About EDS

Kindly click on any of the topics below to read its content.

What are the Ehlers-Danlos Syndromes?

Ehlers-Danlos syndromes are a group of connective tissue disorders that can be inherited and are varied both in how affect the body and in their genetic causes. They are generally characterized by joint hypermobility (joints that stretch further than normal), skin hyperextensibility (skin that can be stretched further than normal), and tissue fragility.

The Ehlers-Danlos syndromes (EDS) are currently classified into thirteen subtypes. Each EDS subtype has a set of clinical criteria that help guide diagnosis; a patient’s physical signs and symptoms will be matched up to the major and minor criteria to identify the subtype that is the most complete fit. There is substantial symptom overlap between the EDS subtypes and the other connective tissue disorders including hypermobility spectrum disorders, as well as a lot of variability, so a definitive diagnosis for all the EDS subtypes when the gene mutation is known—all but hypermobile EDS (hEDS)—also calls for confirmation by testing to identify the responsible variant for the gene affected in each subtype.

For those who meet the minimal clinical requirements for an EDS subtype—but who have no access to molecular confirmation; or whose genetic testing shows one (or more) gene variants of uncertain significance in the genes identified for one of the EDS subtypes; or in whom no causative variants are identified in any of the EDS-subtype-specific genes—a “provisional clinical diagnosis” of an EDS subtype can be made. These patients should be followed clinically, but alternative diagnoses and expanded molecular testing should be considered.

Please remember that an individual’s experience with an EDS is their own, and may not necessarily be the same as another person’s experience. Diagnostic criteria are meant solely to distinguish an EDS from other connective tissue disorders, and there are many more possible symptoms for each EDS than there are criteria.

What are the symptoms of Ehlers-Danlos Syndrome?

Clinical manifestations of Ehlers-Danlos Syndrome are most often joint and skin related and may include:

Joints

Joint hypermobility; loose/unstable joints which are prone to frequent dislocations and/or subluxations; joint pain; hyperextensible joints (they move beyond the joint’s normal range); early onset of osteoarthritis.

Skin

Soft velvety-like skin; variable skin hyper-extensibility; fragile skin that tears or bruises easily (bruising may be severe); severe scarring; slow and poor wound healing; development of molluscoid pseudo tumors (fleshy lesions associated with scars over pressure areas).

Miscellaneous/Less Common

Chronic, early onset, debilitating musculoskeletal pain (usually associated with the Hypermobility Type); arterial/intestinal/uterine fragility or rupture (usually associated with the Vascular Type); scoliosis at birth and scleral fragility (associated with the Kyphoscoliosis Type); poor muscle tone (associated with the Arthrochalasia Type); mitral valve prolapse; and gum disease.

Each type of Ehlers-Danlos Syndrome is defined as a distinct problem in making or using one of the types of collagen. Collagen is what the body uses to provide strength and elasticity to tissue; normal collagen is a strong protein that allows tissue to be stretched but not beyond its limit, and then safely returns that tissue to normal. Collagen is found throughout the body, and Ehlers-Danlos Syndrome is a structural problem. An analogy: If one builds a house with bad materials, with cheap nails or only half the wood required, problems will arise. Some problems are more likely to show up than others, but because the bad or missing materials are everywhere and not necessarily visible, one can be surprised where some problems occur.

It is much the same thing with Ehlers-Danlos Syndrome and collagen. The collagen with which a person with Ehlers-Danlos Syndrome is built is not structured the way it should be, or only part of it is produced. With a badly built or processed collagen, the tissue that relies on it can be pulled beyond normal limits and thus be damaged. Collagen is the most abundant protein in the body and types of collagen can be found almost anywhere: in skin, muscles, tendons and ligaments, blood vessels, organs, gums, eyes, and so on.

The problems resulting from one’s body being built out of a protein that behaves unreliably can be widespread and in a wide range of severity. It shows up in places that seem unrelated until the underlying connection to Ehlers-Danlos Syndrome is recognized.

What are the types of Ehlers-Danlos Syndrome?

There are thirteen defined types of Ehlers-Danlos Syndrome, as well as a number of mutations identified as Ehlers-Danlos Syndrome that fall outside the current system. The major types of Ehlers-Danlos Syndrome are classified according to the signs and symptoms that are manifested. Each type of Ehlers-Danlos Syndrome is a distinct disorder that “runs true” in a family. An individual with Vascular Type Ehlers-Danlos Syndrome will not have a child with Classical Type Ehlers-Danlos Syndrome.

How is Ehlers-Danlos Syndrome diagnosed?

If you think you might have one of the Ehlers-Danlos syndromes (EDS) or hypermobility spectrum disorders (HSD), and particularly if someone in your immediate family has been diagnosed, ask your doctor if a diagnosis fits your symptoms. If they choose to, any doctor who can diagnosis a disease is able to diagnose EDS/HSD; but most likely you’ll be given a referral to a geneticist, because EDS are genetic disorders and geneticists are most adept at distinguishing between those diseases, as well as in doing any testing necessary to differentiate EDS/HSD from the more than 200 other heritable connective tissue disorders.

A diagnosis is important because, although EDS/HSD are not curable, they are treatable. Knowing the type of EDS/HSD gives you and your medical team some idea of where problems might come from and why they’re happening. When eventually there is a cure, you’ll know to use it. And as more of us are diagnosed, EDS/HSD gain the attention all of us need, increasing the likelihood of expanded research that might lead to finding that cure.

Your path to an EDS/HSD diagnosis starts with an examination. There may be physical testing: using the Beighton Scale to assess how mobile your joints are, a search for abnormal scarring and testing your skin to determine what it feels like and how much it stretches, as well as any additional tests your particular doctor feels are needed. There’s likely to be a look into your medical history to look for conditions and problems associated with EDS/HSD, and a discussion of your family to help determine if an EDS/HSD was inherited.

Diagnosis of an EDS subtype comes by finding the one that most matches your symptoms. There are clinical criteria that help guide diagnosis; your signs and symptoms will be matched up to the major and minor criteria to identify the subtype that is the most complete fit. There is substantial symptom overlap between the EDS subtypes and the other connective tissue disorders including HSD, as well as a lot of variability between them. So a definitive diagnosis for all the EDS subtypes—except for hypermobile EDS (hEDS)—also calls for confirmation by testing to identify the responsible variant for the gene affected in each subtype. These molecular testing results also provide the basis for genetic counseling for our families, guidance on treatment options for ourselves, and help in reaching research goals.

The genetic basis for hypermobile EDS is still unknown, so an hEDS (or HSD) diagnosis rests on the criteria and what your doctor finds during your examination. The hEDS criteria also established serious consideration of joint hypermobility with all related symptoms and conditions, with hEDS at one end of the spectrum. HSD can be no less consequential than hEDS, either to your health or concern for treatment.

How prevalent is Ehlers-Danlos Syndrome?

At this time, research statistics of Ehlers-Danlos Syndrome show the prevalence as 1 in 2,500 to 1 in 5,000 people. Recent clinical experience suggests Ehlers-Danlos Syndrome is more common. The condition is known to affect both males and females of all racial and ethnic backgrounds.

How is Ehlers-Danlos Syndrome inherited?

The two known inheritance patterns for Ehlers-Danlos Syndrome include autosomal dominant and autosomal recessive Regardless of the inheritance pattern, we have no choice in which genes we pass on to our children.

What is the prognosis of someone with Ehlers-Danlos Syndrome?

The prognosis depends on the type of Ehlers-Danlos Syndrome and the individual. Life expectancy can be shortened for those with the Vascular Type of Ehlers-Danlos Syndrome due to the possibility of organ and vessel rupture. Life expectancy is usually not affected in the other types. There can be a wide or narrow range of severity within a family, but each person’s case of Ehlers-Danlos Syndrome will be unique. While there is no cure for Ehlers-Danlos Syndrome, there is treatment for symptoms, and there are preventative measures that are helpful for most.

What is HSD?

Hypermobility spectrum disorders (HSD) are a group of conditions related to joint hypermobility (JH). HSD are intended to be diagnosed after other possible answers are excluded, such as any of the Ehlers-Danlos syndromes (EDS) including hypermobile EDS (hEDS). HSD, just like hEDS, can have significant effects on our health. Whatever the problems that arise, whatever the diagnosis, it is important that these effects are managed appropriately and that each person is treated as an individual. HSD and hEDS can be equal in severity, but more importantly, both need similar management, validation, and care.

The Mechanics

Joint hypermobility is a term to describe the capability of joints to move beyond normal limits. It can exist by itself or be a part of a more complex diagnosis. Those with joint hypermobility in a couple of joints (fewer than five) have localized joint hypermobility (LJH). Those of us with joint hypermobility in five or more joints are described as having generalized joint hypermobility (GJH). Unlike LJH, GJH is more often something we’re born with and possibly inherited, although acquired forms of GJH exist (training such as dance, widespread inflammatory or degenerative diseases of the joints, musculoskeletal tissues, and nerves, and hypothyroidism and other endocrine disorders).

There are other types of JH. Peripheral joint hypermobility is a form of that affects the hands and/or feet only. It is common in infants, toddlers, and children, in whom it is usually mild or has no serious effect. Another is proposed for older adults who have progressively lost JH, called historical joint hypermobility.

Joint hypermobility ranges from asymptomatic JH and GJH through to hEDS as part of the EDS. Along that continuum fall localized general spectrum disorder (L-HSD), peripheral hypermobility spectrum disorder (P-HSD), historical hypermobility spectrum disorder (H-HSD), and generalized hypermobility spectrum disorder (G-HSD).

  • Generalized (joint) HSD (G-HSD): GJH objectively assessed (e.g., by the Beighton score) plus one or more secondary musculoskeletal manifestations identified below. The pattern and severity of the musculoskeletal involvement should be carefully assessed in order to explore the possibility full-blown hEDS.
  • Peripheral (joint) HSD (P-HSD): JH limited to hands and feet plus one or more secondary musculoskeletal manifestations.
  • Localized (joint) HSD (L-HSD): JH at single joints or group of joints plus one or more secondary musculoskeletal manifestations regionally related to the hypermobile joint(s).
  • Historical (joint) HSD (H-HSD): self-reported (historical) GJH with negative Beighton score plus one or more secondary musculoskeletal manifestations. Physical examination aimed at excluding the alternative diagnoses of G-HSD, P-HSD, and L-HSD as well as other rheumatologic conditions is mandatory.

The Spectrum of Joint Hypermobility

Type Beighton score Musculoskeletal
involvement
Notes
Asymptomatic GJH Positive Absent
Asymptomatic PJH Usually negative Absent JH typically limited to hands and/or feet
Asymptomatic LJH Negative Absent JH limited to single joints or body parts
G-HSD Positive Present
P-HSD Usually negative Present JH typically limited to hands and/or feet
L-HSD Negative Present JH limited to single joints or body parts
H-HSD Negative Present Historical presence of JH
hEDS Positive Possible

Secondary Musculoskeletal Manifestations

Joint hypermobility can be symptomless apart from the unusual mobility, but there is a series of other symptoms that result from that mobility. These should be evaluated for a diagnosis of HSD (and treated, of course).

Trauma

Macrotrauma includes dislocation, subluxations, and connected soft tissue damage (ligaments, tendons, muscles). It can cause acute pain and loss of joint function. Microtrauma are injuries too small for them to be noticed as they happen. Over time, they may make one susceptible to recurrent or persistent pain, and possibly early joint degeneration like osteoarthritis.

Chronic Pain

Occasional, recurring pain is a natural result of the trauma, but chronic pain can develop—perhaps because of unusual sensitivity to pain (hyperalgesia), perhaps because of an impaired connective tissue function (as suggested by the discovery of small fiber neuropathy in adults with classical, hypermobile, and vascular EDS).

Disturbed Proprioception

Proprioception—the sense of the relative position of parts of the body and how much effort is needed for movement—can be reduced. Not understanding where our joints are and how much muscle strength it takes to use them can lead to a cycle that increasingly limits our abilities to manage every day life.

Other Musculoskeletal Traits

Those with GJH often have other minor musculoskeletal physical traits, which may be the result of the interactions between “softer” musculoskeletal tissues and mechanical forces during growth. These include flat feet (flexible type), misaligned bones in the elbow and big toes, mild to moderate scoliosis (side to side curvature of the spine), kyphosis (outward curvature) of the upper spine and lordosis (inner curvature) of the lower spine. There may be an indirect association with mild reduced bone mass as a result of many factors—lack of proprioception, muscle weakness, and the resulting reduced activity.

Associated Problems Not Based in the Musculoskeletal System

There are quite a few issues that are not the direct result of the mechanics of joint hypermobility. These associations are very real; they seriously affect quality of life and they need to be managed as part of treatment. The strongest (but not only) associations noted so far are anxiety disorders, orthostatic tachycardia, a variety of functional gastrointestinal disorders, and pelvic and bladder dysfunction. These additional problems need to be evaluated and treated when an HSD is diagnosed.

2017 EDS International Classification

In the last decade, growing attention has been placed on joint hypermobility and related disorders. The new nosology for the Ehlers-Danlos syndromes (EDS), identifies 13 different types of EDS, and highlights the need for an updated and more reliable criteria. For the first time management and care guidelines have also been produced for the co-morbidities that can occur within EDS and HSDs.

As part of this work, the terminology of joint hypermobility and related disorders is summarised and a group of hypermobility spectrum disorders is proposed.

American Journal of Medical Genetics Part C: Seminars in Medical Genetics

Supplement to the American Journal of Genetics

Please visit the the American Journal of Medical Genetics Part C: Seminars in Medical Genetics for the full supplement of papers.

Issue Information

Table of Contents, Volume 175C, Number 1, March 2017 (pages 1–2) Publication schedule for 2017 (page 3)

Introduction

The international consortium on the Ehlers–Danlos syndromes (pages 5–7) Lara Bloom, Peter Byers, Clair Francomano, Brad Tinkle, Fransiska Malfait and on behalf of the Steering Committee of The International Consortium on the Ehlers-Danlos Syndromes

Research Article

The 2017 international classification of the Ehlers–Danlos syndromes (pages 8–26) Fransiska Malfait, Clair Francomano, Peter Byers, John Belmont, Britta Berglund, James Black, Lara Bloom, Jessica M. Bowen, Angela F. Brady, Nigel P. Burrows, Marco Castori, Helen Cohen, Marina Colombi, Serwet Demirdas, Julie De Backer, Anne De Paepe, Sylvie Fournel-Gigleux, Michael Frank, Neeti Ghali, Cecilia Giunta, Rodney Grahame, Alan Hakim, Xavier Jeunemaitre, Diana Johnson, Birgit Juul-Kristensen, Ines Kapferer-Seebacher, Hanadi Kazkaz, Tomoki Kosho, Mark E. Lavallee, Howard Levy, Roberto Mendoza-Londono, Melanie Pepin, F. Michael Pope, Eyal Reinstein, Leema Robert, Marianne Rohrbach, Lynn Sanders, Glenda J. Sobey, Tim Van Damme, Anthony Vandersteen, Caroline van Mourik, Nicol Voermans, Nigel Wheeldon, Johannes Zschocke and Brad Tinkle

Research Review

Ehlers–Danlos syndrome, classical type (pages 27–39) Jessica M. Bowen, Glenda J. Sobey, Nigel P. Burrows, Marina Colombi, Mark E. Lavallee, Fransiska Malfait and Clair A. Francomano

Research Articles

Diagnosis, natural history, and management in vascular Ehlers–Danlos syndrome (pages 40–47) Peter H. Byers, John Belmont, James Black, Julie De Backer, Michael Frank, Xavier Jeunemaitre, Diana Johnson, Melanie Pepin, Leema Robert, Lynn Sanders and Nigel Wheeldon

Hypermobile Ehlers–Danlos syndrome (a.k.a. Ehlers–Danlos syndrome Type III and Ehlers–Danlos syndrome hypermobility type): Clinical description and natural history (pages 48–69) Brad Tinkle, Marco Castori, Britta Berglund, Helen Cohen, Rodney Grahame, Hanadi Kazkaz and Howard Levy

Research Reviews

The Ehlers–Danlos syndromes, rare types (pages 70–115) Angela F. Brady, Serwet Demirdas, Sylvie Fournel-Gigleux, Neeti Ghali, Cecilia Giunta, Ines Kapferer-Seebacher, Tomoki Kosho, Roberto Mendoza-Londono, Michael F. Pope, Marianne Rohrbach, Tim Van Damme, Anthony Vandersteen, Caroline van Mourik, Nicol Voermans, Johannes Zschocke and Fransiska Malfait

Measurement properties of clinical assessment methods for classifying generalized joint hypermobility—A systematic review (pages 116–147) Birgit Juul-Kristensen, Karoline Schmedling, Lies Rombaut, Hans Lund and Raoul H. H. Engelbert

Research Articles

A framework for the classification of joint hypermobility and related conditions (pages 148–157) Marco Castori, Brad Tinkle, Howard Levy, Rodney Grahame, Fransiska Malfait and Alan Hakim

The evidence-based rationale for physical therapy treatment of children, adolescents, and adults diagnosed with joint hypermobility syndrome/hypermobile Ehlers Danlos syndrome (pages 158–167) Raoul H.H. Engelbert, Birgit Juul-Kristensen, Verity Pacey, Inge de Wandele, Sandy Smeenk, Nicoleta Woinarosky, Stephanie Sabo, Mark C. Scheper, Leslie Russek and Jane V. Simmonds

Cardiovascular autonomic dysfunction in Ehlers–Danlos syndrome—Hypermobile type (pages 168–174) Alan Hakim, Chris O’Callaghan, Inge De Wandele, Lauren Stiles, Alan Pocinki and Peter Rowe.

Chronic fatigue in Ehlers–Danlos syndrome—Hypermobile type (pages 175–180) Alan Hakim, Inge De Wandele, Chris O’Callaghan, Alan Pocinki and Peter Rowe

Gastrointestinal involvement in the Ehlers–Danlos syndromes (pages 181–187) Asma Fikree, Gisela Chelimsky, Heidi Collins, Katcha Kovacic and Qasim Aziz

Orthopaedic management of the Ehlers–Danlos syndromes (pages 188–194) William B. Ericson Jr. and Roger Wolman

Research Reviews

Neurological and spinal manifestations of the Ehlers–Danlos syndromes (pages 195–211) Fraser C. Henderson Sr., Claudiu Austin, Edward Benzel, Paolo Bolognese, Richard Ellenbogen, Clair A. Francomano, Candace Ireton, Petra Klinge, Myles Koby, Donlin Long, Sunil Patel, Eric L. Singman and Nicol C. Voermans

Pain management in the Ehlers–Danlos syndromes (pages 212–219) Pradeep Chopra, Brad Tinkle, Claude Hamonet, Isabelle Brock, Anne Gompel, Antonio Bulbena and Clair Francomano

Research Article

Oral and mandibular manifestations in the Ehlers–Danlos syndromes (pages 220–225)
John Mitakides and Brad T. Tinkle

Research Reviews

Mast cell disorders in Ehlers–Danlos syndrome (pages 226–236)
Suranjith L. Seneviratne, Anne Maitland and Lawrence Afrin

Psychiatric and psychological aspects in the Ehlers–Danlos syndromes (pages 237–245)
Antonio Bulbena, Carolina Baeza-Velasco, Andrea Bulbena-Cabré, Guillem Pailhez, Hugo Critchley, Pradeep Chopra, Nuria Mallorquí-Bagué, Charissa Frank and Stephen Porges

American Journal of Medical Genetics Part C: Seminars in Medical Genetics Supplement to the American Journal of Genetics

Please visit the the American Journal of Medical Genetics Part C: Seminars in Medical Genetics for the full supplement of papers.

Issue Information

Table of Contents, Volume 175C, Number 1, March 2017 (pages 1–2) Publication schedule for 2017 (page 3)

Introduction

The international consortium on the Ehlers–Danlos syndromes (pages 5–7) Lara Bloom, Peter Byers, Clair Francomano, Brad Tinkle, Fransiska Malfait and on behalf of the Steering Committee of The International Consortium on the Ehlers-Danlos Syndromes

Research Article

The 2017 international classification of the Ehlers–Danlos syndromes (pages 8–26)
Fransiska Malfait, Clair Francomano, Peter Byers, John Belmont, Britta Berglund, James Black, Lara Bloom, Jessica M. Bowen, Angela F. Brady, Nigel P. Burrows, Marco Castori, Helen Cohen, Marina Colombi, Serwet Demirdas, Julie De Backer, Anne De Paepe, Sylvie Fournel-Gigleux, Michael Frank, Neeti Ghali, Cecilia Giunta, Rodney Grahame, Alan Hakim, Xavier Jeunemaitre, Diana Johnson, Birgit Juul-Kristensen, Ines Kapferer-Seebacher, Hanadi Kazkaz, Tomoki Kosho, Mark E. Lavallee, Howard Levy, Roberto Mendoza-Londono, Melanie Pepin, F. Michael Pope, Eyal Reinstein, Leema Robert, Marianne Rohrbach, Lynn Sanders, Glenda J. Sobey, Tim Van Damme, Anthony Vandersteen, Caroline van Mourik, Nicol Voermans, Nigel Wheeldon, Johannes Zschocke and Brad Tinkle

Research Review

Ehlers–Danlos syndrome, classical type (pages 27–39)
Jessica M. Bowen, Glenda J. Sobey, Nigel P. Burrows, Marina Colombi, Mark E. Lavallee, Fransiska Malfait and Clair A. Francomano

Research Articles

Diagnosis, natural history, and management in vascular Ehlers–Danlos syndrome (pages 40–47)
Peter H. Byers, John Belmont, James Black, Julie De Backer, Michael Frank, Xavier Jeunemaitre, Diana Johnson, Melanie Pepin, Leema Robert, Lynn Sanders and Nigel Wheeldon

Hypermobile Ehlers–Danlos syndrome (a.k.a. Ehlers–Danlos syndrome Type III and Ehlers–Danlos syndrome hypermobility type): Clinical description and natural history (pages 48–69)
Brad Tinkle, Marco Castori, Britta Berglund, Helen Cohen, Rodney Grahame, Hanadi Kazkaz and Howard Levy

Research Reviews

The Ehlers–Danlos syndromes, rare types (pages 70–115)
Angela F. Brady, Serwet Demirdas, Sylvie Fournel-Gigleux, Neeti Ghali, Cecilia Giunta, Ines Kapferer-Seebacher, Tomoki Kosho, Roberto Mendoza-Londono, Michael F. Pope, Marianne Rohrbach, Tim Van Damme, Anthony Vandersteen, Caroline van Mourik, Nicol Voermans, Johannes Zschocke and Fransiska Malfait

Measurement properties of clinical assessment methods for classifying generalized joint hypermobility—A systematic review (pages 116–147)
Birgit Juul-Kristensen, Karoline Schmedling, Lies Rombaut, Hans Lund and Raoul H. H. Engelbert

Research Articles

A framework for the classification of joint hypermobility and related conditions (pages 148–157)
Marco Castori, Brad Tinkle, Howard Levy, Rodney Grahame, Fransiska Malfait and Alan Hakim

The evidence-based rationale for physical therapy treatment of children, adolescents, and adults diagnosed with joint hypermobility syndrome/hypermobile Ehlers Danlos syndrome (pages 158–167)
Raoul H.H. Engelbert, Birgit Juul-Kristensen, Verity Pacey, Inge de Wandele, Sandy Smeenk, Nicoleta Woinarosky, Stephanie Sabo, Mark C. Scheper, Leslie Russek and Jane V. Simmonds

Cardiovascular autonomic dysfunction in Ehlers–Danlos syndrome—Hypermobile type (pages 168–174)
Alan Hakim, Chris O’Callaghan, Inge De Wandele, Lauren Stiles, Alan Pocinki and Peter Rowe

Chronic fatigue in Ehlers–Danlos syndrome—Hypermobile type (pages 175–180)
Alan Hakim, Inge De Wandele, Chris O’Callaghan, Alan Pocinki and Peter Rowe

Gastrointestinal involvement in the Ehlers–Danlos syndromes (pages 181–187)
Asma Fikree, Gisela Chelimsky, Heidi Collins, Katcha Kovacic and Qasim Aziz

Orthopaedic management of the Ehlers–Danlos syndromes (pages 188–194)
William B. Ericson Jr. and Roger Wolman

Research Reviews

Neurological and spinal manifestations of the Ehlers–Danlos syndromes (pages 195–211)
Fraser C. Henderson Sr., Claudiu Austin, Edward Benzel, Paolo Bolognese, Richard Ellenbogen, Clair A. Francomano, Candace Ireton, Petra Klinge, Myles Koby, Donlin Long, Sunil Patel, Eric L. Singman and Nicol C. Voermans

Pain management in the Ehlers–Danlos syndromes (pages 212–219)
Pradeep Chopra, Brad Tinkle, Claude Hamonet, Isabelle Brock, Anne Gompel, Antonio Bulbena and Clair Francomano

Research Article

Oral and mandibular manifestations in the Ehlers–Danlos syndromes (pages 220–225)
John Mitakides and Brad T. Tinkle

Research Reviews

Mast cell disorders in Ehlers–Danlos syndrome (pages 226–236)
Suranjith L. Seneviratne, Anne Maitland and Lawrence Afrin

Psychiatric and psychological aspects in the Ehlers–Danlos syndromes (pages 237–245)
Antonio Bulbena, Carolina Baeza-Velasco, Andrea Bulbena-Cabré, Guillem Pailhez, Hugo Critchley, Pradeep Chopra, Nuria Mallorquí-Bagué, Charissa Frank and Stephen Porges

EDS Types


Please note that this page is being updated as more information is made available to us.

Ehlers-Danlos syndromes are a group of connective tissue disorders that can be inherited and are varied both in how affect the body and in their genetic causes. They are generally characterized by joint hypermobility (joints that stretch further than normal), skin hyperextensibility (skin that can be stretched further than normal), and tissue fragility.

The Ehlers-Danlos syndromes (EDS) are currently classified in a system of thirteen subtypes. Each EDS subtype has a set of clinical criteria that help guide diagnosis; a patient’s physical signs and symptoms will be matched up to the major and minor criteria to identify the subtype that is the most complete fit. There is substantial symptom overlap between the EDS subtypes and the other connective tissue disorders including hypermobility spectrum disorders, as well as a lot of variability, so a definitive diagnosis for all the EDS subtypes—except for hypermobile EDS (hEDS)—also calls for confirmation by testing to identify the responsible variant for the gene affected in each subtype.

Molecular diagnostic strategies should rely on NGS technologies, which offer the potential for parallel sequencing of multiple genes. Targeted resequencing of a panel of genes is a time- and cost-effective approach. When no mutation (or in case of an autosomal recessive condition only one mutation) is identified, this approach should be complemented with a copy number variant (CNV) detection strategy to identify large deletions or duplications.

For those who meet the minimal clinical requirements for an EDS subtype—but who have no access to molecular confirmation; or whose genetic testing shows one (or more) gene variants of uncertain significance in the genes identified for one of the EDS subtypes; or in whom no causative variants are identified in any of the EDS-subtype-specific genes—a “provisional clinical diagnosis” of an EDS subtype can be made. These patients should be followed clinically, but alternative diagnoses and expanded molecular testing should be considered.

Please remember that an individual’s experience with an EDS is their own, and may not necessarily be the same as another person’s experience. Diagnostic criteria are meant solely to distinguish an EDS from other connective tissue disorders, and there are many more possible symptoms for each EDS than there are criteria.

2017 International Diagnostic Criteria


EDS Types Chart

* Inheritance Pattern: AD = autosomal dominant; AR = autosomal recessive


Classical EDS (cEDS)

Major criteria are:

  • Skin hyperextensibility and atrophic scarring; and
  • Generalized joint hypermobility (GJH).

There are nine minor criteria. Minimal clinical standards suggesting cEDS are the first major criterion plus either the second major criterion or at least three minor criteria.

A final diagnosis requires confirmation by molecular testing. More than 90% of those with cEDS have a heterozygous mutation in one of the genes encoding type V collagen (COL5A1 and COL5A2). Rarely, specific mutations in the genes encoding type I collagen can be associated with the characteristics of cEDS. Classical EDS is inherited in the autosomal dominant pattern.

Notes:

Skin is hyperextensible if it can be stretched over a standardized cut off in the following areas: 1.5 cm for the distal part of the forearms and the dorsum of the hands; 3 cm for neck, elbow and knees; 1 cm on the volar surface of the hand (palm).

Abnormal scarring can range in severity. Most with cEDS have extensive atrophic scars at a number of sites. A minority are more mildly affected. The relevance of surgical scars should be considered with caution in classical EDS, they can appear normal in patients with classical EDS if well managed. Atrophic surgical scars can be found in the general population due to mechanical factors and site of the incision.

Joint hypermobility is evaluated according to the Beighton score; a Beighton score of >5 is considered positive for the presence of generalized joint hypermobility. Since joint hypermobility decreases with age, patients with a Beighton score <5/9 may be considered positive based on their historical observations. For more detailed information, please visit the cEDS page. [link coming soon]


Classical-like EDS (clEDS)

Major criteria are:

  1. Skin hyperextensibility with velvety skin texture and absence of atrophic scarring;
  2. Generalized joint hypermobility (GJH) with or without recurrent dislocations (most often shoulder and ankle); and
  3. Easily bruised skin or spontaneous ecchymoses (discolorations of the skin resulting from bleeding underneath).

There are seven minor criteria. Minimal clinical standards suggesting clEDS are all three major criteria plus a family history compatible with autosomal recessive transmission. Please see the full criteria here [link coming soon].

A final diagnosis requires molecular testing; clEDS is caused by a complete lack of Tenascin XB (due to biallelic TNXB mutations, that lead to nonsense-mediated mRNA decay, or biallelic deletion of TNXB). TNXB is the only gene associated with clEDS. Classical-like EDS is inherited in the autosomal recessive pattern.

Note: skin hyperextensibility and joint hypermobility are defined as in cEDS.

For more detailed information, please visit the clEDS page. [link coming soon]


Cardiac valvular EDS (cvEDS)

 Major criteria are:

  1. Severe progressive cardiac-valvular problems (aortic valve, mitral valve);
  2. Skin involvement: skin hyperextensibility, atrophic scars, thin skin, easy bruising; and
  3. Joint hypermobility (generalized or restricted to small joints).

There are four minor criteria. Minimal clinical standards suggesting cvEDS are the first major criterion plus a family history compatible with autosomal recessive transmission, and either one other major criterion or at least two minor criteria.

A final diagnosis requires confirmation by molecular testing; cvEDS is caused by a complete lack of the proa2-chain of type I collagen due to biallelic COL1A2 mutations, that lead to nonsense-mediated mRNA decay. COL1A2 is the only gene associated with cvEDS. Cardiac-valvular EDS is inherited in the autosomal recessive pattern.

For more detailed information, please visit the cvEDS page. [link coming soon]


Vascular EDS (vEDS)

Major criteria are:

  1. Family history of vEDS with documented causative variant in COL3A1;
  2. Arterial rupture at a young age;
  3. Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology;
  4. Uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears; and
  5. Carotid-cavernous sinus fistula (CCSF) formation in the absence of trauma.

There are twelve minor criteria. Minimal clinical standards suggesting vEDS diagnostic studies should be performed are: a family history of the disorder, arterial rupture or dissection in individuals less than 40 years of age; unexplained sigmoid colon rupture: or spontaneous pneumothorax in the presence of other features consistent with vEDS. Testing for vEDS should also be considered in the presence of a combination of the other “minor” criteria.

A final diagnosis requires confirmation by molecular testing. Patients with vEDS typically have a heterozygous mutation in the COL3A1 gene, with the rare exception of specific heterozygous arginine-to-cysteine substitution mutations in COL1A1 that are also associated with vascular fragility and mimic COL3A1-vEDS (see also “Ehlers-Danlos Syndrome, Rare Types” [link coming soon]). In very rare instances, biallelic pathogenic variants in COL3A1 may be identified. Vascular EDS is inherited in the autosomal dominant pattern.

For more detailed information, please visit the vEDS page. [link coming soon]


Hypermobile EDS

The diagnosis of hypermobile EDS (hEDS) remains clinical; there is no molecular, genetic cause yet identified, so there is no test available for almost all with hEDS.

There is a clinical spectrum ranging from asymptomatic joint hypermobility, through “non-syndromic” hypermobility with secondary manifestations, to hEDS (see the page “Hypermobility Spectrum Disorders” [link coming soon] or “A Framework for the Classification of Joint Hypermobility and Related Conditions” by Castori et al. [link coming soon]).

A diagnosis of hEDS should be assigned only in those who meet all of the criteria, which should help research efforts to discover the underlying genetic cause(s) which, in turn, may help clinical management. As this is a clinical diagnosis, it’s important to be relatively confident that the diagnosis is not instead one of the many other disorders of connective tissue. Hypermobile EDS is inherited in the autosomal dominant pattern.

The clinical diagnosis of hEDS needs the simultaneous presence of criteria 1 and 2 and 3. This is a complex set of criteria, and there is much more detail than presented in this overview; please see the page for hypermobile EDS. [link coming soon]

  1. Generalized joint hypermobility (GJH); and
  2. Two or more of the following features must be present (A & B, A & C, B & C, or A & B & C):

            Feature A—systemic manifestations of a more generalized connective tissue disorder (a total of five out of twelve must be present)

            Feature B—positive family history, with one or more first degree relatives independently meeting the current diagnostic criteria for hEDS

            Feature C—musculoskeletal complications (must have at least one of three); and

  1. All these prerequisites must be met: absence of unusual skin fragility, exclusion of other heritable and acquired connective tissue disorders including autoimmune rheumatologic conditions, and exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity.

There is a range of conditions which can accompany hEDS, although there is not enough data for them to become diagnostic criteria. While they’re associated with hEDS, they’re not proven to be the result of hEDS and they’re not specific enough to be criteria for diagnosis. Some of these include sleep disturbance, fatigue, postural orthostatic tachycardia, functional gastrointestinal disorders, dysautonomia, anxiety, and depression. These conditions may be more debilitating the joint symptoms; they often impair daily life, and they should be considered and treated.

Dermatosparaxis EDS (dEDS)

There are nine major criteria and eleven minor criteria. Minimal criteria suggestive of dEDS include the two major criteria of extreme skin fragility and characteristic craniofacial features, plus either: one other major criterion, or three minor criteria.

A final diagnosis requires confirmation by molecular testing; dEDS is caused by biallelic mutations in ADAMTS2. It is the only gene associated with dEDS. Dermatosparaxis EDS is inherited in the autosomal recessive pattern.

For more detailed information, please visit the dEDS page. [link coming soon]


Kyphoscoliotic EDS (kEDS)

Major criteria are:

  1. Congenital muscle hypotonia;
  2. Congenital or early onset kyphoscoliosis (progressive or non-progressive); and
  3. GJH with dislocations/subluxations (shoulders, hips and knees in particular).

There are ten minor criteria, as well as gene-specific minor criteria (four for PLOD1 and four for FKBP14). Minimal criteria suggestive for kEDS are 1 and 2 of the major criteria—congenital muscle hypotonia and congential/early onset kyphoscoliosis—plus either: major criterion 3, or three minor criteria (either general of gene-specific).

A final diagnosis requires confirmation by testing. The majority of patients with kEDS harbor biallelic mutations in PLOD1; recently, biallelic mutations have been identified in FKBP14 in patients displaying a phenotype that clinically largely overlaps with kEDS-PLOD1. Laboratory confirmation should start with a urine test using high-performance liquid chromatography (to evaluate the ratio of lysyl-pyridinoline to hydroxylysyl-pyridinoline crosslinks; a normal ratio is ~0.2, whereas kEDS-PLOD1 range is 2-9). This method is fast and cost-effective and it can also be used to determine the pathogenic status of a variant of uncertain significance. Molecular analysis can follow if the urine test is normal. Whereas absence of an abnormal urinary LP/HP ratio excludes the diagnosis of kEDS-PLOD1, absence of the confirmatory genetic findings does not exclude the diagnosis of kEDS, as other yet-to-be-discovered genes may be associated with this phenotype; however, alternative diagnoses should be considered in the absence of PLOD1 or FKBP14 mutations. Kyphoscoliotic EDS is inherited in the autosomal recessive pattern.

For more detailed information, please visit the kEDS page. [link coming soon]


Brittle Cornea Syndrome (BCS)

Major criteria are:

  1. Thin cornea, with or without rupture (central corneal thickness often <400 µm);
  2. Early onset progressive keratoconus;
  3. Early onset progressive keratoglobus; and
  4. Blue sclerae.

There are fourteen minor criteria. Minimal criteria required to suggest BCS are the first major criterion, plus either: at least one other major criterion; or three minor criteria.

A final diagnosis requires confirmation through molecular testing. BCS is caused by biallelic mutations in either ZNF469 or PRDM5. At least one family with a clinical BCS phenotype did not harbor mutations in these genes, suggesting that at least one other gene might be associated with BCS. Brittle cornea syndrome is inherited in the autosomal recessive pattern.

For more detailed information please visit the “Rarer Types of EDS” page. [link coming soon]


Spondylodysplastic EDS (spEDS)

Major criteria are:

  1. Short stature (progressive in childhood);
  2. Muscle hypotonia (ranging from severe congenital, to mild later-onset); and
  3. Bowing of limbs.

There are five general minor criteria, plus gene-specific criteria for B4GALT7, B3GALT6, and SLC39A13. Minimal criteria required to suggest a diagnosis for spEDS are the first and second major criteria, plus characteristic radiographic abnormalities and at least three minor criteria (either general or gene-specific). Spondylodysplastic EDS is inherited in the autosomal recessive pattern.

Final diagnosis requires confirmation through molecular testing. For more detailed information please visit the “Rarer Types of EDS” page. [link coming soon]


Musculocontractural EDS (mcEDS)

Major criteria are:

  1. Congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot);
  2. Characteristic craniofacial features, which are evident at birth or in early infancy; and
  3. Characteristic cutaneous features including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling.

There are fifteen minor criteria. The minimum criteria required to suggest mcEDS are: at birth or in early childhood, major criteria 1 and 2; in adolescence and adulthood, major criteria 1 and 3.

A final diagnosis requires confirmation through molecular testing. Musculocontractural EDS is caused by biallelic mutations in CHST14. A few mutations have been identified in the DSE gene in patients with a similar phenotype. Musculocontractural EDS is inherited in the autosomal recessive pattern.

For more detailed information please visit the “Rarer Types of EDS” page. [link coming soon]


Myopathic EDS (mEDS)

Major criteria are:

  1. Congenital muscle hypotonia, and/or muscle atrophy, that improves with age;
  2. Proximal joint contractures (knee, hip and elbow); and
  3. Hypermobility of distal joints.

There are four minor criteria. The minimal criteria required to suggest a diagnosis of mEDS are the first major criterion plus either: one other major criterion, or three minor criteria.

A final diagnosis requires molecular testing; mEDS is caused by heterozygous or biallelic mutations in COL12A1, and the clinical phenotype highly overlaps with collagen type VI-related myopathies. It is currently unknown whether other, yet to be discovered genes, are associated with this phenotype. In case no COL12A1 mutations are identified alternative diagnoses, especially collagen VI-related Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy, should be considered. Myopathic EDS is inherited in either the autosomal dominant or the autosomal recessive pattern.

For more detailed information please visit the “Rarer Types of EDS” page. [link coming soon]


Periodontal EDS (pEDS)

Major criteria are:

  1. Severe and intractable periodontitis of early onset (childhood or adolescence);
  2. Lack of attached gingiva;
  3. Pretibial plaques; and
  4. Family history of a first-degree relative who meets clinical criteria.

There are eight minor criteria. The minimal criteria required to suggest pEDS are the first criterion or the second criterion, plus at least two other major criteria and one minor criterion.

A final diagnosis requires molecular testing; pEDS is caused by heterozygous gain-of-function mutations in C1R or C1S. At present it cannot be stated whether absence of a C1R or C1S mutations excludes the diagnosis because the experience with the molecular diagnosis is limited. Periodontal EDS (pEDS) is inherited in the autosomal recessive pattern.

For more detailed information please visit the “Rarer Types of EDS” page. [link coming soon]


 

Pathogenetic mechanisms underlying the Ehlers-Danlos syndromes

There is an additional genetic classification structure of the EDS into groups according to similarities in the way the responsible genes affect the body.

Group A: Disorders of collagen primary structure and collagen processing, comprised of cEDS, vEDS, aEDS, dEDS, and cvEDS.

Group B: Disorders of collagen folding and collagen crosslinking, comprised of kEDS-PLOD1 and kEDSS-FKB14.

Group C: Disorders of structure and function of the myomatrix, comprised of clEDS and mEDS.

Group D: Disorders of glycosaminoglycan biosynthesis, comprised of spEDS-B4GALT7, spEDS-b3GALT6, mcEDS-CHST14, and mcEDS-DSE.

Group E: Defects in complement pathway, comprised of pEDS.

Group F: Disorders of intracellular processes, comprised of spEDS-SLC39A13 and BCS.

Group G: Unresolved forms of EDS, comprised of hEDS.

Conditions no longer included in the EDS spectrum are occipital horn syndrome, fibronectin-deficient (EDS X), familial articular hypermobility (EDS XI), X-linked EDS with muscle hematoma (EDS V), and filamin A related EDS with periventricular nodular heterotopia.

Assessing Joint Hypermobility

Check your JH score: Assess Joint Hypermobility using the Beighton Scale

Joint hypermobility, defined as a more-than-normal range of movement (ROM) in a joint, is either localized (increased ROM of a single joint) or generalized. Joint hypermobility depends on age, gender, family and ethnic background. A score of 5/9 or greater defines hypermobility. The total score is obtained by:

  1. Forward flexion of the trunk with knees fully extended so that the palms of the hand rest flat* on the floor – one point
  2. Hyperextension of the elbows beyond 10 degrees* – one point for each elbow
  3. Hyperextension of the knees beyond 10 degrees* – one point for each knee
  4. Passive apposition of the thumbs to the flexor aspect of the forearm* – one point for each hand
  5. Passive dorsiflexion of the little fingers beyond 90 degrees* – one point for each hand

*Note: Picture may indicate a degree of hypermobility not required by the diagnostic criteria.

Beighton Criteria

An important landmark was passed in July 2000 with the publication in the Journal of Rheumatology (2000; 27: 1777-1779) of the Brighton Diagnostic criteria for the Joint Hypermobility Syndrome (JHS).

EDS Diagnostics 2017

The path to an EDS/HSD diagnosis starts with an examination. This usually includes physical testing:

  • An assessment of hypermobility using the Beighton Scale to assess how mobile the joints are
  • A search for abnormal scarring and testing the skin to determine what it feels like and how much it stretches
  • There’s likely to be a look into your medical history to look for conditions and problems associated with EDS/HSD, and a discussion of your family to help determine if an EDS/HSD was inherited.
  • Additional tests the physician feels are needed.

If you believe that you, or someone you know, has one of the Ehlers-Danlos syndromes (EDS) or hypermobility spectrum disorders (HSD), you should ask your doctor to compare your symptoms to the new diagnostic criteria.

If an immediate family member has been diagnosed with one of the Ehlers-Danlos syndromes or HSD, it is important they have a medical evaluation if they are also symptomatic and experiencing problems. If a diagnosis of vascular EDS has been made then all immediate family members should be tested as soon as possible.

Most medical doctors should be able to diagnose EDS/HSD. However, because the Ehlers-Danlos syndromes are genetic disorders, primary care physicians often provide their patients with referrals to a geneticist.

Geneticists have specialized experience in determining which testing is necessary to differentiate EDS/HSD from the more than 200 other heritable connective tissue disorders.

Early diagnosis is important—to everyone

At the present time, EDS/HSD are not curable, but they are treatable. Early diagnosis is important. When patients and their medical team know which type of EDS or HSD they are dealing with, they can determine the proper course of treatment, therapy, and lifestyle adjustments necessary to build a healthy, happy, and productive life.

Diagnosis determines type

Diagnosis of an EDS subtype comes by finding the one that most matches the patient’s symptoms. There are clinical criteria [Link coming soon] that help guide diagnosis; your signs and symptoms will be matched up to the major and minor criteria to identify the subtype that is the most complete fit. There is substantial symptom overlap between the EDS subtypes and the other connective tissue disorders including HSD, as well as a lot of variability between them. So a definitive diagnosis for all the EDS subtypes—except for hypermobile EDS (hEDS)—also calls for confirmation by testing to identify the responsible variant for the gene affected in each subtype. These molecular testing results also provide the basis for genetic counseling for our families, guidance on treatment options for ourselves, and help in reaching research goals.

Hypermobile EDS, Physical Examination, and Family History

The genetic basis for hypermobile EDS is still unknown. An hEDS (or HSD) diagnosis rests on the criteria [Link coming soon] physical examination, and quite often, a detailed family history. The 2017 hEDS criteria establishes serious consideration of joint hypermobility with all related symptoms and conditions, with hEDS at one end of the spectrum. HSD can be no less consequential than hEDS, either to your health or concern for treatment.

As more of people are diagnosed, EDS/HSD gain the attention necessary to increase the likelihood that expanded research might eventually lead to finding that cure.

Our strength begins with hope.

“WHEN YOU HEAR THE SOUNDS OF A HOOVES YOU THINK HORSES NOT ZEBRAS. WE ARE THOSE ZEBRAS.”

"WHEN YOU HEAR THE SOUNDS OF A HOOVES YOU THINK HORSES NOT ZEBRAS. WE ARE THOSE ZEBRAS.

2017 EDS International Classification

Clair A. Francomano, MD on behalf of The International Consortium on EDS and Related Disorders