Ehlers-Danlos Syndrome (EDS)

Heterogeneous group (six major types) of inherited connective tissue disorders characterized by joint hyperlaxity, skin hyperextensibility, and tissue fragility.

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Ehlers-Danlos Disease; Chernogubov Syndrome; Cutis Elastica; Danlos Syndrome; Meekeren-Ehlers-Danlos Syndrome; Van Meekeren Syndrome I; Sack Syndrome; Sack-Barabas Syndrome; Indian Rubber Man.

First described by the Dutch surgeon J.J. van Meekeren in 1668, when he described a young Spanish sailor man who was able to pull the skin of his chin up to the eyes and down to the chest. In 1892, the Russian dermatologist Nikolai A. Chernogubov described this syndrome in a 17-year-old boy, but this description went unnoticed in Western medicine. In 1899, Edvard L. Ehlers, a Danish dermatologist, presented a patient with this disorder at a meeting in Paris, France, before his findings were published in 1901. Seven years later, Henri A. Danlos, a French dermatologist, published his view of the syndrome. The Italian composer Niccolo Paganini (1782-1840) was one of the famous persons suffering from this disorder.

Incidence of EDS ranges from 1:150,000-300,000 and the prevalence ranges from 1:5000-10,000. The disorder affects males and females of all racial and ethnic backgrounds. EDS types I and III account for 90% of all cases (each approximately 30%).

The classic, hypermobility, vascular, and arthrochalasis types are autosomal dominant inherited, whereas the kyphoscoliosis and dermatosparaxis types are autosomal recessive transmitted. In a few cases, X-linked inheritance has been described.

Depends on the type of EDS. Generally, collagen synthesis is abnormal, resulting in reduced strength of the collagen in numerous tissues.

Prenatal diagnosis is possible by detection of abnormally low lysyl hydroxylase enzyme activity in cultured amniotic fluid cells. The soft, hyperextensible, velvety skin (so-called marshmallow skin), joint hypermobility, scoliosis, and ocular fragility (severe myopia), all features of Marfan Syndrome, are also features of EDS. Instability is a result of the marked joint laxity and leads to delayed motor development in affected children.

The clinical picture is highly variable and depends on the type of EDS. The skin is generally hyperelastic and hyperextensible (difficult to assess in neonates and infants) but most often is thin and highly vulnerable with a tendency to hematomas associated with already minor trauma. Patients often have impaired wound healing with inappropriate (either hypertrophic or atrophic) scarring, particularly affecting the most exposed body areas (knee, shin bone). The occurrence of knuckle pads on hands and feet, molluscoid pseudotumors from scars on elbows and knees, subcutaneous calcifications, spheroids (small, mobile, hard nodules on forearms and lower legs), and acrogeria are common findings. Easy bruising is noticed in infancy, commonly occurring in exposed body areas and often presenting as spontaneous ecchymoses that later change into areas of brownish discoloration. This is explained by increased tissue fragility. The laxity of the ligaments not only leads to hyperextensibility of the joints, which is most pronounced in (but not limited to) shoulder, elbow, ankle, and temporomandibular joint and may result in recurrent (sub)luxations, but also to skeletal anomalies (e.g., kyphoscoliosis, clubfoot). The Beighton Score is used to assess the degree of joint hyperextensibility and the criteria include (1) passive dorsiflexion of the little fingers beyond 90 degrees, (2) passive apposition of the thumb to flexor aspect of the forearm, (3) hyperextension of the elbow beyond 10 degrees, (4) hyperextension of the knees beyond 10 degrees (genua recurvatum), and (5) forward flexion of the trunk with the knees fully extended so that the palms of the hand rest flat on the floor. Chronic joint and musculoskeletal pain is a common problem in EDS patients. Cardiovascular anomalies include multiple aneurysms (rarely of the aorta) and rupture and dissection of arteries, varicosis, mitral valve prolapse (common), orthostatic hypotension, and acrocyanosis. Although dilatation of the aortic root is rare, it should be kept in mind and checked on a regular basis (echocardiography) because sudden cardiac death secondary to aortic rupture has been described. Facial appearance is often (but not always) typical in vascular type of EDS, presenting with a slender face, sunken cheeks, thin or pinched nose, thin (upper) lips, prominent eyes with periorbital pigmentation, and firm, lobeless ears. Vascular type of EDS is the most severe form, with arterial rupture occurring in 25% of these patients before age 20 years and in 80% before age 40 years. This complication is the most common cause of death in these patients, whose average life expectancy is 48 years. Arterial rupture may present with acute abdominal or flank pain, which should prompt urgent investigations in these patients. Because of the increased tissue fragility, which also involves the arteries, the repair is often very difficult or even impossible. Ophthalmologic features may include strabismus, ptosis, keratoconus, blue sclerae, glaucoma, photophobia, (sub)luxation of the lens, rupture of the globe, and blindness from recurrent retinal hemorrhages. Gastroesophageal, inguinal, and umbilical hernias, anal prolapse, and spontaneous ruptures of intestinal organs have been reported.

The heterogeneous nature of EDS results in a mixed picture in many cases. Obtain a thorough history of complications with previous surgeries and ask about excessive bleeding after minor trauma. The clinical examination should also determine the degree of cardiorespiratory compromise associated with kyphoscoliosis (restrictive lung disease, cor pulmonale). Lung function tests (including arterial blood gas analysis) and echocardiography should be considered. Aortic and mitral insufficiency may be associated with the classic and vascular types and should be graded by echocardiography. Right bundle branch block and left anterior hemiblock have been described, so a preoperative electrocardiogram is recommended. Excessive bleeding is a feature of the classic and vascular types of EDS and may manifest as increased bleeding time rather than abnormal coagulation tests. The patient's blood should be cross-matched prior to surgery, and adequate amounts of blood products should be easily available. Check for difficult airway management because mandibular hypoplasia, recurrent temporomandibular joint dislocations, and gingival anomalies have been described. Atlantoaxial instability has been described as a feature of the vascular type of EDS.

Care with positioning of the surgical patient is needed to prevent damage to the delicate skin and to avoid joint dislocations. Venous access must be adequate to cope with potential heavy blood loss, which often results from delicate skin. Central venous access may be complicated by mediastinal or pleural hematomas. Arterial cannulation may be complicated by aneurysm formation or excessive hematoma formation. Both central venous and arterial monitoring should be used only when essential to patient management. Regional techniques have been described, but central blocks are associated with a higher risk of hematoma formation. These should be kept in mind and checked accordingly if regional anesthesia has been performed. Local anesthesia may have an insufficient effect in many patients with the hypermobility type of EDS. General anesthesia should be accomplished using minimal airway trauma. Mask anesthesia is probably the management of choice, but when appropriate, airway intubation and extubation should be accomplished as gently as possible to minimize airway bruising. Avoid temporomandibular joint dislocation or subluxation and cervical spine subluxation. Peak airway pressure must be kept as low as possible to reduce the risk of pneumothorax. Avoid wide swings in blood pressure to reduce the risk of hemorrhage and aneurysm rupture. The risk of cerebral hemorrhage from intracranial aneurysms is considered low but should be kept in mind for patients with the vascular type of EDS. The same type of EDS also has a high risk of uterine rupture in parturients, with pregnancy-related mortality of up to 25% reported (secondary to uterine, aortic, pulmonary artery, or vena cava rupture). However, severe hemorrhage may also occur in the early postpartum period. Epidural anesthesia has been used successfully in some of these patients. Large-bore intravenous access (although sometimes difficult to establish in these patients) and availability of blood products are recommended for these women. Despite normal parameters, prolonged bleeding has been described in EDS patients.

There are no strict contraindications, but agents interfering with blood coagulation and hemostasis should be used with considerable care. Subacute bacterial endocarditis prophylaxis usually is recommended if mitral valve prolapse is associated with thickened leaflets and/or mitral regurgitation.

Marfan Syndrome: Familial disorder of generalized connective tissue abnormalities leading to connective tissue weakness with hyperextensible joints, eye anomalies (dislocation of the lens), increased risk of valvular/aortic disease, and spontaneous pneumothorax.