecular diagnostics in confirming clinical suspicions and guiding patient management.

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The Historical Evolution of Ehlers-Danlos Syndrome Classification

Ehlers-Danlos Syndrome (EDS) has undergone significant changes in classification over the past several decades. These updates reflect advancements in genetic testing, molecular biology, and clinical research, aiming to better define the diverse presentations of this complex connective tissue disorder.

Early Efforts: The Roman Numeral System

The earliest classification of EDS relied on Roman numerals, organizing subtypes based on clinical features such as skin hyperextensibility, joint hypermobility, and vascular fragility. Although groundbreaking at the time, this system lacked the precision and genetic insights needed for accurate diagnosis and management.

Transition to the Villefranche Nosology

In 1997, the Villefranche nosology replaced the Roman numeral system, simplifying the classification into six subtypes. This framework introduced clearer diagnostic criteria, emphasizing clinical and genetic findings. However, limitations remained, particularly for hypermobile EDS (hEDS), which lacked a confirmed genetic marker.

The 2017 International Classification

Recognizing the need for greater accuracy, the 2017 International Classification of Ehlers-Danlos Syndromes expanded the subtypes to 13, integrating genetic advances and clinical observations. This updated framework represents the most comprehensive classification to date and serves as the foundation for ongoing research and refinement.

Types of EDS: Historical Classification Systems

The 2017 classification owes its structure to earlier frameworks, which served as stepping stones in the evolution of EDS nosology.

Roman Numeral Classification

The Roman numeral system, established in the mid-20th century, categorized EDS into several distinct subtypes based on clinical manifestations and inheritance patterns:

• Types I and II: Now recognized as Classical EDS (cEDS).
• Type III: Known today as Hypermobile EDS (hEDS), though its genetic basis remains unclear.
• Type IV: Corresponds to Vascular EDS (vEDS).
• Type VI: Now identified as Kyphoscoliotic EDS (kEDS).
• Type VII: Split into Arthrochalasia EDS (aEDS) and Dermatosparaxis EDS (dEDS).
• Type VIII: Mapped to Periodontal EDS (pEDS).

This system provided an initial framework for distinguishing between EDS presentations but lacked the genetic specificity required for accurate diagnosis.

Villefranche Nosology

Introduced in 1997, the Villefranche nosology sought to refine and simplify the Roman numeral system. It reduced EDS to six major categories:

• Classical EDS: Combined Types I and II.
• Hypermobility EDS: Directly based on Type III.
• Vascular EDS: Correlating with Type IV.
• Kyphoscoliotic EDS: Derived from Type VI.
• Arthrochalasia EDS: Merging Types VIIa and VIIb.
• Dermatosparaxis EDS: Aligning with Type VIIc.

Villefranche prioritized clinical accessibility by introducing diagnostic criteria based on major and minor features. However, it could not fully address emerging subtypes and variations as genetic research advanced.

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The New EDS 2026 Classification Update

Future of EDS Classification

The 2017 classification marked a pivotal advancement in the understanding and diagnosis of Ehlers-Danlos Syndromes (EDS), but it also highlighted areas requiring further research and refinement. The evolution of EDS classification continues as science uncovers more about the genetic and clinical complexities of this group of disorders.

The Vision in 2017

The 2017 classification represented a significant leap forward in EDS research and clinical care. However, its creators acknowledged that further progress would be necessary to address outstanding challenges.

Three major areas for future focus were identified:

1. Identifying the Genetic Basis for Hypermobile EDS (hEDS):
   Hypermobile EDS remains the only subtype without an identified genetic marker, relying instead on clinical diagnostic criteria. The need to identify a genetic basis for hEDS is critical for improving diagnostic accuracy, understanding its inheritance patterns, and distinguishing it from other connective tissue disorders.
2. Expanding Knowledge of Rare and Emerging Subtypes:
   The 2017 classification brought greater attention to rare subtypes like Myopathic EDS (mEDS) and Periodontal EDS (pEDS). However, the full spectrum of EDS phenotypes, including potential yet-to-be-defined subtypes, remains an area for exploration.
3. Developing More Precise Diagnostic Criteria:
   Enhanced criteria are necessary to facilitate earlier detection and better management. This includes refining tools for clinical differentiation and incorporating advances in molecular genetics.

These areas of focus set the stage for ongoing research efforts aimed at addressing the gaps in EDS understanding and improving patient outcomes.

The Road to 2026: Advancing EDS and HSD Care

Building on the foundation of the 2017 classification, the Road to 2026 is a global initiative led by the International Consortium on Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders (IC). This effort seeks to refine the classification further, enhance diagnostic accuracy, and improve care pathways for both EDS and hypermobility spectrum disorders (HSD).

The Road to 2026 emphasizes advancing the classification framework and creating user-friendly diagnostic pathways and evidence-based management guidelines. Recent studies, such as the HEDGE (Hypermobile Ehlers-Danlos Genetic Evaluation) Study and the hEDS/HSD Criteria Review Study, are integral to shaping these updates. A key feature of the initiative is the development of interactive digital diagnostic tools. These tools aim to reduce diagnostic delays, ensure accessibility for healthcare providers unfamiliar with EDS, and integrate patient experiences into the diagnostic process.

Progress and Timeline

The initiative, spanning 2024 to 2026, includes multiple phases of research, collaboration, and implementation:

• 2024-2025: The committee is reviewing existing literature, integrating findings from new genetic and clinical studies, and refining diagnostic pathways. Community feedback has been actively sought and incorporated into this process.
• Mid-2025: Preliminary findings will be shared at the International Scientific Symposium in Toronto, engaging the broader research and medical community.
• Late 2026: Final recommendations, including revised classification criteria and diagnostic pathways, will be published in an open-access format to ensure global accessibility for healthcare providers and patients.

Impact on the EDS and HSD Community

The Road to 2026 has the potential to transform EDS and HSD care by addressing long-standing challenges in diagnosis and management. Patients are expected to benefit from:

• Shorter Diagnostic Timelines: Clearer and more precise criteria will aid in earlier detection and treatment.
• Improved Symptom Management: Evidence-based pathways will enhance care for comorbidities, including chronic pain and joint instability.
• Enhanced Accessibility: Digital diagnostic tools will empower healthcare providers worldwide to make informed diagnoses, even in resource-limited settings.

Equally important is the initiative's commitment to incorporating the voices of patients and advocacy groups. By prioritizing the principle of "Nothing About Us, Without Us," the Road to 2026 ensures that scientific recommendations are grounded in lived experiences and address real-world challenges.

Conclusion

The 2017 classification of Ehlers-Danlos Syndromes marked a turning point in understanding this group of connective tissue disorders. By expanding subtypes, integrating genetic discoveries, and providing detailed criteria, it laid the foundation for more precise diagnoses and improved patient care. However, the journey toward a comprehensive understanding of EDS is far from complete.

The Road to 2026 represents the next step in this evolution, aiming to refine classification criteria, enhance diagnostic tools, and bridge gaps in care. With a focus on collaboration among clinicians, researchers, and patients, the initiative promises to bring meaningful advancements to EDS and HSD management, offering hope for better outcomes and quality of life for individuals worldwide.

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FAQ

What are the different classifications of Ehlers-Danlos syndrome (EDS)?

EDS has been classified through several systems over time. Initially, the Roman numeral system categorized EDS into Types I-VIII based on clinical features. The Villefranche nosology (1997) simplified this into six major types: Classical, Hypermobility, Vascular, Kyphoscoliotic, Arthrochalasia, and Dermatosparaxis. The 2017 International Classification expanded EDS to 13 subtypes, incorporating genetic and clinical data, such as Classical EDS (cEDS), Hypermobile EDS (hEDS), and Vascular EDS (vEDS).

How is EDS classified?

EDS is classified based on genetic markers and clinical presentation. The 2017 International Classification identifies 13 subtypes, each linked to specific gene mutations (except for hEDS, which remains clinically diagnosed). This classification reflects advancements in genetic testing and clinical understanding, providing a framework for accurate diagnosis and management.

What is the difference between EDS Type I and Type II?

In the Roman numeral system, EDS Type I and Type II were distinct subtypes. However, the Villefranche nosology combined them into a single subtype called Classical EDS (cEDS). Both types shared features like skin hyperextensibility, atrophic scarring, and joint hypermobility, differing only in severity.

What does EDS Type III mean?

EDS Type III in the Roman numeral system is now known as Hypermobile EDS (hEDS). It is the most common subtype and is unique because no genetic marker has been identified yet. Diagnosis is based on clinical criteria such as generalized joint hypermobility, chronic pain, and other associated symptoms.

What are the three main types of EDS?

Historically, the three most recognized types of EDS were:

1. Classical EDS (cEDS): Characterized by skin hyperextensibility and scarring.
2. Hypermobility EDS (hEDS): Primarily affecting joint hypermobility and chronic pain.
3. Vascular EDS (vEDS): Marked by vascular and organ fragility.

These remain the most widely recognized and studied types of EDS.

What is the mildest form of EDS?

Hypermobility EDS (hEDS) is often considered the mildest form in terms of life-threatening complications, as it does not typically involve significant vascular or organ fragility. However, its symptoms, such as chronic pain and joint instability, can still significantly impact quality of life.

Are there 13 or 14 types of EDS?

As of the 2017 International Classification, there are 13 recognized subtypes of EDS. These include Classical EDS (cEDS), Hypermobile EDS (hEDS), Vascular EDS (vEDS), and 10 other rarer subtypes, each defined by specific genetic mutations.

What is the difference between EDS Type I and Type II?

In the Roman numeral system, EDS Type I and Type II were distinct subtypes. However, the Villefranche nosology combined them into a single subtype called Classical EDS (cEDS). Both types shared features like skin hyperextensibility, atrophic scarring, and joint hypermobility, differing only in severity.

What are the six Ehlers-Danlos syndrome types?

The six types of EDS recognized under the Villefranche nosology (1997) were:

1. Classical EDS (Types I & II).
2. Hypermobility EDS (Type III).
3. Vascular EDS (Type IV).
4. Kyphoscoliotic EDS (Type VI).
5. Arthrochalasia EDS (Type VIIa & VIIb).
6. Dermatosparaxis EDS (Type VIIc).

These were later expanded to 13 subtypes in the 2017 classification.

Is EDS Type III a disability?

Hypermobility EDS (formerly EDS Type III) can be considered a disability depending on the severity of symptoms. Chronic pain, joint instability, and fatigue can significantly limit daily activities and quality of life, qualifying some individuals for disability support. However, this varies by country and individual circumstances.

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Reference

Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet. 2017;175(1):8-26. doi:10.1002/ajmg.c.31552