Symptoms of EDS
The EDS are a group of uncommon connective tissue disorders resulting primarily in joint and skin laxity and arterial wall abnormalities. As a group, EDS affects 1 in 5000 individuals. Increased joint mobility and increased skin fragility and hyperextensibility occur, though there is a wide variability in involvement. Hyperextensibility in patients with EDS may be greater in the small joints than large joints and may diminish with age. Skin hyperextensibility is defined as a capacity to stretch the skin 3 cm at the neck, elbows, and knees and 1.5 cm at the distal forearm or the dorsum of the hand (see Fig. 55.1 ). Skin laxity and fragility may manifest as easy bruisability, inability of stretched skin to return to normal, “cigarette paper” or “papyraceous-appearing” scars over the knees and other extensor surfaces, gaping wounds from minor trauma, or the inability of skin to retain sutures. Pes planus, pectus excavatum, and a high-arched palate can be present in all forms. Arteries may develop aneurysms or rupture because of elastic tissue laxity. There are several recognized clinical types of EDS. Most involve some abnormality in collagen synthesis or enzymatic modification of collagen. The 2017 International Classification of the EDS recognizes 13 types of EDS.
1. Classical (formerly classic EDS types I and II): hypermobility with joint dislocations, skin hyperextensibility, soft doughy skin, wide atrophic papyraceous scars, easy bruising ranging from mild to severe, and colluscoid pseudotumors of skin. Cervical insufficiency, uterine prolapse, scoliosis, and hernias can be seen. Associated with the null allele for collagen type V (COL5A1 or COL5A2) and has AD inheritance. The classical type of EDS accounts for roughly 80% of EDS cases reported in the literature.
2. Classical-like: Skin hyperextensibility with velvety skin, joint hypermobility, easily bruised skin, and absence of atrophic scarring typify this category of EDS. Due to a mutation in the TNXB gene causing tenascin X (ECM glycoprotein) deficiency. AR inheritance. Note that tenascin X associates with type I collagen and is important for its stability and deposition.
3. Cardiac-valvular: severe progressive cardiac-valvular problems, skin hyperextensibility, atrophic scars, easy bruising, and joint hypermobility. COL1A2 mutations leading to lack of proα2-chain of type I collagen. AR inheritance.
4. Hypermobile (formerly EDS type III): marked hypermobility of large and small joints with soft skin but no scars. Much more common than other types of EDS, with a prevalence of 1 in 5000. Autonomic dysfunction including postural orthostatic tachycardia syndrome and postural acrocyanosis has been reported. Chronic joint pain, which may resemble fibromyalgia, is common. Collagen/ECM protein defect unknown. Inheritance is suspected to be AD.
5. Vascular (formerly EDS IV): normal joint mobility, translucent skin with prominent venous pattern, marked bruising, aortic/arterial aneurysms, arterial rupture/dissections, rupture of uterus/bowel (sigmoid colon), and carotid-cavernous sinus fistula formation. Spontaneous hemopneumothorax and mitral valve prolapse can occur. No hyperelastic skin. Increased risk of maternal mortality during pregnancy. Surgery can be difficult due to friable arteries and organ tissue. Caused by various mutations in genes encoding for Type III collagen (COL3A1), which is found primarily in the skin, blood vessels, and walls of hollow viscera. AD inheritance.
6. Kyphoscoliotic (formerly EDS type VI): severe kyphoscoliosis with muscle hypotonia associated with joint laxity noted at birth, recurrent joint dislocation, and hyperextensible, fragile skin that develops gaping wounds with minor trauma and heals poorly. Unlike other EDS types, these patients have ocular fragility, blue sclerae, retinal detachment, glaucoma, and globe rupture that can lead to blindness. Mutations of the lysyl hydroxylase gene (PLOD1) results in deficiency of the enzyme. This enzyme is necessary for the conversion of lysyl residues to hydroxylysine on procollagen peptides, which is important for crosslinking and subsequent collagen stabilization. AR inheritance.
7. Arthrochalasia (formerly EDS VIIA and VIIB): significant hypermobility with large joint dislocations starting in newborn period (congenital hip dislocation), moderate skin hyperextensibility and bruising, kyphoscoliosis, muscle hypotonia, frequent fractures, and short stature. Defect in type I collagen (COL1A1, COL1A2) involves lack of N-proteinase cleavage site, so type I collagen retains its N-terminal peptide resulting in abnormal collagen fibrils. AD inheritance.
8. Dermatosparaxis (formerly EDS VIIC): marked joint hypermobility, micrognathia, extremely fragile skin with bruising but no scars, sagging redundant skin, and blue sclerae. Large umbilical hernias are common. Short limbs, hands, and feet. Due to mutation in ADAMTS2 leading to a deficiency of procollagen N-propeptidase and abnormal type I collagen. AR inheritance.
9. Brittle cornea syndrome: thin cornea, early onset progressive keratoconus and keratoglobus, blue sclerae. Mutation in ZNF469, a zinc finger protein. AR Inheritance.
10. Spondylodysplastic: short stature, muscle hypotonia, bowing of limbs. Multiple gene mutations lead to glycosaminoglycan deficiency. AR inheritance.
11. Musculocontractural: Multiple congenital contractures, specific craniofacial features with broad forehead, micrognathia in infancy, protruding jaw in adolescence, low-set rotated ears, hyperextensible thin skin, atrophic skin, and organ fragility. Caused by a defect in the gene CHST14 (involved in glycosaminoglycan synthesis) or in the DSE gene. AR inheritance.
12. Myopathic: congenital muscle hypotonia and/or muscle atrophy, proximal joint contractures, hypermobility of distal joints. Defect involving COL12A1 gene for Type XII collagen. Inheritance is AR or AD.
13. Periodontal (formerly EDS IX): severe periodontitis of childhood, lack of attached gingiva, pretibial plaques, joint hypermobility, and skin hyperextensibility. Gain of function mutations in C1R and C1S, involved in the classical pathway of complement. AD inheritance.
