Genetics of Ehlers-Danlos Syndrome
- Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD more...
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. 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.
People with lax joints and multiple scars were first described in the medical writings of Hippocrates, dating back to 400 BCE. 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.
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. 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. Examples of hyperextensibility and hypermobility are shown in the following images.
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. 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. 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. 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).
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 :
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.
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. Rectal prolapse can occur, as described in the classical type EDS (types I and II) patients.
Ehlers-Danlos syndrome equally affects all races.
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).
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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|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|
*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)|
|Type||Old Nomenclature||Protein Abnormality||Gene Abnormality||Chromosome Locus|
|Classical||Types I and II||Type V collagen||*COL5A1,COL5A2
|Hypermobility||Type III||Type III collagen
|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