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.

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 nondominant 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 an individual's age, sex, 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

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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.

Establishing the Diagnosis

The diagnosis of classic EDS is established in a proband with the minimal clinical diagnostic criteria and a heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in Table 2 identified by molecular genetic testing.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in one of the genes listed in Table 2 does not establish or rule out the diagnosis.

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 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.

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 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.

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.

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 dilatation 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.

Mode of Inheritance

Classic Ehlers-Danlos syndrome (cEDS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• It is estimated that 50% of individuals diagnosed with cEDS have an affected parent.
• It is estimated that 50% of individuals diagnosed with cEDS have the disorder as the result of a de novo pathogenic variant.
• The parents of a proband with an apparent de novo pathogenic variant should be evaluated by physical examination of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
• The family history of some individuals diagnosed with cEDS may appear to be negative because of failure to recognize the disorder in family members or, theoretically, reduced penetrance (it is unknown whether penetrance is 100% or reduced). Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected/known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial phenotypic variability is observed.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated at 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low.

Offspring of a proband. Each child of an individual with classic EDS has a 50% chance of inheriting the pathogenic variant. Intrafamilial phenotypic variability is observed.

Other family members The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

At-risk individuals. The severity, specific symptoms, and progression of the disorder are variable and cannot be predicted based on family history or results of molecular genetic testing.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA of probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Revision History

• 26 July 2018 (ha) Comprehensive update posted live
• 18 August 2011 (me) Comprehensive update posted live
• 11 May 2010 (cd) Revision: changes in testing
• 24 July 2008 (me) Comprehensive update posted live
• 29 May 2007 (cd) Revision: sequence analysis of entire coding region available for COL5A1 and COL5A2 and prenatal testing available
• 10 April 2006 (me) Comprehensive update posted live
• 29 October 2003 (ca) Review posted live
• 20 June 2003 (rw, ad) Original submission

Published Guidelines / Consensus Statements

• Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F, Francomano CA. Ehlers-Danlos syndrome, classical type. Am J Med Genet C Semin Med Genet. 2017;175:27-39. [PubMed]
• Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8-26. [PubMed]

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