Ehlers Danlos syndrome

Last edited 06/2018

Ehlers-Danlos syndrome (EDS) is a condition where abnormalities of collagen production result in bruising, wide scars, laxity of joints and hyperelasticity of the skin.

Ehlers-Danlos syndromes (EDS) are heritable connective tissue disorders affecting the quality of collagen in every part of the body

  • are generally characterized by joint hypermobility, skin hyperextensibility, and tissue fragility
  • there are 13 types of Ehlers-Danlos syndrome, most of which are rare
    • in 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that defined the number of types to six and gave them descriptive names based on their major features
    • in 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were discovered more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.
  • the hypermobile type of EDS (and associated hypermobility spectrum disorder) is thought to be common, although many of the clinical features can also occur across the other EDS types
  • the old diagnosis of Joint Hypermobility syndrome (JHS) is now considered part of the spectrum of Hypermobile EDS (1)

Prevalence of hEDS:

  • EDS occurs in at least 1 in 5000 of the population, 80-90% of which could be cases of hEDS (1)
    • the classical type probably occurs in 1 in 20,000 to 40,000 people (2) Other forms of Ehlers-Danlos syndrome are rare, often with only a few cases or affected families described in the medical literature

Genetics (2):

  • mutations in at least 19 genes have been found to cause the Ehlers-Danlos syndromes
    • mutations in the COL5A1 or COL5A2 gene, or rarely in the COL1A1 gene, can cause the classical type
    • mutations in the TNXB gene cause the classical-like type and have been reported in a very small percentage of cases of the hypermobile type (although in most people with this type, the cause is unknown)
    • cardiac-valvular type and some cases of the arthrochalasia type - due to gene mutations of COL1A2 gene;
      • mutations in the COL1A1 gene have also been found in people with the arthrochalasia type
    • vascular type - most result from mutations in the COL3A1 gene, although rarely this type is caused by certain COL1A1 gene mutations
    • dermatosparaxis type due to mutations in the ADAMTS2 gene
    • kyphoscoliotic type due to gene mutations in PLOD1 or FKBP14

Inheritance pattern

  • varies by type (2)
    • classical, vascular, arthrochalasia, and periodontal forms of the disorder, and likely the hypermobile type, have an autosomal dominant pattern of inheritance
    • classical-like, cardiac-valvular, dermatosparaxis, kyphoscoliotic, spondylodysplastic, and musculocontractural types of Ehlers-Danlos syndrome, as well as brittle cornea syndrome, are inherited in an autosomal recessive pattern

Subytpes of EDS

  • Hypermobile EDS - characterized primarily by joint hypermobility affecting both large and small joints
    • may cause recurrent joint dislocations and subluxations
    • in this type of EDS other possible features include soft, smooth and velvety skin with easy bruising and chronic pain of the muscles and/or bones

  • Classical EDS - associated with skin hyperextensibility, smooth skin that is fragile and bruises easily; wide, atrophic scars (flat or depressed scars); and joint hypermobility
    • molluscoid pseudotumors (calcified hematomas over pressure points such as the elbow) and spheroids (fat-containing cysts on forearms and shins) occur frequently
    • hypotonia and delayed motor development may occur
    • more than 90% of those with cEDS have a heterozygous mutation in one of the genes encoding type V collagen (COL5A1 and COL5A2)
      • rarely, specific mutations in the genes encoding type I collagen can be associated with the characteristics of cEDS
    • inherited in the autosomal dominant pattern

  • Vascular EDS
    • thin, translucent skin that is extremely fragile and bruises easily
    • arteries and certain organs such as the intestines and uterus are also fragile and prone to rupture
    • typically have short stature; thin scalp hair; and characteristic facial features including large eyes, a thin nose, and lobeless ears
    • joint hypermobility is present, but generally confined to the small joints (fingers, toes)
    • other common features include club foot; tendon and/or muscle rupture; acrogeria (premature aging of the skin of the hands and feet); early onset varicose veins; pneumothorax (collapse of a lung); recession of the gums; and a decreased amount of fat under the skin
    • typically have a heterozygous mutation in the COL3A1 gene, with the rare exception of specific heterozygous arginine-to-cysteine substitution mutations in COL1A1 that are also associated with vascular fragility and mimic COL3A1-vEDS. In very rare instances, biallelic pathogenic variants in COL3A1 may be identified
    • inherited in the autosomal dominant pattern

  • Kyphoscoliosis EDS
    • associated with severe hypotonia at birth, delayed motor development, progressive scoliosis (present from birth), and scleral fragility
    • may also have easy bruising; fragile arteries that are prone to rupture; unusually small corneas; and osteopenia (low bone density)
    • other possible features include a "marfanoid habitus" which is characterized by long, slender fingers (arachnodactyly); unusually long limbs; and a sunken chest (pectus excavatum) or protruding chest (pectus carinatum)
    • majority of patients with kEDS harbor biallelic mutations in PLOD1; recently, biallelic mutations have been identified in FKBP14 in patients displaying a phenotype that clinically largely overlaps with kEDS-PLOD1

  • Arthrochalasia EDS
    • characterized by severe joint hypermobility and congenital hip dislocation
    • other common features include fragile, elastic skin with easy bruising; hypotonia; kyphoscoliosis (kyphosis and scoliosis); and mild osteopenia
    • caused by heterozygous mutations in either COL1A1 or COL1A2, that cause entire or partial loss of exon 6 of the respective gene. No other genes are associated with aEDS. Absence of a causative mutation in COL1A1 or COL1A2 that leads to complete or partial deletion of the exon 6 of either gene excludes the diagnosis of aEDS. Arthrochalasia EDS
    • inherited in the autosomal dominant pattern

  • Dermatosparaxis EDS

  • Brittle Cornea Syndrome (BCS)
    • characterized by thin cornea, early onset progressive keratoglobus; and blue sclerae

  • Classical-like EDS (clEDS)
    • characterized by skin hyperextensibility with velvety skin texture and absence of atrophic scarring, generalized joint hypermobility (GJH) with or without recurrent dislocations (most often shoulder and ankle), and easily bruised skin or spontaneous ecchymoses (discolorations of the skin resulting from bleeding underneath)
    • caused by a complete lack of Tenascin XB (due to biallelic TNXB mutations, that lead to nonsense-mediated mRNA decay, or biallelic deletion of TNXB). TNXB is the only gene associated with clEDS
    • inherited in the autosomal recessive pattern

  • Spondylodysplastic EDS (spEDS)
    • characterized by short stature (progressive in childhood), muscle hypotonia (ranging from severe congenital, to mild later-onset), and bowing of limbs

  • Musculocontractural EDS (mcEDS)
    • characterized by congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot), characteristic craniofacial features, which are evident at birth or in early infancy, and skin features such as skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling

  • Myopathic EDS (mEDS)
    • characterized by congenital muscle hypotonia, and/or muscle atrophy, that improves with age, Proximal joint contractures (joints of the knee, hip and elbow); and hypermobility of distal joints (joints of the ankles, wrists, feet and hands)

  • Periodontal EDS (pEDS)
    • characterized by severe and intractable periodontitis of early onset (childhood or adolescence), lack of attached gingiva, pretibial plaques; and family history of a first-degree relative who meets clinical criteria

  • Cardiac-valvular EDS (cvEDS)
    • characterized by severe progressive cardiac-valvular problems (aortic valve, mitral valve), skin problems (hyperextensibility, atrophic scars, thin skin, easy bruising) and joint hypermobility (generalized or restricted to small joints).

Management

  • no curative treatment is available
  • treatment is supportive - includes monitoring and additional interventions tailored to the particular manifestations or complications that may occur with each form of EDS

Prognosis:

  • varies by subtype
    • vascular type is typically the most severe form of EDS and is often associated with a shortened lifespan
      • median life expectancy of 48 years and many will have a major event
    • lifespan of people with the kyphoscoliosis form is also decreased
      • due mainly to the vascular involvement and the potential for restrictive lung disease
    • in other subtypes the majority of patients have a normal life expectancy despite possible complicatons associated with the form of EDS

Click here for example images of this condition

Reference:

Related pages:

hypermobility spectrum disorders (HSD)

skin hyperextensibility

hypermobile EDS