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

The term Ehlers-Danlos syndrome (EDS) does not describe a specific disease but a group of connective tissue disorders that share the clinically manifestations of skin hyperextensibility, articular hypermobility and tissue fragility [1]. In the “Villefranche” classification, the formerly used Roman numerals were replaced by six descriptive main types (Table 1). Besides the six main types, EDS also includes a series of “other” types, that are either not clearly classified or poorly characterized [2, 3].

EDS arthrochalasis type is an autosomal dominant connective tissue disorder characterized by severe generalized joint hypermobility with recurrent joint dislocations and congenital bilateral hip dislocation. Other features include skin hyperextensibility and easy bruising. It is caused by complete or partial loss of exon 6 encoding the cleavage site for collagen-I and the intermolecular cross-linking lysine, either in the pro-a1(I) chain (EDS VIIA), or the pro-a2(I) chain (EDS VIIB). As a result cleavage of the N-propeptide and cross-linking is partially deficient [4].

Table 1: Villefranche classification of the six main types of EDS.

Descriptive type Numerical type Genes
Classic type EDS I (Gravis)
EDS II (Mitis)
COL5A1
COL5A2
COL1A1
Hypermobility type EDS III TNXB
COL3A1*
Vascular type EDS IV COL3A1
Kyphoscoliosis type EDS VI PLOD1
Arthrochalasia type EDS VIIA
EDS VIIB
COL1A1
COL1A2
Dermatosparaxis type EDS VIIC ADAMTS2

*Only one patient has been reported to carry a mutation in the COL3A1 gene.

Clinical Description

The clinical hallmark of EDS arthrochalasis type 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 2). Muscular hypotonia is prominent, causing a delay in gross motor development. Short stature [5] 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 [6] and sometimes a history of fractures.

Table 2: 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 1 0 1 2
Hyperextension of the knees beyond 1 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

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 biochemicalconfirmation 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.

Treatment

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, appears to be the best way to achieve and maintain 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
Beighton P. The Ehlers-Danlos syndromes. In: Beighton P. (ed.) : McKusick's Heritable Disorders of Connective Tissue. 5th ed. St. Louis: Mosby 1993. Pp. 189-251.

2
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. (1998) Ehlers-Danlos Syndromes: Revised Nosology, Villefranche, 1997. Am J Med Genet 77:31-37.

3
Byers PH, Murray ML. (2012) Heritable Collagen Disorders: The Paradigm of the Ehlers-Danlos Syndrome. J Invest Dermatol 132(E1):E6-E11.

4
Byers PH, Duvic M, Atkinson M, Robinow M, Smith LT, Krane SM, Greally MT, Ludman M, Matalon R, Pauker S, Quanbeck D, Schwarze U. (1997) 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 72:94-105.

5
Lichtenstein JR, Martin GR, Kohn LD, Byers PH, McKusick VA. (1973) Defect in conversion of procollagen to collagen in a form of Ehlers-Danlos syndrome. Science 182:298-299.

6
Viljoen D, Goldblatt J, Thompson D, Beighton P. (1987) Ehlers-Danlos syndrome: yet another type? Clin Genet 32:196-201.

7
Cole WG, Chan D, Chambers GW, Walker ID, Bateman JF. (1986) 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 261:5496-5503.

8
Wirtz MK, Glanville RW, Steinmann B, Rao VH, Hollister DW. (1987) 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 262:16376-16385.