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)

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

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

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

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

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

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

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

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

800-956-2902

http//:www.ednf.org

http//:www.ehlers-danlos.org

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

GeneReviews. EDS, Vascular Type
GeneReviews. EDS, Kyphoscoliotic Form
Genetic Message. Hereditary Connective Tissue Disorders. Vol 2 (1) Winter 1999
Cassidy, Suzanne B., and Judith E. Allanson. Management of Genetic Syndromes. Chapter 8: The Ehlers-Danlos Syndromes. 2001

The information in this outline was last updated in 2002.