Ehlers‐Danlos syndrome (EDS) is an inherited heterogeneous group of connective tissue disorders, displaying hyperextensibility of the skin, hypermobility of joints, tissue fragility demonstrated by easy bruising and delayed wound healing with atrophic scarring (Steinman et al, 2002). The syndrome is named after Edvard Ehlers, a Danish dermatologist, (1863–1937) and Henri‐Alexandre Danlos a French dermatologist (1844–1912). In 1936 an English physician, Frederick Parkes‐Weber, suggested that the disorder be named ‘Ehlers‐Danlos syndrome’ (Enerson, 2004).

It was noted by Hipprocates in 400 BC in his writing ‘Airs, Waters and Places’, that Nomads and Scythians had lax joints and multiple scars. These were thought to have been caused by cauterization which had been applied in an attempt to stiffen up the joints (Littre, 1840).

It was not until 1657 that a Dutch surgeon, Job Janszoon van Meek’ren, observed a boy of Spanish origin who had extreme hyperextensibility of the skin. The boy, George Albes, was presented regularly at the Academy of Leyland, where he demonstrated the remarkable abnormality of his skin. He had the ability to stretch the skin of his chin, reaching his chest, or covering his eyes, and the skin over his knees could be ‘pulled out to the length of half an ell’. However this phenomenon, unusually, was limited to the right side of his body (Beighton, 1970).

Paganini (1782–1840), the world famous ‘Virtuso in Excelsis’, performed unprecedented feats as a violinist; he had hypermobile joints, a slender physique, thoracic deformity and joint laxity, all features consistent with EDS (Mckusick, 1972).

The first comprehensive description of a syndrome displaying laxity and fragility of the skin associated with hypermobility of the large joints was published in 1892 when Dr Tschernogobow presented two patients at the Moscow Venereology and Dermatology Society (Tschernogobow, 1892). The first patient was a 17‐year‐old male with epilepsy who suffered from ‘fragility and hyperelasticity of the skin, and a failure to hold sutures. He also had hypermobility and luxation of joints, and molluscoid pseudo tumours of the knees, elbows, and other areas’, the combination of all the above features are suggestive of EDS (Tschernogobow, 1892). Jansen (1955) gave further credit to Tschernogobow for his first detailed clinical description.

During the late nineteenth century, some patients with EDS displayed their hyperextensibility as performers at travelling shows with titles such as ‘elastic lady’, described by Gould and Pyle (1897) or ‘The India Rubber Man’, as mentioned by Wile (1883).

In 1901, Edvard Lauritz Ehlers (1863–1937), a Danish dermatologist gave further recognition to the syndrome, when he published details of a patient with lax joints, hyperextensible skin and a tendency to bruising. The patient gave a history of delayed walking and frequent subluxations of the knees. This case was demonstrated at the Dermatological Society of Denmark in 1899 (Beighton, 1970).

A further case of EDS was identified by Henri‐Alexandre Danlos, a French physician (1844–1912). In 1908, Danlos re‐examined a patient who had previously been examined by Hallopeau and de Lepinay with a diagnosis of ‘juvenile pseudo‐diabetic xanthoma’ (Beighton, 1970). The patient presented with lesions on the elbows and knees. However, Danlos disagreed with this diagnosis and Pautier (1908) a pathologist assisted Danlos with further investigations. He suggested the skin lesions were vascular and inflammatory due to trauma (Beighton, 1970).

Following these descriptions, isolated case reports of EDS appeared during the early part of the twentieth century (Beighton, 1970). Tobias (1934) reported the first case from the United States. Ronchese (1936) discovered 24 cases in a literature review and reported on three of his own. Mckusick (1956) compiled his monograph documenting less than 100 reports. By 1966, when his third edition was published the total number of reports had risen to 300. Weber (1936) reported six examples in England, the earliest was a boy presented at the old dermatological society in London in 1900 by Sir Malcolm Morris, although his diagnosis was not conclusive. Weber (1936) tried to delineate these conditions, highlighting skin hyperextensibility and fragility, together with joint laxity in his original patients, and the eponym Ehlers‐Danlos syndrome was appropriated to this condition. Johnson and Falls (1949) concluded that EDS was probably inherited as an autosomal dominant trait, following a large kindred investigation of 32 patients. Jansen (1955), after reviewing all the published pedigrees, suggested that a genetic defect of collagen of the connective tissue probably accounted for the phenotype. Sestak (1962) supported this conclusion.

The first molecular defect was discovered by Pinnell et al (1972) with a finding of lysyl hydorxylase deficiency in an autosomal recessive form of Ehlers‐Danlos syndrome. Patients were particularly prone to scoliosis and rupture of the ocular globe; Lichtenstein et al (1972) confirmed this was the first disorder of collagen.

Classification of EDS began in the late 1960s (Beighton, 1970; Mckusick, 1972) and, in 1988 an international nosology of connective tissue that defined nine subcategories of EDS was proposed (Beighton et al, 1998). With recent developments and increased medical expertise, a simplified classification of EDS has been revised into six major types according to the Villefranche nosology (Table I) (Beighton et al, 1998). Based on this refined classification, one in 5000 people is said to be affected by Ehlers‐Danlos syndrome (Pyeritz, 2000). It affects males and females equally of all racial backgrounds (Ceccolini & Schwartz, 2005).

Table I. Revised classification of the Ehlers‐Danlos syndrome based on the Villefranche nosology ( ). Type Mode of inheritance Defect Examples of clinical presentations Classical (EDS I and II) AD Abnormal type V collagen Skin laxity, scars (Fig 4), joint hypermobility, easy bruising, muscle hypotonia, hernias. Hypermobility (EDS III) AD Unknown Skin laxity (Fig 1), velvet skin, joint hypermobility, recurrent joint dislocations. Vascular (EDS IV) AD Abnormal type III collagen Arterial rupture, easy bruising (Fig 5), hypermobility of small joints, varicose veins. Kyphoscoliosis (EDS VI) AR Deficiency of LH Joint laxity, muscle hypotonia in infants, scoliosis from birth, sclera fragility. Arthroclasia (part of EDS VII) AD Deficiency of chains in type I collagen Joint hypermobility (Figs 2 and 3) and dislocations, skin laxity, easy bruising, muscle hypotonia, kyphoscoliosis. Dermatosparaxis (was included in EDS VII) AR Deficiency of enzyme in type I collagen Sagging redundant skin, soft, dough skin texture, easy bruising, hernias, premature rupture of fetal membranes.

Figure 4 Open in figure viewer PowerPoint Abnormal scarring after surgery. Written permission received from patient.

Figure 1 Open in figure viewer PowerPoint Lax skin of the abdomen. Written permission received from patient.

Figure 5 Open in figure viewer PowerPoint Spontaneous bruising of legs. Written permission received from patient.

Figure 3 Open in figure viewer PowerPoint Hyperextensibility of joints. Written permission received from patient.

The majority of patients have a bleeding diathesis, which is seen in all subtypes (Table I). The symptoms may be mild, consisting simply of a tendency to bruise easily, or they may be severe, with the occurrence of haematoma formation and bleeding from the nose, gut, lungs and urological tract (Beighton, 1970). Laboratory investigations of clotting factors, platelet aggregation and bleeding time are usually within normal limits in patients with connective tissue disorders (De Paepe & Malfait, 2004).

EDS type IV (vascular) has the worst prognosis because of its association with severe and often fatal rupture of the bowel, other organs, and large arteries (Pepin et al, 2000). EDS type IV can be a cause of cerebrovascular bleeding in young adults. The mean age of intracranial aneurismal rupture, spontaneous carotid‐cavernous sinus fistula and cervical artery aneurysm is 28 years (North et al, 1995). Unlike other types of EDS, the skin is not hyperelastic, but rather thin and translucent, showing a visible pattern over the chest, abdomen and extremities (Beighton, 1993; Steinman et al, 2002).

Approximately 12% of neonates with vascular EDS are born with clubfoot and 3% have congenital dislocation of the hips (Germain, 2002; Pepin & Byers, 2005). Children may present with pneumothorax, inguinal hernia and recurrent joint dislocation. Excessive bruising in children can often be a presenting symptom to paediatricians, therefore it is imperative that a careful evaluation of the medical and family history and thorough physical examination is performed, paying attention to the skin features that are characteristic of EDS (De Paepe & Malfait, 2004). Facial features in infants with vascular‐type EDS may initiate suspicion of the diagnosis, including prominent eyes (due to the lack of subcutaneous adipose tissue around the eyes), small lips, a pinched nose, hollow cheeks and lobeless ears (De Paepe & Malfait, 2004).

Vascular‐type EDS can be identified by mutations in COL3A1 (Jones, 1997; Beighton et al, 1998; Sybert, 2001). This particular gene provides instructions for making the components of collagen. Molecular genetic testing to identify mutations in COL3A1 is available to patients with biochemically confirmed diagnosis of vascular EDS (Dalgleish, 1998).

Progress in the management of EDS has been slow as there is no specific treatment. Tranexamic acid postoperatively has been used to reduce episodes of bleeding (Bolton‐Maggs et al, 2004). There are reports of improvements in the bleeding time in patients treated with DDAVP (James et al, 2001). For the vascular type of EDS, prophylactic measures are also of special importance, including the avoidance of contact sports or isometric exercises (Pepin & Byers, 2002). Refraining from drugs which interfere with platelet function is also advised. Management of EDS has been reviewed in the British Journal of Haematology (Bolton‐Maggs et al, 2004).