eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics
Ehlers-Danlos Syndrome
Updated: Mar 25, 2009
Introduction
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
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.
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. 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).
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. Rectal prolapse can occur.4
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.
Clinical
History
Although much has been learned regarding the molecular basis of some forms of Ehlers-Danlos syndrome (EDS), an accurate clinical diagnosis is the primary means of identifying affected individuals. Currently, diagnosis of relatively few of the known types of Ehlers-Danlos syndrome (vascular form [IV], lysyl hydroxylase deficiency [VI], arthrochalasia [VIIA and B], and dermatosparaxis [Ehlers-Danlos syndrome VIIC]) can be confirmed using molecular or biochemical laboratory testing. All forms of Ehlers-Danlos syndrome share the following primary features to varying degrees:
- Skin hyperextensibility
- Joint hypermobility and excessive dislocations
- Tissue fragility
- Poor wound healing, leading to wide thin scars: The classic description of abnormal scar formation in Ehlers-Danlos syndrome is "cigarette paper scars."
- Easy bruising
Physical
Clinical forms of Ehlers-Danlos syndrome
At least 6 discernible phenotypes of Ehlers-Danlos syndrome are recognized; however, a great deal of overlap among the phenotypes is observed, making absolute clinical diagnosis difficult, if not impossible, at times. As many as 50% of patients with Ehlers-Danlos syndrome do not have a type or form that can be classified easily on clinical basis alone. This complicates the diagnostic process, because specific molecular diagnosis or confirmation (if available) may not be possible until a clinical subtype has been defined.
The table below lists the identifiable forms of Ehlers-Danlos syndrome proposed by a group of clinical experts from the medical advisory board of the Ehlers-Danlos National Foundation (EDNF) in 1997.5 This nosology is currently used in the clinical setting.
Table 1. Types of Ehlers-Danlos Syndromes5
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Table
Type | Inheritance | Previous Nomenclature | Major Diagnostic Criteria | Minor Diagnostic Criteria |
Classic | Autosomal dominant | Types I and II | Skin 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) |
Hypermobility | Autosomal dominant | Type III | Skin involvement (soft, smooth and velvety), joint hypermobility | Recurrent joint dislocation; chronic joint pain, limb pain, or both; positive family history |
Vascular | Autosomal dominant | Type IV | Thin, translucent skin; arterial/intestinal fragility or rupture; extensive bruising; characteristic facial appearance | Acrogeria, 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 |
Kyphoscoliosis | Autosomal recessive | Type VI – lysyl hydroxylase deficiency | Joint laxity, severe hypotonia at birth, scoliosis, progressive scleral fragility or rupture of globe | Tissue fragility, easy bruising, arterial rupture, marfanoid, microcornea, osteopenia, positive family history (affected sibling) |
Arthrochalasia | Autosomal dominant | Type VII A, B | Congenital bilateral dislocated hips, severe joint hypermobility, recurrent subluxations | Skin hyperextensibility, tissue fragility with atrophic scars, muscle hypotonia, easy bruising, kyphoscoliosis, mild osteopenia |
Dermatosparaxis | Autosomal recessive | Type VII C | Severe skin fragility; saggy, redundant skin | Soft, doughy skin; easy bruising; premature rupture of membranes; hernias (umbilical and inguinal) |
Type | Inheritance | Previous Nomenclature | Major Diagnostic Criteria | Minor Diagnostic Criteria |
Classic | Autosomal dominant | Types I and II | Skin 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) |
Hypermobility | Autosomal dominant | Type III | Skin involvement (soft, smooth and velvety), joint hypermobility | Recurrent joint dislocation; chronic joint pain, limb pain, or both; positive family history |
Vascular | Autosomal dominant | Type IV | Thin, translucent skin; arterial/intestinal fragility or rupture; extensive bruising; characteristic facial appearance | Acrogeria, 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 |
Kyphoscoliosis | Autosomal recessive | Type VI – lysyl hydroxylase deficiency | Joint laxity, severe hypotonia at birth, scoliosis, progressive scleral fragility or rupture of globe | Tissue fragility, easy bruising, arterial rupture, marfanoid, microcornea, osteopenia, positive family history (affected sibling) |
Arthrochalasia | Autosomal dominant | Type VII A, B | Congenital bilateral dislocated hips, severe joint hypermobility, recurrent subluxations | Skin hyperextensibility, tissue fragility with atrophic scars, muscle hypotonia, easy bruising, kyphoscoliosis, mild osteopenia |
Dermatosparaxis | Autosomal recessive | Type VII C | Severe skin fragility; saggy, redundant skin | Soft, doughy skin; easy bruising; premature rupture of membranes; hernias (umbilical and inguinal) |
The major diagnostic criteria are highly specific. The presence of one or more major criteria is necessary for clinical diagnosis and is highly indicative and warrants laboratory confirmation whenever possible. One or more minor diagnostic criteria aid in clinical diagnosis but are not sufficient.
Other forms of the syndrome have been reported. Type V Ehlers-Danlos syndrome was described in a single family. Type VIII is similar to classic Ehlers-Danlos syndrome but is also associated with periodontal disease; it is not a clearly distinct clinical entity. Type IX has been reclassified as an allelic form of Menkes disease. Type X was described in one family. Type XI was described as familial hypermobility syndrome and was previously removed from classifications. Ehlers-Danlos–like syndrome from tenascin-X deficiency has recently been described. Type I collagen mutations can cause an arthrochalasia-type syndrome with predisposition to arterial rupture in early adulthood.
The Online Mendelian Inheritance in Man (OMIM) database provides updated information on the clinical and molecular understanding of single gene (monogenic) disorders. The inheritance pattern, OMIM number, and original clinical descriptions of 10 major types of Ehlers-Danlos syndrome are listed below. The OMIM entries were reviewed in developing the Villefranche classification and include the following:
- Ehlers-Danlos syndrome type I (OMIM #130000, autosomal dominant): Distinguishing features include easy bruising, mitral valve prolapse, premature rupture of the fetal membranes, and premature birth.
- Ehlers-Danlos syndrome type II (OMIM #130010, autosomal dominant): This phenotype is similar to type 1, but the effects are milder.
- Ehlers-Danlos syndrome type III (OMIM #130020, autosomal dominant): Features include striking joint hypermobility and minimal skin changes.
- Ehlers-Danlos syndrome type IV (OMIM #130050, autosomal dominant): Type IV is the vascular/ecchymotic form. Patients with type IV Ehlers-Danlos syndrome have prominent venous markings, which are readily visible through the skin. Diagnostically, this type is most important because patients are subject to spontaneous rupture of the bowel, medium-sized arteries, or both. Often, rupture leads to early death. Median life expectancy in these patients is 45-50 years.
- Ehlers-Danlos syndrome type V (OMIM #305200, X-linked recessive): This phenotype is similar to, if not indistinguishable from, type 2; however, in familial cases, type V exhibits X-linked recessive inheritance.
- Ehlers-Danlos syndrome type VI (OMIM #225400, autosomal recessive): Patients may present with retinal detachments, microcornea, myopia, and scoliosis. Differentiating hypermobility from neuromuscular hypotonia in these patients may be difficult.6
- Ehlers-Danlos syndrome type VII (OMIM #130060, types VIIA and VIIB, autosomal dominant; OMIM #225410, type VIIC, autosomal recessive): Patients exhibit arthrochalasis multiplex congenita (hyperflaccidity of the joints without hyperelasticity of the skin), short stature, and micrognathia. Multiple congenital skull fractures have been reported in Ehlers-Danlos syndrome type VIIC.7
- Ehlers-Danlos syndrome type VIII (OMIM #130080, autosomal dominant): In addition to the other notable features, patients with type VIII Ehlers-Danlos syndrome have multiple skin striae and significant dental problems, including early tooth loss, periodontitis, and alveolar bone loss.
- Ehlers-Danlos syndrome type IX (OMIM #304150, X-linked recessive): Features include occipital exostoses, bladder diverticula or rupture, bony dysplasias, and decreased copper and ceruloplasmin. Ehlers-Danlos syndrome type IX is no longer a subtype. Once the gene was identified, type IX was removed from the Ehlers-Danlos syndrome classification. The gene is related to a condition termed cutis laxa or occipital horn syndrome (see Causes).
- Ehlers-Danlos syndrome type X (OMIM #225310, autosomal recessive): Patients exhibit poor wound healing, petechiae, and a platelet aggregation defect, which can be corrected with fibronectin supplementation.
Since the classification scheme was accepted, a possibly new form has been described. Six patients from 2 consanguineous families were reported to have Ehlers-Danlos syndrome–like features and radiological findings of a skeletal dysplasia.8 Findings included hyperelastic, thin, and bruisable skin; hypermobile small joints with a tendency to contractures; and protuberant eyes with bluish sclerae.
The affected individuals had platyspondyly with moderate short stature, osteopenia, and widened metaphyses. All patients in the initial report had a homozygous c.483_491 del9 SLC39A13 mutation that encodes for a membrane-bound zinc transporter SLC39A13. These data suggested a new entity the authors designated spondylocheiro dysplastic form of Ehlers-Danlos syndrome to indicate a generalized skeletal dysplasia that mainly involves the spine (spondylo) and striking clinical abnormalities of the hands (cheiro) in addition to the Ehlers-Danlos syndrome–like features.
Causes
Recently, the progress of the Human Genome Project and other advances in molecular genetics have provided much information regarding the molecular basis of Ehlers-Danlos syndrome. Physical positions of involved genes and their locations on chromosomal maps are provided in the table below.
Table 2. Molecular Basis of Ehlers-Danlos Syndrome
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Table
Type | Old Nomenclature | Protein Abnormality | Gene Abnormality | Chromosome Locus |
Classic | Type I/II | Type V collagen | COL5A1, COL5A2 | 9q34.2-34.3 2q31 |
Hypermobility | Type III | Unknown | Unknown | Unknown |
Vascular | Type IV | Type III collagen | COL3A1 | 2q31 |
Kyphoscoliosis | Type VI | Lysyl hydroxylase deficiency (some) | PLOD1 | 1p36.3-36.2 |
Arthrochalasia | Type VII A/B | Type I collagen | COL1A1 COL1A2 | 17q31-22.5 7q22.1 |
Dermatosparaxis | Type VIIC | N-proteinase | ADAMST2 | 5q23-24 |
Type | Old Nomenclature | Protein Abnormality | Gene Abnormality | Chromosome Locus |
Classic | Type I/II | Type V collagen | COL5A1, COL5A2 | 9q34.2-34.3 2q31 |
Hypermobility | Type III | Unknown | Unknown | Unknown |
Vascular | Type IV | Type III collagen | COL3A1 | 2q31 |
Kyphoscoliosis | Type VI | Lysyl hydroxylase deficiency (some) | PLOD1 | 1p36.3-36.2 |
Arthrochalasia | Type VII A/B | Type I collagen | COL1A1 COL1A2 | 17q31-22.5 7q22.1 |
Dermatosparaxis | Type VIIC | N-proteinase | ADAMST2 | 5q23-24 |
More on Ehlers-Danlos Syndrome |
Overview: Ehlers-Danlos Syndrome |
Differential Diagnoses & Workup: Ehlers-Danlos Syndrome |
Treatment & Medication: Ehlers-Danlos Syndrome |
Follow-up: Ehlers-Danlos Syndrome |
Multimedia: Ehlers-Danlos Syndrome |
References |
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References
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Further Reading
Keywords
Ehlers-Danlos syndrome, EDS, connective tissue disorders, joint laxity, articular hypermobility, skin laxity, hyperextensible skin, abnormal wound healing, hypermobility syndrome, collagen abnormalities, lysyl hydroxylase deficiency, periodontitis, fibronectin, platelet aggregation defect, acrogeria, tissue fragility, vascular rupture, colonic perforation, excessive bruising, easy bruising, prominent venous plexus, petechiae, retinal detachment, dystrophic scarring, Ehlers-Danlos syndrome type 1, Ehlers-Danlos syndrome classic type, Marfan syndrome, Williams syndrome, rectal prolapse, Menkes disease, mitral valve prolapse, microcornea, myopia, scoliosis, neonatal hypotonia, short stature, micrognathia, molluscoid pseudotumors, muscle hypotonia, early onset varicose veins, pneumothorax