Classical-Like Ehlers-Danlos Syndrome  (clEDS)

Classical-like Ehlers-Danlos syndrome (clEDS) is a heritable connective tissue disorder that causes severe skin hyperextensibility, velvety skin texture, generalized joint hypermobility, and easy bruising. 

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

Key signs and symptoms of clEDS include:

• Generalized joint hypermobility
• Soft, stretchy skin without atrophic scarring
• Easy bruising

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

Genetic Basis 

clEDS is caused by genetic variants in the TNXB gene. The TNXB gene provides instructions for making the tenascin-X protein. Tenascin-X is present at high levels in the connective tissue of the heart, skeletal muscles, tendons, ligaments, skin, and digestive tract. 

Humans have two copies of each gene because we inherit one from each parent. People with clEDS have pathogenic variants in both copies of the TNXB gene. As a result, the tenascin-X protein is completely absent in people with clEDS. 

Inheritance 

clEDS 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 clEDS will always pass on one pathogenic variant to their children. Their children will only have clEDS 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 clEDS themselves but may pass the genetic variant on to their children. 

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

To meet the diagnostic criteria for clEDS, a person must meet all three major criteria AND have a family history compatible with autosomal recessive inheritance. 

Major Criteria 

1. Skin hyperextensibility, with velvety skin texture and absence of atrophic scarring 
2. Generalized joint hypermobility, with or without recurrent dislocations (most commonly shoulder and ankle) 
3. Easily bruisable skin/spontaneous ecchymoses 

Minor Criteria 

1. Foot deformities (broad/plump forefoot; brachydactyly with excessive skin; pes planus; hallux valgus; piezogenic papules) 
2. Edema in the legs in the absence of cardiac failure 
3. Mild proximal and distal muscle weakness 
4. Axonal polyneuropathy 
5. Atrophy of muscles in hands and feet 
6. Acrogeric hands, mallet finger(s), clinodactyly, brachydactyly 
7. Vaginal/uterus/rectal prolapse 

clEDS is managed by addressing the symptoms a person is experiencing. Key aspects of care focus on managing skin and joint issues. 

clEDS can cause a variety of symptoms in different areas of the body, so people with clEDS may require multiple providers in different specialties to manage their care. Each person should work with their care team to develop a care plan that meets their needs. 

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 

Clinical and molecular delineation of classical-like Ehlers–Danlos syndrome through a comprehensive next-generation sequencing-based screening system (Yamaguchi et al., 2023) 
https://doi.org/10.3389/fgene.2023.1234804 

Tenascin-X as a causal gene for classical-like Ehlers-Danlos syndrome (Ashitaka et al., 2023) 
https://doi.org/10.3389/fgene.2023.1107787 

TNXB-Related Classical-Like Ehlers-Danlos Syndrome (Van Dijk et al., 2022) 
https://www.ncbi.nlm.nih.gov/books/NBK584019/ 

Classical-like Ehlers–Danlos syndrome: a clinical description of 20 newly identified individuals with evidence of tissue fragility (Green et al., 2020) 
https://doi.org/10.1038/s41436-020-0850-1 

Biallelic mutations in Tenascin-X cause classical-like Ehlers-Danlos syndrome with slowly progressive muscular weakness (Brisset et al., 2020) 
https://doi.org/10.1016/j.nmd.2020.09.002 

Novel TNXB Variants in Two Italian Patients with Classical-Like Ehlers-Danlos Syndrome (Micale et al., 2019) 
https://doi.org/10.3390/genes10120967 

Clinical and Molecular Characterization of Classical-Like Ehlers-Danlos Syndrome Due to a Novel TNXB Variant (Rymen et al., 2019) 
https://doi.org/10.3390/genes10110843 

Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients (Demirdas et al., 2016) 
https://doi.org/10.1111/cge.12853 

Tenascin-X: beyond the architectural function (Valcourt et al., 2015) 
https://doi.org/10.4161%2F19336918.2014.994893 

Recurrent gastrointestinal perforation in a patient with Ehlers–Danlos syndrome due to tenascin-X deficiency (Sakiyama et al., 2015) 
https://doi.org/10.1111/1346-8138.12829 

Compound heterozygous mutations of the TNXB gene cause primary myopathy (Pénisson-Besnier et al., 2013) 
https://doi.org/10.1016/j.nmd.2013.04.009 

Well-defined clinical presentation of Ehlers-Danlos syndrome in patients with tenascin-X deficiency: a report of four cases (Hendriks et al., 2012) 
https://doi.org/10.1097/mcd.0b013e32834c4bb7 

Tenascin-X deficiency and Ehlers-Danlos syndrome: a case report and review of the literature (O’Connell et al., 2010) 
https://doi.org/10.1111/j.1365-2133.2010.09949.x 

Analysis of obstetric complications and uterine connective tissue in tenascin-X-deficient humans and mice (Egging et al., 2008) 
https://doi.org/10.1007/s00441-008-0591-y 

Reduced quantitative muscle function in tenascin-X deficient Ehlers-Danlos patients (Voermans et al., 2007) 
https://doi.org/10.1016/j.nmd.2007.04.004 

A clinical and cardiovascular survey of Ehlers-Danlos syndrome patients with complete deficiency of tenascin-X (Peeters et al., 2004) 
https://pubmed.ncbi.nlm.nih.gov/15366699/ 

The Ehlers-Danlos syndrome: On beyond collagens (Mao et al., 2001) 
https://doi.org/10.1172/jci12881 

A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency (Schalkwijk et al., 2001) 
https://doi.org/10.1056/nejmoa002939 

Tenascin–X deficiency is associated with Ehlers-Danlos syndrome (Burch et al., 1997) 
https://doi.org/10.1038/ng0997-104 

AEBP1 Research 

Clinical and Molecular Characterization of a Novel Homozygous Frameshift Variant in AEBP1-Related Classical-like Ehlers Danlos Syndrome Type 2 with Comparison to Previously Reported Rare Cases (Ha et al., 2024) 
https://doi.org/10.3390/genes15040461 

Case report: Two individuals with AEBP1-related classical-like EDS: Further clinical characterisation and description of novel AEBP1 variants (Angwin et al., 2023) 
https://doi.org/10.3389/fgene.2023.1148224 

Case report: further delineation of AEBP1-related Ehlers–Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature (Yamaguchi et al., 2023) 
https://doi.org/10.3389/fgene.2023.1102101 

The detailed obstetric course of the first Japanese patient with AEBP1-related Ehlers–Danlos syndrome (classical-like EDS, type 2) (Sanai et al., 2023) 
https://doi.org/10.1111/jog.15541 

Congenital Defects in a Patient Carrying a Novel Homozygous AEBP1 Variant: Further Expansion of the Phenotypic Spectrum of Ehlers–Danlos Syndrome Classical-like Type 2? (Giosaffatte et al., 2022) 
https://doi.org/10.3390/genes13122358 

Expanding the Clinical and Mutational Spectrum of Recessive AEBP1-Related Classical-Like Ehlers-Danlos Syndrome (Ritelli et al., 2019) 
https://doi.org/10.3390/genes10020135 

Bi-allelic AEBP1 mutations in two patients with Ehlers–Danlos syndrome (Syx et al., 2019) 
https://doi.org/10.1093/hmg/ddz024 

A biallelic truncating AEBP1 variant causes connective tissue disorder in two siblings (Hebebrand et al., 2018) 
https://doi.org/10.1002/ajmg.a.60679