Handbook of Genetic Counseling/Ehlers-Danlos Syndrome

Ehlers-Danlos Syndrome Contracting Introductions, acknowledge any prior contact Assess main concerns of patient Why are they visiting Genetics today? What do they hope to gain from the session? Assess knowledge of diagnosis -- any questions? Overview of today's session Restate patient's concerns Medical history, family history, physical exam, genetics, recurrence risk, testing options and limitations Pediatric Intake Pregnancy and Medical History umbilical/unguinal hernia? prematurity? cervical incompetence? Developmental History learning disabilities? Family History heart problems? joint hypermobility? stretchy skin? fragile skin? easy to scar? scoliosis? easy bruising? congenital hip dislocations? stroke? umbilical/inguinal hernias? early loss of teeth? Incidence and Carrier Frequency no well-founded figures for prevalence for all forms, estimates of 1/5000 have been made Clinical Features a group of clinically diverse inherited connective tissue disorders that have joint laxity and dermal features in common ** Classical (Type I and Type II) 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 Hypermobility Type (Type III) 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 Vascular Type (Type IV) Major diagnostic criteria Characteristic facial appearance Thin, delicate, "pinched" nose Thick 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 Kyphoscoliosis type (type VI) 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 Arthrochalasia type (types VIIA, VIIB) 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 Inheritance Autosomal dominant Testing Demonstration of exon 6 skipping in cDNAs of COL1A1 or COL1A2 followed by mutational analysis Dermatosporaxis type (type VIIC) 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 variants (VIII, V X-linked, X) 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 and Treatment 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 P/T can improve strength of muscles surrounding lax joints Surgical procedures can correct dislocation Intervention for pain management is necessary An 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 Psychosocial Issues Self esteem scars, bruising, scoliosis Financial concerns? Guilt at passing on mutation Pain management issues support network? family? friends? church? Support Groups and 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 References www.geneclinics.org Management of Genetic Syndromes (Allanson and Cassidy) OMIM #130000, #130010, #130020, #130050, #305200, #225400, #130060, #130080 Notes The information in this outline was last updated in 2002.