# 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

## References

* 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

## Notes

The information in this outline was last updated in 2002.