Ehlers-Danlos Syndrome 

Updated: Mar 17, 2020
Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD 

Overview

Background

Ehlers-Danlos syndromes (EDS), the name given to a group of more than 10 different inherited, clinically and genetically heterogeneous group of connective-tissue disorders, involves a genetic defect in collagen and connective-tissue synthesis and structure. In 2017, a new international classification was proposed with 13 different variants.[1, 2]

Ehlers-Danlos syndrome can affect the skin, joints, and blood vessels. This syndrome is clinically heterogeneous and has been classically divided into six types (classical, hypermobile, vascular, kyphoscoliotic, arthrochalasis, and dermatosparaxis), with the underlying collagen abnormality being different for each type. Asymptomatic, nonsyndromic joint hypermobility, hypermobility spectrum disorders, and Ehlers-Danlos syndrome (particularly, the hypermobile type) are the most common phenotypes evident in association with joint hypermobility.[1] One should not regard these syndromes as curiosities and should be aware that systemic features, including chronic pain, gastrointestinal dysmotility, dysautonomia, mast cell activation and anxiety and phobic states, may be complications.[3] Advances have shown more complexities with novel, clinically overlapping, rare Ehlers-Danlos syndrome variants identified, some associated with specific genetic defects.[4] Clinical recognition of the various types of Ehlers-Danlos syndrome is important, which is particularly true for the vascular type, as it is associated with arterial rupture and visceral perforation, with possible life-threatening consequences.[5]

Pathophysiology

Ehlers-Danlos syndrome (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 at least six of the many types of Ehlers-Danlos syndrome. The vascular form, sometimes referred to as type IV, is characterized by a decreased amount of type III collagen. It is autosomal dominant and caused by mutations in the COL3A1 gene that result in increased fragility of connective tissue with arterial, intestinal, and uterine ruptures and premature death.[6, 7] 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.[8]  Among 31 female and 13 male Polish patients with classic Ehlers-Danlos syndrome, nine new mutations of the COL5A1 gene were delineated (8 missense mutations and 1 splice site).[2]

Bouma et al evaluated 3 generations in a family with Ehlers-Danlos syndrome type II.[9] 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.[9]

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.[10] Type V collagen mutations are pivotal in classic Ehlers-Danlos syndrome.[11]

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 two 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 two of these mutations in five 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.[12]

Tenascin-X is a large extracellular matrix protein, a deficiency of which causes a clinically distinct recessive form of this syndrome.[13] 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.[14]

Vascular Ehlers Danlos syndrome (vEDS), characterized by arterial aneurysm, dissection and rupture, bowel rupture, and rupture of the gravid uterus, results from pathogenic variants in COL3A1, which encodes the chains of type III procollagen.[5] Pathogenic variants in COL3A1, most frequently glycine substitutions, with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, also were delineated.[7] A novel point mutation has been found in the vascular type of Ehlers-Danlos syndrome. The mutation occurs in the second position of exon 24 of COL3A1.[5, 15]

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.[16]

Ehlers-Danlos syndrome pediatric patients have been shown to have deficiencies in three genes of the glutathione S-transferase family (GSTM1, GSTT1, GSTP1). This leads to the generation of reactive oxygen species.[17]

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

Biallelic mutations in FKBP14 may result in a recessive form of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, hearing loss, and, possibly, an increased risk for vascular complications.[18]

Etiology

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 (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 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.

Epidemiology

Frequency

The prevalence of Ehlers-Danlos syndrome (EDS) 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. The frequency of vascular Ehlers-Danlos syndrome has been estimated at 1 case in 50,000 to 1 case in 200,000.[5]

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.

Prognosis

Type IV Ehlers-Danlos syndrome (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.[19] 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 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.

Patient Education

For patient education resources, visit the Skin Conditions and Beauty Center. Additionally, see the patient education article Bruises.

 

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]

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.

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. Ayoub et al noted congenital bilateral hip dislocations, severe generalized joint hypermobility, recurrent joint (sub)luxations, and skin hyperextensibility.[36]

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.[37]

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.[38]

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.[39]

 

DDx

Diagnostic Considerations

Also consider the following:

  • Turner syndrome

  • Cartilage-hair hypoplasia syndrome

  • Muscular hypotonia (kyphoscoliotic type)

  • Loeys-Dietz syndrome[40]

  • Child abuse: Ehlers-Danlos syndrome may resemble child abuse in some patients, a potential medicolegal concern and challenge.[41]

  • Systemic connective-tissue disorder with polyvalvular heart; generalized joint hypermobility and related musculoskeletal complications; soft, velvety, and hyperextensible skin; short limbs; hearing impairment; and facial dysmorphism associated with TAB2 mutations [42]

Differential Diagnoses

 

Workup

Imaging Studies

Calcification of small, deep, palpable, and movable nodules (often present in the subcutaneous tissue) can lead to opacity on radiographs. MRI study of the hypermobility type may document specific white matter lesions.[35]

Other Tests

For type IV, a prenatal diagnosis by means of polymorphic restriction genetic studies is possible.

For type VI, measurements of lysyl hydroxylase (LH) in the amniotic fluid can be used to predict the outcome of pregnancy.

In one patient, the vascular type of Ehlers-Danlos syndrome (EDS) was associated with mild hemophilia A.[43]

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.

Rombaut et al performed a cross-sectional study of self-reported medication use, surgery, and physiotherapy in 79 patients with hypermobility-type Ehlers-Danlos syndrome (EDS) (type III), finding that 73 patients (92.4%) were taking medication, 56 (70.9%) had undergone surgery, and 41 (51.9%) were currently receiving physical therapy.[44] The patients taking medication all took analgesics; many also reported using antidepressants. Severe pain was frequent; patients taking strong opiates made more complaints and experienced greater functional impairment than those using weaker analgesics.

Rehabilitation programs specifically designed for musculoskeletal disorders of Ehlers-Danlos syndrome patients, such as a scapular motor control program with multidirectional severe shoulder instability, are desirable.[45]

A 2020 pilot study noted that custom-made foot orthoses improved foot pain, disability related to foot pain, foot function, fatigue, and mental health–related quality of life in Ehlers-Danlos syndrome patients.[46]

Surgical Care

Extreme caution is mandatory in any surgical maneuver. Type IV Ehlers-Danlos syndrome (EDS) 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.

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.[47] Lethal arterial events may occur.[48]  Fernandez-Alcantud reviewed management of anesthesia in vascular type IV Ehlers-Danlos syndrome patients.[49]  Jones reports the use of local anesthesia for elective cesarian delivery in a type III Ehlers-Danlos syndrome woman.[50]

Recombinant factor VIIa has been successful in the treatment of intractable bleeding in vascular-type Ehlers-Danlos syndrome.[51]

Activity

Patients with Ehlers-Danlos syndrome (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

Medication Summary

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

Vitamins

Class Summary

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

Ascorbic acid (Cecon, Cevalin, Cevi-Bid)

Ascorbic acid helps with collagen synthesis and tissue repair.

 

Questions & Answers

Overview

What is Ehlers-Danlos syndrome (EDS)?

How is Ehlers-Danlos syndrome (EDS) categorized?

What is the pathophysiology of Ehlers-Danlos syndrome (EDS) type IV?

What is the pathophysiology of Ehlers-Danlos syndrome (EDS)?

Which genes are involved in the pathogenesis of Ehlers-Danlos syndrome (EDS) types I and II?

Which genomic defect is associated with Ehlers-Danlos syndrome (EDS)?

Which genetic mutations are identified in the pathogenesis of Ehlers-Danlos syndrome (EDS) type VI?

What is the role of tenascin-X in the pathogenesis of Ehlers-Danlos syndrome (EDS)?

Which novel mutation has been reported in Ehlers-Danlos syndrome (EDS)?

Which genetic mutations are involved in the pathogenesis of vascular Ehlers Danlos syndrome (vEDS)?

What is a typical feature of Ehlers-Danlos syndrome (EDS)?

Which genetic deficiencies have been reported in pediatric Ehlers-Danlos syndrome (EDS)?

Which enzyme deficiency is associated with the progeriform Ehlers-Danlos syndrome (EDS)?

What is the role of biallelic mutations in the pathogenesis of Ehlers-Danlos syndrome (EDS)?

What is the role of collagens in the etiology of Ehlers-Danlos syndrome (EDS)?

What is the prevalence of Ehlers-Danlos syndrome (EDS)?

What are the racial predilections of Ehlers-Danlos syndrome (EDS)?

How does the prevalence of Ehlers-Danlos syndrome (EDS) vary by sex?

In what age group in Ehlers-Danlos syndrome (EDS) most commonly diagnosed?

What is the prognosis of Ehlers-Danlos syndrome (EDS)?

Where can patient education resources be found for Ehlers-Danlos syndrome (EDS)?

Presentation

What are the signs and symptoms of Ehlers-Danlos syndrome (EDS)?

How does Ehlers-Danlos syndrome (EDS) affect mental development?

What are the signs and symptoms of tenascin-X form of Ehlers-Danlos syndrome (EDS)?

What are dental symptoms of Ehlers-Danlos syndrome (EDS)?

What causes splenic rupture in vascular Ehlers-Danlos syndrome (EDS)?

What are cutaneous symptoms of Ehlers-Danlos syndrome (EDS)?

What is the relationship between multiple sclerosis (MS) and Ehlers-Danlos syndrome (EDS)?

What is a suggested diagnostic criterion for Ehlers-Danlos syndrome (EDS)?

Which clinical conditions have been reported with Ehlers-Danlos syndrome (EDS)?

Where can photos of patients with Ehlers-Danlos syndrome (EDS) be found?

What are physical findings characteristic of Ehlers-Danlos syndrome (EDS)?

How are the joints affected by Ehlers-Danlos syndrome (EDS)?

What are the characteristics of type I (gravis form) Ehlers-Danlos syndrome (EDS)?

What are the characteristics of type II (mitis form) Ehlers-Danlos syndrome (EDS)?

What are the characteristics of type III (benign familiar hypermobile form) Ehlers-Danlos syndrome (EDS)?

What are the characteristics of type IV (ecchymotic or arterial form) Ehlers-Danlos syndrome (EDS)?

What are the characteristics of type V (X-linked form) Ehlers-Danlos syndrome (EDS)?

What are the characteristics of type VI (ocular form) Ehlers-Danlos syndrome (EDS)?

What are the characteristics of type VII (arthrochalasis multiplex congenita) Ehlers-Danlos syndrome (EDS)?

What are the characteristics of type VIII (periodontal form) Ehlers-Danlos syndrome (EDS)?

What are the characteristics of type IX (X-linked cutis laxa) Ehlers-Danlos syndrome (EDS)?

What are the characteristics of type X (fibronectin deficiency) and XI (benign hypermobile joint syndrome) Ehlers-Danlos syndrome (EDS)?

What is the 1997 classification system for Ehlers-Danlos syndrome (EDS)?

What is the 2017 Ehlers-Danlos syndrome international classification system?

What are the possible complications of Ehlers-Danlos syndrome (EDS)?

DDX

Which conditions should be included in the differential diagnoses of Ehlers-Danlos syndrome (EDS)?

What are the differential diagnoses for Ehlers-Danlos Syndrome?

Workup

What is the role of imaging studies in the diagnosis of Ehlers-Danlos syndrome (EDS)?

Which other tests may be used to diagnose Ehlers-Danlos syndrome (EDS) during pregnancy?

What are the histologic findings characteristic of Ehlers-Danlos syndrome (EDS)?

Treatment

What are the medical treatment options for Ehlers-Danlos syndrome (EDS)?

Why does surgery pose a mortality risk for patients with Ehlers-Danlos syndrome (EDS)?

When are activity modifications needed in patients with Ehlers-Danlos syndrome (EDS)?

Medications

Which medications in the drug class Vitamins are used in the treatment of Ehlers-Danlos Syndrome?