Ehlers danlos syndrome = متلازمة اهلير دانلوس |
▪ EHLERS-DANLOS SYNDROMES
The Ehlers-Danlos syndromes (EDSs) are a heterogeneous group of disorders characterized by hypermobile joints, hyperextensible skin, and fragile tissues that are extremely susceptible to trauma. As many as 1 in 5000 individuals may be affected by some form of the disease.The seven sub-types of EDS have been categorized based on clinical and corresponding molecular pathogenetic findings in collagen types I, III, and V, or processing enzymes. These collagen types are all fibrillar types of collagen with cross-banding that are expressed in different locations in the skin and in other tissues . Pathogenic alterations of fibrillar collagens in EDS result from deficient collagen-processing enzymes, haploinsufficiency, or mutations in collagen α chains. A uniform finding in all types of EDS is generalized joint hypermobility, which can be assessed clinically according to the Beighton scale Classical Type
EPIDEMIOLOGY
The classical form of EDS is one of the most common, occurring in 1 in 10,000 to 20,000 infants.9
ETIOLOGY AND PATHOGENESIS
The classical type of EDS is characterized by an alteration in type V fibrillary collagen and is inherited in an autosomal dominant (AD) fashion. Mutations in COL5A1 and COL5A2 have been shown to cause this variant in up to 50 percent of cases. The abnormal allele leads to dominant-negative effects or haploinsufficiency, depending on the mutation. At least one other locus is involved, because several families are discordant for linkage to both COL5A1 and COL5A2. A few patients have shown mutations in COL1A1, a gene more commonly mutated in osteogenesis imperfecta (OI; see Osteogenesis Imperfecta).
EHLERS-DANLOS SYNDROMES AT A GLANCE
Ultrastructural findings show thickened collagen fibrils in skin,with an approximate 25 percent increase in diameter, underscoring the function of collagen V in limiting fibril diameter, as shown in vitro.22 This effect is thought to be due to the negative charge of the amino terminus of α1(V), conferred by abundant tyrosine residues, which inhibits fibril growth. Another hallmark of classical EDS is the presence of rare composite fibrils also known as “collagen cauliflowers.” These abnormalities are present in less than 5 percent of fibrils, suggesting that other factors may be responsible for the severe clinical phenotype, such as the arrangement of collagen fibrils in tissue. This disorganized arrangement of collagen fibrils and their interaction with other extracellular matrix (ECM) proteins is thought to cause the altered biomechanical properties of EDS skin.24
CLINICAL FINDINGS
Classical EDS is characterized by joint laxity, hyperextensibility of skin, and poor wound healing. The skin manifestations can vary in severity from mild to severe; milder forms were previously termed the “mitis” type, or type II, EDS. The skin is soft, velvety, and can be stretched easily . It is not lax, except in late stages. Skin hyperextensibility should be determined at the volar surface of the forearm or some other site that is not subjected to mechanical forces or scarring. Approximately 50 percent of patients with Ehlers-Danlos of the classic and hypermobile types can touch the tip of their nose with their tongue (Gorlin's sign), in contrast to 10 percent of individuals who do not have EDS
The dermis is fragile and easily bruised. The shins show persistent discoloration, often beginning in early childhood . When the skin splits from trauma, it is relatively painless and does not bleed excessively, but the wounds tend to gape. The wound margins tend to retract, heal slowly, and often become infected. Dehiscence is common, and complete wound breakdown
hyperextensibility and fragility.
Musculoskeletal features seen in classical EDS include joint hyperextensibility in all patients and a fairly high frequency of scoliosis and pes planus.26 Patients tend to have “double-jointed” fingers and frequent sprains or subluxation of larger joints , either spontaneously or after slight trauma. Affected individuals complain of chronic joint and limb pain despite normal skeletal radiographs.27 The joint hypermobility can lead to the onset of osteoarthritis in the third or fourth decade. Muscle hypotonia and delayed gross motor development have been described. Dyspareunia and sexual dysfunction have been reported, and the signs of classical EDS may be aggravated by pregnancy. Forty percent of affected individuals and 21 percent of babies of affected mothers are born prematurely, typically between 32 and 37 weeks, owing to premature rupture of fetal membranes or infection of the chorioamnionic membrane. Fetuses with classical EDS may exhibit retarded growth, hernias, and joint dislocations. A significant number of individuals with EDS have abnormal cardiac echocardiographic parameters, showing aberrant vessels and incompetent valves.31 Aortic root dilatation has been described in 29 percent of patients with the classical and hypermobile forms of EDS, especially in the former, and may lead to rupture. The most commonly affected site is the sinus of Valsalva. Initial screening of all EDS patients by echocardiography is recommended. Aortic valve incompetence, aortic rupture, and dissection occur far less commonly than in Marfan syndrome. β Blocker therapy with agents such as atenolol has been attempted in individual cases, but too few data exist to determine whether therapy is indicated or effective. Mitral valve prolapse (MVP) occurs no more frequently than in the general population. The diagnosis is confirmed by clinical examination, family history, and the identification of mutations in COL5A1 or COL5A2, a test not commercially available.
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