Classic Ehlers-Danlos Syndrome
Summary
Clinical characteristics.
Classic Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft and doughy to the touch, and hyperextensible, extending easily and snapping back after release (unlike lax, redundant skin, as in cutis laxa). The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is poor, and stretching of scars after apparently successful primary wound healing is characteristic. Complications of joint hypermobility, such as dislocations of the shoulder, patella, digits, hip, radius, and clavicle, usually resolve spontaneously or are easily managed by the affected individual. Other features include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Mitral valve prolapse can occur infrequently, but tends to be of little clinical consequence. Aortic root dilatation has been reported, appears to be more common in young individuals, and rarely progresses.
Diagnosis/testing.
The diagnosis of cEDS is established in a proband with the minimal clinical diagnostic criteria (skin hyperextensibility and atrophic scarring and either GJH or ≥3 minor clinical criteria) and identification on molecular genetic testing of a heterozygous pathogenic variant in COL5A1, COL5A2, or (less commonly) COL1A1.
Management.
Treatment of manifestations: Children with hypotonia and delayed motor development benefit from physiotherapy. Non-weight-bearing exercise promotes muscle strength and coordination. Anti-inflammatory drugs may alleviate joint pain. Those with hypotonia, joint instability, and chronic pain may need to adapt lifestyles accordingly. Dermal wounds are closed without tension, preferably in two layers. For other wounds, deep stitches are applied generously; cutaneous stitches are left in place twice as long as usual; and the borders of adjacent skin are carefully taped to prevent stretching of the scar. DDAVP® (deamino-delta-D-arginine vasopressin) may be useful to normalize bleeding time. Cardiovascular problems are treated in a standard manner.
Prevention of primary manifestations: Young children with skin fragility can wear pads or bandages over the forehead, knees, and shins to avoid skin tears. Older children can wear soccer pads or ski stockings with shin padding during activities. Ascorbic acid (vitamin C) may reduce bruising.
Surveillance: Yearly echocardiogram when aortic dilatation and/or mitral valve prolapse are present.
Agents/circumstances to avoid: Sports with heavy joint strain; acetylsalicylate (aspirin).
Genetic counseling.
Classic EDS is inherited in an autosomal dominant manner. It is estimated that approximately 50% of affected individuals have an affected parent, and approximately 50% of affected individuals have the disorder as the result of a de novo pathogenic variant. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
The diagnosis of classic Ehlers-Danlos syndrome (cEDS) can be suspected based on clinical examination and family history. Diagnostic criteria were developed by a medical advisory group in a conference at Villefranche in 1997 [Beighton et al 1998] and recently revised by the International EDS Consortium [Malfait et al 2017].
- A major criterion has high diagnostic specificity because it is present in the vast majority of affected individuals and/or it is characteristic for the disorder and allows differentiation from other EDS subtypes and/or other heritable connective tissue disorders.
- A minor criterion is a sign of lesser diagnostic specificity, but its presence supports the diagnosis.
Major Diagnostic Criteria for cEDS
Skin hyperextensibility. See Figure 1.
Figure 1.
Skin hyperextensibility
- Skin hyperextensibility should be measured by pinching and lifting the cutaneous and subcutaneous layers of the skin on the volar surface at the middle of the non-dominant forearm as described by Remvig et al [2009].
- Skin is hyperextensible if it can be stretched over a standardized cutoff in three of the following areas: 1.5 cm for the distal part of the forearms and the dorsum of the hands; 3 cm for neck, elbows, and knees.
Atrophic scarring. See Figure 2.
Figure 2.
Widened atrophic scars
Generalized joint hypermobility (GJH). Joint hypermobility (see Figure 3) depends on age, gender, and family and ethnic background.
Figure 3.
Passive flexion of thumbs to the forearm: manifestation of joint hypermobility
- Joint hypermobility in cEDS is general, affecting both large and small joints, and is usually noted when a child starts to walk.
- It should be assessed using the Beighton scale, the most widely accepted grading system for the objective semi-quantification of joint hypermobility (see Table 1).
- Since laxity decreases with age, individuals with a Beighton score of <5 may be considered positive based on historical observations (see Five-point questionnaire).
Table 1.
Beighton Criteria for Joint Hypermobility
| Joint/Finding | Negative | Unilateral | Bilateral |
|---|---|---|---|
| Passive dorsiflexion of the 5th finger >90° | 0 | 1 | 2 |
| Passive flexion of thumbs to the forearm | 0 | 1 | 2 |
| Hyperextension of the elbows beyond 10° | 0 | 1 | 2 |
| Hyperextension of the knees beyond 10° | 0 | 1 | 2 |
| Forward flexion of the trunk with knees fully extended and palms resting on the floor | 0 | 1 | |
A total score of ≥5 defines hypermobility.
Five-point questionnaire (adapted from Hakim & Grahame [2003])
- 1.
Can you now (or could you ever) place your hands flat on the floor without bending your knees?
- 2.
Can you now (or could you ever) bend your thumb to touch your forearm?
- 3.
As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits?
- 4.
As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?
- 5.
Do you consider yourself "double-jointed?"
Note: A "yes" answer to ≥2 questions suggests joint hypermobility with 80%-85% sensitivity and 80%-90% specificity.
Minor Diagnostic Criteria for cEDS
- Easy bruising
- Soft, doughy skin
- Skin fragility (or traumatic splitting)
- Molluscoid pseudotumors: fleshy, heaped-up lesions associated with scars over pressure points such as the elbows and knees
- Subcutaneous spheroids: small spherical hard bodies, frequently mobile, and palpable on the forearms and shins. Spheroids may be calcified and detectable radiologically.
- Hernia (or history thereof)
- Epicanthal folds
- Complications of joint hypermobility (e.g., sprains, dislocations/subluxations, pain, flexible flat foot)
- Family history of a first-degree relative who meets clinical criteria
Classic Ehlers-Danlos syndrome (cEDS) should be suspected in individuals with both of the following:
- Major criteria skin hyperextensibility and atrophic scarring
- Major criterion GJH and/or ≥3 minor criteria
Establishing the Diagnosis
The diagnosis of classic EDS is established in a proband with the minimal clinical diagnostic criteria and identification of a heterozygous pathogenic variant in one of the genes listed in Table 2.
Molecular genetic testing approaches can include concurrent (or serial) single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
- Concurrent single-gene testing. Sequence analysis of COL5A1, COL5A2, and COL1A1 is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.Note: If serial gene analysis is to be performed, sequence analysis of COL5A1 is performed first, followed by sequence analysis of COL5A2 and then gene-targeted deletion/duplication analysis if no pathogenic variant is found. If the causative variant is not identified, COL1A1 sequencing should be considered.
- A multigene panel that includes COL5A1, COL5A2, COL1A1, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.Note: When a pathogenic variant cannot be found, a type V collagen abnormality can sometimes be demonstrated by the COL5A1 null allele test. The individual being tested must be heterozygous for a polymorphic marker in COL5A1; cDNA from a skin biopsy is then tested to look for the presence of one or both markers. If one marker is not expressed, that allele is assumed to be nonfunctional (i.e., "null"). This type of testing is not widely available.
Table 2.
Molecular Genetic Testing Used in Classic Ehlers-Danlos Syndrome (cEDS)
| Gene 1, 2 | Proportion of cEDS Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| COL1A1 | <1% 6 | 100% 6 | None reported 6 |
| COL5A1 | 75%-78% 7 | 99% 7 | 1% 7 |
| COL5A2 | 14% 7 | 100% 7 | Unknown 8 |
| Unknown | <10% 7 | NA | |
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Brady et al [2017], Malfait et al [2017]
- 7.
Symoens et al [2012], Ritelli et al [2013]
- 8.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Note: If genetic testing is not available, transmission electron microscopy (TEM) findings of collagen flowers on skin biopsy can support the clinical diagnosis, although not confirm it.
Clinical Characteristics
Clinical Description
Classic Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and generalized joint hypermobility. Previously, two subtypes, EDS type I and EDS type II, differing only in phenotypic severity, were recognized; it is now apparent that they form a continuum of clinical findings.
Skin
Cutaneous hyperextensibility is one of the cardinal features of EDS in general and of cEDS in particular. Skin extends easily and snaps back after release (unlike lax, redundant skin, as in cutis laxa).
The skin is soft and doughy to the touch.
The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Skin fragility may cause dehiscence of sutured incisions in skin or mucosa.
Wound healing is poor, and stretching of scars after apparently successful primary wound healing is characteristic. Scars become wide, with a "cigarette-paper"-like (papyraceous) appearance.
Other dermatologic features in cEDS:
- Molluscoid pseudotumors
- Subcutaneous spheroids
- Piezogenic papules: small, painful, reversible herniations of underlying adipose tissue globules through the fascia into the dermis, such as on medial and lateral aspects of the feet upon standing
- Elastosis perforans serpiginosa: a rare skin condition of unknown etiology characterized by skin-colored to erythematous keratotic papules, some enlarging outwards in serpiginous or arcuate configurations, leaving slightly atrophic centers
- Acrocyanosis: a painless disorder caused by constriction or narrowing of the small blood vessels in the skin (affecting mainly the hands) in which the affected areas turn blue and become cold and sweaty; localized swelling may also occur
- Chilblains: cold injuries, characterized by a red swollen skin that is tender and hot to the touch, and may itch; can develop in less than two hours in skin exposed to cold
Tissue Fragility
Manifestations of generalized tissue extensibility and fragility are observed in multiple organs:
- Cervical insufficiency during pregnancy
- Inguinal and umbilical hernia
- Hiatal and incisional hernia
- Recurrent rectal prolapse in early childhood
Joints
Complications of joint hypermobility including dislocations of the shoulder, patella, digits, hip, radius, and clavicle may occur and usually resolve spontaneously or are easily managed by the affected individual. Some individuals with cEDS may experience chronic joint and limb pain, despite normal skeletal radiographs.
Other problems related to the joint hypermobility are joint instability, foot deformities such as congenital clubfoot or pes planus, temporomandibular joint dysfunction, joint effusions, and osteoarthritis [Hagberg et al 2004, De Coster et al 2005a, De Coster et al 2005b].
Neurologic Features
Primary muscular hypotonia may occur and may cause delayed motor development, problems with ambulation, and mild motor disturbance in individuals with cEDS. Fatigue and muscle cramps are relatively frequent. Rarely, CSF leak has been reported to cause postural hypotension and headache [Schievink et al 2004].
Easy Bruising
Easy bruising is a common finding and manifests as spontaneous ecchymoses, frequently recurring in the same areas and causing a characteristic brownish discoloration of the skin, especially in exposed areas such as shins and knees. There is a tendency toward prolonged bleeding (e.g., following brushing of the teeth) in spite of a normal coagulation status.
Cardiovascular
Structural cardiac malformations are uncommon in cEDS.
Mitral valve prolapse and (less frequently) tricuspid valve prolapse may occur. Stringent criteria should be used for the diagnosis of mitral valve prolapse. When it does occur, mitral valve prolapse tends to be of little clinical consequence [Atzinger et al 2011].
Aortic root dilatation has been reported in cEDS [Wenstrup et al 2002, McDonnell et al 2006, Atzinger et al 2011]. It appears to be more common in young individuals and rarely progresses [Atzinger et al 2011].
Spontaneous rupture of large arteries, along with intracranial aneurysms and arteriovenous fistulae, may occur in the rare individual with a severe form of cEDS.
Pregnancy
Pregnancy in a woman with cEDS places both the newborn and the mother at risk for complications (see Pregnancy Management). As a whole, the complications are more frequent than in the normal population, although it is difficult to quantitate the incidence of each complication in affected individuals because no good studies exist.
- Preterm rupture of the membranes and prematurity can occur when the mother is affected, and also when the fetus is affected, especially in the most severe forms.
- Because of hypotonia, breech presentation is more frequent if the baby is affected and may lead to dislocation of the hips or shoulder of the newborn.
Genotype-Phenotype Correlations
No genotype/phenotype correlations have emerged to date.
Although numbers are still limited, pathogenic variants in COL5A2 are thought to result in a phenotype at the more severe end of the classic EDS spectrum.
Penetrance
It is unknown whether penetrance is 100% or reduced. It is presumed to be the same for males and females.
Nomenclature
As a result of the 1997 Villefranche conference on EDS [Beighton et al 1998], the former EDS type I and type II were reclassified as EDS, classic type. In 2017, the International EDS Consortium proposed a revised EDS classification system. The new nomenclature for EDS, classic type is classic EDS, or cEDS [Malfait et al 2017].
Prevalence
The prevalence of cEDS has been estimated at 1:20,000 [Byers 2001]. However, it is likely that some individuals with milder manifestations of the disease, previously classified as EDS type II, do not come to medical attention and thus go undetected.
Differential Diagnosis
Other forms of Ehlers-Danlos syndrome (EDS) should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation. Clinical overlap is seen with all other forms of EDS, in particular with the following subtypes.
Table 3.
Other EDS disorders to Consider in the Differential Diagnosis of Classic EDS
| Disorder | Gene(s) | MOI | Clinical Features of This Disorder | |
|---|---|---|---|---|
| Overlapping w/cEDS | Distinguishing from cEDS | |||
| Classic-like EDS (OMIM 606408) | TNXB | AR |
|
|
| Cardiac-valvular EDS (OMIM 225320) | COL1A2 | AR |
|
|
| Hypermobile EDS | Unknown | AD |
| Absence of truly papyraceous &/or hemosiderotic scars |
| Arthrochalasia EDS (OMIM 130060, 617821) | COL1A1 COL1A2 | AD |
| Bilateral congenital hip dislocation |
| Dermatosparaxis EDS (OMIM 225410) | ADAMTS2 | AR |
|
|
| Kyphoscoliotic EDS | PLOD1 | AR |
| Congenital muscle hypotonia |
| Kyphoscoliotic EDS w/myopathy & neurosensory hearing loss | FKBP14 | AR |
|
|
AD = autosomal dominant; AR = autosomal recessive; GJH = generalized joint hypermobility; MOI = mode of inheritance
Management
For a detailed review of complications and management, see Bowen et al [2017].
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with classic Ehlers-Danlos syndrome (cEDS), the following evaluations are recommended if they have not already been completed:
- Clinical examination of the skin with assessment of skin hyperextensibility, atrophic scars and bruises, and other manifestations of cEDS
- Evaluation of joint mobility with use of the Beighton score
- Evaluation for hypotonia and motor development in infants and children
- A baseline echocardiogram with aortic diameter measurement at diagnosis
- Evaluation of clotting factors if severe easy bruising is present
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
In children with hypotonia and delayed motor development, a physiotherapeutic program is important.
Non-weight-bearing muscular exercise, such as swimming, is useful to promote muscular development and coordination.
Individuals with muscle hypotonia and joint instability with chronic pain may have to adjust lifestyle and professional choices accordingly. Emotional support and behavioral and psychological therapy may help in developing acceptance and coping skills.
Dermal wounds should be closed without tension, preferably in two layers. Deep stitches should be applied generously. Cutaneous stitches should be left in place twice as long as usual and additional fixation of adjacent skin with adhesive tape can help prevent stretching of the scar.
DDAVP® (deamino-delta-D-arginine vasopressin) may be useful to normalize bleeding time. It may be beneficial in case of bruising or epistaxis, or before procedures such as dental extractions.
For recommendations on treatment of joint laxity and dislocations, see Hypermobile EDS. (Note: Surgical stabilization of joints may lead to disappointing, or only temporary, improvement.)
Anti-inflammatory drugs may help with joint pain.
Long-term chronic pain may result in the need for mental health services.
Cardiovascular problems should be treated in a standard manner.
Prevention of Primary Manifestations
Very young children with pronounced skin fragility can wear protective pads or bandages over the forehead, knees, and shins in order to avoid skin tears. Older children who are active can wear soccer pads or ski stockings with shin padding during activities. Contact sports should be avoided.
For recommendations on prevention of primary manifestations of joint laxity and dislocations, see Hypermobile EDS: Management: Prevention of Primary Manifestations.
Ascorbic acid (vitamin C) may reduce easy bruising but has no effect on the primary findings of skin hyperextensibility, atrophic scarring, and joint hypermobility. In general, a dose of two grams per day is recommended for adults, with proportionally reduced doses for children; however, there is no limitation.
Prevention of Secondary Complications
For recommendations on prevention of secondary manifestations of joint laxity and dislocations, see Hypermobile EDS: Management: Prevention of Secondary Complications.
Surveillance
If no abnormalities are found on echocardiogram in an adult, a follow-up echocardiogram is not necessary. (Because longitudinal data on progression of aortic dilation are not available, specific recommendations for follow up in individuals with a normal aortic diameter are not available.)
If no abnormalities are found on echocardiogram in a child, follow up directed by the pediatric cardiologist is recommended.
Yearly echocardiogram is warranted if an abnormality such as aortic dilatation or mitral valve prolapse is present.
Agents/Circumstances to Avoid
The following should be avoided:
- Sports with heavy joint strain (contact sports, fighting sports, football, running)
- Acetylsalicylate (aspirin)
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Because of the increased risk for skin lacerations, postpartum hemorrhages, and prolapse of the uterus and/or bladder, monitoring of women throughout pregnancy and in the postpartum period is recommended.
Ascorbic acid (vitamin C) may reduce easy bruising (see Prevention of Primary Manifestations); in general, 2 g/day is recommended for adults; however, no strict guidelines exist regarding recommended dose during the third trimester of pregnancy.
Monitoring of pregnant women for preterm labor is warranted during the third trimester when the risk for premature rupture of the membranes is increased.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.