Ehlers-danlos syndrome Q79.6

A form of EDS was first described by the Russian dermatologist Chernogubov in 1892. In Russia, the disease is still known today as Chernogubov syndrome. The current name EDS was not given until 1936, based on the description by the Danish dermatologist Edvard Ehlers (1863-1937) and the French dermatologist and internist Henri-Alexandre Danlos (1844-1912).

Ehlers-Danlos syndrome (EDS) is an umbrella term for hypermobile diseases and includes a genetically and phenotypically heterogeneous group of hereditary connective tissue diseases. They are all caused by pathogenic variants of genes involved in the metabolism of collagen or its environment. Known are disorders of collagen primary structure, collagen processing, collagen folding, collagen glycosylation and collagen embedding. Clinically, patients suffer from hyperextensibility of the skin, hyperextensibility of the joints, eye changes, scoliosis and easy tearing of the blood vessels. Depending on the clinical manifestation, genetic and biochemical disorder, a distinction is made between groups A-F (+nn) with 13 different phenotypes, which are attributable to pathogenic variants in 18 genes.

Group A (diseases in which the primary structure of collagen types and their processing is disturbed). This group includes:

• Classical EDS (previously type I): Autosomal dominant inheritance; deficiency of collagen type V (90%), whose gene COL5A1 is mapped on chromosome 9q34.2-q34.3. Mutations of the COL1A1 gene on chromosome 17q2133 are rarer
• Heart valve EDS (collagen I)
• Vascular EDS (previously type IV): Autosomal recessive inheritance; deficiency of type III collagen. Mutation in one of the two COL3A1 genes mapped on chromosome 2q31 with qualitative and/or quantitative deficiency of collagen III (tendency to aneurysm formation).
• Arthrochalasia EDS (previously type VII A/B): Autosomal recessive inheritance; the collagen fibril length is between pro-alpha and alpha collagen. In types A and B, mutations occur in the COL1A1 or COL1A2 genes, which are mapped on chromosomes 17q21.31-q22.05 and 7q221. This results in deletion of the amino-terminal telopeptide of the α1(1) or α2(I) chain of collagen I, resulting in impaired fibril formation and cross-linking.
• Dermatosparaxis EDS (formerly type VII C); the procollagen N collagenase is missing in this type. The gene responsible for this, pN alpha1, is mapped on chromosome 17q21.31-q22.05. The mutation of this gene leads consecutively to impaired fibril formation.

Group B (This group includes EDS types in which the formation of cross-links between the collagen molecules or collagen unfolding is impaired)

• Kypho-scoliotic EDS (formerly type VI): Autosomal recessive inheritance; defect in collagen lysyl hydroxylase I; alternatively, there is a mutation in a protein (FKBP22) that is involved in triple helix formation. The responsible gene PLOD1 is located on chromosome 1p36.3; 1p36.2. The collagen lysyl hydroxylase is inactive in the fibroblasts, so that the cross-linking of the collagen remains unstable; carriers have intermediate activity.

Group C (This group includes subtypes in which the function of the myomatrix, which forms the boundary between muscle and extracellular matrix, is affected.

• Classical-like EDS (not yet assigned); deficiency of tenascin-X [Q79.6]
• Myopathic EDS: mutation of COL12A1 (collagen XII)

Group D (This group includes EDS types with alterations in the biosynthesis of gylycosaminoglycans).

• Spondylo-dysplastic EDS: mutations in galactosytransferase I and II
• Musculo-contractural EDS: mutations in dermatan sulfotransferase, dermatan sulfate epitransferase

Group E

• Periodontal EDS: mutations in complement factors (C1R gene)

Group F (disorders of intracellular processes)

• Spondylo-dysplastic EDS: Mutations in the zinc transporter protein ZIP13
• Brittle cornea syndrome: mutations in the zinc finger protein 469 and the transcription factor PRDM5

Group nn (Not assigned)

• Hypermobile EDS (old name: EDS type III: Autosomal dominant inheritance; deficiency of collagen type III, whose gene COL3A1 is mapped on chromosome 2q31. In some patients a genetic variation of the TNXB gene with a deficiency of the gene product tenascin-X was detected. This is associated with an increased tendency to hematoma.

The new classification according to diagnostic criteria replaces the older classifications according to Villefranche and the Berlin classification. A distinction is now made between 13 (clinical) types (Brinckmann J 2018):

1. Hypermobile EDS (hEDS, formerly type III): The genetic cause is not yet known. The diagnosis is made clinically after a thorough examination.hEDS is characterized primarily by hypermobility of large and small joints. Subluxations and dislocations can occur regularly. hEDS patients often suffer from joint instability and frequently have soft, velvety skin that can be easily damaged. Patients very often suffer from chronic pain. The severity can range from moderate to very severe. Around 90% of EDS sufferers have chronic pain, with the highest pain scores found in hEDS patients (Chopra et al. 2019).
2. Classic EDS (cEDS, formerly types I and II): Around 90% of the genetic cause of this type of EDS is found in the COL5A1 and COL5A2 genes. Mutations in COL1A1 are less common. Major criteria are extremely elastic skin that is fragile and easily injured, atrophic scarring and general joint hypermobility. There are also nine "minor" criteria, such as velvety skin, muscle hypotonia or pseudotumors (Bowen et al.2016).
3. Vascular EDS (vEDS, formerly type IV): The genetic cause can be localized in variations of the COL3A1 gene. There are five major criteria and 12 "minor" criteria that provide a clinical indication of vEDS. Patients often have thin, translucent skin that is very fragile and easily injured. Veins and organs are just as easily damaged. The joints are hypermobile, usually small joints such as fingers or toes. Club feet or torn ligaments and muscles can occur. vEDS is life-threatening, the median age of those affected is 51 years. The lifespan is long, ranging from around 10 to about 80 years. The most common cause of death is arterial dissection or rupture (Byers et al. 2019).
4. Kypho-scoliotic EDS (kEDS, formerly type VI): Triggered by variants in the PLOD1 gene (coding for a "lysylhydroxylase", a membrane-bound homodimeric enzyme localized in the cisternae of the endoplasmic reticulum), more rarely in the FKBP14 gene. Major criteria are congenital muscle hypotonia, congenital or early-onset kyphoscoliosis and generalized hypermobility with (sub)dislocations. There are also minor criteria. Kyphoscoliosis is usually severe and progressive. Other symptoms may include soft, doughy skin, atrophic scarring and poor wound healing (Brady et al. 2017).
5. Arthrochalasia EDS (aEDS, formerly type VII a and b): aEDS is caused by mutations in the COL1A1 and COL1A2 genes. Around 30 cases are currently known. Those affected suffer from pronounced joint hypermobility and congenital, bilateral hip dislocation. In addition, (sub)dislocations of the large and small joints, foot deformities and scoliosis, lordosis and kyphoscoliosis can occur. The skin can be overstretched, velvety and easily damaged (Brady et al. 2017).
6. Dermatosparaxis EDS (formerly type VIIc): this EDS variant is caused by mutations in the ADAMTS2 gene. Symptoms include extremely fragile skin that quickly forms scars. The skin is loose and redundant. Joint hypermobility ranges from mild to severe. dEDS is very rare - around ten cases have been reported to date (Brady et al. 2017).
7. Brittle cornea syndrome (BCS): BCS occurs in two types. Variant 1 is caused by a mutation in the ZNF469 gene, variant 2 by a mutation in the PRDM5 gene. BCS is characterized by progressive thinning of the cornea of the eye. Keratoglobus or keratoconus may occur early, as well as myopia, hearing loss and blue sclera. Classical EDS symptoms, such as hypermobile joints and hyperextensible skin, are frequently observed (Brady et al. 2017).
8. Classical-like EDS (clEDS): Mutations in the TNXB gene lead to clEDS. The skin is usually hyperextensible and velvety, but does not show atrophic scarring. There is often general joint hypermobility, (sub)dislocations can occur, mainly affecting the shoulders and ankles (Brady et al. 2017).
9. Spondylo-dysplastic EDS (spEDS): spEDS is caused by mutations in the B4GALT7, B3GALT6 and SLC39A13 genes. Affected individuals are often short in stature and exhibit muscle hypotonia (Brady et al. 2017).
10. Musculo-contractural EDS (mcEDS): Mutations in the CHST14 and DSE genes are the cause of mcEDS. It is characterized by skin hyperextensibility, increased skin vulnerability, atrophic scarring and increased wrinkling in the palms. mcEDS leads to congenital contractures (Brady et al. 2017).
11. Myopathic EDS (mEDS): Mutations in the COL12A1 gene lead to mEDS. mEDS affected individuals suffer from congenital muscle hypotonia and/or muscle atrophy that progresses with age. Proximal joint contractures and joint hypermobility of distal joints may occur (Brady et al. 2017).
12. Periodontal EDS (pEDS): pEDS is caused by mutations in the C1R gene. pEDS leads to severe, persistent periodontitis that occurs in childhood or adolescence. The gums are often not sufficiently attached to the tooth (lack of attachment) (Brady et al. 2017).
13. Heart valve EDS (cvEDS): COL1A2 mutations can lead to cvEDS. Severe progressive cardio-valvular symptoms, such as at the mitral valve, and an overstretchable, easily injured skin prone to atrophic scarring characterize cvEDS. In addition, joint hypermobility occurs, which can either be generalized or limited to the small joints (Brady et al. 2017).

Note: Osteogenesis imperfecta/Ehlers-Danlos(OI/EDS) overlap syndrome is a connective tissue disorder characterized by a mutation of the COL1A1 (17q21.33) or COL1A2 (7q21.3) genes involved in the α-1 and α-2 chain of type 1 collagen synthesis.The clinical spectrum of this clinical entity exhibits features of both osteogenesis imperfecta (bone fragility, long bone fractures, blue sclerae, short stature) and Ehlers-Danlos syndrome (joint hyperextensibility, soft and hyperextensible skin, abnormal wound healing, easy bruising, vascular fragility).

Ehlers-Danlos syndrome used to be considered a rare disease. For many years, a prevalence of 1: 5000 was assumed. Since the pragmatic proposal to consider the "hypermobile spectrum disorder" and the "hypermobile type of EDS" as one entity, disorders with the umbrella term EDS are being diagnosed more frequently. An electronic cohort study carried out in Wales on the hypermobile type of EDS and hypermobile spectrum disorder showed a prevalence of 1: 500 . From this it can be concluded that all EDS disorders taken together are not a rare disorder after all. Ethnic dominance is not known; m:f=1:1.

Mostly in childhood.

Types I-III: no histological features. Rarely, especially in type I, thin collagen fibers without bundling. In these cases, increase in elastic fibers compared to collagen fibers, overall thinned skin.

Type IV: thinning of the skin, elastic fibers increased, shortened and broken. Pseudotumors: fibrosis, numerous capillaries, foreign body giant cells.

Clinic: The suspected diagnosis of EDS is made purely clinically. Medical history and physical examination for hypermobility are decisive. No imaging, clinical laboratory test or technical examination can detect EDS.

Genetics: Confirmation of the diagnosis of EDS disease and definitive determination of the subtype is done by genetic testing (Malfait F et al. (2017). The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 175:8-26. Genetic diagnostics should be performed as panel diagnostics or exome diagnostics and include all genes relevant to a connective tissue disease. Parallel sequencing with high-throughput sequencing (next generation sequencing) is suitable for this purpose, as it simultaneously covers all relevant EDS genes as well as genes of important diseases for differential diagnosis. The variations detected within the gene segments are then computer-based compared with already known pathogenic variations. In the case of undescribed variants, an assessment of pathogenicity must be carried out in accordance with the guidelines of the American College of Medical Genetics (ACMG).

Prenatal diagnosis: possible for types IV, VI A, VII A and B and IX from chorionic villus sampling or amniotic cells.

• Cutis hyperelastica, Cutis laxa (genes: ELN, FBLN5)
• Noonan syndrome
• Marfan syndrome (FBN1 gene)
• Loeys-Dietz syndrome (genes: TGFBR1, TGFBR2, SMAD3, SMAD2, TGFB2, TGFB3)
• Osteogenesis imperfecta phenotypes(genes: COL1A1, COL1A2Bethlem myopathy COL6A1, COL6A2, COL6A3, COL12A1)
• Vascular: aortic aneurysm, bicuspid aortic valve, mitral valve prolapse, chordae tendineae rupture
• Other symptoms: spontaneous pneumothorax, intestinal perforation, uterine rupture, muscle or tendon rupture, syncope, vague abdominal pain, impaired function of bowel movements and urination
• Abnormal bleeding tendency, vulnerability and wound healing: various coagulation disorders (various forms of hemophilia, Willebrand v.-Jürgens disease), factor XIII deficiency, dysfibrinogenemia, platelet disorders, child abuse, neurotic self-harm, osteogenesis imperfecta, scurvy.
• Joint hyperextensibility: Marfan syndrome, Marfanoid hypermobility syndrome, familial hypermobility syndrome.

No known causal therapy.

• Protection from trauma (head, knees, shins) is important in childhood; freshening of the wound edges and optimal adaptation with the finest atraumatic sutures and plasters. Symptomatic treatment, orthopaedic and ophthalmologic check-ups. Physiotherapy to strengthen the muscles and support the joints, possibly high shoes and splints, arthrodesis if necessary; surgical correction of habitual dislocations; symptomatic treatment for sprains and joint effusions.
• Type IV: Emergency card; treat retroperitoneal or interstitial bleeding as conservatively as possible. Treat intra-abdominal and intrathoracic bleeding surgically. Avoid angiography and drugs that interfere with coagulation or platelet function (danger to life!); subtotal colectomy for colonic ruptures. Monitoring of pregnancies and planned births in a specialized center. Avoidance of coughing, constipation, heavy isometric training, team sports is required.

See below the individual variants. Apart from valvular EDS and vascular EDS, life expectancy is usually normal for the other types.

Diagnostic tools

- www.bundesverband-eds.de/pdf/Diagnosehilfe_alle-EDS-Formen.pdf

- www.bundesverband-eds.de/de/EDS-HMS/EDS-Typen/005-Hypermobiler-Typ.php

Self-help groups

- Federal Ehlers-Danlos Self-Help Association: www.bundesverband-eds.de

- German Ehlers-Danlos Initiative: www.ehlers-danlos-initiative.de

- Ehlers-Danlos organization: www.ehlers-danlos-organisation.de

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