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. (For information about the hypermobility spectrum disorders, please visit “About HSD”.)

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 Critera

Click the links below to jump to your desired section


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.

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


Arthrochalasia EDS (aEDS)

Major criteria are:

  1. Congenital bilateral hip dislocation;
  2. Severe GJH, with multiple dislocations/subluxations; and
  3. Skin hyperextensibility.

There are five minor criteria. Minimal criteria for aEDS are congenital bilateral hip dislocation (major criterion 1) plus either: skin hyperextensibility (major criterion 3); or severe GJH (major criterion 2) with at least two minor criteria.

A final diagnosis requires confirmation by molecular testing; aEDS is caused by heterozygous mutations in either COL1A1 or COL1A2, that cause entire or partial loss of exon 6 of the respective gene. No other genes are associated with aEDS. Absence of a causative mutation in COL1A1 or COL1A2 that leads to complete or partial deletion of the exon 6 of either gene excludes the diagnosis of aEDS. Arthrochalasia EDS is inherited in the autosomal dominant pattern.

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


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.