Ehlers-Danlos syndrome (EDS): types, symptoms, causes and genetics

Ehlers-Danlos syndrome (EDS) is not one syndrome but a group of clinically and genetically heterogeneous connective tissue disorders. There are currently 13 EDS subtypes that vary in worldwide prevalence but are all rare diseases.

What is Ehlers-Danlos syndrome (EDS)?

Ehlers-Danlos syndrome refers to a clinically and genetically heterogeneous group of connective tissue disorders characterized by joint hypermobility, highly elastic (stretchy) skin, and tissue fragility [1]. EDS is caused by abnormalities in the structure, production, and/or processing of collagen.

The revised international classification of 2017 proposes 13 subtypes based on clinical criteria, which are inherited in an autosomal dominant or recessive pattern and, with the exception of the hypermobile EDS subtype, can be confirmed by genetic data [2].

Variants in about 29 genes have been associated with Ehlers-Danlos syndrome (EDS) with specific variants linked to different subtypes of EDS. These variants may be inherited from a person’s biological parents, or they may have occurred randomly in the affected individual (de novo).

Genetic testing can be used to identify these variants. This may be helpful in diagnosing EDS and determining the disease type. Identifying those who do not have EDS but are at risk of passing it on to their biological offspring (carriers) may also be helpful.

The clinical differentiation of EDS subtypes is often difficult as they can overlap with other connective tissue diseases, such as osteogenesis imperfecta, Marfan syndrome, and Loeys-Dietz syndrome. A genetic diagnosis can support differentiation.

What are the EDS types?

There are currently 13 EDS subtypes that are inherited in an autosomal dominant or recessive pattern [2].

Autosomal dominant subtypes include arthrochalasia EDS (aEDS), classical EDS (cEDS), hypermobile EDS (hEDS), periodontal EDS (pEDS) and vascular EDS (vEDS).

Autosomal recessive subtypes include brittle cornea syndrome (BCS), cardiac-valvular EDS (cvEDS), classical-like (clEDS), dermatosparaxis EDS (dEDS), kyphoscoliotic EDS (kEDS), musculocontractural EDS (mcEDS) and spondylodysplastic EDS (spEDS).

Myopathic EDS (mEDS) can be inherited in an autosomal dominant or recessive manner.

Tab 1. Prevalence and inheritance patterns of EDS subtypes

What are the symptoms of EDS?

The Ehlers-Danlos syndromes are most often accompanied by pain and fatigue [3]. However, EDS can affect people in different ways depending on the type of EDS and the affected gene. Clinical signs of EDS generally involve the joints and skin and may include

Joints

• Joint pain (arthralgia) and deformity
• Muscle pain (myalgia) and nerve pain (neuralgia)
• Loose/unstable joints which are prone to frequent dislocations and/or subluxations and injury
• Muscle tension and weakness
• Weakness of the voice box and larynx
• Hernias
• Pelvic floor weakness and prolapses of the rectum, bladder or vaginal wall and uterus
• Nerve disorders (neuropathy) from cord and nerve entrapment or sensory nerve damage

Skin

• Soft velvety-like skin
• Variable skin hyperextensibility
• Fragile skin that tears or bruises easily, bruising may be severe including clots under the skin (hematoma)
• Severe scarring
• Slow and poor wound healing
• Development of molluscoid pseudotumors (fleshy lesions associated with scars over pressure areas)

Tissue fragility

• Arterial/intestinal/uterine fragility or rupture (usually associated with vEDS)
• Scoliosis at birth and scleral fragility (associated with the kEDS)
• Congenital hip dislocations
• Poor muscle tone
• Severe gum disease

EDS and comorbidities

Several disorders are associated with EDS and in particular the hypermobile variant (hEDS). Among the most common of these are upper and lower gastrointestinal tract complications, such as

• Swallow difficulties and sluggish stomach and large bowel, causing nausea, vomiting, acid reflux, bloating, pain, and malabsorption and food intolerance
• Autonomic disturbances of heart rate and blood pressure, bowel and bladder function, and temperature regulation
• Anxiety, depression, and phobias
• Organ/systemic inflammation related to mast cell activation

What causes EDS? 

EDS is caused by abnormalities in the structure, production, and/or processing of collagen. Genetic changes in a number of genes may lead to the weakening of the connective tissue. The EDS subtypes can be divided into different groups based on defects in

• collagen biosynthesis and processing
• collagen folding
• the structure and function of the interface between muscle and the extracellular matrix
• glycosaminoglycan biosynthesis
• the complement pathway
• intracellular processes

Collagen biosynthesis, processing, and the assembly of collagen fibrils is impaired at different stages in the different EDS subtypes:

1. Synthesis and stability: haploinsufficiency of mutant COL5A1 mRNA leading to decreased synthesis of alpha-1-procollagen(V) is the cause in approximately 60% of classical EDS (cEDS).
2. Hydroxylation of lysine and proline in procollagen chains: lack of hydroxylation due to lysyl hydroxylase deficiency is the cause of kyphoscoliotic EDS (kEDS).
3. Processing and secretion: pathogenic variants in COL3A1 affecting the triple helix domain of procollagen alpha chains prevent normal processing in the rough endoplasmic reticulum and the subsequent secretion of homotrimers. They are the cause of vascular EDS (vEDS).
4. Cleavage of N-terminal propeptides in the extracellular matrix: dominant pathogenic variants in COL1A1 and COL1A2 that prevent the recognition sequence cleaving N-terminal propeptides in the extracellular matrix are the cause of arthrochalasia EDS (aEDS). Autosomal recessive mutations in the gene encoding procollagen N-peptidase result in dermatosparaxis EDS (dEDS).
5. Fibril formation: dominant-negative pathogenic variants in COL5A1 and COL5A2 can prevent collagen molecules from assembling into heterotopic fibrils and cause approximately 30% of classical EDS (cEDS).
6. Interaction with extracellular matrix proteins: if the tissue-specific arrangement of collagen fibrils and the interaction with extracellular matrix proteins such as tenascin-X is disturbed, EDS with tenascin-X deficiency or classical-like EDS (clEDS) may result.

Since the clinical differentiation of individual EDS subtypes is often difficult and there may be overlaps with other connective tissue diseases such as cutis laxa, a genetic diagnosis using NGS may help in classification.

Tab 2. Affected gene(s) in EDS subtypes

How is EDS diagnosed? 

The diagnostic journey starts with a comprehensive analysis of the medical and family history along with a physical examination that focuses on the joints, skin, and any other parts of the body that might be affected [3].

There is a substantial overlap of symptoms between the EDS subtypes and other connective tissue disorders, as well as a lot of variability between them. Therefore, a definitive diagnosis for all the EDS subtypes – except (hEDS) – depends on finding the subtype that most closely matches the symptoms and the diagnostic criteria and on genetic testing to identify the responsible gene variant. 

Knowing the type of EDS might explain the cause of symptoms allowing for better treatment and improved health outcomes. 

How can EDS be treated?

Ehlers-Danlos syndrome is not curable but treatment can help to manage symptoms and prevent further complications [4].

Medication

• To relieve pain. Mainly non-prescription painkillers, including acetaminophen, ibuprofen, and naproxen sodium. Stronger medications are only prescribed for acute injuries.
• To reduce blood pressure. Blood vessels are more fragile in some EDS subtypes; hence, keeping the blood pressure low reduces the stress on the vessels.

Physiotherapy

• To strengthen muscles and joints. Joints with weak connective tissue are more likely to dislocate. Exercises to strengthen the muscles and stabilize joints are the primary treatment for EDS. Specific braces to help prevent joint dislocations might also be recommended.

Surgery

• Surgery to repair the damage. Surgery may be recommended to repair joints damaged by repeated dislocations or to repair ruptured areas in blood vessels and organs. However, the surgical wounds may not heal properly because the fragile tissue might not hold the stitches.

Summary

EDS is a group of connective tissue disorders based on different molecular defects of the collagen metabolism​

• Prevalence 1 in 20,000-1,000,000​ (depending on EDS subtype)
• Caused by pathogenic variants in genes involved in the structure, production, and/or processing of collagen or proteins that interact with collagen
• Genes include COL5A1, COL5A2, COL1A1, COL3A1, TNXB, PLOD1, COL1A2, FKBP14 and ADAMTS2​
• Autosomal dominant or​ recessive​ inheritance
• Key symptoms are skin hyperextensibility, tissue fragility, joint hypermobility, and various skeletal, cardiovascular, and gastrointestinal symptoms​
• Treatment includes preventing serious complications and relieving associated symptoms by involving the relevant medical specialists for each affected body system
• Management includes cardiovascular workup, physical therapy, pain management, and psychological follow-up​

References

[1] Cortini F et al. Understanding the basis of Ehlers-Danlos syndrome in the era of the next-generation sequencing. Arch Dermatol Res. 2019 May;311(4):265-275. doi: 10.1007/s00403-019-01894-0. Epub 2019 Mar 2. PMID: 30826961. https://doi.org/10.1007/s00403-019-01894-0

[2] Malfait F et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):8-26. doi: 10.1002/ajmg.c.31552. PMID: 28306229. https://doi.org/10.1002/ajmg.c.31552

[3] Ehlers-Danlos Society. What are the Ehlers-Danlos syndromes? Retrieved 11 July 2022 from https://www.ehlers-danlos.com/what-is-eds/

[4] Mayoclinic. Ehlers-Danlos syndrome. Retrieved 12 July 2022 from https://www.mayoclinic.org/diseases-conditions/ehlers-danlos-syndrome/diagnosis-treatment/drc-20362149