geneskin

Ehlers-Danlos Syndrome, Arthrochalasis Type

DISEASE CARD

Disease group Connective tissue disorders
DISEASE NAME EHLERS-DANLOS SYNDROME, ARTHROCHALASIS TYPE
Synonymous Ehlers-Danlos Syndrome VIIA , Ehlers-Danlos syndrome VIIB, Ehlers-Danlos syndrome multiplex congenita
Estimated prevalence < 1 / 1.000.000
OMIM 130060
Inheritance Autosomal dominant
Gene (s) COL1A1 (120150), COL1A2 (120160)

Definition

Arthrochalasia EDS (aEDS) is an autosomal dominant connective tissue disorder characterized by severe generalized joint hypermobility with recurrent joint dislocations and congenital bilateral hip dislocation. It is caused by mutations in the COL1A1 or COL1A2 gene.1

 

Clinical Description

The clinical hallmark of aEDS is congenital bilateral hip dislocation. There is severe generalized joint hypermobility with recurrent dislocations of large and small joints and ligamentous tears. Joint hypermobility is determined according to the Beighton scale (Table). Muscular hypotonia is prominent, causing a delay in gross motor development. Short stature is frequently present due to thoracolumbar scoliosis and hip dislocation. The skin is variably involved with skin hyperextensibility, a velvety touch, and poor wound healing with formation of cigarette paper-like scars. Other features include easy bruising, soft tissue fragility and osteopenia with wormian bones and sometimes a history of fractures.

There may be phenotypic overlap with osteogenesis imperfect that is also caused by type I collagen defects.2-5

 

Table 1: Beighton scale of hypermobility.

 Joint/Finding

Negative

Unilateral

Bilateral

 Passive dorsiflexion of the 5th finger >90°

0

1

2

 Passive flexion of thumbs to the forearm

0

1

2

 Hyperextension of the elbows beyond 10°

0

1

2

 Hyperextension of the knees beyond 10°

0

1

2

 Forward flexion of the trunk with knees fully extended and palms resting on the floor

0

1

 A total score of at least 5 defines hypermobility

 

Diagnostic criteria:

Major criteria:

  1. Congenital bilateral hip dislocation
  2. Severe generalized joint hypermobility, with multiple dislocations/subluxations
  3. Skin hyperextensibility

Minor criteria:

  1. Muscle hypotonia
  2. Kyphoscoliosis
  3. Radiologically mild osteopenia
  4. Tissue fragility, including atrophic scars
  5. Easy bruisable skin

Minimal criteria suggestive for aEDS: I. plus either III. or II. and at least two other minor criteria

 

Pathogenesis

EDS arthrochalasis type results from mutations leading to loss of exon 6, or part of it, of the mRNA coding for one of the a1 chains (EDS type VIIA) or for the a2 chain (EDS type VIIB) of type I collagen. This exon-skipping mutation leads to the loss of the amino (N)-terminal telopeptide, which links the N- propeptide to the main triple-helical domain. This N-telopeptide contains the N-proteinase cleavage site as well as the critical cross-linking lysyl residue and the cleavage sites for proteinases such as pepsin and a-chymotrypsin. Hence lack of this segment leads to a deficient processing of the N-propeptide and cross-linking of type I collagen.7, 8

 

Diagnosis

The diagnosis of EDS arthrochalasis types I based on clinical evaluation. Ultrastructural studies of dermal collagen fibrils show fibrils that are near-circular in cross-section, with irregular fibril contours, a decreased and more variable fibril diameter and decreased fibril density.7

The biochemical confirmation of the diagnosis is based on electrophoretic demonstration of pro-N-a1(I) (type A) or pro-N-a2(I) (type B) chains of collagen type I extracted from dermal collagen or harvested from cultured skin fibroblasts.

Molecular analysis can be performed in order to confirm the biochemical findings and shows complete or partial skipping of exon 6 at the cDNA-level of the COL1A1 or the COL1A2 gene, respectively, usually caused by splice site mutations at the genomic DNA level. Absence of a mutation in COL1A1 or COL1A2 that leads to complete or partial deletion of the exon 6 of either gene excludes the diagnosis of aEDS.6

 

Treatment

See article “Ehlers-Danlos Syndrome

The principal orthopaedic problem is bilateral congenital dislocation of the hips. The outcome of orthopaedic surgery is often disappointing because of premature degenerative arthritis of the hips and other joints. Open reduction of the dislocated hips, with capsulorrhaphy and iliac osteotomy, and with addition of femoral osteotomy in some cases, is one way with a high chance for achieving and maintaining stable reduction. Muscular hypotonia and generalized joint hypermobility are prominent features during infancy and aids such as knee-ankle-foot orthoses are often required to stabilize the lower limb joints. Adequate physical and occupational therapy is needed to assist with standing, walking and activities of daily life.

 

References

1.  Byers PH, Duvic M, Atkinson M, Robinow M, Smith LT, Krane SM, et al. Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am J Med Genet. 1997;72(1):94-105.

2. Ayoub S, Ghali N, Angwin C, Baker D, Baffini S, Brady AF, et al. Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome. 2020;182(5):994-1007.

3.  Lichtenstein JR, Martin GR, Kohn LD, Byers PH, McKusick VA. Defect in conversion of procollagen to collagen in a form of Ehlers-Danlos syndrome. Science. 1973;182(4109):298-300.

4.  Viljoen D, Goldblatt J, Thompson D, Beighton P. Ehlers-Danlos syndrome: yet another type? Clin Genet. 1987;32(3):196-201.

5. Lund A, Joensen F, Christensen E, Dunø M, Skovby F, Schwartz M. A novel arginine-to-cysteine substitution in the triple helical region of the alpha1(I) collagen chain in a family with an osteogenesis imperfecta/Ehlers-Danlos phenotype. Clin Genet. 2008;73(1):97-101.

6. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26.

7. Cole WG, Chan D, Chambers GW, Walker ID, Bateman JF. Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII. J Biol Chem. 1986;261(12):5496-5503.

8. Wirtz MK, Glanville RW, Steinmann B, Rao VH, Hollister DW. Ehlers-Danlos syndrome type VIIB. Deletion of 18 amino acids comprising the N-telopeptide region of a pro-alpha 2(I) chain. J Biol Chem. 1987;262(34):16376-16385.