Types of Ehlers-Danlos Syndromes (EDS)

There are many types of Ehlers-Danlos syndromes (EDS). Based on the inheritance pattern, EDS can be classified as 1) autosomal dominant, 2) autosomal recessive, and 3) autosomal dominant or recessive. In all these types, a set of major and minor criteria is identified and a minimal criterion is arrived at for the physicians to suggest the EDS types. Molecular testing is done to confirm final diagnosis.

Autosomal Dominant

Below are the types of EDS that are caused due to an autosomal dominant inheritance pattern.

• Classical
• Vascular
• Hypermobile
• Arthrochalasia
• Periodontal

The two major criteria for Classical EDS (cEDS) are 1) atrophic scarring and hyperextensibility of the skin and 2) generalized joint hypermobility (GJH). When these two major criteria or the first major criterion in combination with a minimum of three minor criteria (out of 9 minor criteria) is present, cEDS is suggested.

The heterozygous mutation of the gene COL3A1 causes Vascular EDS (vEDS). Testing is considered when the disorder is present in family history along with a few major criteria (out of the 5) identified combines with few other minor criteria (out of 12) that is established.

There is no sufficient data established as criteria to diagnose Hypermobile EDS (hEDS), whereas three major and five minor criteria are established for Arthrochalasia EDS (aEDS). Diagnosis is suggested when the major criteria 1 & 3 are present OR when major criterion 2 combines with a minimum of two minor criteria.

When the C1R gene is absent or C1S gene mutations exists, it leads to Periodontal EDS (pEDS).

Autosomal Recessive

Autosomal recessive inheritance type results in the type of EDS listed below:

• Classical-like
• Cardiac-valvular
• Dermatosparaxis
• Kyphoscoliotic
• Brittle Cornea Syndrome
• Spondylodysplastic
• Musculocontractural

Classical-like EDS (clEDS) is caused by absence of Tenascin XB, the only gene related with clEDS. Even though seven minor criteria are identified, physicians suggest for clEDS only when all the three major criteria and autosomal recessive inheritance family history are present.

Cardiac-valvular EDS (cvEDS) is caused by biallelic mutations of the gene COL1A2—the only gene related with cvEDS. Recommendations for this type of EDS happens when there is a family history of autosomal recessive type combined with the first major criterion and either 1) one other major criterion or 2) a minimum of two minor criteria.

With 9 major and 11 minor criteria defined, Dermatosparaxis EDS (dEDS) is suggested when the extreme fragility of the skin and distinctive craniofacial features—two major criteria are present along with either 1) one major criterion or 2) three minor criteria. The only gene connected with dEDS is ADAMTS2 and its biallelic mutations result in dEDS.

Kyphoscoliotic EDS (kEDS) is suggested when the first two major criteria are present along with either the 1) third major criteria or 2) three general or gene-related criteria. Mutations of the genes PLOD1 or FKBP14 result in kEDS.

Brittle Cornea Syndrome (BCS) is due to the biallelic mutations of either ZNF469 gene or PRDM5 gene. Diagnosis is recommended when 1) first major criteria (thin cornea with thickness of central corneal less than 400 µm without rupture or sometimes ruptured) is present along with one more major criteria—early start of keratoconus, early beginning of keratoglobus that are progressive, and blue sclera or 2) first major criterion combines with any 3 of the 14 minor criteria.

For Spondylodysplastic EDS (spEDS), three major, five minor, and specific criteria related to genes B4GALT7, B3GALT6, and SLC39A13 are identified. Diagnosis is suggested when the first two major criteria, distinctive radiographic abnormalities, are present in combination with a minimum of three minor criteria that are either general or specific to gene.

Biallelic mutations of the gene CHST14 are responsible for Musculocontractural EDS (mcEDS). Though 15 minor criteria are defined, suggestion for this type of EDS is based on the identified three major criteria. When the first two major criteria are present in the individual at birth or during early childhood or when the first and third major criteria are present in adolescents and adults, mcEDS is suggested.

Autosomal Dominant or Recessive

Myopathic EDS (mEDS) is either autosomal dominant or recessive. Biallelic mutations of the gene COL12A1 is the cause of this type of EDS in which Type X11 Collagen protein is involved. With three major and four minor criteria defined, physicians suggest a diagnosis if the first major criterion is present with either 1) one other major criterion or 2) three minor criteria.

EDS Groups

Based on the similarities of the EDS causing genes affecting human body, EDS can also be grouped as below:

Group	Disorder/defects in	EDS types
Group A	Primary structure of collagen and processing of collagen	Ceds vEDS aEDS dEDS cvEDS
Group B	Folding and crosslinking of collagen	kEDS-PLOD1 kEDSS-FKB14
Group C	Structure and role of the myomatrix	ClEDS mEDS
Group D	Biosynthesis of glycosaminoglycan	spEDS-B4GALT7 spEDS-b3GALT6 mcEDS-CHST14 mcEDS-DSE
Group E	Complement pathway	pEDS
Group F	Intracellular processes	spEDS-SLC39A13 BCS
Group G	Form of EDS that is not resolved	hEDS

Further Reading

• All Ehlers-Danlos Syndrome Content
• What is Ehlers-Danlos Syndrome?
• Living with Ehlers-Danlos Syndrome

Written by

Afsaneh Khetrapal

Afsaneh graduated from Warwick University with a First class honours degree in Biomedical science. During her time here her love for neuroscience and scientific journalism only grew and have now steered her into a career with the journal, Scientific Reports under Springer Nature. Of course, she isn’t always immersed in all things science and literary; her free time involves a lot of oil painting and beach-side walks too.