# 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.