Patient Presentation
A 28-year-old man presented with skin hyperextensibility and multiple scars on his legs and arms. On physical examination there was a broad hyperpigmented atrophic fibrotic plaque on his elbow. The patient had noticed impressive hyperextensibility of the elbow and neck skin. Further questioning of the patient and his family, as well as medical and laboratory investigations, did not reveal any associated cardiovascular diseases or gastrointestinal abnormalities.

What Is Your Diagnosis?

Diagnosis: Ehlers-Danlos Syndrome (EDS)

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inheritable connective tissue disorders with six major subcategories. The archetypical features include skin hyperextensibility, tissue fragility and joint hypermobility. Internal organ involvement may progress to vascular emergencies or fatal organ rupture.1 The prevalence of EDS varies between 1:10,0002 and 1:150,0003 depending on the series, and the disorder affects both males and females of all racial and ethnic groups.

Historical Note
Edvard Ehlers, a Danish dermatologist, observed the association between joint laxity and subcutaneous hemorrhages in 1901.4 Subsequently, Henri-Alexandre Danlos, a French physician, noted a similar case with additional molluscoid pseudotumors.5 Nearly 30 years later, the eponymous title Ehlers-Danlos was proposed.6 The genetic heterogeneity emerged in the 1960s, and the first molecular defects in collagen synthesis were described in 1972.

Classification
The original classification divided EDS into subgroups I-XI according to clinical phenotype. In 1986, the International Nosology of Heritable Disorders of Connective Tissue redefined EDS into subtypes I-VIII & X.7 A new simplified classification of EDS was revised in 1997, which intended to provide uniformity of diagnosis and emphasized the molecular basis of each form (see table 1).8 In addition, major and minor diagnostic criteria are defined for each type and complemented whenever possible with laboratory findings.9 The classic hypermobile and vascular types of EDS are the most common subtypes, while the kyphoscoliosis, arthrochalasis and dermatosparaxis types represent very rare conditions. Of note, there are several unclassified EDS variants in which the underlying molecular defects remain unknown.

Genetics
Most EDS subtypes are caused by mutations in genes encoding the fibrillar collagens type I, III and V, or in genes coding for enzymes involved in post-translational modification of these collagens.10

The first molecular defect discovered was a lysyl hydroxylase deficiency in an autosomal recessive form of EDS.11 Subsequently, several mutations have been identified. Most recently, Lindor discovered an autosomal recessive form of EDS caused by a tenascin-X deficiency.12

The molecular genetics of EDS are complex, and a concise review has been published.13

Clinical Presentations
The clinical presentation of EDS ranges from minor symptomatologies that remain undiagnosed to vascular emergencies and premature death. The skin is hyperextensible but retains its normal elastic recoil.13 Redundant skin (acquired cutis laxa) may be evident overlying elbows and knees.

Skin hyperextensibility is best tested at a neutral site, such as the volar surface of the forearm. It is measured by pulling the skin until resistance is felt. Scars may be observed over trauma-prone sites such as the elbows, shins, forehead and chin. Clinically, scars manifest as a splitting of the skin following relatively minor trauma with the formation of wide and thin “cigarette-paper” scars. In areas of repetitive trauma, hemosiderin deposition may lead to dark discoloration of the skin, and fibrous lumps (molluscoid pseudotumors) of 2 cm to 3 cm may develop. Other cutaneous findings may include subcutaneous fibrosed fat lobules (often with calcium deposition), epicanthic folds, and keratosis pilaris-like changes around the elbows and knees.

Joint laxity is a cardinal manifestation of EDS that tends to be generalized, affecting both large and small joints. In severe cases it may lead to occasional or habitual dislocations or subluxations, chronic musculoskeletal pain and premature osteoarthritis. It is worth emphasizing that hypermobility may be a positive factor for entry into ballet or acrobatics.9

Hypermobile joints can be assessed by the Beighton scale — a scoring system measuring the range of passive movement at individual joints.14 A score of 5/9 or greater defines joint hypermobility.

Abnormalities such as keratoconus, blue sclera, lens subluxation or retinal detachment have also been described.13

The tendency to bruise easily is present in all subtypes of EDS to a variable degree. This is a secondary phenomenon to fragile capillaries and the perivascular connective tissues; bruising is most pronounced in the vascular subtype. These patients may develop extensive bruising, spontaneous arterial rupture and severe internal bleeding, leading to premature death or internal organ rupture.10

Other features of EDS syndromes may include mitral or tricuspid valve prolapse, and aortic dilatation with risk of dissection.

Vascular EDS
The vascular type of EDS, previously known as EDS type IV, is caused by a structural defect of type III collagen. It has the worst prognosis, due to a high risk of fatal vascular and intestinal complications. In contrast to the other types of EDS, the skin is not hyperelastic, but rather thin and translucent, showing visible venous pattern over the chest, abdomen and extremities.

The most common sign is excessive bruising. Other manifestations may include premature rupture of the membranes, excessive bleeding after tooth extraction, congenital club foot, congenital hip dislocation, inguinal hernia in childhood, pneumothorax, and recurrent joint dislocations or subluxations.15

A characteristic facial appearance may be present that includes prominent eyes, a thin, pinched nose, small lips, hollow cheeks, and lobeless ears. Unusual cutaneous manifestations include elastosis perforins serpiginosa, keloid formation and Raynaud phenomenon.10

These patients are at risk of sudden death secondary to an acute arterial bleeding, myocardial bleeding due to coronary dissection or rupture, spontaneous rupture of the bowel or hemorrhagic pneumothorax.

Differential Diagnosis
Marfan syndrome is an autosomal dominant multi-system disease caused by mutations in fibrillin 1. It affects the eyes, skeleton, heart, aorta and lungs. Notable features include dislocation of the ocular lens and tall stature with particularly long limbs and digits. Other findings may include pectus carniatum or excavatum, abnormal curvature of the spine, mitral and tricuspid valve prolapse, aortic dissection, spontaneous pneumothorax, abnormal skin stretch marks, hernias

and dural extraction. If untreated, patients often die before age 30 or 40 from aortic dissection or congenital heart failure.16

Cutis laxa is a rare extracellular matrix disorder characterized by loose inelastic skin that is pendulous and hangs in folds, giving a prematurely aged appearance. The precise cause is unknown, but may be due to abnormal elastin metabolism, resulting in markedly reduced dermal elastin content. The disease may be acquired, autosomal dominant or autosomal recessive in inheritance.17

Osteogenesis imperfecta is a collagen disorder resulting from defective biosynthesis of type I collagen characterized by brittle, osteoporotic and easily fractured bones. Other features include a blue sclera, loose joints, and imperfect dentition. Four major types of varying severity have been described.16

Pseudoxanthoma elasticum is an inheritable disease of connective tissue affecting the skin, eyes and vasculature. It usually presents after puberty, characteristically with small, circumscribed yellow patches located on the neck, axillae and inguinal folds. A hallmark of this condition is the finding of hyperproliferated elastic fibers in the mid-dermis on histology.16

Menkes syndrome is an X-linked recessive disorder. It is a progressive, genetic, neurodegenerative disorder of copper metabolism characterized by seizures, failure to thrive, subnormal body temperature and easily broken kinky hair that is colorless or steel-
colored. Complications may include neurodegenerative changes in the brain’s gray matter and abnormal cerebral vasculature, leading to rupture or arterial occlusion. Osteoporotic changes may result in premature fractures.18

Management of EDS
Most patients with EDS have normal laboratory findings of clotting factors, platelet aggregation and bleeding times. In the case of suspected vascular EDS, biochemical analysis of type III collagen extracted from cultured skin fibroblasts is needed to confirm the diagnosis.

Currently, no specific treatment is available for any of the subtypes of EDS. However, several palliative and “preventive” guidelines are applicable to all forms, which should include a multi-disciplinary team of physicians. Patient and family education should be emphasized in order to ensure compliance with these measures.

Joint laxity and associated chronic pain may be alleviated with non-steroidal anti-inflammatory drugs (NSAIDs) or tramadol hydrochloride (Ultracet, Ultram).19 Physical therapies such as swimming should be recommended.

Special braces can stabilize and strengthen muscles and preserve articular function. Avoidance of trauma, wearing protective clothing, and special padding over pressure points is essential.

In general, surgical procedures should be avoided, as the fragile tissues tear easily, and wound recovery is often prolonged. Any dermal wounds should be closed without tension, preferably in two layers, and cutaneous stitches should be left in place twice as long as usual.10 Of interest, there are case reports of treating extensive facial elastosis with the CO2 and Erbium:YAG lasers.20

Patients with excessive bruising are advised to avoid contact sports and heavy exercise. Supplemental ascorbic acid, a co-factor for cross-linking collagen fibrils, may ameliorate the tendency toward bruising. Other nutritional supplements of proven benefit include calcium, carnitine, glucosamine, magnesium and vitamin K.21 DDAVP (vasopressin) has been used in patients with chronic bruising, epistaxis or peri-operatively to normalize bleeding time.22

Patients with mitral valve prolapse and regurgitation require antibiotic prophylaxis for bacterial endocarditis. A baseline echocardiogram with aortic diameter measurement is recommended prior to the age of 10 years with follow-up studies timed according to whether an abnormal measurement is found.10

Patients with the vascular type of EDS need special care during pregnancy and delivery. In addition, appropriate precautions and careful monitoring are essential before, during, and after dental or surgical procedures.

This subgroup of patients should refrain from drugs that interfere with platelet function such as NSAIDs and anti-coagulation therapies. The prophylactic use of beta-adrenergic blockade in slowing the rate of aortic dilatation is currently under investigation.10

Affected children should be offered genetic counseling and informed about the 50% risk of passing EDS on to each child.23 Prenatal diagnosis is also available.

Prognosis
All subtypes of EDS have the potential to cause clinical problems such as skin fragility, unsightly bruising, scarring, musculoskeletal discomfort and increased susceptibility to osteoarthritis.24 Although all forms of EDS cause considerable morbidity, only vascular EDS causes premature demise of affected individuals. This subgroup of patients generally die young; most deaths result from arterial rupture,25 myocardial rupture and cardiac tamponade
following a myocardial infarction.26 Postmortem diagnosis is possible but requires specialized testing in unrecognized cases.27

The authors would like to emphasize the need for emotional support and behavioral and psychological therapy in all subtypes of EDS. Referral to a patient support group is also usually recommended.