Cardiac-Valvular Ehlers-Danlos Syndrome (cvEDS)

Cardiac-valvular Ehlers-Danlos syndrome (cvEDS) is a heritable connective tissue disorder that causes severe heart valve problems that may require valve replacement surgery in adulthood. People with cvEDS also have other symptoms, such as joint hypermobility, skin hyperextensibility, and atrophic scarring.

cvEDS is an ultra-rare disorder that affects less than 1 in 1 million people.

Key signs and symptoms of cvEDS include:

• Severe cardiac valve problems
• Joint hypermobility
• Skin hyperextensibility
• Atrophic scarring

You can learn more about the features of cvEDS by selecting different body parts from the menu.

Genetic Basis

cvEDS is caused by genetic variants in the COL1A2 gene. The COL1A2 gene provides instructions for making part of type I collagen, a major protein that supports many tissues throughout the body.

Humans have two copies of each gene because we inherit one from each parent. People with cvEDS have pathogenic variants in both copies of the COL1A2 gene. This results in a complete absence of normal type I collagen.

Inheritance

cvEDS is inherited in an autosomal recessive pattern. Autosomal means it can be passed on and inherited equally by males and females. Recessive means the condition only occurs when both copies of a gene are affected by pathogenic variants.

People with cvEDS will always pass on one pathogenic variant to their children. Their children will only have cvEDS if they inherit a second pathogenic variant in the same gene from their other parent.

People with one recessive pathogenic variant are known as carriers. Carriers do not have cvEDS themselves but may pass the genetic variant on to their children.

If a person meets the diagnostic criteria for cvEDS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has the genetic variants that cause cvEDS.

To meet the diagnostic criteria for cvEDS, a person must meet:

• Major criterion 1 AND family history compatible with autosomal recessive inheritance AND at least one other major criterion
  OR
• Major criterion 1 AND family history compatible with autosomal recessive inheritance AND at least two minor criteria

Major Criteria

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

Minor criteria

1. Inguinal hernia
2. Pectus deformity (especially excavatum)
3. Joint dislocations
4. Foot deformities: pes planus, pes planovalgus, hallux valgus

cvEDS is managed by addressing the symptoms a person is experiencing. cvEDS can cause a variety of symptoms in many different areas of the body, so people with cvEDS may require multiple providers in different specialties to manage their care. The key aspects of care focus on monitoring and managing cardiac valve issues.

Specific management guidelines include:

• Measurement of aortic root size and assessment of heart valves by echocardiogram at the time of diagnosis or by age 5
• Yearly echocardiogram, even if the initial echocardiogram is normal
• Cardiac valve replacement surgery if necessary
• Consider bone densitometry evaluation

The Ehlers-Danlos Syndromes, Rare Types (Brady et al., 2017) 
https://doi.org/10.1002/ajmg.c.31550 

The 2017 International Classification of the Ehlers-Danlos Syndromes (Malfait et al., 2017) 
https://doi.org/10.1002/ajmg.c.31552 

Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2 (Guarnieri et al., 2019) 
https://doi.org/10.1002/ajmg.a.61100 

Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems (Malfait et al., 2006) 
https://doi.org/10.1136/jmg.2005.038224 

Rare Autosomal Recessive Cardiac Valvular Form of Ehlers-Danlos Syndrome Results from Mutations in the COL1A2 Gene That Activate the Nonsense-Mediated RNA Decay Pathway (Schwarze et al., 2004) 
https://doi.org/10.1086/420794 

Homozygosity for a splice site mutation of the COL1A2 gene yields a non-functional proα2(I) chain and an EDS/OI clinical phenotype (Nicholls et al., 2001) 
https://doi.org/10.1136/jmg.38.2.132 

Case Report and Study of Collagen Metabolism in Ehlers-Danlos Syndrome Type II (Kojima et al., 1988) 
https://doi.org/10.1111/j.1346-8138.1988.tb03668.x 

Existence of malfunctioning proα2(I) collagen genes in a patient with a proα2(I)-chain-defective variant of Ehlers-Danlos syndrome (Hata et al., 1988) 
https://doi.org/10.1111/j.1432-1033.1988.tb14087.x 

Ehlers-Danlos Syndrome: A Variant Characterized by the Deficiency of Proa2 Chain of Type I Procollagen (Sasaki et al., 1987) 
https://doi.org/10.1001/archderm.1987.01660250082024