Scientific Background


The very rare, autosomal recessively inherited cardiac-valvular EDS (cvEDS) is characterized by severe heart valve involvement with mitral valve regurgitation, aortic valve regurgitation, atrial septal defect, ventricular dilatation, and ventricular hypertrophy, which usually requires mitral and aortic valve replacement. Other EDS-specific symptoms include variable skin hyperextensibility, atrophic scarring and generalized joint hypermobility.

To date, only eight patients from six families have been described, in whom homozygous or combined heterozygous variants in the COL1A2 gene have been identified. These are so-called null alleles, which lead to transcript instability, so that no pro-α2(I) collagen chains are detectable in collagen electrophoresis. In contrast to patients with osteogenesis imperfecta, there is no increased bone fragility in cvEDS.


1 gene: COL1A2



Guarnieri et al. 2019, Am J Med Genet A 179:846 / Brady et al. 2017, Am J Med Genet C 175:70 / Malfait et al. 2006, J Med Genet 43:e36 / Schwarze et al. 2004, Am J Hum Genet 74:917 / Nicholls et al. 2001, J Med Genet 38:132




In the current EDS classification of 2017, the autosomal recessively inherited EDS due to tenascin-X deficiency is designated as classical-like Ehlers-Danlos syndrome (clEDS). The minimum requirement for a clinical diagnosis of clEDS is the presence of all three major criteria: velvety hyperextensible skin without atrophic scarring, generalized joint hypermobility without dislocations, and increased skin fragility with spontaneous ecchymosis. Thus, with respect to joint and skin involvement, there is clinical overlap with classical EDS (cEDS), but without cigarette-paper-like scarring, and to hypermobile EDS (hEDS), which in turn does not show increased skin fragility.


Classical-Like EDS Type 1 due to Tenascin Deficiency

EDS due to tenascin-X deficiency (EDSCLL1) was genetically identified in a patient with adrenogenital syndrome and 21-hydroxylase deficiency who also had clinical symptoms of classical EDS. The cause was a 30 kb deletion on chromosome 6p21.3 that included both the CYP21A2 gene and the partially overlapping TNXB gene, thus representing a contiguous gene syndrome. Molecular causes of tenascin-X deficiency are homozygous or combined heterozygous variants in the TNXB gene. To date, the Human Gene Mutation Database and the Ehlers-Danlos Syndrome Variant Database (LOVD) include only six pathogenic missense variants, six nonsense variants, five small frameshift variants, two splice variants, and two large genomic rearrangements in the TNXB gene. Homozygosity and combined heterozygosity of variants leading to premature translational arrest resulting in complete absence of the tenascin-X gene product at the RNA and protein levels. In patients, tenascin-X is no longer detectable in serum. Tenascin-X is a glycoprotein synthesized in the extracellular matrix of skin, tendons, muscles and blood vessels. Some patients with tenascin-X deficiency have myopathic symptoms that are characteristic for Bethlem myopathy or Ullrich muscular dystrophy. The absence of tenascin-X in serum causes decreased expression of type VI collagen expression.

The absence of tenascin-X in serum supports the clinical diagnosis of EDS due to tenascin-X deficiency.


Classical-Like EDS Type 2

In 2018, another autosomal recessively inherited form of the classical-like EDS subtype was described: classical-like EDS type 2 (EDSCLL2). It is characterized by massive skin and musculoskeletal involvement with phenotypic variability and clinical overlap with other EDS subtypes. Skin manifestations include hyperextensible, loose, fragile skin, which may be translucent, with delayed wound healing and atrophic scarring. In addition to generalized joint hypermobility, joint dislocations and subluxations, early onset osteoporosis or osteopenia is typical. In addition, cardiovascular complications have been described. Skin biopsy in the patients studied to date showed an ultrastructure of irregular cross-sections of collagen fibrils and frayed collagen fibers.

The molecular causes are homozygous or combined heterozygous loss-of-function variants in the AEBP1 gene. AEBP1 encodes the aortic carboxypeptidase-like protein ACLP, which is associated with collagen within the extracellular matrix and is involved in the proliferation of fibroblasts and mesenchymal stem cells into collagen-producing cells. One hypothesis for the pathophysiology of ACLP deficiency is abnormal collagen fibril assembly and impaired wound healing due to reduced TGFβ receptor signaling.


2 genes: AEBP1, TNXB



Syx et al. 2019, Hum Mol Genet 28:1853 / Ritelli et al. 2019, Genes (Basel) 10, pii:E135 / Blackburn et al. 2018, Am J Hum Genet 102:696 / Malfait et al. 2017, Am J Med Genet C 175:8 / Brady et al. 2017, Am J Med Genet C 175:70 / Demirdas et al. 2017, Clin Genet 91:411 / Chen et al. 2016, Hum Mutat 37(9):893 / Morissette et al. 2015, J Clin Endocrinol Metab 100:E1143 / Pénisson-Besnier et al. 2013, Neuromuscul Disord 23:664 / Merke et al. 2013, J Clin Endocrinol Metab 98:E379 / Schalkwijk et al. 2001, N Engl J Med 345:1167




The very rare, autosomal recessively inherited dermatosparaxis EDS (dEDS) is characterized by extremely fragile, loose skin that appears excessive, especially on the face, and resembles cutis laxa. Other symptoms include easy bruising, premature rupture of fetal membranes, fragile internal organs, large umbilical and inguinal hernias, as well as short stature and short fingers.

The molecular cause is a procollagen I-N proteinase deficiency that leads to the incorporation of immature pNa1(I) and pNa2(I) pro-collagen chains into collagen fibrils during maturation of the pro-α1 (I) and pro-α2 (I) collagen chains. As a result, the assembly of the collagen fibrils is disturbed so that pathogenic hieroglyphic-like structures are visible in a cross-section of the dermis under electron microscopy.

The ADAMTS2 gene codes for the procollagen I-N proteinase, a zinc metalloproteinase of the ADAMTS family, which separates the aminopropeptides of type I, type II and type III procollagens. ADAMTS (A Disintegrin-like And Metalloproteinase with ThromboSpondin motifs type 1) are extracellular matrix anchor proteins. To date, 11 different inactivating ADAMTS2 variants have been described that lead to premature translational arrest or involve genomic rearrangements. The variants are mostly homozygous and more rarely combined heterozygous.


1 gene: ADAMTS2



Brady et al. 2017, Am J Med Genet C 175:70 / Van Damme et al. 2016, Genet Med 18: / Colige et al. 2004, J Invest Dermatol 123:656 / Malfait et al. 2004, Am J Med Genet 131A:18




The autosomal recessively inherited kyphoscoliotic EDS (kEDS) is genetically heterogeneous. Characteristic clinical symptoms include kyphoscoliosis, muscle hypotonia, thin, fragile hyperextensible skin, atrophic scarring, hypermobile joints, and variable eye involvement. Further symptoms are various craniofacial abnormalities, joint contractures, and wrinkled palms.

In the majority of patients, the disease is caused by homozygous or combined heterozygous variants in the PLOD1 gene, which encodes the enzyme lysylhydroxylase 1 (LH) (kEDS-PLOD1). LH is responsible for the hydroxylysine-dependent pyridinoline cross-linking of type I and type III collagen that is mainly found in the skeleton. The absence of the LH enzyme can also be detected by an increased ratio of lysyl-pyridinoline (LP) to hydroxylysyl-pyrodinoline (HP) cross-links in urine.

A small number of patients with nearly identical clinical presentation have an inconspicuous urinary LP/HP ratio and no PLOD1 variants. In 2012, another autosomal recessive EDS type with an inconspicuous LP/HP ratio was described as differential to kEDS-PLOD1 and initially named Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss (EDSKMH). Here, in addition to progressive kyphoscoliosis, muscle hypotonia, joint hypermobility, hyperextensible skin, and myopathy, sensineural hearing loss is particularly characteristic. As a result of clinical overlap with kEDS-PLOD1, EDSKMH is also classified in the kyphoscoliotic EDS (kEDS) group in the current EDS classification, where it is referred to as kEDS-FKBP14. kEDS-FKBP14 is caused by variants in the FKBP14 gene, which encodes FK506-binding protein 22, a member of the peptidyl-prolyl cis-trans isomerases (PPIases).


2 genes: FKBP14, PLOD1



Giunta in: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews® (May 23, 2019) / Giunta et al. 2018, Genet Med 20:42 / Yeowell and Steinmann in: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews® (updated 2018 Oct 18) / Brady et al. 2017, Am J Med Genet C 175:70 / Baumann et al. 2012, Am J Hum Genet 90:201 / Rohrbach et al. 2011, Orphanet J Rare Dis 6:46 / Giunta et al. 2005, Mol Genet Metab 86:269 / Yeowell et al. 2000, Mol Genet Metab 71:212




The autosomal recessively inherited musculocontractural EDS (mcEDS) is genetically heterogeneous and in the 1998 Villfranche classification was included in the group of kyphoscoliotic EDS with inconspicuous LP/HP ratio (EDS type VIB). Today, a distinction is made between mcEDS patients with a D4ST1 deficiency (type 1) and mcEDS patients with a DSE deficiency (type 2).

mcEDS is a differential diagnosis to neuromuscular diseases within the group of connective tissue diseases. It is characterized by an asthenic physique, instability of the large joints, tapering fingers , brachycephaly and characteristic facial features, hyperextensible and fragile skin, and recurrent subcutaneous hematomas.

The molecular cause of D4ST1 deficiency (mcEDS type 1) is homozygous or combined heterozygous variants in the CHST14 gene (carbohydrate sulfotransferase 14), which encodes dermatan 4-O-sulfotransferase 1 (D4ST1). The molecular cause of DSE deficiency (mcEDS type 2) is homozygous or combined heterozygous variants in the DSE gene encoding dermatan sulfate epimerase (DSE). Both enzymes are involved in dermatan sulfate biosynthesis. DSE catalyzes the epimerization of D‑glucuronic acid (D-GlcA) to L-iduronic acid (L-IdoA) allowing D4ST1 to catalyze the 4-O-sulfonation of N-acetyl-D-galactosamine.


2 genes: CHST14, DSE



Brady et al. 2017, Am J Med Genet C 175:70 / Van Damme et al. 2016, Genet Med 18:882 / Colige et al. 2004, J Invest Dermatol 123:656 / Malfait et al. 2004, Am J Med Genet 131A:18




EDS caused by B4GALT7 deficiency (spEDS-B4GALT7) and B3GALT6 deficiency (spEDS-B3GALT6)

Characteristic clinical symptoms of spondylodysplastic Ehlers-Danlos syndromes (spEDS), previously referred to as progeroid subtypes, include an aged appearance, developmental delay, short stature, craniofacial dysproportion, generalized osteopenia, impaired wound healing, hypermobile joints, muscle hypotonia, and loose but elastic skin.

Molecular causes are homozygous or combined heterozygous variants in the B4GALT7 and B3GALT6 genes. Both genes encode a UDP-galactose: O-beta-D-xylosylprotein 4-beta-D-galactosyltransferase and beta-1,3-galactosyltransferase 6, respectively. Galactosyltransferase I deficiency results in deficiency of small proteodermatan sulfates within glycosaminoglycan biosynthesis. B3GALT6 variants were originally identified in spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL1).


EDS caused by SLC39A13 variants (spEDS-SLC39A13)

Patients with the very rare EDS type formerly known as spondylocheirodysplastic EDS (SCD-EDS) have thin, translucent, hyperextensible, velvety, fragile skin with atrophic scars; slender, tapered fingers; and joint contractures. Additional characteristic clinical symptoms include skeletal dysplasia (spondylo) with moderate short stature, and characteristic hand abnormalities with wrinkled palms and atrophy of the muscles at the base of the thumb and palm of the hand (cheiro).

spEDS-SLC39A13 is caused by variants in the zinc transporter gene SLC39A13. To date, only three homozygous loss-of-function variants in the SLC39A13 gene have been described in nine patients from three families. Patients with spEDS-SLC39A13 have a urinary LP/HP ratio of approximately 1.0, which is a value between controls and patients with kyphoscoliotic EDS (kEDS-PLOD1).


3 genes: B3GALT6, B4GALT7, SLC39A13



Van Damme et al. 2018, Hum Mol Genet 27:3475 / Brady et al. 2017, Am J Med Genet C 175:70 / Ritelli et al. 2017, Orphanet J Rare Dis 12:153 / Vorster et al. 2014, Clin Genet 87:492) / Guo et al. 2013, Am J Med Genet A 161:2519 / Nakajima et al. 2013, Am J Hum Genet 92:927 / Giunta et al 2008, Am J Hum Genet 82:1290 / Fukada et al. 2008, PLoS One 3:e3642 / Faiyaz-Ul-Haque et al. 2004, Am J Med Genet 128A:39 / Okajima et al. 1999, J Biol Chem 274:28841




Myopathic EDS (mEDS) is characterized by muscle weakness that manifests in childhood with proximal contractures of the large joints and distal joint hypermobility. Typically, muscle weakness improves in young adulthood, although it may deteriorate again in the fourth decade of life. The spectrum of disorders characterized by muscle weakness, hypotonia, myopathy, and connective tissue symptomatology was originally associated with collagen type VI disorders.

Pathogenic variants in COL12A1, which encodes the α1-chain of type XII collagen, are the molecular cause of mEDS. Collagen XII is present as a homotrimer on the surface of type I collagen fibers. It forms a link between type I collagen fibers and extracellular matrix components such as decorin, fibromodulin, and tenascin. To date, mEDS has been described in both an autosomal dominantly inherited form with heterozygous missense variants and an autosomal recessively inherited form with homozygous frameshift variants.


1 gene: COL12A1



Delbaere et al. 2019, Genet Med 22:112 / Jezela-Stanek et al. 2019, Clin Genet 95(6):736 / Punetha et al. 2017, Muscle Nerve 55:277 / Brady et al. 2017, Am J Med Genet C 175:70 / Zou et al. 2014, Hum Mol Genet 23:2339 / Hicks et al. 2014, Hum Mol Genet 23:2353


How to order


Exciting news in genetic research! The Human Pangenome Reference Consortium has unveiled an improved version of the human pangenome reference. This c...

Read more

Duchenne muscular dystrophy, a rare inherited muscle disorder characterized by progressive muscle weakness and degeneration that leads to difficultie...

Read more

May 12 is International Nurses Day. It is celebrated on Florence Nightingale’s birthday. She pioneered the field of modern nursing through her dedi...

Read more

Hair loss is a common problem that affects millions of men and women around the world. While genetics is believed to be the most significant factor c...

Read more

Depression is a serious mental health issue affecting over 280 million people worldwide. Recent research has revealed a potential link between gut he...

Read more

If you are unlucky enough to suffer from migraines, you will know that a migraine is not just a bad headache. The headache and accompanying symptoms ...

Read more

Autism spectrum disorder (ASD) is a neurological developmental disorder that affects brain development and function. This affects how people learn, b...

Read more

Researchers have developed a method called "Mendelian Phenotype Search Engine" (MPSE) to identify which sick infants in the neonatal intensive care u...

Read more

Did you know that wisdom teeth are actually an evolutionary leftover from our ancient ancestors that no longer serve their original purpose? These mo...

Read more

Azoospermia is a medical condition characterized by the absence of sperm in the ejaculate and is a major cause of male infertility. It affects 1 in 1...

Read more