Handbook of Genetic Counseling/Ehlers-Danlos Syndrome-2

Ehlers-Danlos Syndrome

Introduction

 * Ehlers-Danlos syndromes are a genetically, biochemically, and clinically diverse group of heritable connective tissue disorders
 * They have joint laxity and dermal features in common
 * Manly clinical reports, especially before the mid 1980s, do not distinguish between different subtypes
 * There are very few large or population-based series that might provide information about the full range of therapeutic outcomes or accurate estimates of the prevalence of certain complications of EDS
 * Prior classification has included up to 11 disorders
 * New classification includes
 * Classical type (types I and II)
 * Hypermobility type (type III)
 * Vascular type (type IV)
 * Kyphoscoliosis type (type VI)
 * Arthrochalasia type (types VIIA, VIIB)
 * Dermatosporaxis type (type VIIC)
 * Other variants (VIII, V X-linked, X)

Incidence

 * There are no well-founded figures for prevalence
 * For all forms, estimates of 1/5000 have been made

The Classical Type

 * Major diagnostic criteria
 * Hyperextensibility of the skin
 * Widened atrophic scars
 * Joint hypermobility
 * Can lead to osteoarthritis in the 3rd or 4th decade
 * Other features
 * Poor wound healing
 * ½ of affected individuals are delivered up to 1 month premature due to premature rupture of fetal membranes
 * Some have cardiac abnormalities
 * Mitral valve prolapse
 * Aortic root dilation with occasional rupture
 * Scoliosis
 * Pes planus (flatfoot)
 * Molluscoid pseudotumors (calcified hematomas) may be associated with scars
 * Inheritance
 * Autosomal dominant single-gene disorder
 * Etiology
 * A major cause is mutations in type V collagen
 * At least 3 loci are involved
 * Biochemical Defects
 * Thickened collagen fibrils in skin as well as "cauliflower" deformities of collagen fibrils
 * Mutations in COL5A1 and COL5A2 have been seen in some families
 * Testing
 * No biochemical or molecular based testing methods have been devised to provide reliable results

The Hypermobility Type

 * Primary characteristics
 * Hyperextensibility of large and small joints
 * Soft, velvety skin
 * Other features
 * May have normal scarring but stretchy skin
 * Dilatation and/or rupture of the ascending aorta
 * Scoliosis
 * Pes planus
 * Inheritance
 * Autosomal dominant single-gene disorder
 * Diagnosis is clinical

The Vascular Type

 * Major diagnostic criteria
 * Characteristic facial appearance
 * Thin, delicate, "pinched" nose
 * Think lips
 * Hollow cheeks
 * Some have staring appearance due to decreased adipose tissue below the eyes
 * Thin, translucent skin
 * In fair-skinned individuals, subcutaneous vasculature is easily visible beneath the skin
 * Arterial/intestinal/uterine fragility or rupture which can be life threatening
 * Extensive bruising
 * Other characteristics
 * Normal scar formation
 * May be increased incidence of stroke
 * Acrogeria (aged appearance to extremities, particularly hands)_
 * ¼ of affected individuals experience a significant medical problem by age 20
 * Median age of death is 48 years old
 * Inheritance
 * Autosomal dominant as demonstrated by linkage analysis
 * Etiology (COL3A1 gene)
 * Dominant mutations in the gene for the pro-alpha 1 chain of type II collagen
 * Caused by abnormal synthesis, structure, or secretion of type II collagen
 * 50% have new disease-causing mutations
 * Over 250 COL3A1 disease-causing mutations have been found
 * Testing
 * Can be reliably accomplished by analysis of type III procollagen and collagen chains harvested from cultured dermal fibroblasts

The Kyphoscoliosis Type

 * Key features
 * Neonatal onset of joint laxity
 * Kyphoscoliosis (lateral curvature of the spine accompanying an anteroposterior hump)
 * Muscle hypotonia
 * Other features
 * Ocular fragility
 * Skin fragility
 * Easy bruisability
 * Dermal hyperextensibility
 * Risk for arterial rupture
 * Most have radiologically detectable osteopenia (decreased bone density), but pathological fractures are rare
 * Intelligence is normal
 * Lifespan may be normal
 * Etiology
 * Caused by deficient activity of the enzyme procollagen lysine hydroxylase
 * Inheritance
 * Autosomal recessive
 * Testing
 * Diagnosis depends on demonstration of increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by HPLC
 * Mutation analysis of the PLOD gene that encodes the enzyme procollagen lysine hydroxylase is available on a research basis
 * Carrier testing is not available

The Arthrochalasia Type

 * Major criteria
 * Severe generalized joint hypermobility
 * Congenital bilateral hip dislocations that are difficult to repair surgically
 * Other features
 * Tissue fragility including atrophic scars
 * Kyphoscoliosis
 * Skin hyperextensibility
 * Etiology
 * Caused by a failure to accomplish normal cleavage of the amino-terminal propeptide of type I collagen in all tissues
 * Mutations that remove exon 6 in COL1A1 and COL1A2 are seen
 * This exon encodes the amino-terminal propeptide cleave site
 * Inheritance
 * Autosomal dominant
 * Testing
 * Demonstration of exon 6 skipping in cDNAs of COL1A1 or COL1A2 followed by mutational analysis

The Dermatosporaxis Type

 * Very rare form of EDS
 * Diagnostic Features
 * Dermal fragility: the skin is lax but not stretchy
 * Other features
 * Joint dislocation is usually not a feature
 * Infants have been reported with premature rupture of membranes and umbilical/inguinal hernias
 * Etiology
 * Caused by failure to cleave off the amino-terminal propeptide of type I collagen due to deficiency of the procolagen I N-peptidase gene
 * Inheritance
 * Autosomal recessive

Other Ehlers-Danlos Syndrome Variants

 * Type VIII
 * Rare autosomal dominant condition
 * Characterized by soft, hyperextensible skin, abnormal scarring, easy bruising, hyperextensible joints and generalized periodontitis
 * Resembles type I, but is distinguished by early loss of teeth and characteristic purplish discoloration of scars on the shins
 * Molecular basis is unknown
 * Not clear if it is truly distinct from classical form
 * Type V X-linked
 * Similar to mild classical type
 * X-linked recessive inheritance
 * Unknown molecular defect
 * Type X
 * Joint hyperextensibility, mitral valve prolapse, easy bruising, poor wound healing, clotting disorder
 * Clotting studies showed a defect in the platelet adhesion that is normally observed in response to exposure of platelets to collagen
 * May be caused by a defect in fibronectin

Management

 * Pregnancy
 * All cases should be referred to high-risk obstetric practice
 * Prematurity is a concern
 * Cervical incompetence can be treated with bed rest and the Trendelenburg position
 * Musculoskeletal
 * Physical therapy can improve strength of muscles surrounding lax joints
 * Surgical procedures can correct dislocation
 * Intervention for pain management is necessary
 * A regular exercise program can strengthen muscles and stabilize joints
 * Cardiovascular
 * Enlarged aortic root can be treated with beta blockers but the efficacy or length of treatment is currently unknown
 * Exercise limitation may be necessary especially competitive sports
 * Surgical complications and intraoperative problems are common
 * Dermatologic
 * Plastic surgery can be done to close facial wounds or other aesthetically significant areas
 * Retention sutures tied at a distance from the incision may help support the skin during scar formation

Resources

 * Ehlers-Danlos National Foundation
 * 800-956-2902
 * http//:www.ednf.org


 * Ehlers-Danlos Support Group
 * http//:www.ehlers-danlos.org


 * Family Village
 * http//:www.familyvillage.wisc.edu/lib_e-ds.htm