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Genetics of Ehlers-Danlos Syndrome

  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
 
Updated: Aug 05, 2015
 

Background

Ehlers-Danlos syndrome (EDS) comprises a group of inherited heterogeneous disorders that share a common decrease in the tensile strength and integrity of the skin, joints, and other connective tissues.[1] This group of connective-tissue disorders is characterized by abnormal collagen synthesis causing hyperextensibility of the skin, hypermobility of the joints, and tissue fragility, as is seen by easy bruising and delayed wound healing with atrophic scarring.[2]

People with lax joints and multiple scars were first described in the medical writings of Hippocrates, dating back to 400 BCE.[3] In 1892, Dr. Tschernogobow, a Russian dermatologist, presented 2 case studies of patients to the Moscow Venereology and Dermatology Society who had marked loose fragile skin, and hypermobile large joints. His work reports the first detailed clinical description of EDS.[2, 4]

The syndrome derives its name from additional clinical case reports presented by 2 physicians: Edvard Ehlers, a Danish dermatologist, in 1901, and Henri-Alexandre Danlos, a French physician with expertise in chemistry of skin disorders, in 1908. Both physicians combined the pertinent features of the syndrome and accurately delineated the phenotypic features of this group of inherited disorders. The name, Ehlers-Danlos syndrome, was coined in 1936.[2]

Some patients with EDS can demonstrate amazing, almost unnatural, contortions, often arousing the curiosity of onlookers. The famous Italian violinist, Paganini (1782-1840), capable of miraculous feats in his playing owing to his hypermobile and loose joints, had phenotypic traits of EDS.[5] In the late 19th century, historians described performers with EDS who displayed their hyperextensible maneuvers publically in circuses and travelling shows. Some achieved celebrity status, acquiring titles such as "The India Rubber Man," "The Elastic Lady," and "The Human Pretzel."

Patients displaying clinical capabilities such as these raise suspicion of the diagnosis when identified on physical examination. Unfortunately, patients with EDS are often not diagnosed for many years.[6] Examples of hyperextensibility and hypermobility are shown in the following images.

Patient with Ehlers-Danlos syndrome. Note the abno 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 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 h Patient 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 (EDS) demonstrate connective-tissue abnormalities due to defects in the inherent strength, elasticity, integrity, and healing properties of the tissues.[7] The specific characteristics of a particular form of EDS stem from the tissue-specific distribution of various components of the extracellular matrix (ECM). The ECM is defined as the outer cell components of tissue that provide structural support to the cells. It is the distinguishing feature of connective tissue. Each tissue and organ system has an array of connective proteins. Unique to each connective protein array is the path of production, its relative proportion, and distribution in tissues or organs. In addition, the defined interactions of various components of the matrix are tissue specific.

Major constituents of the extracellular matrix

EDS is caused by various abnormalities in the synthesis and metabolism of collagen and other connective-tissue proteins in the ECM, such as elastin, proteoglycans, and macromolecular proteins.

Collagen is the most abundant protein in the body and is the most common protein found in the ECM.[8] Collagen proteins are multimeric, occurring in trimers with a central triple helical region. A minimum of 29 genes contribute to collagen protein structure, and these genes are located on 15 different human chromosomes, genetically coding for no less than 19 identifiable forms of collagen molecules.

Elastins, in contrast to the structural support of collagens, give elasticity to the tissues. Elastin allows for the tissues to stretch and return to their original state and hence is present in the ECM of blood vessels, lungs, and skin.[9] 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. Fibrillin-1 gene mutations on chromosome 15 produce an abnormal fibrillin, as is characteristic of 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 patients.

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, entactin) and the ECM (fibronectin, tenascin).

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Epidemiology

Frequency

International

Worldwide, more than 1.5 million people are diagnosed with Ehlers-Danlos syndrome (EDS). EDS (all types combined) is reported to have a 1 in 5,000-10,000 population frequency. The population occurrence of EDS varies dependent on which 1 of the 6 major types according to the Villefranche nosology is diagnosed. EDS types and their population occurrence (from most to least common) are as follows[10] :

  • Hypermobility type EDS (type III) is the most common, occurring in 1 in 10,000-15,000 persons
  • Classical type EDS (types I and II) occurs in 1 in 20,000-50,000 persons
  • Vascular type EDS (type IV), considered the most serious type of EDS, is rare, occurring 1 in 100,000-250,000 persons

Kyphoscoliosis type EDS (type VI), arthrochalasia type EDS (type VII A and B), and dermatosparaxis type EDS (type VIIC) are all very rare, with dermatosparaxis type EDS being the rarest.[11]

Mortality/Morbidity

Reduced life expectancy is not generally a feature of Ehlers-Danlos syndrome (EDS), with the exception of vascular type EDS (type IV). Median life expectancy for patients with vascular type EDS is 50 years because medium-sized arteries, and the intestinal tract, can spontaneously rupture. Uterine rupture during pregnancy has also been reported.

Morbidity in EDS is related to the primary pathophysiology and includes dislocations, pain, or both from chronic joint laxity and instability. Aberrant wound healing and scarring due to abnormal tensile strength of the skin also happens.[12] Rectal prolapse can occur, as described in the classical type EDS (types I and II) patients.[13]

Race

Ehlers-Danlos syndrome equally affects all races.

Sex

Of the 6 major types of Ehlers-Danlos syndrome classified by Villefranche nosology, both males and females are equally affected, as the genetic coding causing the differing phenotypes are located on the autosomes (chromosomes 1-22) and not the sex chromosomes (X or Y).

Age

Ehlers-Danlos syndrome is a genetic disorder. As such, this syndrome and its various types are present at birth; however, symptoms may not become apparent until later in life.

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Contributor Information and Disclosures
Author

Germaine L Defendi, MD, MS, FAAP Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Specialty Editor Board

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.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

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: Radiation Research Society, American Society for Biochemistry and Molecular Biology, Genetics Society of America, Environmental Mutagenesis and Genomics Society

Disclosure: Nothing to disclose.

Acknowledgements

Melanie G Pepin, MS, CGC Health Services Manager, Collagen Diagnostic Laboratory; Genetic Counselor, Department of Pathology, University of Washington School of Medicine

Disclosure: Nothing to disclose.

G Bradley Schaefer, MD Director of Hattie B Munroe Center for Human Genetics, Department of Pediatrics, Professor, University of Nebraska Medical Center

Disclosure: Nothing to disclose.

Robert D Steiner, MD Executive Director, Marshfield Clinic Research Foundation; Chief Science Officer, Marshfield Clinic; Associate Executive Director, Institute for Clinical and Translational Research, University of Wisconsin School of Medicine and Public Health

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, 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; Zacharon Consulting

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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 Syndrome [10, 11]
Type Inheritance Previous Nomenclature Major Diagnostic Criteria Minor Diagnostic Criteria
Classical Autosomal dominant Types I and II Marked skin hyperextensibility, wide atrophic scars, joint hypermobility Smooth, velvety skin; easy bruising; tissue fragility; molluscoid pseudotumors (calcified hematomas over pressure points, eg, elbows); subcutaneous spheroids (fat-containing cysts on forearms and shins); joint hypermobility (eg, sprains, dislocations, subluxations); flat feet; muscle hypotonia; gross motor delays; postoperative complications (eg, hernia); manifestations of tissue fragility (eg, hiatal hernia, anal prolapse, cervical insufficiency); positive family history
Hypermobility Autosomal dominant Type III Generalized joint hypermobility, affecting both large (elbows, knees) and small (fingers, toes) joints; skin involvement (soft, smooth and velvety) Recurrent joint dislocations and subluxations of shoulder, patella, and temporomandibular joints; chronic joint pain; limb pain; musculoskeletal pain; bruising tendencies; positive family history
Vascular



*Considered most serious EDS type, owing to risk of spontaneous arterial or organ rupture



Autosomal dominant Type IV Thin, translucent skin, easy to see vasculature through the skin, especially chest and abdomen; arterial/intestinal fragility or rupture; extensive bruising with minor trauma; characteristic facial appearance of large eyes, thin nose, lobeless ears; short stature; thin scalp hair Acrogeria, aging skin; decrease of subcutaneous tissue in the face and extremities; gingival recession; hypermobile small joints; tendon/muscle rupture; clubfoot; early onset varicose veins; arteriovenous fistula; carotid-cavernous fistula; pulmonary conditions, pneumothorax, pneumohemothorax; positive family history; sudden death in close relative
Kyphoscoliosis Autosomal recessive Type VI



(Lysyl hydroxylase deficiency-collagen-modifying enzyme)



Generalized joint laxity; severe hypotonia at birth; delayed gross motor development; progressive scoliosis (present at birth); scleral fragility or ocular globe rupture post minor trauma Tissue fragility; atrophic scars; easy bruising; spontaneous arterial rupture; marfanoid habitus; microcornea; osteopenia; positive family history (affected sibling)
Arthrochalasia Autosomal dominant Type VII A and B Congenital hip dislocation; severe generalized joint hypermobility; recurrent subluxations Skin hyperextensibility with easy bruising; tissue fragility with atrophic scars; muscle hypotonia; kyphoscoliosis, mild osteopenia
Dermatosparaxis Autosomal recessive Type VIIC Severe skin fragility; marked bruising; saggy, redundant skin, especially of the face; scars not atrophic Soft, doughy skin; premature rupture of membranes; hernias (umbilical and inguinal)
Table 2. Molecular Basis of EDS
Type Old Nomenclature Protein Abnormality Gene Abnormality Chromosome Locus
Classical Types I and II Type V collagen *COL5A1,COL5A2



COL1A1



*9q34.3



2q32.3



17q21.3



Hypermobility Type III Type III collagen



Tenascin-XB



COL3A1



TNXB



2q32.2



6p21.3



Vascular Type IV Type III collagen COL3A1 2q32.2
Kyphoscoliosis Type VI Lysyl hydroxylase deficiency (some) PLOD1 1p36.22
Arthrochalasia Type VII A and B Type I collagen A: COL1A1



B: COL1A2



17q21.33



7q21.3



Dermatosparaxis Type VIIC N-proteinase ADAMTS2 5q35.3
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