Ehlers-Danlos Syndromes

The birth prevalence of the EDS is about 1 in 5000 births, although this is likely an underestimate, particularly of milder forms. One commonly used classification recognizes six EDS types based on clinical features, modes of inheritance, and biochemical and molecular genetic findings. It is apparent, however, that many patients have clinical findings that overlap between recognized types and cases without a defined genetic etiology are not uncommon. Reconsideration of the nosology is needed and will require elucidation of as yet undescribed genetic etiologies. Nevertheless, in those forms of EDS with a defined etiology, the unifying features appear to be abnormalities in the expression or structure of the fibrillar collagens types I, III, and V. This is sometimes due to mutations in the genes of these collagens and in other instances due to mutations in genes coding for proteins involved in the post-translational modification or regulation of these fibrillar collagens.

The currently recognized major types of EDS include the following: classic type, hypermobility type, vascular type, kyphoscoliosis type, arthrochalasia type, and dermatosparaxis form. Classic EDS is characterized by hyperextensible, fragile, and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility. Hypermobility EDS is characterized by generalized joint hypermobility with frequent subluxations and dislocations and mild skin involvement. Vascular EDS is notable for characteristic facies, excessive bruising, thin and translucent skin, and a markedly increased risk of arterial, intestinal, and uterine fragility or rupture. Kyphoscoliotic EDS is notable for severe congenital hypotonia and kyphoscoliosis, generalized joint laxity, and risk of rupture of the globe. Arthrochalasia EDS is characterized by congenital hip dislocation, severe generalized joint hypermobility with recurrent subluxations, skin hyperextensibility, and atrophic scars. The dermatosparaxis form of EDS is notable for characteristic facies, severe skin fragility, sagging and redundant skin, excessive bruising, growth retardation, frequent umbilical hernias, and delayed closure of the anterior fontanel.

Classic, hypermobility, vascular, and arthrochalasia types of EDS are associated with autosomal dominant inheritance; kyphoscoliosis and dermatosparaxis types are inherited in an autosomal recessive manner. Heterozygous mutations in the COL5A1 and COL5A2 genes are noted in about 50% of persons with classic EDS and result in haploinsufficiency of type V procollagen. The most common subtype of EDS, the hypermobility type, is, in most instances, etiologically undefined, although heterozygous mutations of the TNX-B gene, coding for the extracellular matrix protein tenascin-X, have been reported. Vascular EDS is due to heterozygous mutations of the COL3A1 gene that result in deposition of a structurally abnormal type III collagen or in a diminished amount of normal type III collagen. Arthrochalasia EDS is associated with a loss of a procollagen-N-proteinase cleavage site on either proα1(I) or proα2(I) polypeptides due to heterozygous deletions of exon 6 of COL1A1 or COL1A2 genes, respectively. Kyphoscoliotic EDS is due to a deficiency of lysyl hydroxylase-I activity, an enzyme needed for collagen crosslinking, and which is due to homozygous mutations of the PLOD1 gene. Finally, deficient activity of procollagen-N-proteinase due to mutations in the ADAMTS-2 gene prevent the physiologic cleavage of the N-terminal of type I collagen and result in the dermatosparaxis type of EDS.

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Jul 3, 2016 | Posted by in MUSCULOSKELETAL MEDICINE | Comments Off on Ehlers-Danlos Syndromes
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