Genetics of Ehlers-Danlos Syndrome 

Updated: Sep 05, 2019
Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD 

Overview

Practice Essentials

Ehlers-Danlos syndrome (EDS) consists of a group of inherited heterogeneous disorders that share a common decrease in the tensile strength and integrity of the skin, joints, and other connective tissues.[1] This group of connective-tissue disorders is characterized by abnormal collagen synthesis causing hyperextensibility of the skin, hypermobility of the joints,[2] and tissue fragility, as is seen by easy bruising and delayed wound healing with atrophic scarring.[3]  Depending on the type, EDS can be diagnosed through laboratory studies or clinical examination. Once the syndrome has been diagnosed, preventative measures should be taken.

People with lax joints and multiple scars were first described in the medical writings of Hippocrates, dating back to 400 BCE.[4] In 1892, Dr. A. Tschernogobow, a Russian dermatologist, presented 2 case studies of patients to the Moscow Venereology and Dermatology Society who had marked loose fragile skin, and hypermobile large joints. His work reports the first detailed clinical description of EDS.[3, 5]

The syndrome derives its name from additional clinical case reports presented by 2 physicians: Edvard Ehlers, a Danish dermatologist, in 1901, and Henri-Alexandre Danlos, a French physician with expertise in chemistry of skin disorders, in 1908. Both physicians combined the pertinent features of the syndrome and accurately delineated the phenotypic features of this group of inherited disorders. The name, Ehlers-Danlos syndrome, was coined in 1936.[3]

Some patients with EDS can demonstrate amazing, almost unnatural, contortions, often arousing the curiosity of onlookers. Niccolo Paganini (1782-1840) the famous Italian violinist, who was capable of miraculous feats in his playing owing to his hypermobile and loose joints, had phenotypic traits of EDS.[6] In the late 19th century, historians described performers with traits of EDS who displayed their hyperextensible maneuvers publicly in circuses and travelling shows. Some achieved celebrity status, acquiring titles such as "The India Rubber Man," "The Elastic Lady," and "The Human Pretzel."

Patients displaying clinical capabilities such as these raise suspicion of the diagnosis when identified on physical examination. Unfortunately, patients with EDS are often not diagnosed for many years.[7] Examples of hyperextensibility and hypermobility are shown in the following images.

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.

Signs and symptoms of Ehlers-Danlos syndrome

All EDS types share the following cutaneous features:

  • Loose, hyperextensible, fragile skin
  • Poor wound healing
  • Tendency to bruise easily
  • Atrophic scars that are wide and thin, known as "cigarette paper scars"

The following extracutaneous features are also shared:

  • Fragility of blood vessels
  • Hyperextensible, hypermobile joints
  • Propensity for spontaneous joint dislocations/subluxations

Workup in Ehlers-Danlos syndrome

The following laboratory studies may be indicated in patients diagnosed with EDS:

  • Diagnosis of the vascular-type EDS (type IV), arthrochalasia-type EDS (types VIIA and VIIB), and dermatosparaxis-type EDS (type VIIC) requires a skin biopsy; biochemical studies performed on cultured skin fibroblasts can detect alterations in collagen molecules
  • Molecular (DNA-based) testing is available for the vascular, arthrochalasia, and dermatosparaxis types
  • Kyphoscoliosis-type EDS (type VI) can be identified by urine enzyme assay

The remaining types of EDS—classical-type EDS and hypermobility-type EDS—are diagnosed through clinical examination.

Management

Recommend low-resistance exercise for patients with EDS to help increase muscle tone and stabilize loose joints. Physical therapy guided by a therapist who is experienced in working with patients with connective-tissue abnormalities and joint dysfunction can be very helpful in the management of long-term health.

Instruct patients with EDS to avoid excessive or repetitive heavy lifting and other movements that produce undue strain or stress on their already hypermobile joints (eg, finger hyperextension that occurs with pushing off of a wall with the palms of the hands).[8] Advise patients to minimize joint trauma by avoiding joint hyperextension or joint locking.

Surgery may be indicated to correct fractures and stabilize dislocated joints. Preferential use of staples or tape (rather than stitches) for wound closure should be strongly considered.[9]

Comprehensive, accurate genetic counseling is one of the most critical issues in the treatment of patients with EDS. Provide the family with detailed information regarding EDS’s inheritance pattern and recurrence risks, as well as identification of at-risk family members. Screen pertinent individuals in the family for subtle signs and symptoms of the condition, regardless of whether signs or symptoms are suggested by family history.

Pathophysiology

Individuals with Ehlers-Danlos syndrome (EDS) demonstrate connective-tissue abnormalities due to defects in the inherent strength, elasticity, integrity, and healing properties of the tissues.[10] The specific characteristics of a particular form of EDS stem from the tissue-specific distribution of various components of the extracellular matrix (ECM). The ECM is defined as the outer cell components of tissue that provide structural support to the cells; it is the distinguishing feature of connective tissue. Each tissue and organ system has an array of connective proteins. Unique to each connective protein array is the path of production, its relative proportion, and distribution in tissues or organs. In addition, the defined interactions of various components of the matrix are tissue specific.

Major constituents of the extracellular matrix

Ehlers-Danlos syndrome (EDS) is caused by various abnormalities in the synthesis and metabolism of collagen and other connective-tissue proteins in the ECM, such as elastin, proteoglycans, and macromolecular proteins.

Collagen is the most abundant protein in the body and is the most common protein found in the ECM.[11] Collagen proteins are multimeric, occurring in trimers with a central triple helical region. A minimum of 29 genes contribute to collagen protein structure, and these genes are located on 15 different human chromosomes, genetically coding for no less than 19 identifiable forms of collagen molecules.

Elastins, in contrast to the structural support of collagens, give elasticity to the tissues. Elastin allows for the tissues to stretch and return to their original state and hence is present in the ECM of blood vessels, lungs, and skin.[12] Elastic fibers are created by the association of elastin with an underlying microfibrillar array. The underlying basis of all connective-tissue matrices is the microfibrillar array. An example of a microfibrillar protein is fibrillin. Fibrillin-1 gene mutations on chromosome 15 produce an abnormal fibrillin, as is characteristic of patients with Marfan syndrome.

Elastin and other structural proteins are woven onto the microfibrillar array to provide the basic meshwork for the connective-tissue matrix. Abnormalities of elastin have been associated with other connective-tissue disorders such as cutis laxa. Deletion of the elastin gene occurs in patients with Williams syndrome. 

Proteoglycans are core proteins that are bound to glycosaminoglycans (also commonly termed mucopolysaccharides). Essentially, proteoglycans are the glue of the connective-tissue protein that seal and cement the underlying connective-tissue matrix.

Macromolecular proteins include the glycoproteins of the basement membrane (type IV collagen, laminin, entactin) and the ECM (fibronectin, tenascin).

Epidemiology

Frequency

International

Worldwide, more than 1.5 million people are diagnosed with Ehlers-Danlos syndrome (EDS). EDS (all types combined) is reported to have a 1 in 5,000-10,000 population frequency. The population occurrence of EDS varies dependent on which 1 of the 6 major types according to the Villefranche nosology is diagnosed. EDS types and their population occurrence (from most to least common) are as follows[13] :

  • Hypermobility-type EDS (type III) is the most common, occurring in 1 in 10,000-15,000 persons.

  • Classical-type EDS (types I and II) occurs in 1 in 20,000-50,000 persons.

  • Vascular-type EDS (type IV), considered the most serious type of EDS, is rare, occurring 1 in 100,000-250,000 persons.

Kyphoscoliosis-type EDS (type VI), arthrochalasia-type EDS (type VII A and B), and dermatosparaxis-type EDS (type VIIC) are all very rare, with dermatosparaxis-type EDS being the rarest.[14]

Mortality/Morbidity

Reduced life expectancy is not generally a feature of Ehlers-Danlos syndrome (EDS), with the exception of vascular-type EDS (type IV). Median life expectancy for patients with vascular-type EDS is 50 years because medium-sized arteries, and the gastrointestinal tract, can spontaneously rupture. Uterine rupture during pregnancy has also been reported.

Morbidity in EDS is related to the primary pathophysiology and includes dislocations, pain, or both from chronic joint laxity and instability. Aberrant wound healing and scarring due to abnormal tensile strength of the skin also happens.[15]  Rectal prolapse can occur, as described in the classical-type EDS (types I and II) patients.[16]

A study by Kim et al using the 2000-2012 National Inpatient Sample (NIS) indicated that compared with controls, hospitalized patients with EDS have a significantly greater likelihood of suffering from various cerebrovascular conditions, including carotid dissection, vertebral dissection, cervical artery aneurysm, cerebral aneurysm, and cerebrovascular malformation.[17]

Race

Ehlers-Danlos syndrome equally affects all races.

Sex

Of the 6 major types of Ehlers-Danlos syndrome classified by Villefranche nosology, both males and females are equally affected, as the genetic coding causing the differing phenotypes are located on the autosomes (chromosomes 1-22) and not the sex chromosomes (X or Y).

Age

Ehlers-Danlos syndrome is a genetic disorder. As such, this syndrome and its various types are present at birth; however, symptoms may not become apparent until later in life.

 

Presentation

History

The main approach used to identify individuals affected with Ehlers-Danlos syndrome (EDS) is by completing a thorough medical history and physical examination to reveal salient diagnostic clues. Currently, some of the known EDS types can be confirmed and diagnosed using molecular or biochemical laboratory testing; namely, vascular type (type IV), kyphoscoliosis type (type VI), arthrochalasia type (types VII A and B), and dermatosparaxis type (type VIIC). All EDS types share the following clinical features to varying degrees:

Cutaneous features include the following:

  • Loose, hyperextensible, fragile skin

  • Poor wound healing

  • Tendency to bruise easily

  • Atrophic scars that are wide and thin, known as "cigarette paper scars"

Extracutaneous features include the following:

  • Fragility of blood vessels

  • Hyperextensible, hypermobile joints

  • Propensity for spontaneous joint dislocations/subluxations

Physical

Clinical forms of Ehlers-Danlos syndrome

Six discernible types of Ehlers-Danlos syndrome (EDS) are recognized as established by the Villefranche nosology.[13] A great deal of overlap exists among these phenotypes; hence, it can be difficult to make a clear clinical diagnosis for a specific EDS type. About 50% of patients diagnosed with EDS do not have a type that can be classified easily on clinical basis alone. This complicates the diagnostic process, because specific molecular diagnosis for confirmation (if available) may not be possible until a clinical EDS type has been diagnosed.

Table 1 (below) lists the identifiable EDS types (termed the Villefranche nosology) established in 1997, by a group of clinicians on the medical advisory board of The Ehlers-Danlos National Foundation (now The Ehlers-Danlos Society).[13] Villefranche nosology is currently used in the clinical setting and is regularly updated.

Table 1. Types of Ehlers-Danlos Syndrome [13, 14] (Open Table in a new window)

Type

Inheritance

Previous Nomenclature

Major Diagnostic Criteria

Minor Diagnostic Criteria

Classical

Autosomal dominant

Types I and II

Marked skin hyperextensibility, wide atrophic scars, joint hypermobility

Smooth, velvety skin; easy bruising; tissue fragility; molluscoid pseudotumors (calcified hematomas over pressure points, eg, elbows); subcutaneous spheroids (fat-containing cysts on forearms and shins); joint hypermobility (eg, sprains, dislocations, subluxations); flat feet; muscle hypotonia; gross motor delays; postoperative complications (eg, hernia); manifestations of tissue fragility (eg, hiatal hernia, anal prolapse, cervical insufficiency); positive family history

Hypermobility

Autosomal dominant

Type III

Generalized joint hypermobility, affecting both large (elbows, knees) and small (fingers, toes) joints; skin involvement (soft, smooth and velvety)

Recurrent joint dislocations and subluxations of shoulder, patella, and temporomandibular joints; chronic joint pain; limb pain; musculoskeletal pain; bruising tendencies; positive family history

Vascular

*Considered most serious EDS type, owing to risk of spontaneous arterial or organ rupture

Autosomal dominant

Type IV

Thin, translucent skin, easy to see vasculature through the skin, especially chest and abdomen; arterial/intestinal fragility or rupture; extensive bruising with minor trauma; characteristic facial appearance of large eyes, thin nose, lobeless ears; short stature; thin scalp hair

Acrogeria, aging skin; decrease of subcutaneous tissue in the face and extremities; gingival recession; hypermobile small joints; tendon/muscle rupture; clubfoot; early onset varicose veins; arteriovenous fistula; carotid-cavernous fistula; pulmonary conditions, pneumothorax, pneumohemothorax; positive family history; sudden death in close relative

Kyphoscoliosis

Autosomal recessive

Type VI

(Lysyl hydroxylase deficiency-collagen-modifying enzyme)

Generalized joint laxity; severe hypotonia at birth; delayed gross motor development; progressive scoliosis (present at birth); scleral fragility or ocular globe rupture post minor trauma

Tissue fragility; atrophic scars; easy bruising; spontaneous arterial rupture; marfanoid habitus; microcornea; osteopenia; positive family history (affected sibling)

Arthrochalasia

Autosomal dominant

Types VIIA and VIIB

Congenital hip dislocation; severe generalized joint hypermobility; recurrent subluxations

Skin hyperextensibility with easy bruising; tissue fragility with atrophic scars; muscle hypotonia; kyphoscoliosis, mild osteopenia

Dermatosparaxis

Autosomal recessive

Type VIIC

Severe skin fragility; marked bruising; saggy, redundant skin, especially of the face; scars not atrophic

Soft, doughy skin; premature rupture of membranes; hernias (umbilical and inguinal)

The major diagnostic criteria are highly specific for each EDS type. The presence of one or more major criteria is highly indicative, required for clinical diagnosis, and warrants laboratory confirmation, whenever possible. One or more minor diagnostic criteria aid in the clinical diagnosis but are not sufficient.

Hypermobility and joint laxity can be objectively determined and are measured by the Beighton Hypermobility Score.[18] The Beighton scale adds 1 point for extreme range of motion in each of 9 joints. Normal joint laxity in a young adult has a score ranging from 4-6. High scores (>6), alone, cannot be used to diagnose EDS.[19] Skin hyperextensibility is assessed by pulling the skin outward until there is resistance. An ideal location to test is the palmar side of the forearm. Typical skin stretch height in a patient without EDS is 1-1.5 cm. The skin area tested cannot be damaged or scarred or show evidence of redundancy. Not every skin site must show hyperextensibility to confirm this diagnostic feature.[14]

Historically, EDS was subdivided into 11 distinct types (types I-XI). This list was pared down to 6 in 1997, with the resulting Villefranche nosology. The following list cites some of those variants that were a part of the original group of 11 and were within the EDS spectrum:

  • Type V was described in a single family and is inherited as X-linked recessive.

  • Type VIII is similar to classical-type EDS (types I and II), but is associated with periodontal (gum) disease; it is not considered a distinct clinical entity.

  • Type IX, also known as occipital horn syndrome, has been reclassified as a variant form of Menkes disease. It is inherited as an X-linked recessive.

  • Type X was described in one family. Hematological abnormalities, such as a platelet aggregation defect, are present.

  • Type XI was called familial joint hypermobility syndrome and has been removed from EDS classification. Its relationship to EDS remains unclear.

  • Ehlers-Danlos–like syndrome from tenascin-X deficiency has been described.[20] Tenascin is a macromolecular protein in the extracellular matrix.

  • Type I collagen mutations can cause an arthrochalasia-type EDS (types VIIA and VIIB) with a predisposition to arterial rupture in early adulthood.

The Online Mendelian Inheritance in Man (OMIM) database provides updated information on the clinical and molecular understanding of single gene (monogenic) disorders. The inheritance pattern, OMIM number, and original clinical descriptions of 10 major types of EDS are listed below. The OMIM entries were reviewed to assist in the development of the Villefranche nosology in 1997 and include the following:

  • EDS type I (OMIM #130000, autosomal dominant): Distinguishing features include easy bruising, mitral valve prolapse, premature rupture of the fetal membranes, and premature birth.

  • EDS type II (OMIM #130010, autosomal dominant): This phenotype is similar to type I, but with milder clinical effects.

  • EDS type III (OMIM #130020, autosomal dominant): Features include striking joint hypermobility and minimal skin changes.

  • EDS type IV (OMIM #130050, autosomal dominant): Type IV is the vascular/ecchymotic form. Patients with EDS type IV have prominent venous markings, which are readily visible through the skin. This EDS type is very important to diagnose because patients are at risk for spontaneous rupture of the bowel, medium-sized arteries, or both. Often, rupture leads to early death. Median life expectancy in these patients is 45-50 years.[21, 22]

  • EDS type V (OMIM #305200, X-linked recessive): This phenotype is similar to, if not indistinguishable from, type II; however, in familial cases, type V exhibits X-linked recessive inheritance.

  • EDS type VI (OMIM #225400, autosomal recessive): Patients may present with retinal detachments, microcornea, myopia, and scoliosis. Differentiating hypermobility from neuromuscular hypotonia in these patients may be difficult.[23]

  • EDS type VII (OMIM #130060, types VIIA and VIIB, autosomal dominant; OMIM #225410, type VIIC, autosomal recessive): Patients exhibit arthrochalasis multiplex congenita (hyperflaccidity of the joints without hyperelasticity of the skin), short stature, and micrognathia. Multiple congenital skull fractures have been reported in EDS type VIIC.[24, 25]

  • EDS type VIII (OMIM #130080, autosomal dominant): In addition to the other notable features, patients with EDS type VIII have multiple skin striae and significant dental problems, including early tooth loss, periodontitis, and alveolar bone loss. The existence and classification of type VIII is presently under debate.[26]

  • EDS type IX (OMIM #304150, X-linked recessive): Features include occipital exostoses, bladder diverticula or rupture, bony dysplasias, and decreased copper and ceruloplasmin. EDS type IX is no longer a subtype. Once the gene was identified, type IX was removed from the EDS classification. The gene is related to a condition termed cutis laxa or occipital horn syndrome (see Causes).

  • EDS type X (OMIM #225310, autosomal recessive): Patients exhibit poor wound healing, petechiae, and a platelet aggregation defect. This platelet defect can be corrected with fibronectin supplementation.[27]

A new type of EDS also has been described. Six patients from 2 consanguineous families were reported to have EDS-like features and radiologic findings of a skeletal dysplasia.[28] Findings included hyperelastic, thin, and easily bruisable skin; hypermobile small joints with a tendency toward contractures; atrophy of the thenar muscles; tapering fingers; and protuberant eyes with bluish sclerae. The affected individuals had platyspondyly with moderate short stature, osteopenia, and widened metaphyses. Patients described in the report had a homozygous c.483_491 del9 SLC39A13 mutation that encodes for a membrane-bound zinc transporter, SLC39A13. This data suggest a new entity designated as spondylocheirodysplasia, EDS-like. The medical terminology indicates a generalized skeletal dysplasia that mainly involves the spine (spondylo) and striking clinical abnormalities of the hands (cheiro), in addition to the EDS-like features.[29] The OMIM database refers to this syndrome as the spondylocheirodysplastic form of EDS (SCD-EDS), (OMIM #612350, autosomal recessive).

In addition, a galactosyltransferase I deficiency form of progeroid EDS (OMIM #130070, autosomal recessive) has been described.[30]  Patients have short stature and limb anomalies (Ehlers-Danlos syndrome with short stature and limb anomalies [EDSSLA]).

Causes

The Human Genome Project (HGP) and further advances in molecular genetics have provided much information regarding the molecular basis of Ehlers-Danlos syndrome (EDS). Physical positions of involved genes and their locations on chromosomal maps are cited in Table 2, below.

Table 2. Molecular Basis of EDS (Open Table in a new window)

Type

Old Nomenclature

Protein Abnormality

Gene Abnormality

Chromosome Locus

Classical

Types I and II

Type V collagen

*COL5A1,COL5A2

COL1A1

*9q34.3

2q32.3

17q21.3

Hypermobility

Type III

Type III collagen

Tenascin-XB

COL3A1

TNXB

2q32.2

6p21.3

Vascular

Type IV

Type III collagen

COL3A1

2q32.2

Kyphoscoliosis

Type VI

Lysyl hydroxylase deficiency (some)

PLOD1

1p36.22

Arthrochalasia

Types VIIA and VIIB

Type I collagen

A: COL1A1

B: COL1A2

17q21.33

7q21.3

Dermatosparaxis

Type VIIC

N-proteinase

ADAMTS2

5q35.3

*Indicates classical type II has a specific gene abnormality COL5A1 with locus 9q34.3, whereas all 3 gene abnormalities and corresponding loci are present for type I. The protein abnormality type V collagen is involved in both classical forms of EDS.

 

DDx

Diagnostic Considerations

These include the following:

  • Stickler syndrome

  • Cutis laxa (elastolysis)

  • TGFBR-related phenotype (transforming growth factor beta receptor–related phenotype)

  • Ehlers-Danlos–like syndrome due to tenascin-X deficiency (OMIM #606408)

  • Neuromuscular disease

  • Ehlers-Danlos/osteogenesis imperfecta overlap syndromes

  • Vasculitis[31]

Differential Diagnoses

 

Workup

Laboratory Studies

The following laboratory studies may be indicated in patients diagnosed with Ehlers-Danlos syndrome (EDS):

  • Diagnosis of the vascular-type EDS (type IV), arthrochalasia-type EDS (types VIIA and VIIB), and dermatosparaxis-type EDS (type VIIC) requires a skin biopsy. Biochemical studies performed on cultured skin fibroblasts can detect alterations in collagen molecules.

  • Molecular (DNA-based) testing is available for the vascular, arthrochalasia, and dermatosparaxis types.

  • Kyphoscoliosis-type EDS (type VI) can be identified by urine enzyme assay.

The remaining types of EDS—classical-type EDS and hypermobility-type EDS—are diagnosed through clinical examination.

A multi-institutional, cross-sectional, retrospective study by Shalhub et al demonstrated the pitfalls of using clinical criteria alone in diagnosing vascular-type EDS. Patients who were diagnosed only through clinical evaluation had a higher rate of symptoms characteristic of other forms of EDS, specifically, mitral valve prolapse and joint hypermobility, than did patients whose diagnosis was confirmed via testing for pathogenic COL3A1 variants (10.5% vs 1.2% and 68.4% vs 40.7%, respectively). The clinical diagnosis–only cohort also had a lower rate of symptoms characteristic of vascular-type EDS than did the genetic-testing group, including easy bruising (23.7% vs 64%, respectively), thin translucent skin (17.1% vs 48.8%, respectively), intestinal perforation (3.9% vs 16.3%, respectively), spontaneous pneumothorax/hemothorax (3.9% vs 14%, respectively), and arterial rupture (9.2% vs 17.4%, respectively).[32]

 

Imaging Studies

Patients diagnosed with vascular-type Ehlers-Danlos syndrome (type IV) have positive findings on various imaging studies, namely computed tomography (CT) scan, magnetic resonance imaging (MRI) scan, ultrasonography, and angiography. The most common imaging abnormalities are arterial aneurysms and arterial dissections, followed by arterial ectasias and arterial occlusions.[33]

Other Tests

Ultrastructural examination of collagen fibrils may be a useful diagnostic tool to support the diagnosis of classical-type Ehlers-Danlos syndrome (EDS) (types I and II), but also for arthrochalasia-type EDS (types VIIA and VIIB) and to help further differentiate subtype VIIA from subtype VIIB.[34]

Histologic Findings

Presently, histopathologic analyses of skin biopsy specimens are nondiagnostic.

 

Treatment

Medical Care

The correct diagnosis for patients with Ehlers-Danlos syndrome (EDS) is critical and must be determined, if possible.

Biochemical studies on collagen molecules are possible with cultured skin fibroblasts to confirm vascular-type EDS (type IV), arthrochalasia-type EDS (types VIIA and VIIB), and dermatosparaxis-type EDS (type VIIC). A diagnostic assay of urinary pyridinoline cross-links identifies the kyphoscoliosis-type EDS (type VI). Therefore, if the clinical diagnosis suggests the vascular type, kyphoscoliosis type, or a subtype of arthrochalasia-type EDS, perform biochemical or molecular studies.

Once a diagnosis of EDS is made, preventative measures should be taken. Wearing a MedicAlert bracelet identifying a patient with EDS can help in case of a life-threatening emergency, such as arterial rupture or carotid-cavernous fistula.

In patients with EDS, in the event of skin lacerations or other injuries, take extreme care with the use of suture closure. Seriously consider alternatives to sutures, such as wound glues and adhesive strips.

Monitor patients for scoliosis. Instruct them to avoid excessive or repetitive lifting and other activities that produce undue strain or stress on their already hypermobile joints. Recommend low-resistance exercise to help increase muscle tone and stabilize loose joints. Physical therapy guided by a therapist who is experienced in working with patients with connective-tissue abnormalities and joint dysfunction can be very helpful in the management of long-term health. In patients with EDS who report reduced physical activity, dual-energy x-ray absorptiometry (DEXA) scanning, also known as bone densitometry, is recommended to assess for low bone density (a common finding in these patients).

Pay careful attention to cardiac auscultation and evaluation. The murmur of mitral valve prolapse (particularly in classical and hypermobility types of EDS) should be noted. Perform a baseline echocardiogram, including views of the aortic arch and aorta. Recent studies indicate a risk for thoracic aortic enlargement in patients with classical-type EDS (types I and II). Children with normal results should be reevaluated every 1-2 years and adults every 3-5 years. Any indication of aortic enlargement should be reevaluated every 1-2 years. If mitral valve prolapse is diagnosed, monitoring and screening are indicated to address subacute bacterial endocarditis precautions.

Adults with vascular-type EDS (type IV) are at risk for arterial aneurysm and rupture, noninvasive visualization of the arterial tree may be indicated.[19]

High-dose (1-4 g/d) ascorbic acid (vitamin C) therapy has been tried and, in theory, has a potential effect. Clinical studies suggest that wound healing, even in patients who are not deficient in vitamin C, can improve with supplementation above the recommended daily allowance. In patients with kyphoscoliosis-type EDS, bleeding time, wound healing, and muscle strength seem to improve after 1 year of daily oral, high-dose vitamin C therapy; however, at present, high-dose vitamin C therapy is not considered standard of care and requires medical clearance for use.

Recombinant factor VIIa has been used to help control surgical bleeding, but experience is limited and the usual surgical precautions for patients with EDS should be followed.[35] Desmopressin may also be effective in normalizing bleeding time, but the safety and efficacy of desmopressin in the treatment of bleeding in EDS remains to be established.[36, 37]

Pregnancy

Pregnancy represents a special issue in patients with certain types of Ehlers-Danlos syndrome (EDS). The critical elements are clearly prepregnancy identification of the syndrome and anticipation of potential complications or problems. EDS presents a specific set of risks for both mother and fetus/newborn.

Maternal risks are cervical insufficiency, uterine prolapse, uterine tear, poor wound healing during the postpartum period, and excessive bleeding both during and postdelivery.

Newborn risks are premature rupture of membranes with secondary premature delivery and all inherent complications. Be aware that significant joint laxity present in the newborn period may be mistaken for hypotonia, resulting in a misdirected diagnostic evaluation.[38]

Kyphoscoliosis-type EDS (type VI), diagnosed in a pregnant woman, was reported to be associated with both maternal and infant mortality.[39]

Surgical Care

Surgery may be indicated to correct fractures and stabilize dislocated joints. Surgical teams caring for patients with Ehlers-Danlos syndrome (EDS) need to be informed of any history of vascular problems or bleeding concerns. Preferential use of staples or tape (rather than stitches) for wound closure should be strongly considered.[9]

A study by Larson et al indicated that patients with hypermobility-type EDS suffering from femoroacetabular impingement (FAI) and extreme capsular laxity (soft-tissue hip instability) can be effectively treated with capsular plication, arthroscopic correction of FAI, and labral preservation, without the occurrence of iatrogenic dislocations. The study, which included 16 hips and had a mean follow-up period of 45 months, reported significant patient improvement on the modified Harris Hip Score, the 12-Item Short Form Health Survey, and a visual analogue scale for pain.[40]

Consultations

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

Consultation with a dentist is necessary. Patients with connective-tissue disorders must practice meticulous dental care, which cannot be neglected. Temporomandibular disorders, facial/jaw pain, and bone/tooth density need proper assessment and care. Treat periodontitis aggressively. Patients with kyphoscoliosis-type EDS (type VI) are at particular risk.

Comprehensive, accurate genetic counseling is one of the most critical issues in the treatment of patients with EDS. Provide the family with detailed information regarding the inheritance pattern, recurrence risks, and identification of at-risk family members. Screen pertinent individuals in the family for subtle signs and symptoms of the condition, regardless of whether signs or symptoms are suggested by family history. Discuss the prognosis and natural history of the particular EDS type in detail with the family. A key element in the genetic counseling process includes triage toward indicated medical services and, most importantly, resource identification. Identify support group resources and provide other information to the family. The Ehlers-Danlos Society is a valuble resource.

Provide referrals for mental health support with a psychologist and/or psychiatrist to discuss with the patient the impact of living with a chronic illness and the toll of daily life limitations. Caregivers and family members can also benefit from this assistance.[14, 9]

Activity

Instruct patients with Ehlers-Danlos syndrome to avoid excessive or repetitive heavy lifting and other movements that produce undue strain or stress on their already hypermobile joints (eg, finger hyperextension that occurs with pushing off of a wall with the palms of the hands).[8] Advise patients to minimize joint trauma by avoiding joint hyperextension or joint locking. Recurrent hyperextension of the joints may lead to a traumatic arthritis with associated joint pain.[9] However, appropriate strengthening exercises and carefully monitored low-level weight training may improve joint stability. Guidance from a physical therapist is recommended.

 

Medication

Medication Summary

Daily intake of high-dose ascorbic acid (vitamin C) has been used, although presently it is not considered standard of care (see Medical Care).

Desmopressin may help to normalize bleeding time for patients with Ehlers-Danlos syndrome, but further studies are needed to establish the safety and efficacy of this medication in the treatment and/or prevention of bleeding.[36]

 

Follow-up

Inpatient & Outpatient Medications

Wound healing may be improved in patients with Ehlers-Danlos syndrome (EDS) with vitamin C supplementation above the recommended daily allowance (see Medical Care). Prophylaxis for subacute bacterial endocarditis may be indicated in the presence of mitral valve prolapse as in classical EDS type I.

Deterrence/Prevention

Protecting joints and minimizing joint injury helps patients with Ehlers-Danlos syndrome reduce pain, conserve energy, and maintain an active lifestyle.

Activities that involve overextension of the joints should be avoided.

Minimize the risks of slips and falls in the home by keeping walkways and corridors clear of toys and other small items. The use of throw rugs is not recommended.

If reaching or stretching causes pain or an increased risk of subluxation and/or dislocation of the joints, consider using devices such as long–handled combs and reachers to help patients accomplish daily tasks. Consider arranging home storage areas to keep frequently used items within easy grasp.[9]

Complications

Complications are related to the primary pathophysiology and include joint dislocations, wound healing problems, and scarring. Individuals with vascular-type Ehlers-Danlos syndrome (type IV) are at risk for spontaneous arterial rupture, bowel perforation (especially the sigmoid colon), and other hollow organ perforation.

Prognosis

Median life expectancy for patients with vascular-type Ehlers-Danlos syndrome (EDS) (type IV) is 50 years. In patients with other EDS types, life expectancy is usually within the normal range for the population. Patients with vascular-type EDS (type IV) caused by null mutations in the COL3A1 gene often have a milder form of EDS than do type IV patients whose condition is due to missense and splicing mutations. The former individuals may have a longer lifespan; hence, a delayed onset of vascular complications is seen in this null mutation EDS type.[41]

Patient Education

The diversity and complexity of Ehlers-Danlos syndrome (EDS) serve to highlight several important principles of clinical human genetics. These principles must be accurately conveyed to and understood by the family members through genetic counseling.

Genetic heterogeneity illustrates that mutations in different genes can produce the same phenotype. For example, classical-type EDS (type I) can result from mutations in two collagen genes, either COL5A1 (bands 9q34.2-34.3) or COL5A2 (band 2q32.3).

Variable expression (ie, variability in severity of disease expression) is a hallmark of autosomal dominant conditions. Autosomal dominant EDS exhibits both intrafamilial and interfamilial variability, which is a critical counseling issue in regard to recurrences. In addition, closely examining families for members who may not have been diagnosed in the past, is important because of a potential milder degree of expression.

An indeterminate diagnosis of a clinical type of EDS may not be possible in about 50% of patients. The clinician must tell patients when the diagnosis is either unknown or unclear, rather than guess and provide incorrect information. Types of EDS are associated with differences in modes of inheritance and long-term prognoses.

Currently, the diagnosis of only a few types of EDS can be confirmed using the practical laboratory studies available. A prevailing misconception is that specific skin biopsy findings can confirm or exclude the specific diagnosis of EDS. No specific histopathologic skin biopsy findings identify patients with EDS; therefore, skin biopsies should not be performed to confirm or exclude the diagnosis. A skin biopsy may be indicated to obtain cultured skin fibroblasts for specific biochemical and molecular studies, but most clinicians primarily rely on their knowledge and clinical diagnostic skills.

Elucidating the pathophysiology of a specific clinical disorder often leads to rethinking the phenotypic classification. For example, the previously designated EDS type IX is now known to be due to a mutation in a copper transport gene and is an allelic variant to Menkes (kinky hair) disease.

Patients should protect their joints and avoid undue trauma. Instruct patients to avoid entertaining other persons by performing maneuvers "showing off" their joint laxity. Continued excessive stretching of the joints may further exacerbate the underlying disorder.

Teach patients to avoid excessive or repetitive heavy lifting and other movements that produce undue strain or stress on already hypermobile joints.

Patients with EDS must practice meticulous dental care. Monitor dental hygiene and treat periodontitis aggressively. Gingival recession is a noted concern for vascular-type EDS (type IV).

Instruct patients with EDS to visit the ophthalmologist regularly for myopia, retinal tears, and keratoconus screening. This advice is especially important for patients with kyphoscoliosis-type EDS (type VI).

Instruct patients with EDS to avoid undue trauma to the skin and other organ systems because of poor wound healing and skin fragility. In particular, the primary care physician should strongly discourage potentially traumatic recreational activities.