eMedicine Specialties > Dermatology > Pediatric Diseases

Ehlers-Danlos Syndrome

Enrico Ceccolini, MD, Consulting Staff, Department of Dermatology, University of Bologna, Italy
Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School

Updated: Feb 18, 2009

Introduction

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.

Ehlers-Danlos syndrome 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 Ehlers-Danlos syndrome is important. One type, type IV, is associated with arterial rupture and visceral perforation, with possible life-threatening consequences.

Pathophysiology

Ehlers-Danlos syndrome 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 Ehlers-Danlos syndrome. 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 Ehlers-Danlos syndrome 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 Ehlers-Danlos syndrome, the disease appears to be linked to loci that contain the COL5A1 or COL5A2 genes. Although half of the mutations that cause Ehlers-Danlos syndrome types I and II are likely to affect the COL5A1 gene, a significant portion of the mutations result in low levels of mRNA from the mutant allele as a consequence of nonsense-mediated mRNA decay.¹

Bouma et al evaluated 3 generations in a family with Ehlers-Danlos syndrome 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.²

Wenstrup and associates identified haploinsufficiency of the COL5A1 gene that encodes the proalpha1(V) chain of type V collagen in the classic form of Ehlers-Danlos syndrome. Eight of 28 probands with classic Ehlers-Danlos syndrome 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 Ehlers-Danlos syndrome 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.³

Autosomal recessive–type VI Ehlers-Danlos syndrome, 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 Ehlers-Danlos syndrome 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.⁴

Tenascin-X is a large extracellular matrix protein, a deficiency of which causes a clinically distinct recessive form of this syndrome.⁵ 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. Crystal structure of human type III, in the structure G991-G1032 cystine knot, shows both 7/2 and 10/3 symmetries.⁶

A novel point mutation has been found in the vascular type of Ehlers-Danlos syndrome. The mutation took place in the second position of exon 24 of COL3A1.⁷

Impaired wound healing is a typical feature of Ehlers-Danlos syndrome, probably for a fibroblast defect. Wound repair can be achieved using exogenous type V collagen.⁸

Ehlers-Danlos syndrome pediatric patients have been shown to have deficiencies in 3 genes of the glutathione S-transferase family (GSTM1, GSTT1, GSTP1). This leads to the generation of reactive oxygen species.⁹

Reduced activity of beta4-galactosyltransferase 7 (beta4GalT-7) is associated with the progeriform Ehlers-Danlos syndrome.

Frequency

United States

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

International

The prevalence of Ehlers-Danlos syndrome is reported to be 1 case in approximately 400,000 people, but mild or incomplete forms appear to be underdiagnosed and more common than other forms.

Mortality/Morbidity

Type IV Ehlers-Danlos syndrome 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.¹⁰ 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 other races.

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. Ehlers-Danlos syndrome is usually diagnosed in young adults.

Clinical

History

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

• Muscle weakness is often present, and patients report a tendency to fall down easily and have 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.⁵
  • 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.
• Dental pathology is common in these patients. Findings include hypodontia of permanent teeth, delayed eruption, and dentin dysplasia.¹¹
• In one patient, splenic rupture due to peliosis led to the diagnosis of vascular Ehlers-Danlos syndrome.¹²
• Two Ehlers-Danlos syndrome patients with cutaneous metaplastic synovial cysts are described in the literature.¹³
• Multiple sclerosis can be associated with Ehlers-Danlos syndrome.¹⁴
• Absence of the inferior labial or lingual frenula in Ehlers-Danlos syndrome patients has been suggested as a new diagnostic criterion.¹⁵
• Baba et al showed an association of Ehlers-Danlos syndrome and solitary rectal ulcer syndrome.¹⁶
• Subependymal periventricular heterotopia is not a rarity in Ehlers-Danlos syndrome patients.¹⁷
• Ehlers-Danlos syndrome and anorexia nervosa have been described in the same patient.¹⁸
• Several articles review pregnancy in Ehlers-Danlos syndrome patients.¹⁹

Physical

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

• Common to almost all groups is a unique appearance of the skin (see Media Files 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 patients with 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 Ehlers-Danlos syndrome 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 Ehlers-Danlos syndrome. Some suggest that these types are so similar that they are better classified as one type rather than 2.
• In 1997, a new, simpler classification was proposed in an attempt to eliminate the confusion associated with the former classification. Although many dermatology books continue to include both classifications, the Ehlers-Danlos syndrome clinical forms can now be classified as follows:
  • Classic type was formerly types I and II.
  • Hypermobility type was formerly type III.
  • Vascular type was formerly type IV.
  • Kyphoscoliosis type was formerly type VI.
  • Arthrochalasis type was formerly type VII, characterized by deficiency of proA1 or proA2 chains of collagen type I.
  • Dermatosparaxis type was formerly type VII, characterized by deficiency of procollagen N -terminal peptidase.
  • Other was formerly types V, VIII, IX, X and XI.
• A review of Ehlers-Danlos syndrome type VIII showed distinctive clinical features. The precise underlying molecular defect is unknown, but patients with this type are similar clinically.

Causes

• Collagens are a family of proteins that are widely distributed in all organs of the body. Thirteen different subtypes are 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 Ehlers-Danlos syndrome, 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 Ehlers-Danlos syndrome, 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.

Differential Diagnoses

Cutis Laxa (Elastolysis)
Loeys-Dietz syndrome
Pseudoxanthoma Elasticum

Other Problems to Be Considered

Turner syndrome
Cartilage-hair hypoplasia syndrome
Muscular hypotonia (kyphoscoliotic type)
Loeys-Dietz syndrome²⁰

Workup

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.
• In one patient, the vascular type of Ehlers-Danlos syndrome was associated with mild hemophilia A.²¹
• One patient with Ehlers-Danlos syndrome type IV has been diagnosed with gastric adenocarcinoma.

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

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 Ehlers-Danlos syndrome, 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.²²
• Recombinant factor VIIa has been successful in the treatment of intractable bleeding in vascular-type Ehlers-Danlos syndrome.²³

Activity

• Patients with Ehlers-Danlos syndrome 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

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

Vitamins

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

Ascorbic acid (Cecon, Cevalin, Cevi-Bid)

For collagen synthesis and tissue repair.

Dosing

Adult

100-250 mg PO qd/bid for at least 2 wk

Pediatric

100-300 mg PO in divided doses for at least 2 wk

Interactions

Decreases effects of warfarin and fluphenazine; increases aspirin levels

Contraindications

Pregnancy if large doses given

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Prolonged high doses may cause renal calculi, especially in diabetes

Follow-up

Further Inpatient Care

• Type IV Ehlers-Danlos syndrome patients should be carefully monitored because they are at high risk for spontaneous rupture of a large artery (eg, splenic artery, aorta) or perforation of internal organs. These patients should be educated that surgery can pose life-threatening risks.
• Fernandez-Alcantud reviewed management of anesthesia in vascular type IV Ehlers-Danlos syndrome patients.²⁴
• Jones reports the use of local anesthesia for elective cesarian delivery in a type III Ehlers-Danlos syndrome woman.²⁵

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

• Ehlers-Danlos syndrome 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. Additionally, see eMedicine's patient education article Bruises.

Miscellaneous

Medicolegal 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

Media file 1: Patient with Ehlers-Danlos syndrome. Note the abnormal ability to elevate the right toe. Courtesy of Enrico Ceccolini, MD.

Media file 2: Girl with Ehlers-Danlos syndrome. Dorsiflexion of all the fingers is easy and absolutely painless. Courtesy of Enrico Ceccolini, MD.

Media file 3: Patient with Ehlers-Danlos syndrome mitis. Joint hypermobility is less intense than with other conditions. Courtesy of Enrico Ceccolini, MD.

Media file 4: Dorsal view of a patient with Ehlers-Danlos syndrome. Note the S-curved spinal column. Courtesy of Enrico Ceccolini, MD.

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.

Media file 6: Criteria for Ehlers-Danlos syndrome are shown in Media Files 6-11. Dorsiflexion of the little finger by more than 90°with the forearm flat on the table.

Media file 7: Passive apposition of the thumb to the flexor forearm.

Media file 8: Hyperextension of the elbow by more than 90°.

Media file 9: Hyperextension of the knee by more than 10°.

Media file 10: Forward flexion of the trunk until the palms of the hands rest easily on the floor.

Media file 11: Evaluation of skin extensibility.

References

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Keywords

Ehlers-Danlos syndrome, EDS, tenascin-X deficiency syndrome, lysyl hydroxylase deficiency syndrome, inherited connective tissue disorders, inherited connective-tissue disorders, connective-tissue disorder, connective tissue disorder

Contributor Information and Disclosures

Author

Enrico Ceccolini, MD, Consulting Staff, Department of Dermatology, University of Bologna, Italy
Enrico Ceccolini, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Optigenex Consulting fee Independent contractor

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey
Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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