Ehlers-danlos syndromeQ79.6

Chernogubov 1891; Ehlers 1901; Danlos 1908

Group of genetically heterogeneous diseases characterized by changes in connective tissue. Clinically, patients suffer from hyperextensibility of the skin, hyperextensibility of the joints, eye changes, scoliosis, and easy tearing of the vessels. Depending on the clinical expression, genetic and biochemical disorder, 8 groups with different types are distinguished.

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. Rarer are mutations of the gene COL1A1 on chromosome 17q2133.
• Cardiac 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 to chromosome 2q31, with qualitative and/or quantitative deficiency of collagen III (predisposition to aneurysm formation).
• Arthrochalasia EDS (previously type VII A/B): Autosomal recessive inheritance; collagen fibril length is between pro-alpha and alpha collagen. In type A and B, mutations occur in COL1A1 or COL1A2 genes mapped on chromosomes 17q21.31-q22.05 and 7q221. Thus, deletion of the amino-terminal telopeptide of the α1(1) or α2(I) chain of collagen I; thereby, impaired fibril formation and cross-linking.
• Dermatosparaxis EDS (formerly type VII C); in this type, procollagen N collagenase is absent. The gene responsible for this, pN alpha1, is mapped to chromosome 17q21.31-q22.05. 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 collagen molecules or collagen unfolding is impaired).

• Kypho-scoliotic EDS (formerly type VI): Autosomal recessive inheritance; defect in collagen lysylhydroxylase I; alternatively, there is a mutation of a protein (FKBP22) involved in triple helix formation. The responsible gene PLOD1 is located on chromosome 1p36.3; 1p36.2. Collagen lysyl hydroxylase is inactive in fibroblasts, leaving collagen cross-linking unstable; transmitters 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 (previously unassigned); deficiency of tenascin-X [Q79.6].
• Myopathic EDS: mutation of COL12A1 (collagen XII).

Group D (This group lists 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 zinc finger protein 469 and 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 pat. a gene variation of the TNXB gene has been detected with a deficiency of the gene product tenascin-X. Associated is an increased hematoma tendency.

The new classification according to diagnostic criteria replaces the older classifications according to Villefranche or the Berlin classification. It is now differentiated according to 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 mainly characterized by hypermobility of large and small joints. Subluxations and dislocations may occur regularly. hEDS sufferers often suffer from joint instability and often have soft, velvety skin that can be easily vulnerable. Very often, patients suffer from chronic pain. The severity can be moderate to very severe. Approximately 90% of EDS sufferers present with chronic pain, with the highest pain scores found in hEDS patients (Chopra et al.2019).
2. Classic EDS (cEDS, formerly type I and II): The genetic cause of this type of EDS is found in approximately 90% of cases in the COL5A1 and COL5A2 genes. More rarely, mutations are present in COL1A1. Major criteria are extremely elastic skin that is fragile and easily injured, atrophic scarring, and general joint hypermobility. In addition, there are 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 clinical clues to vEDS. Patients often present with thin, translucent skin that is very fragile and easily damaged. Veins and organs are equally easily vulnerable. Joints are hypermobile, usually small joints such as fingers or toes. Club feet or torn ligaments and muscles can occur. vEDS is life-threatening, with a median age of 51 years for those affected. The life span is wide, ranging from about 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): Triggering variants are in the PLOD1 gene (encoding a "lysylhydroxylase" , a membrane-bound homodimeric enzyme localized in the cisternae of the endoplasmic reticulum), less commonly in the FKBP14 gene. Major criteria are congenital muscle hypotonia, congenital or early-onset kyphoscoliosis, and generalized hypermobility with (sub)luxations. In addition, there are 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. Currently, about 30 cases are known. Affected individuals suffer from pronounced joint hypermobility and congenital bilateral hip dislocation. In addition, (sub)luxations of the large and small joints, foot deformities and scoliosis, lordosis and kyphoscoliosis may occur. The skin may be hyperextensible, velvety, and easily injured (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 scars quickly. There is loose and excess skin. Joint hypermobility ranges from mildly marked to severe. dEDS is very rare - approximately ten cases have been reported to date (Brady et al. 2017).
7. Brittle cornea syndrome (BCS): BCS occurs in two types. Variant 1 results from a mutation in the ZNF469 gene, and variant 2 results from a mutation in the PRDM5 gene. BCS is characterized by progressive thinning of the cornea of the eye. Early on, keratoglobus or keratoconus may appear, as well as myopia, hearing loss, and blue sclerae. Classical-like EDS symptoms, such as hypermobile joints and hyperextensible skin, are commonly 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. General joint hypermobility is often present, (sub)dislocations may 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 small in stature and exhibit muscle hypotonia (Brady et al. 2017).
10. Musculo-contractural EDS (mcEDS): Triggering mcEDS are mutations in the CHST14 and DSE genes. It is characterized by skin hyperextensibility, increased skin vulnerability, atrophic scarring, and increased wrinkling of the palms. mcEDS results in 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 results in severe, persistent periodontitis that occurs in childhood or adolescence. The gingiva often does not adequately attach to the tooth (missing attachment) (Brady et al. 2017).
13. Cardiac valve EDS (cvEDS): COL1A2 mutations can lead to cvEDS. Severe progressive cardio-valvular symptoms, such as at the mitral valve, and hyperextensible, easily injured skin prone to atrophic scarring characterize cvEDS. Joint hypermobility also occurs and may be either 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 chains of type 1 collagen synthesis.The clinical spectrum of this clinical entity has features of both osteogenesis imperfecta (bone fragility, long bone fractures, blue sclerae, short stature) and Ehlers-Danlos syndrome (hyperextensibility of joints, soft and hyperextensible skin, abnormal wound healing, easy bruising, vascular fragility).

Prevalence about 1:400.000. No ethnic dominance; m:f=1:1.

Mostly in childhood.

• Type I-III: no histological features. Rarely, especially in type I, thin collagen fibers without bundling. In these cases, increase of elastic fibers compared to collagen fibers, overall thinned skin.
• Type IV: thinning of the skin, elastic fibres increased, shortened and broken. Pseudotumours: fibrosis, numerous capillaries, giant foreign body cells.

Cutis hyperelastica, cutis laxa, gerodermia osteodysplastica, Noonan syndrome.

Abnormal bleeding tendency, vulnerability and wound healing: various coagulation disorders (various forms of haemophilia, Willebrand v. Jürgens disease), factor XIII deficiency, dysfibrinogenemia, platelet disorders, child abuse, neurotic self-harm, osteogenesis imperfecta, scurvy.

Joint hyperextensibility: Marfan's syndrome, Marfanoid hypermobility syndrome, familial hypermobility syndrome.

No causal therapy known.

• Protection in childhood against trauma (head, knee, shins); freshening of the wound edges and optimal adaptation with finest atraumatic sutures and plasters. Symptomatic treatment, orthopaedic and ophthalmological checks. Physiotherapy to strengthen the muscles and support the joints, possibly high shoes and splints, arthrodeses if necessary; surgical correction of habitual luxations; symptomatic treatment of sprains and joint effusions.
• Type IV: emergency card; approach bleeding retroperitoneally or interstitially as conservatively as possible. Surgically treat intra-abdominal and intrathoracic bleeding. Avoid angiography and drugs that interfere with coagulation or platelet function (danger to life!); in the case of colon ruptures, subtotal colectomy. Monitoring of pregnancies and planned births in a specialised centre. 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.

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