Genetics of Ehlers-Danlos Syndrome 

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

Background

The Ehlers-Danlos family of disorders is a group of related conditions that share a common decrease in the tensile strength and integrity of the skin, joints, and other connective tissues.

In 1993, Beighton discussed the history of Ehlers-Danlos syndrome (EDS), beginning with a description of it in the fourth century BC.[1] The first detailed clinical description of the syndrome is attributed to Tschernogobow in 1892.[2] The syndrome derives its name from reports by Edward Ehlers, a Danish dermatologist, in 1901 and by Henri-Alexandre Danlos, a French physician with expertise in chemistry of skin disorders, in 1908. These 2 physicians combined the pertinent features of the condition and accurately delineated the phenotype of this group of disorders.

The amazing, almost unnatural, contortions that some patients with Ehlers-Danlos syndrome can perform often arouse curiosity. Historically, some patients with Ehlers-Danlos syndrome displayed the maneuvers publically in circuses, shows, and performance tours. Some achieved modest degrees of fame and bore titles such as "The India Rubber Man," "The Elastic Lady," and "The Human Pretzel." Such clinical features also raise suspicion of the diagnosis when identified upon physical examination. Unfortunately, patients often go many years before being diagnosed.[3] Examples are shown in the images below.

Patient with Ehlers-Danlos syndrome. Note the abnoPatient 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 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 hPatient with Ehlers-Danlos syndrome mitis. Joint hypermobility is less intense than with other conditions. Courtesy of Enrico Ceccolini, MD.
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Pathophysiology

Individuals with Ehlers-Danlos syndrome demonstrate connective tissue abnormalities as a result of defects in the inherent strength, elasticity, integrity, and healing properties of the tissues.[4] The specific characteristics of a particular form of Ehlers-Danlos syndrome stem from the tissue-specific distribution of various components of the extracellular matrix. Each tissue and organ system expresses an array of connective proteins. The means of production and relative proportion and distribution of each protein array are unique. In addition, the specific interactions of various components of the matrix are tissue specific.

Major constituents of the extracellular matrix

Ehlers-Danlos syndrome is caused by various abnormalities in the synthesis and metabolism of collagen (a component of the matrix) and other connective tissue proteins.

Collagen comprises the most abundant proteins in the body. Collagen proteins are multimeric, occurring in trimers with a central triple helical region. A minimum of 29 genes contribute to the collagen protein structure, and the genes are located on 15 of the 24 human chromosomes and form at least 19 identifiable forms of collagen molecules.

Elastic fibers are created by the association of elastin with an underlying microfibrillar array. The underlying basis of all connective tissue matrices is the microfibrillar array. An example of a microfibrillar protein is fibrillin, which is the abnormal protein found in patients with Marfan syndrome. Elastin and other structural proteins are woven onto the microfibrillar array to provide the basic meshwork for the connective tissue matrix. Abnormalities of elastin have been associated with other connective tissue disorders, such as cutis laxa. Deletion of the elastin gene is involved in many of the pathophysiologic processes seen in Williams syndrome.

Proteoglycans are core proteins that are bound to glycosaminoglycans (also commonly termed mucopolysaccharides). Essentially, proteoglycans are the glue of the connective tissue protein that seal and cement the underlying connective tissue matrix.

Macromolecular proteins include the glycoproteins of the basement membrane (type IV collagen, laminin, nidogen) and the extracellular matrix (fibronectin, tenascin).

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Epidemiology

Frequency

International

Frequency of Ehlers-Danlos syndrome (all types combined) has been reported as 1 per 5000 to 1 per 10,000 population; however, the exact prevalence and incidence of Ehlers-Danlos syndrome are unknown.

Mortality/Morbidity

Reduced life expectancy is not generally a feature of Ehlers-Danlos syndrome, with the exception of the vascular form of Ehlers-Danlos syndrome (Ehlers-Danlos syndrome type IV). Median life expectancy for patients with type IV Ehlers-Danlos syndrome is 50 years because medium-sized arteries, the GI tract, and other organs tend to spontaneously rupture.

Morbidity in Ehlers-Danlos syndrome is related to the primary pathophysiology and includes dislocations, pain, or both from chronic joint laxity as well as aberrant scarring and wound healing from abnormal tensile strength of the skin.[5]Rectal prolapse can occur.[6]

Race

Ehlers-Danlos syndrome equally affects all races.

Age

Ehlers-Danlos syndromes are heritable disorders. As such, the disorders are present at birth; however, symptoms may not be noticeable until later in life.

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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.

References

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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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