Ehlers-danlos syndrome Q79.6

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Arthrochalasis multiplex congenita; Chalasodermia; Chernogubov Syndrome; cutis hyperelastica; Danlos Syndrome; Dermatochalasis; Dermatolysis; Dermatorrhexis; Dermatosparaxis; dystrophia mesodermalis; dystrophia mesodermalis congenita; ECM diseases; Ehlers-Danlos-Meekeren syndrome, Meekeren-Ehlers-Danlos syndrome, Van-Meekeren syndrome; Ehlers Danlos Syndrome; Ehlers-Danlos syndromes; Ehlers-Danlos Syndromes; Elastorrhexis generalisata and systemica; Extracellular matrix disease; Extracellular matrix diseases; fibrodysplasia elastica generalisata; fibrodysplasia elastica generalistica; Indian rubber skin; Laxity articulaire congénitale multiple; Rubber skin; Sack Barabas Syndrome

History
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Chernogubov 1891; Ehlers 1901; Danlos 1908

Definition
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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 manifestation, 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):

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

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

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

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

Group D (In this group EDS types are listed with changes in the biosynthesis of gylycosaminoglycans)

Group E

Group F (disturbances of intracellular processes)

Group nn (Not assigned)

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

Classification
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The new classification according to diagnostic criteria replaces the older Villefranche or 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 mainly characterized by hypermobility of large and small joints. Subluxations and luxations can occur regularly. hEDS sufferers often suffer from joint instability and often have soft, velvety skin that can be easily damaged. Very often patients suffer from chronic pain. The severity can be moderate to very severe. About 90% of EDS sufferers have chronic pain, with the highest pain scores found in hEDS patients (Chopra et al.2019).
  2. Classical EDS (cEDS, formerly type I and II): The genetic cause of this type of EDS is found in the genes COL5A2 and COL5A in about 90% of cases. Mutations in COL1A1 are rarely present. Major criteria are an extremely elastic skin which is fragile and easily vulnerable, atrophic scarring and general joint hypermobility. In addition, there are nine "minor" criteria, such as velvety skin, muscle hypotension or pseudotumors (Bowen et al.2016).
  3. Vascular EDS (vEDS, formerly type IV): The genetic cause can be localised in variations of the COL3A1 gene. There are five major criteria and 12 minor criteria that give a clinical indication of vEDS. Patients* often have thin, translucent skin that is very fragile and easily vulnerable. Veins and organs are also easily damaged. The joints are over-mobile, usually small joints such as fingers or toes. Lumpy feet or torn ligaments and muscles can occur. vEDS is life-threatening, with a median age of 51 years. The life span is long, ranging from about 10 to about 80 years. The most frequent cause of death is arterial dissections or ruptures (Byers et al. 2019).
  4. Kypho-scoliotic EDS (kEDS, formerly type VI): Triggering are variants in the PLOD1 gene, more rarely in the FKBP 14 gene. Major criteria are congenital muscular hypotension, congenital or early onset kyphoscoliosis and generalized hypermobility with (sub)luxations. Minor criteria are also included. Kyphoscoliosis is usually severe and progressive. Further 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. Those affected suffer from pronounced joint hypermobility and congenital bilateral hip luxation. In addition, (sub)luxations of the large and small joints, foot deformities and scoliosis, lordosis and kyphoscoliosis can occur. The skin can be overstretched, velvety and easily vulnerable (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 excess. Joint hypermobility ranges from mild to severe. dEDS is very rare - about ten cases have been reported so far (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 a progressive thinning of the cornea of the eye. Early on, a keratoglobus or keratoconus can occur, as well as myopia, hearing loss and blue sclerae. Classical EDS symptoms, such as hyperactive joints and overstretched 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 overstretchable and velvety, but does not show atrophic scarring. There is often general joint hypermobility, (sub)luxations can occur, especially the shoulders and ankles are affected (Brady et al. 2017).
  9. Spondylo-dysplastic EDS (spEDS): spEDS is caused by mutations in the genes B4GALT7, B3GALT6 and SLC39A13. Affected individuals are often small and show muscular hypotension (Brady et al. 2017).
  10. Musculo-contractival EDS (mcEDS): mcEDS is triggered by mutations in the genes CHST14 and DSE. Characteristic features are hyperextensibility of the skin, increased skin vulnerability, atrophic scarring and increased wrinkling of the palms. mcEDS leads to congenital contractures (Brady et al. 2017).
  11. Myopathic EDS (mEDS): Mutations in the COL12A1 gene lead to mEDS. mEDS sufferers suffer from congenital muscular hypotonia and/or muscular 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, which occurs in childhood or adolescence. The gums often do not lie sufficiently close 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 those of the mitral valve, and an overstretchable, easily vulnerable skin prone to atrophic scarring characterize cvEDS. In addition, joint hypermobility occurs, which may be either generalized or limited to the small joints (Brady et al. 2017).

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

Manifestation
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Mostly in childhood.

Histology
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  • 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.

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

Differential diagnosis
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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.

Therapy
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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.

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

Tables
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EDS type according to Villefranche classification *

Previous classifications

Classical type

EDS type I (gravis) and II (mitis)

Hypermobility type

EDS type III

Vascular type

EDS type IV (arterial form)

Kyphoscoliosis Type

EDS Type VI

Arthrochalasia Type

EDS type VIIa, VIIb

Dermato-sparaxis Type

EDS type VII

Other forms

EDS type V, VIII, X, XI, progeroids EDS, unspecified forms

* The Villefranche classification was established in the sense of a clinically simplified diagnosis of Ehlers-Danlos syndrome and to distinguish between diseases that overlap with EDS.

Literature
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  1. Beighton P, De Paepe A, Steinmann B, et al. (1998) Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997 Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). At J Med Genet 77: 31-37
  2. Brinckmann J et al (1999) Ehlers-Danlos syndrome. dermatologist 50: 257-265
  3. Byers PH (2001) An exception to the rule. N Engl J Med 345: 1203-1205
  4. Chernogubov NA (1891) About a case of Cutis laxa. (Presentation at the first meeting of Moscow Dermatologic and Venerologic Society). Monthly journals for practical dermatology (Hamburg) 14: 76
  5. Danlos H (1908) Un cas de cutis laxa avec tumeurs par contusion chronique des coudes et des genoux (xanthome juvénile pseudo-diabetique de MM Hallopeau et Macé de Lépinay) Bulletin of the French Society of Dermatology and Xenography (Paris) 19: 70-72
  6. De Felice C et al (2001) Absence of the inferior labial and lingual frenula in Ehlers-Danlos syndrome. Lancet 357: 1500-1502
  7. Ehlers EL (1901) Cutis laxa. Tendency to hemorrhages in the skin, loosening of several articulations. Dermatol Zeitschr (Berlin) 8: 173-174
  8. Germain DP (2002) Clinical and genetic features of vascular Ehlers-Danlos syndrome. Ann Vasc Surgery 16: 391-397
  9. Lind J et al (2002) Pregnancy and the Ehlers-Danlos syndrome: a retrospective study in a Dutch population. Acta Obstet Gynecol Scand 81: 293-300
  10. Krieg T, Ihme A et al. (1981) The Ehlers-Danlos syndrome. dermatologist 31: 366-371
  11. Mao JR, Bristow J et al (2001) The Ehlers-Danlos syndrome: on beyond collagens. J Clin Invest 107: 1063-1069
  12. Steinmann B, Royce PM, Superti-Furga A (1993) The Ehlers-Danlos Syndrome. In: Royce PM, Steinmann B (eds) Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects, pp 351-407. Wiley-Liss, New York
  13. De Felice C (2001) Absence of the inferior labial and lingual frenula in Ehlers-Danlos syndrome. Lancet 357: 1500-1502
  14. Palmeri S et al (2003) Neurological presentation of Ehlers-Danlos syndrome type IV in a family with parental mosaicism. Clin Genet 63: 510-515
  15. Rahman N et al (2003) Ehlers-Danlos syndrome with severe early-onset periodontal disease (EDS-VIII) is a distinct, heterogeneous disorder with one predisposition gene at chromosome 12p13. At J Hum Genet 73: 198-204

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Last updated on: 29.10.2020