Ehlers-Danlos syndrome

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Ehlers-Danlos syndrome(EDS) is a heterogeneous group of inherited connective tissue disorders. Phenotype classification is based on the Villefranche classification[1] but the complexity has lead to multiple names and reversion to the Roman number classification for the common presentations.

  1. Classic EDS (EDS I, EDS II)
  2. Hypermobility EDS(EDS III)
  3. Vascular EDS (EDS IV)
  4. Kyphoscoliosis EDS (EDS VI)
  5. Arthrochalasia EDS (EDS VIIA and VIIB)
  6. Dermatosparaxis EDS (EDS VIIC)
  7. Unspecified forms of EDS

All forms tend to have either or both skin hyperelasticity and joint hypermobility. The classic syndromes also have aortic root dilation. Some forms have specific organ manifestations such as with corneal rupture. There are complex mixed genetic syndromes. In common are defects in either collagen genes or the genes for enzymes that process collagen from pro-collagen. Several phenotypes have multiple genetic causes with a common failure at collagen cleavage.

Type III EDS might be advantageous for dancers and acrobats and could by analogy be associated with osteoarthritis in later life.

Ehlers-Danlos type syndomes
Type(Alternative names) Genetics Phenotype
Type I (severe classical EDS) Multiple genes and mutations:
  • COL5A1 gene at 9q34.2-q34.3 coding for the collagen alpha-1(V) chain
  • COL5A2 gene at 2q31 coding for the collagen alpha-2(V) chain
  • COL1A1 gene at 17q21.31-q22 coding for the collagen alpha-1(I) chain
  • Skin hyperelasticity
  • Joint hypermobility
  • Healing with cigarette-paper scars
Type II (mild classical EDS, MITIS EDS)
  • COL5A1 gene at 9q34.2-q34.3 coding for the collagen alpha-1(V) chain
  • COL5A2 gene at 2q31 coding for the collagen alpha-2(V) chain
  • Skin hyperelasticity
  • Joint hypermobility
  • Healing with cigarette-paper scars
Type III(hypermobility type EDS) Joint hypermobility
Type IV (vascular EDS, ecchymotic EDS, Sack-Barabas EDS, malignant EDS)
  • Spontaneous rupture of bowel
  • Spontaneous rupture large arteries
  • Skin hyperelasticity
  • Joint hypermobility
Type V (kyphoscoliosis type EDS) X linked
  • Skin hyperelasticity
  • Bruising
Type VIa (type 6a EDS, oculoscoliotic EDS) PLOD1 gene at 1p36.3-p36.2 coding for lysyl hydroxylase
  • Poor cross-linking of collagen making for easily soluble skin collagen.
  • Severe scoliosis
  • Recurrent joint dislocation
  • Skin hyperelasticity
  • Joint hypermobility
  • Floppiness
  • Nevo syndrome is also caused by a PLOD1 mutation and may really be a subtype
Type VI (type 6b EDS) ZNF469 gene at 16q24 coding for zinc finger protein 469
  • Poor cross-linking of collagen making for easily soluble skin collagen.
  • Blue sclera
  • Corneal fragility/rupture after minor trauma
  • Keratoconus or keratoglobus
  • Skin hyperelasticity
  • Joint hypermobility
Type VIIa (arthrochalasia type EDS)
  • COL1A1 gene at 17q21.31-q22 coding for the collagen alpha-1(I) chain
  • Autosomial dominant
  • Unable to convert type I procollagen to collagen
  • Congenital hip dislocation
  • Extreme joint hypermobility
  • Minimal skin involvement
Type VIIb (arthrochalasia type EDS)
  • COL1A2 gene at at 7q22.1 coding for the collagen alpha-1(II) chain
  • Autosomial dominant
  • Unable to convert type I procollagen to collagen
  • Congenital hip dislocation
  • Extreme joint hypermobility
  • Minimal skin involvement
Type VIIc (dermatosparaxis type EDS)
  • Unable to convert type I procollagen to collagen
  • Congenital hip dislocation
  • Extreme joint hypermobility
  • Minimal skin involvement
Type VIII (periodontitis type EDS) Coded by gene at 12p13
  • Peridontal disease - early loss of teeth
  • Necrobiosis lipoidica diabeticorum type lesions
  • Cigarette-paper scars over knees
EDS with fibronectin and platelet defects
Cardiac valvular EDS Coded by COL1A2 gene at 7q22.1 coding for the collagen alpha-1(II) chain
Periventricular heterotopia Ehlers-Danlos variant (periventricular nodular heterotopia type 4, PVNH4) FLNA gene that codes for filamin-A
  • Nodular brain heterotopia
  • Joint hypermobility
  • Aortic dilatation
Progeroid EDS Coded by B4GALT7 gene at 5q35.2-q35.3 coding for beta-1,4-galactosyltransferase 7 (xylosylprotein 4-beta-galactosyltransferase)
Ehlers-Danlos syndrome-like spondylocheirodysplasia (SCD-EDS) SLC39A13 gene at 11p11.2 that codes for Zinc transporter ZIP13
  • Skeletal dysplasia
  • Skin hyperelasticity
  • Joint hypermobility
  • Protuberant eyes with bluish sclerae
  • Abnormal hands
    • Finely wrinkled palms
    • Thenar atrophy
    • Tapering fingers
Musculocontractural EDS Mutations of CHST14 gene coding for carbohydrate sulfotransferase 14 (dermatan 4-O-sulfotransferase-1)

References