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.