AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Ehlers-Danlos syndrome (EDS) is the name given to a group of more than 10 different inherited disorders; all involve a genetic defect in collagen and connective-tissue synthesis and structure.

EDS can affect the skin, joints, and blood vessels. This syndrome is clinically heterogeneous; the underlying collagen abnormality is different for each type. Clinical recognition of the types of EDS is important. One type, type IV, is associated with arterial rupture and visceral perforation, with possible life-threatening consequences.

Pathophysiology

EDS is a heterogeneous group of inherited connective-tissue disorders characterized by joint hypermobility, cutaneous fragility, and hyperextensibility. The collagen defect has been identified in only 6 of the 11 types of EDS. Type IV is characterized by a decreased amount of type III collagen. Types V and VI are characterized by deficiencies in hydroxylase and lysyl oxidase, an important posttranslational modifying enzyme in collagen biosynthesis. Type VII has an amino-terminal procollagen peptidase deficiency. Type IX has abnormal copper metabolism. Type X has nonfunctioning plasma fibronectin.

In EDS types I and II, the classic variety, identifying the molecular structure in most individuals who are affected is difficult. Causative mutations may involve the COL5A1, COL5A2, and tenascin-X genes and are implied to be in the COL1A2 gene. Nonetheless, in most families with autosomal dominant EDS, the disease appears to be linked to loci that contain the COL5A1 or COL5A2 genes. Although one half of the mutations that cause EDS types I and II are likely to affect the COL5A1 gene, a significant portion of the mutations result in low levels of messenger RNA (mRNA) from the mutant allele as a consequence of nonsense-mediated mRNA decay (Schwarze, 2000).

Bouma et al evaluated 3 generations in a family with EDS type II. The genomic defect was an A(-2)®G substitution at the exon 14 splice acceptor site. Transmission electron micrographs of type I collagen fibrils in a proband dermal biopsy specimen demonstrated heterogeneity in fibril diameter that was greater than that of a matched control sample. The proband was found to have a greater proportion of both larger and smaller fibrils, and occasional fibrils with a cauliflower configuration were observed.

Wenstrup and associates identified haploinsufficiency of the COL5A1 gene that encodes the proalpha1(V) chain of type V collagen in the classic form of EDS. Eight of 28 probands with classic EDS who were heterozygous for expressed polymorphisms in COL5A1 had complete or nearly complete loss of expression of one COL5A1 allele. One third of individuals with classic EDS were estimated to have mutations of COL5A1 that result in haploinsufficiency. These findings suggest that the normal formation of the heterotypic collagen fibrils that contain types I, III, and V collagen requires the expression of both COL5A1 alleles.

Autosomal recessive–type VI EDS, also known as the kyphoscoliotic type, is characterized by neonatal kyphoscoliosis, generalized joint laxity, skin fragility, and severe muscle hypotonia at birth. Biochemically, this type is attributed to a deficiency in lysyl hydroxylase (LH), the enzyme that hydroxylates specific lysine residues in the collagen molecule to form hydroxylysines with 2 important functions. The residues are attachment sites for galactose and glucosylgalactose, and they act as precursors of the cross-linking process that gives collagen its tensile strength.

More than 20 mutations are identified in the LH1 gene that contributes to LH deficiency and clinical EDS type VI. Yeowell and Walker identified 2 of these mutations in 5 or more unrelated patients: (1) a large duplication of exons 10-16, which arise from a homologous recombination of intronic Alu sequences, and (2) a nonsense mutation, Y511X, in exon 14 of the LH1 gene. Both mutations seem to originate from a single ancestral gene.

Tenascin-X is a large extracellular matrix protein, a deficiency of which causes a clinically distinct recessive form of this syndrome (Schalkwijk, 2001). Thus, factors other than collagens or collagen-processing enzymes may cause this syndrome. This newly described form may be associated with additional anomalies.

A case with colonic perforation in a young girl, with a fatal outcome, was related to a novel mutation of the COL3A1 gene.

Frequency

United States

In America, the prevalence is approximately 1 case in 400,000 people.

International

The prevalence of EDS is reported to be 1 case in about 400,000 people, but mild or incomplete forms appear to be underdiagnosed and more common than other forms.

Mortality/Morbidity

• Type IV EDS is a severe form. Patients often have a shortened lifespan because of the spontaneous rupture of a large artery (eg, splenic artery, aorta) or the perforation of internal organs. Surgery can pose life-threatening risks in these patients.
• The other types are usually not as dangerous, and affected individuals can live a healthy if somewhat restricted life.
• Type VI is also somewhat dangerous, although it is rare.

Race

No racial predominance seems to exist; however, some believe that whites probably are affected more than others.

Sex

The sex-related prevalences are almost equal.

Age

The disease has clinical features (eg, joint mobility, skin extendibility, scarring tendency) that are easily recognizable beginning in early childhood.

• The other clinical manifestations require more time to become evident.
• EDS is usually diagnosed in young adults.

CLINICAL

Section 3 of 11  

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History

The biochemical collagen defect is present at birth, but clinical manifestations become evident later.

• Muscle weakness is often present, and patients complain of an easy tendency to fall down and poor body control.
• Sometimes, patients have difficulty walking.
• Mental development is normal.
• The newly described tenascin-X deficient form was described in 8 patients with hyperelastic skin and hypermobile joints (Schalkwijk, 2001).
• • Each patient bruised easily, and most had velvety skin.
  • A few patients also had joint pain and multiple subluxations.
  • None had delayed wound healing or atrophic scars.
  • Additional findings in some patients included congenital adrenal hyperplasia, mitral valvular prolapse, stroke, gut bleeding, and premature arteriosclerosis.
• Development dental pathologies are common in these patients. Findings include hypodontia of permanent teeth, delayed eruption and dentin dysplasia.

Physical

To date, 11 variants of EDS are identified; all have genetic, biochemical, and clinical differences. More than one third of persons with EDS do not fit exactly into a single type; overlap is common.

• Common to almost all groups is a unique appearance of the skin (see Images 1-5).
• • The skin is usually white and soft, and underlying vessels are sometimes visible.
  • The skin has a doughy feel.
  • The skin is easily hyperextensible. It is easy to pull, and, once released, it immediately returns to its original state.
• Molluscoid pseudotumors are small, spongy tumors found over scars and pressure points.
• • Molluscoid pseudotumors consist of fat surrounded by a fibrous capsule.
  • They are commonly seen in type I.
• Smaller, deep, palpable, and movable nodules are often present in the subcutaneous tissue.
• • These nodules can be found in the arms and over the tibias.
  • Calcification leads to opacity on radiographs.
• Fragility of dermal skin is common, with frequent bruises and lacerations.
• • Poor wound healing is not rare.
  • The use of sutures is usually a problem in patients, in whom easy dehiscence and cigarette-paper–like scars may be observed. Frequently, these scars are found on the knees.
• The joints are hyperextensible, sometimes dramatically, but the degree of involvement is variable.
• • The digit joints are most commonly affected, but all the joints can show alterations.
  • Dislocations can occur, but patients are usually able to quickly reduce them with no pain.
• Type I, the gravis form, affects 43% of patients and is inherited in an autosomal dominant pattern.
• • In this type, the clinical features are usually severe.
  • Patients have marked skin extensibility with frequent lacerations and subsequent scarring in different body locations.
  • Surgical sutures heal poorly, with easy dehiscence.
  • Joint hypermobility is severe and affects all parts of the body.
  • Spontaneous dislocations can occur, but immediate reduction is easy.
  • Varicosities and molluscoid pseudotumors are common.
  • Musculoskeletal features are easily found. These features include kyphoscoliosis, hallus valgus, pes planus (ie, flat feet), and genu recurvatum; bruises are less common in this type than in other forms.
  • Cardiac defects, especially mitral valvular prolapse, are sometimes present.
  • Prematurity with rupture of the fetal membranes is specific to this type.
• Type II, the mitis form, affects 35% of patients and is inherited in an autosomal dominant pattern.
• • This group is characterized by a mild appearance of the same features of type I.
  • Wide scars are common, but the skin has somewhat less fragility and bruisability.
  • The joints are moderately hyperextensible, and the digits are usually the only body sites affected.
• Type III, the benign familiar hypermobile form, affects 10% of patients and is inherited in an autosomal dominant pattern.
• • Patients with this variant have minimal or no skin changes, but they do have a striking hyperextensibility in many joints.
  • This hyperextensibility usually causes orthopedic consequences (eg, severe osteoarthritis) in the long term.
• Type IV, the ecchymotic or arterial forms, affects 6% of patients and is inherited in an autosomal recessive or sometimes autosomal dominant pattern.
• • This variant is relatively rare.
  • Clinically, patients have unique, white, translucent skin, and the underlying vessels are easy to see.
  • The skin is also fragile but not extensible.
  • Scars and molluscoid pseudotumors are numerous, as are bruises and purpuric lesions.
  • Keloids and hyperpigmentation of the scars are common.
  • Joint hyperextensibility is rare or absent.
  • Arterial aneurysms, valvular prolapse, and spontaneous pneumothorax are common complications.
  • Patients also have low weight and short stature.
  • The prognosis for this type is poor, and the patient's life span is shortened.
  • Sudden death can occur after visceral perforation or after the rupture of a large vessel, most commonly an abdominal or splenic vessel.
  • A prenatal diagnosis by means of polymorphic restriction genetic studies is possible.
• Type V, the X-linked form, affects 5% of patients and is inherited in an X-linked recessive pattern.
• • The skin of patients with this form of EDS is highly extensible, and orthopedic abnormalities are common.
  • Bruising and hyperextensibility are rare.
• Type VI, the ocular form, affects 2% of patients and is inherited in an autosomal recessive pattern.
• • Patients with this type are clinically and severely affected by the disease.
  • The skin is extensible, bruises are common, and wound healing is poor.
  • Patients may have several scars, some of which can be hyperpigmented.
  • The joints are hyperextensible.
  • This subgroup has unique ocular clinical signs. The ocular fragility can cause retinal hemorrhage and detachment, glaucoma, and coloration of the sclera. Rupture of the globe is rare but possible.
  • Measurements of LH in the amniotic fluid can be used to predict the outcome of pregnancy.
• Type VII, or arthrochalasis multiplex congenita, affects 3% of patients and is inherited in an autosomal recessive or autosomal dominant pattern.
• • Patients with this type have noticeable joint hyperextensibility, but skin changes are less severe than those of other types.
  • Patients have spontaneous joint dislocation, usually with rapid reduction.
  • Patients with this type are usually short in stature.
• Type VIII, the periodontal form, is rare and inherited in an autosomal dominant pattern.
• • Patients with this type have dental involvement with gingival periodontal inflammation.
  • Skin laxity, joint hyperextensibility, and bruisability are variable.
  • Gingival resorption and permanent loss of the teeth are common by the time the patient is aged 30 years.
• Type IX, or X-linked cutis laxa, is rare and inherited in an X-linked recessive pattern.
• • Patients with type IX have characteristic bilateral bony prominences on the occiput.
  • Rarely, the skin and joints are dramatically affected.
  • Chronic diarrhea and orthostatic hypotension are unique findings in this group.
  • Scars are usually evident because healing is poor.
  • Patients with this type have a defect in intracellular copper-dependent enzymes, similar to that of patients with Menkes syndrome.
• Type X (fibronectin deficiency) and type XI (benign hypermobile joint syndrome) are rare forms of EDS. Some suggest that these types are so similar that they are better classified as one type rather than two.
• In 1997, a new, simpler classification was proposed in an attempt to eliminate the confusing associated with the former classification. Although many dermatology books continue to include both classifications, the EDS clinical forms can now be classified as follows:
• • Classic type (formerly types I and II)
  • Hypermobility type (formerly type III)
  • Vascular type (formerly type IV)
  • Kyphoscoliosis type (formerly type VI)
  • Arthrochalasis type (formerly type VII, deficiency of proA1 or proA2 chains of collagen type I)
  • Dermatosparaxis type (formerly type VII, deficiency of procollagen N-terminal peptidase)
  • Other (formerly types V, VIII, IX, X and XI)

Causes

• Collagens are a family of proteins that are widely distributed in all organs of the body. Thirteen different subtypes are now known, and the number increases constantly.
• The joints, blood vessels, and skin have different kinds of collagen in their structure; in all these locations, collagen is organized into bundles.
• Collagen organization is not easily visible by means of light microscopy, and abnormalities are better detected with electron microscopy.
• Collagen disorganization and/or abnormal bundle size is correlated with clinical evidence in the joints, skin, and blood vessels.
• In EDS, skin collagen alteration can be seen in the reticular dermis.
• • Two abnormalities are evident: irregularities in the diameter of the fibrils and irregular collagen shapes.
  • Fibrils can be large and irregular in some types (types I-III), but they can also be small or varied in others.
  • The most severe form of EDS, type IV, is the best studied; biochemically, this type has decreased or absent type III collagen synthesis. Pathologic findings in other skin layers are visible but nonspecific.

DIFFERENTIALS

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Other Problems to be Considered

Turner syndrome
Cartilage-hair hypoplasia syndrome

WORKUP

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Imaging Studies

• Calcification of small, deep, palpable, and movable nodules (often present in the subcutaneous tissue) can lead to opacity on radiographs.

Other Tests

• For type IV, a prenatal diagnosis by means of polymorphic restriction genetic studies is possible.
• For type VI, measurements of LH in the amniotic fluid can be used to predict the outcome of pregnancy.

Histologic Findings

Histologic findings in skin biopsy specimens are variable and sometimes normal. Dermal collagen fibers are disorderly arranged, with a whorled appearance. Elastic fibers show irregularities in size and orientation.

Electron microscopy reveals defects in the striations of the collagen fibers, with large or small fibrils.

TREATMENT

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Medical Care

• Treatment is unsatisfactory.
• One isolated report showed that patients with type VI disease benefited from oral vitamin C at 4 g/d. Scars and bleeding time seemed to improve with this treatment.

Surgical Care

• Extreme caution is mandatory in any surgical maneuver.
• Plastic re-excision of scars sometimes provides acceptable cosmetic results.
• Anesthetic implications, although rare, are very important in EDS, especially in the type IV (or vascular) patients. Risk of complications is higher, spontaneous vascular rupture can occur, and cervical spine and airway trauma must be kept in mind. Bleeding is also reported.

Activity

• Patients with EDS types IV or VI should avoid participating in dangerous contact sports.
• Some authors mention risks with activities that can increase intracranial pressure as a result of the Valsalva effect. An example of one such activity is playing the trumpet.

MEDICATION

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The goals of pharmacotherapy are to prevent complications and reduce morbidity.

Drug Category: Vitamins

Vitamin C may improve morbidity. It is a critical cofactor for collagen fibril synthesis.

FOLLOW-UP

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Further Inpatient Care

• Type IV EDS should be carefully monitored because they are at high risk for spontaneous rupture of a large artery (eg, splenic artery, aorta) or the perforation of internal organs. These patients should be educated that surgery can pose life-threatening risks.

Deterrence/Prevention

• Patients should avoid trauma and participation in contact sports.
• Pregnancy is dangerous for some patients.
• Bleeding risk should be considered in surgical operations.

Prognosis

• EDS type IV is a severe form, and patients with this disease often have a shortened lifespan.
• • Arterial aneurysms, valvular prolapse, and spontaneous pneumothorax are common complications.
  • The prognosis with this type is poor.
  • Sudden death can occur after visceral perforation or after the rupture of a large vessel, most commonly an abdominal and splenic vessel.
• The other types usually are not as dangerous, and affected individuals can live healthy if somewhat restricted lives.

Patient Education

• For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Bruises.

MISCELLANEOUS

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Medical/Legal Pitfalls

• This diagnosis can be important, especially with regard to the severe form, type IV, in which skin also is fragile but not extensible.

Special Concerns

• Pregnancy is dangerous for some patients.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Patient with Ehlers-Danlos syndrome. Note the abnormal ability to elevate the right toe. Courtesy of Enrico Ceccolini, MD.
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Media file 2:  Girl with Ehlers-Danlos syndrome. Dorsiflexion of all the fingers is easy and absolutely painless. Courtesy of Enrico Ceccolini, MD.
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Media file 3:  Patient with Ehlers-Danlos Syndrome mitis. Joint hypermobility is less intense than with other conditions. Courtesy of Enrico Ceccolini, MD.
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Media file 4:  Dorsal view of a patient with Ehlers-Danlos syndrome. Note the S-curved spinal column. Courtesy of Enrico Ceccolini, MD.
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Media file 5:  Cigarette-paper–like scars over the knees of a patient with Ehlers-Danlos syndrome. Note also the deformity of the left knee.Courtesy of Enrico Ceccolini, MD.
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Media file 6:  Criteria for Ehlers-Danlos syndrome are shown in Images 6-11. Dorsiflexion of the little finger by more than 90° with the forearm flat on the table.
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Media file 7:  Passive apposition of the thumb to the flexor forearm.
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Media file 8:  Hyperextension of the elbow by more than 90°.
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Media file 9:  Hyperextension of the knee by more than 10°.
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Media file 10:  Forward flexion of the trunk until the palms of the hands rest easily on the floor.
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Media file 11:  Evaluation of skin extensibility.
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REFERENCES

Section 11 of 11

• Authors and Editors
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• Yassin OM, Rihani FB. Multiple developmental dental anomalies and hypermobility type Ehlers-Danlos syndrome. J Clin Pediatr Dent. Summer 2006;30 (4):337-341. [Medline].
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Article Last Updated: Sep 19, 2006