Ehlers-Danlos syndrome has varied molecular mechanisms

Abstract

Ehlers-Danlos syndrome (EDS) is a group of variable clinical entities which share a propensity to skin fragility, joint laxity, and ligamentous fragility or shortening. Tschernogobow, Ehlers, and Danlos independently described unusual bruising, excessive cutaneous extensibility, and molluscoid pseudotumours. The eponym of Ehlers-Danlos syndrome (EDS) was first suggested by Poumeau-Delille and Soulie. Spectacular early examples were retrospectively commented upon by Beighton. Morris described a notable British patient who Beighton re-examined more than 60 years later. The proband had classical EDS. Beighton not only showed impressive pictures of the so-called 'Elastic Lady' but also included the original lithograph of a Spaniard with unilateral cutaneous hyperextensibility investigated in Leyden almost 300 years before, who was very probably a somatic mosaic. In Ehlers's time there was considerable difficulty in distinguishing clearly between cutis hyperelastica (overextensible skin), dermatorrhexis (easy splitting of skin), and both localised and generalised dermatochalasis (pendulous or redundant skin). To this day the similarities of such physical signs still cause confusion. In practice the designations hyperelastic, pendulous, and lax skin often overlap and can even occur at different times in the same patient. For example, EDS skin is hyperelastic early in life but later becomes lax or drooping, especially in old age. The systemic implications, complications, and associations of EDS were largely unrecognised for many years although the association of congenital hip dislocations was described early. In 1960 Mories first described a four-fold increase in fetal prematurity. He also noticed that the dermis was collagen depleted and elastin rich. Thirdly, he described catastrophic lethal arterial bleeding in a 15 year old adolescent boy with a traumatic arterial tear which was surgically unrepairable because of the extreme venous and arterial fragility. Very probably the patients with prematurity had EDS I/II while the vascular fragility was caused by acrogeric EDS IV. Subsequent clinical, molecular, and genetic progress has been rapid. For example, Barabas first proposed three distinct subsets. These included classical forms with prematurity a milder type with venous varicosity, and a third, potentially lethal, form with minor cutaneous and joint changes but extreme arterial fragility (which we now call EDS IV). Soon afterwards, Beighton also clearly described the frequent prematurity. He added an X linked form, while dividing Barabas's first group into 'gravis' and 'mitis' variants, which we now call EDS I and II respectively, to make five subtypes. He also delineated the wide clinical heterogeneity with various rheumatological, orthopaedic, surgical, and cutaneous complications and was also fully familiar with such surgical complications as arterial aneurysms, venous varicosities, arteriovenous fistulas, and inguinal, umbilical, and hiatus hernias. He also documented reflux hydronephrosis, bladder neck obstruction, colonic diverticulae with perforation, and pleuroperitoneal rupture (leading to pneumo- or haemothorax). These complications are now recognised as particularly common in EDS types IV, VI, and VII. In 1972, McKusick added two further subtypes (types VI and VII). We now know that the former is caused by lysyl underhydroxylation, while the latter results from the misprocessing of procollagen (to collagen). In 1988 Beighton et al. published an International Nosology of Connective Tissue Disease where nine subcategories of EDS were defined. Subsequently, he correlated the subtypes with the various biochemical and molecular abnormalities (table 1) and also published the equivalent Molecular Nosology.