Genetics of Ehlers-Danlos Syndrome Follow-up

  • Author: Robert D Steiner, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Aug 17, 2011
 

Inpatient & Outpatient Medications

Wound healing may be improved in patients with Ehlers-Danlos syndrome (EDS) with vitamin C supplementation above the recommended daily allowance (see Medical Care). Subacute bacterial endocarditis (SBE) prophylaxis may be appropriate in the presence of mitral valve prolapse.

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Complications

Complications are related to the primary pathophysiology and include joint dislocations, wound healing problems, and scarring. Individuals with vascular Ehlers-Danlos syndrome are at risk for spontaneous arterial rupture and bowel perforation, particularly the sigmoid colon, as well as other hollow organ perforation or rupture.

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Prognosis

Median life expectancy for patients with type IV Ehlers-Danlos syndrome is 50 years. In patients with other Ehlers-Danlos syndrome types, life expectancy is usually normal. It appears that patients with type IV Ehlers-Danlos caused by null mutations in the COL IIIA1 gene often have a milder form of the condition compared with those with missense and splicing mutations. Such individuals may have a longer lifespan and complications limited to the vasculature.[20]

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Patient Education

The diversity and complexity of Ehlers-Danlos syndrome serve to highlight several important principles of clinical human genetics. That these principles must be accurately relayed to and understood by the family during counseling.

Genetic heterogeneity refers to the fact that mutations in different genes can produce the same phenotype. For example, type I Ehlers-Danlos syndrome can result from mutations in 2 collagen genes, either COL5A1 (chromosome bands 9q34.2-34.3) or COL5A2 (band 2q31).

Variable expression (ie, variability in severity of disease expression) is a hallmark of autosomal dominant conditions. Autosomal dominant Ehlers-Danlos syndrome exhibits both intrafamilial and interfamilial variability, which is a critical counseling issue in regard to recurrences. In addition, closely examining families for members who may not have been diagnosed in the past is important because of the mild degree of expression.

An indeterminate diagnosis of a clinical subtype of Ehlers-Danlos syndrome may not be possible in as many as 50% of patients. The clinician must tell patients when the diagnosis is either unknown or unclear, rather than guess and provide incorrect information. The subtypes of Ehlers-Danlos syndrome are associated with differences in modes of inheritance and long-term prognoses.

Currently, the diagnosis of only a few subtypes of Ehlers-Danlos syndrome can be confirmed using the practical laboratory studies available. A prevailing misconception is that specific skin biopsy findings can confirm or exclude the specific diagnosis of Ehlers-Danlos syndrome. No specific histopathologic skin biopsy findings identify patients with Ehlers-Danlos syndrome; therefore, skin biopsies should not be performed to confirm or exclude the diagnosis. A skin biopsy may be indicated to obtain cultured skin fibroblasts for specific biochemical and molecular studies, but most patients and clinicians must simply rely on clinical diagnosis.

Elucidating the pathophysiology of a specific clinical disorder often leads to rethinking the phenotypic classification. For example, the previously designated type IX Ehlers-Danlos syndrome is now known to be the result of a mutation in a copper transport gene and is an allelic variant to Menkes (kinky hair) disease.

Encourage patients to protect their joints and avoid undue trauma. Instruct patients to avoid entertaining other persons by performing maneuvers "showing off" their joint laxity. Continued excessive stretching of the joints may further exacerbate the underlying disorder.

Instruct patients to avoid excessive or repetitive heavy lifting and other movements that produce undue strain or stress on already hypermobile joints.

Instruct patients with connective tissue disorders to practice meticulous dental care. Monitor dental hygiene and treat periodontitis aggressively. This advice is particularly important for patients with type VI Ehlers-Danlos syndrome.

Instruct patients with Ehlers-Danlos syndrome to visit the ophthalmologist regularly for myopia, retinal tears, and keratoconus screening.

Instruct patients with Ehlers-Danlos syndrome to avoid undue trauma to the skin and other organ systems because of poor wound healing and skin fragility. In particular, the primary care physician should strongly discourage potentially traumatic recreational activities.

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Contributor Information and Disclosures
Author

Robert D Steiner, MD  Credit Unions for Kids Professor of Pediatric Research; Faculty, Pediatrics, Molecular and Medical Genetics, and Program in Molecular and Cellular Biosciences; Vice Chair for Research in Pediatrics, Doernbecher Children's Hospital, Oregon Health and Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research

Disclosure: Amicus Honoraria Consulting; Actelion Honoraria Consulting; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Consulting; Genzyme Honoraria Consulting; Shire Honoraria Consulting

Specialty Editor Board

Michael Fasullo, PhD  Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College

Michael Fasullo, PhD is a member of the following medical societies: American Society for Biochemistry and Molecular Biology, Environmental Mutagen Society, Genetics Society of America, and Radiation Research Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG  Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous coauthors G Bradley Schaefer, MD, and Melanie G Pepin, MS, CGC, to the original writing and development of this article.

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Patient with Ehlers-Danlos syndrome. Note the abnormal ability to elevate the right toe. Courtesy of Enrico Ceccolini, MD.
Girl with Ehlers-Danlos syndrome. Dorsiflexion of all the fingers is easy and absolutely painless. Courtesy of Enrico Ceccolini, MD.
Patient with Ehlers-Danlos syndrome mitis. Joint hypermobility is less intense than with other conditions. Courtesy of Enrico Ceccolini, MD.
Table 1. Types of Ehlers-Danlos Syndromes[7]
TypeInheritancePrevious NomenclatureMajor Diagnostic CriteriaMinor Diagnostic Criteria
ClassicAutosomal dominantTypes I and IISkin hyperextensibility,



wide atrophic scars, joint hypermobility



Smooth, velvety skin; easy bruising; molluscoid pseudotumors; subcutaneous spheroids; joint hypermobility; muscle hypotonia; postoperative complication (eg, hernia); positive family history; manifestations of tissue fragility (eg, hernia, prolapse)
HypermobilityAutosomal dominantType IIISkin involvement (soft, smooth and velvety), joint hypermobilityRecurrent joint dislocation; chronic joint pain, limb pain, or both; positive family history
VascularAutosomal dominantType IVThin, translucent skin; arterial/intestinal fragility or rupture; extensive bruising; characteristic facial appearanceAcrogeria,



hypermobile small joints; tendon/muscle rupture; clubfoot; early onset varicose veins; arteriovenous, carotid-cavernous sinus fistula;



pneumothorax;



gingival recession; positive family history; sudden death in close relative



KyphoscoliosisAutosomal recessive Type VI – lysyl hydroxylase deficiencyJoint laxity, severe hypotonia at birth, scoliosis, progressive scleral fragility or rupture of globeTissue fragility,



easy bruising, arterial rupture,



marfanoid,



microcornea,



osteopenia,



positive family



history (affected sibling)



ArthrochalasiaAutosomal dominantType VII A, BCongenital bilateral dislocated hips,



severe joint hypermobility,



recurrent subluxations



Skin hyperextensibility,



tissue fragility with atrophic scars, muscle hypotonia,



easy bruising,



kyphoscoliosis, mild osteopenia



DermatosparaxisAutosomal recessiveType VII CSevere skin fragility; saggy, redundant skinSoft, doughy skin;



easy bruising; premature rupture of membranes; hernias (umbilical and inguinal)



Table 2. Molecular Basis of Ehlers-Danlos Syndrome
TypeOld NomenclatureProtein AbnormalityGene AbnormalityChromosome Locus
ClassicType I/IIType V collagenCOL5A1,COL5A29q34.2-34.3



2q31



HypermobilityType IIIUnknownUnknownUnknown
VascularType IVType III collagenCOL3A12q31
KyphoscoliosisType VILysyl hydroxylase deficiency (some)PLOD11p36.3-36.2
ArthrochalasiaType VII A/BType I collagenCOL1A1



COL1A2



17q31-22.5



7q22.1



DermatosparaxisType VIICN-proteinaseADAMST25q23-24
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