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.