Ehlers-Danlos Syndrome Clinical Presentation

Updated: Apr 12, 2019
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD  more...
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Presentation

History

The biochemical collagen defect is present at birth, but clinical manifestations become evident later. Shoulder dislocation is often the initial sign of Ehlers-Danlos syndrome (EDS). Regrettably, the value of clinical tests for generalized joint hypermobility, Ehlers-Danlos syndrome, hypermobility type, and joint hypermobility syndrome may be less than ideal. [20] The skin findings provide the diagnostic criterion of Ehlers-Danlos syndrome, hypermobility type and joint hypermobility syndrome; there is no supportive laboratory test. [21] These children tend to have many complaints, especially orthostatic intolerance, urinary incontinence, and diarrhea, as well as poor postural control, pain, and fatigue. [22] Muscle weakness is often present, with patients reporting 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. [13] 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. [23]

In one patient, splenic rupture due to peliosis led to the diagnosis of vascular Ehlers-Danlos syndrome. [24]

Two Ehlers-Danlos syndrome patients with cutaneous metaplastic synovial cysts are described in the literature. [25]

Multiple sclerosis can be associated with Ehlers-Danlos syndrome. [26]

Absence of the inferior labial or lingual frenula in Ehlers-Danlos syndrome patients has been suggested as a new diagnostic criterion. [27]

Baba et al showed an association of Ehlers-Danlos syndrome and solitary rectal ulcer syndrome. [28]

Subependymal periventricular heterotopia is not a rarity in Ehlers-Danlos syndrome patients. [29]

Ehlers-Danlos syndrome and anorexia nervosa have been described in the same patient. [30]

Several articles review pregnancy in Ehlers-Danlos syndrome patients. [31]

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Physical Examination

To date, 11 variants of Ehlers-Danlos syndrome (EDS) 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 the images below).

Patient with Ehlers-Danlos syndrome. Note the abno 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 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 h Patient with Ehlers-Danlos syndrome mitis. Joint hypermobility is less intense than with other conditions. Courtesy of Enrico Ceccolini, MD.
Dorsal view of a patient with Ehlers-Danlos syndro Dorsal view of a patient with Ehlers-Danlos syndrome. Note the S-curved spinal column. Courtesy of Enrico Ceccolini, MD.
Cigarette-paper–like scars over the knees of a pat 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.

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.

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Classifications

Older classification

Older classifications of Ehlers-Danlos syndrome (EDS) are noteworthy and still in use; they are delineated below. Next-generation sequencing has greatly enhanced genetic knowledge in different Ehlers-Danlos syndrome types. [32]

Type I - Gravis form

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. However, according to a retrospective cross-sectional and longitudinal chart analysis of 252 patients with types I, II, and III, mitral valvular prolapse and aortic root dilation were of little clinical significance in these forms of Ehlers-Danlos syndrome. [33]

Prematurity with rupture of the fetal membranes is specific to this type.

Type II - Mitis form

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 - Benign familiar hypermobile form

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.

The hypermobility type of Ehlers-Danlos syndrome may be associated with uterine, rectal, ovarian, and/or heart prolapse, although multiple visceral ptoses are rare. [34] An MRI study of this hypermobility type showed consistent and specific white matter findings after physical trauma. [35]

Type IV - Ecchymotic or arterial form

Type IV, the ecchymotic or arterial form, 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 - X-linked form

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 - Ocular form

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 - Arthrochalasis multiplex congenita

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 - Periodontal form

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.

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.

Type IX - X-linked cutis laxa

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)

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.

1997 classification

A relatively simple classification was proposed in 1997 in an attempt to eliminate the confusion associated with the earlier classification. Although many dermatology texts continue to include both classifications, the Ehlers-Danlos syndrome clinical forms can also 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.

2017 Ehlers-Danlos syndrome international classification

A new schema was disseminated in 2017. [36]

Classical Ehlers-Danlos syndrome (cEDS) is as follows:

  • Inheritance pattern: Autosomal dominant
  • Genetic basis (protein involved): Major - COL5A1 and COL5A2 (type 5 collagen); Rare - COL1A1 c.934C>T, p.(Arg312Cys) (type I collagen)

Classical-like Ehlers-Danlos syndrome (clEDS) is as follows:

  • Inheritance pattern: Autosomal recessive
  • Genetic basis (protein involved): TNXB (tenascin XB)

Cardiac-valvular Ehlers-Danlos syndrome (cvEDS) is as follows:

  • Inheritance pattern: Autosomal recessive
  • Genetic basis (protein involved): COL1A2 (biallelic mutations that lead to COL1A2 nonsense-mediated decay and absence of proa2-chain of type I collagen) (type I collagen)

Vascular Ehlers-Danlos syndrome (vEDS) is as follows:

  • Inheritance pattern: Autosomal dominant
  • Genetic basis (protein involved): Major - COL3A1 (type III collagen); Rare - COL1A1 c934C>T, p.(Arg321Cys)/c.1720C>T, p.(Arg574Cys)/c.3227C>T, p.(Arg1093Cys) (type I collagen)

Hypermobile Ehlers-Danlos syndrome is as follows:

  • Inheritance pattern: Autosomal dominant
  • Genetic basis (protein involved): Unknown (unknown)

Arthrochalasia Ehlers-Danlos syndrome (aEDS) is as follows:

  • Inheritance pattern: Autosomal dominant
  • Genetic basis (protein involved): COL1A1 or COL1A2(type 1 collagen)

Dermatosparaxis Ehlers-Danlos syndrome (dEDS) is as follows:

  • Inheritance pattern: Autosomal recessive
  • Genetic basis (protein involved): ADAMTS2 (ADAMTS-2)

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is as follows:

  • Inheritance pattern: Autosomal recessive
  • Genetic basis (protein involved): PLOD1 (LH1) or FKBP14 (FKBP22)

Brittle cornea syndrome (BCS) is as follows:

  • Inheritance pattern: Autosomal recessive
  • Genetic basis (protein involved): ZNF469 (ZNF469) or PRDM5 (PRDM5)

Spondylodysplastic Ehlers-Danlos syndrome (spEDS) is as follows:

  • Inheritance pattern: Autosomal recessive
  • Genetic basis (protein involved): B4GALT7 ( β 4GalT7), B3GALT6 ( β 4GalT6), and SLC39A13 (ZIP13)

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is as follows:

  • Inheritance pattern: Autosomal recessive
  • Genetic basis (protein involved): CHST14 (D4ST1) or DSE (DSE)

Myopathic Ehlers-Danlos syndrome (mEDS) is as follows:

  • Inheritance pattern: Autosomal dominant or autosomal recessive
  • Genetic basis (protein involved): COL12A1 (type XII collagen)

Periodontal Ehlers-Danlos syndrome (pEDS) is as follows:

  • Inheritance pattern: Autosomal dominant
  • Genetic basis (protein involved): C1R (C1r)

As with many genodermatoses, classification may become a hybrid based upon clinical features and demonstrated gene mutations. [37]

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Complications

Patients should avoid trauma and participation in contact sports.

Pregnancy is dangerous for some patients.

Bleeding risk should be considered in surgical operations.

Patients may be at an increased risk for depression, attention-deficit/hyperactivity disorder, autism spectrum disorders, and obsessive-compulsive personality disorder. [38]

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