Synonyms and related 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

AUTHOR INFORMATION

Author: Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital

Coauthor(s): G Bradley Schaefer, MD, Director of Hattie B Munroe Center for Human Genetics, Professor, Department of Pediatrics, University of Nebraska Medical Center; Melanie G Pepin, MS, CGC, Health Services Manager, Collagen Diagnostic Laboratory; Genetic Counselor, Department of Pathology, University of Washington

Editor(s): Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

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. The first detailed clinical description of the syndrome is attributed to Tschernogobow in 1892. 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 on physical examination.

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 a variety of 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:

• Internationally: 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 rupture spontaneously.

   

• 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.

   

Race: Ehlers-Danlos syndrome affects all races equally.

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, 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 lab 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 exist (see Table 1); however, a great deal of overlap exists in the phenotypes, 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. Table 1 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. This nosology is currently used in the clinical setting.

Table 1. Types of Ehlers-Danlos Syndromes (Villefranche, 1997 classification)

The major diagnostic criteria are highly specific. The presence of one or more major criteria is either necessary for clinical diagnosis or highly indicative and warrant lab confirmation whenever possible. One or more minor diagnostic criteria contribute but are not sufficient for the clinical diagnosis.
   *AD = autosomal dominant
   †AR = autosomal recessive
   ‡Other forms of EDS: Type V EDS was described in a single family (XLR). Type VIII is similar to classic EDS plus periodontal disease; it is not clearly a distinct clinical entity. Type IX has been reclassified as an allelic form of Menkes (SLR). 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.

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.

• 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) - 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, since 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) - Penotype 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, scoliosis, and neonatal hypotonia.

   

• 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.

   

• 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.

   

Ehlers-Danlos–like syndrome from tenascin-X deficiency (OMIM #606408, autosomal recessive) has recently been described.

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 Table 2.

Table 2. Molecular Basis of Ehlers-Danlos Syndrome

DIFFERENTIALS

 Williams Syndrome

Other Problems to be Considered:

Stickler syndrome
Cutis laxa
TGFBR-related phenotype
Ehlers-Danlos–like syndrome from tenascin-X deficiency (OMIM #606408)

WORKUP

Lab Studies:

• To confirm the diagnosis of the vascular form of Ehlers-Danlos syndrome, (Ehlers-Danlos syndrome type IV) and for arthrochalasia (Ehlers-Danlos syndrome type VIIA and VIIB) and dermatosparaxis (Ehlers-Danlos syndrome VIIC), biochemical studies can detect alterations in collagen molecules in cultured skin fibroblasts. Molecular (DNA-based) testing is available for Ehlers-Danlos syndrome types IV and VII as well. With the exception of kyphoscoliotic type (Ehlers-Danlos syndrome type VI), which can be identified by urinary analyte assay, the most common and remaining forms of Ehlers-Danlos syndrome are identified by clinical examination.

   

Procedures:

• Skin biopsy findings (performed for histopathologic analysis) are nondiagnostic.

   

TREATMENT

 Medical Care:

• A correct diagnosis is critical and must be determined if possible. Confirmation using biochemical studies on collagen molecules is possible with cultured skin fibroblasts for the vascular form (Ehlers-Danlos syndrome type IV), for arthrochalasia (Ehlers-Danlos syndrome type VIIA and VIIB), and for dermatosparaxis (Ehlers-Danlos syndrome type VIIC). A diagnostic assay of urinary pyridinoline cross-links identifies the kyphoscoliosis type (Ehlers-Danlos syndrome type VI) Therefore, if the clinical diagnosis is type IV, type VI, and some of the forms of type VII Ehlers-Danlos syndrome, perform biochemical or molecular studies. Once a diagnosis of Ehlers-Danlos syndrome has been made, preventative measures should be undertaken. Wearing a MedicAlert bracelet may be helpful in case of life-threatening events.

   

• In the event of skin lacerations or other injuries, take extreme care with the use of sutures. Seriously consider alternatives to sutures, including adhesive strips and wound glues.

   

• Monitor patients for scoliosis and instruct them to avoid excessive or repetitive lifting and other activities that produce undue strain or stress on their already hypermobile joints.

   

• Pay careful attention to cardiac auscultation and evaluation. The murmur of mitral valve prolapse (particularly in classic and hypermobile Ehlers-Danlos syndrome) should be noted; if indicated, perform an echocardiogram. In the presence of mitral valve prolapse, monitoring and screening are indicated, as is the use of subacute bacterial endocarditis (SBE) precautions. As adults with vascular Ehlers-Danlos syndrome are at risk for arterial aneurysm and rupture, noninvasive visualization of the arterial tree may be indicated. Initial echocardiogram including the aortic arch is recommended for adults with classic Ehlers-Danlos syndrome, as recent studies indicate possible risk for thoracic aortic enlargement. There is not enough current evidence to guide the approach to monitoring for this potential complication.

   

• High-dose (1-4 g/d) ascorbic acid therapy has been tried and, in theory, has a potential effect. Clinical studies suggest that wound healing, even in patients not deficient in vitamin C, can be improved with supplementation above the recommended daily allowance. In patients with type VI Ehlers-Danlos syndrome, bleeding time, wound healing, and muscle strength seemed to improve after 1 year of high-dose vitamin C therapy; however, high-dose vitamin C therapy is not the standard of care.

   

Consultations:

• Consultation with an ophthalmologist may be necessary. Patients with Ehlers-Danlos syndrome should be screened for myopia, retinal tears, and keratoconus. Recommend regular eye examinations.

   

• Consultation with a dentist may be necessary. Patients with connective tissue disorders should practice meticulous dental care, which should be monitored. Treat periodontitis aggressively. In particular, good dental care is important in patients with type VI Ehlers-Danlos syndrome.

   

• Accurate genetic counseling is one of the most critical issues in the treatment of patients with Ehlers-Danlos syndrome.

   

• Provide the family with detailed information regarding the inheritance pattern, recurrence risks, and identification of at-risk family members. Screen pertinent individuals in the family for subtle signs and symptoms of the condition regardless of whether signs or symptoms are suggested by the family history. Discuss the prognosis and natural history of the particular Ehlers-Danlos syndrome type in detail with the family.

   

• A key element in the genetic counseling process includes triage toward indicated medical services and, most importantly, resource identification. Identify support group resources and provide other information to the family, such as the Ehlers-Danlos National Foundation.

   

Activity: Instruct patients with Ehlers-Danlos syndrome to avoid excessive or repetitive heavy lifting and other movements that produce undue strain or stress on the already hypermobile joints. However, careful weight training with relatively low weight may be therapeutic. Advise patients to avoid (preventable) significant traum