Summary
Clinical characteristics.
Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft, velvety, or doughy to the touch. In addition, the skin is hyperextensible, meaning that it extends easily and snaps back after release. 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, thinning, and pigmentation of scars is characteristic, leading to the presence of atrophic and/or hemosiderotic scars. Easy bruising is also a hallmark of cEDS. GJH is present in most but not all affected individuals, evidenced by the presence of a Beighton score of five or greater, either on examination or historically. Joint instability complications may comprise sprains and dislocations/subluxations. Mild muscle hypotonia with delayed motor development, fatigue and muscle cramps, and some skeletal morphologic alterations (scoliosis, pectus deformities, genus/hallux valgus, pes planus) are regularly observed. While aortic root dilatation and mitral valve prolapse are seen in cEDS, they are rarely clinically significant. Arterial aneurysm and rupture have been reported in a few individuals with cEDS.
Diagnosis/testing.
The diagnosis of cEDS is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in COL1A1, COL5A1, or COL5A2 identified by molecular genetic testing.
Management.
Treatment of manifestations: 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. 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. Braces as needed to improve joint stability; referral to orthopedist, rheumatologist, or physical therapist and occupational therapist as needed. Mobility devices as needed. Adjust sleep surface as needed to improve sleep quality and decrease pain. Those with hypotonia, joint instability, and chronic pain may need to adapt lifestyles accordingly. Anti-inflammatory drugs may alleviate joint pain. Children with hypotonia and delayed motor development benefit from physiotherapy. Non-weight-bearing exercise promotes muscle strength and coordination. Ascorbic acid (vitamin C) may reduce bruising. DDAVP® (desmopressin) may be useful to normalize bleeding time. Cardiovascular manifestations are treated in a standard manner.
Surveillance: Assess for skin fragility, joint instability, occupational and physical therapy needs, mobility issues, and pain at each visit or as needed. Evaluation for hypotonia and motor development at each visit in infants and children. Assess for easy bruising and/or prolonged bleeding at each visit. Evaluation of clotting factors if severe easy bruising is present. Yearly echocardiogram when aortic dilatation and/or mitral valve prolapse are present.
Agents/circumstances to avoid: Sports with heavy joint strain.
Genetic counseling.
Classic EDS is inherited in an autosomal dominant manner. Approximately 50% of individuals diagnosed with cEDS have an affected parent; approximately 50% of individuals diagnosed with cEDS have the disorder as the result of a de novo pathogenic variant. Each child of an individual with cEDS has a 50% chance of inheriting the pathogenic variant. Once the cEDS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Diagnosis
There are no consensus clinical diagnostic criteria for classic Ehlers-Danlos syndrome (cEDS); diagnosis requires molecular testing.
Suggestive Findings
Classic EDS should be suspected in a proband with either of the following:
- Major criteria skin hyperextensibility and atrophic scarringOR
- Major criterion generalized joint hypermobility (GJH) and/or ≥3 minor criteria
Major criteria
- Skin hyperextensibility (see Figure 1) is 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.)
- GJH (see Figure 3) depends on an individual's age, sex, and family and ethnic background. Joint hypermobility in cEDS is usually 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 semiquantification of joint hypermobility (see Table 1). A Beighton score of ≥5 is considered positive for the presence of GJH.
Table 1.
Beighton Criteria for Joint Hypermobility
Since laxity decreases with age, individuals with a Beighton score of <5 may be considered positive based on historical observations. The five-point questionnaire is as follows (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.
![Figure 1.](/books/NBK1244/bin/eds-Image001.gif)
Figure 1.
Skin hyperextensibility
![Figure 2.](/books/NBK1244/bin/eds-Image002.gif)
Figure 2.
Widened atrophic scars
![Figure 3.](/books/NBK1244/bin/eds-Image003.gif)
Figure 3.
Flexion of the thumb to forearm, illustrating joint hypermobility
Minor criteria
- 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, 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 with a diagnosis of cEDS
Establishing the Diagnosis
The diagnosis of cEDS is established in a proband with suggestive findings 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 variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this GeneReview is understood to include any likely pathogenic variant. (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 a combination of multigene targeted testing and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).
Option 1
Multigene targeted testing. Sequence analysis of COL5A1 and COL5A2 (multigene targeted panels may also include COL1A1 and other EDS-related genes; see Differential Diagnosis) is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. If the multigene panel only includes COL5A1 and COL5A2, targeted testing of COL1A1 pathogenic variant c.934C>T should be done next if no COL5A1 or COL5A2 pathogenic variants are identified. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis of COL5A1 and COL5A2 to detect exon and whole-gene deletions or duplications.
Note: (1) Multigene targeted analysis implies that the coding regions for the genes, included in the multigene panel, are enriched. (2) 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. (3) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (4) 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. (5) 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.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by hypermobility, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible in some diagnostic centers.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
![Table Icon](/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif)
Table 2.
Molecular Genetic Testing Used in Classic Ehlers-Danlos Syndrome
Other Testing
COL5A1 null allele test. If a pathogenic variant cannot be identified on molecular genetic testing, a type V collagen abnormality can sometimes be demonstrated by the COL5A1 null allele test if the proband is heterozygous for a polymorphic marker in COL5A1 at the genomic DNA (gDNA) level. Copy DNA is analyzed from fibroblasts to identify 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.
Transmission electron microscopy (TEM). If molecular genetic testing is not available, TEM findings of collagen flowers on skin biopsy can support the clinical diagnosis, but do not confirm it, as collagen flowers are not pathognomonic for cEDS.
Clinical Characteristics
Clinical Description
Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and generalized joint hypermobility.
Skin. Skin is hyperextensible; it extends easily and snaps back after release (unlike lax, redundant skin, as in cutis laxa).
The skin is soft, velvety, or 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, thinning, and pigmentation of scars is characteristic. Scars become wide, with a "cigarette-paper"-like (papyraceous) appearance, also referred to as atrophic and/or hemosiderotic scars.
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: characterized by skin-colored to erythematous keratotic papules, some enlarging outward in serpiginous or arcuate configurations, leaving slightly atrophic centers
- Acrocyanosis: painless 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 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 can be 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/subluxations of large and small joints (e.g., shoulder, patella, digits, hip, radius, and clavicle) may occur and usually resolve spontaneously or are easily managed by the affected individual. Many individuals with cEDS experience chronic joint and limb pain, despite normal skeletal radiographs.
Other problems related to joint hypermobility are joint instability, foot deformities such as congenital clubfoot or pes planus, and temporomandibular joint dysfunction [Bowen et al 2017].
Neurologic features. Primary muscular hypotonia may occur and may cause delayed motor development, problems with ambulation, and mild motor disturbance in children with cEDS. Fatigue and muscle cramps are relatively frequent.
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 individuals with 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 [Bowen et al 2017].
Individuals with cEDS are at risk for spontaneous rupture of large arteries, although the prevalence of such complications is much lower than in those with vascular EDS.
Dental. Classic EDS may be associated with abnormal dentinogenesis resulting in localized root anomalies, with shortened or bulbous roots, that lead to loosening of the teeth. Calcification of the pulp is another common finding in cEDS. This is usually of little clinical significance but may complicate root canal treatment [Lepperdinger et al 2021].
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 [Kang et al 2020].
- Premature rupture of the membranes and prematurity are reported to be twice as common in fetuses with cEDS born to healthy mothers, compared with fetuses without EDS born to a mother with cEDS.
- 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.
- Intrauterine growth restriction may occur.
- Perineal tearing, postpartum hemorrhage, pelvic prolapse, and incontinence following delivery may occur.
Phenotype Correlations by Gene
COL5A2. Although numbers are still limited, pathogenic variants in COL5A2 are thought to result in a phenotype at the more severe end of the cEDS spectrum [Colman et al 2021].
Genotype-Phenotype Correlations
No genotype-phenotype correlations have emerged to date.
Penetrance
Penetrance is presumably 100% in both males and females, but in some individuals the condition is very mild, and may be undiagnosed.
Nomenclature
As a result of the 1997 Villefranche conference on EDS [Beighton et al 1998], EDS type I and type II were collectively reclassified "EDS, classical type." In 2017, the International EDS Consortium proposed a revised EDS classification system in which the nomenclature for "EDS, classical type" was changed to "classical 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 (previously classified as EDS type II) do not come to medical attention and thus go undetected.
Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this GeneReview are known to be associated with germline pathogenic variants in COL5A2.
Other phenotypes associated with germline pathogenic variants in COL1A1 and COL5A1 are summarized in Table 3.
![Table Icon](/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif)
Table 3.
Allelic Disorders
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 with classic EDS (cEDS) is seen with all other forms of EDS, in particular with hypermobile EDS (hEDS) and the EDS types listed in Table 4.
Hypermobile EDS is generally considered the least severe type of EDS, although significant complications, primarily musculoskeletal, can occur. Similar to cEDS, generalized joint hypermobility, mild atrophic scarring, mild skin hyperextensibility, and soft, velvety skin are seen in hEDS. Unlike cEDS, hEDS is not associated with truly papyraceous and/or hemosiderotic scars. The diagnosis of hEDS is based entirely on clinical evaluation and family history. The gene(s) in which pathogenic variants cause hEDS are unknown.
Management
For a detailed review of complications and management of classic Ehlers-Danlos syndrome (cEDS), see Bowen et al [2017].
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with cEDS, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
![Table Icon](/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif)
Table 5.
Classic Ehlers-Danlos Syndrome: Recommended Evaluations Following Initial Diagnosis
Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).
![Table Icon](/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif)
Table 6.
Classic Ehlers-Danlos Syndrome: Treatment of Manifestations
Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.
![Table Icon](/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif)
Table 7.
Classic Ehlers-Danlos Syndrome: Recommended Surveillance
Agents/Circumstances to Avoid
Sports with heavy joint strain should be avoided (contact sports, fighting sports, football, running).
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. In general, 2 g per day is recommended for adults; however, no strict guidelines exist regarding recommended dose during the third trimester of pregnancy.
Physiotherapist referral should be made to address pelvic instability and pain.
Monitoring for intrauterine growth restriction and cervical insufficiency through cervical length screening can be valuable.
Monitoring of pregnant women for preterm labor is warranted during the third trimester, when the risk for preterm premature rupture of the membranes is increased.
For vaginal delivery, prompt episiotomy should be considered to prevent excessive perineal damage.
Prophylactic desmopressin and tranexamic acid, along with postpartum oxytocin, should be considered in view of the increased risk for postpartum hemorrhage.
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.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.
Mode of Inheritance
Classic Ehlers-Danlos syndrome (cEDS) is inherited in an autosomal dominant manner.
Risk to Family Members
Parents of a proband
- Approximately 50% of individuals diagnosed with cEDS have an affected parent.
- A proband with cEDS may have the disorder as the result of a COL1A1, COL5A1, or COL5A2 pathogenic variant that occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic, apparently unaffected parent. Approximately 50% of individuals diagnosed with cEDS have the disorder as the result of a de novo pathogenic variant.
- If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for both parents of the proband include:
- Evaluation for manifestations of cEDS (i.e., 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 for the cEDS-related pathogenic variant identified in the proband to evaluate the genetic status of the parents and inform recurrence risk assessment.
- If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
- The proband has a de novo pathogenic variant.
- The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Chesneau et al 2021, Micale et al 2021]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
- The family history of some individuals diagnosed with cEDS may appear to be negative because of failure to recognize the disorder in family members with very mild phenotypes. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in 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 and/or known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial phenotypic variability is observed; the severity, specific manifestations, and progression of the disorder are variable and cannot be predicted in a sib who inherits a pathogenic variant.
- If the cEDS-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental germline mosaicism. Paternal mosaicism for a COL5A1 pathogenic variant has been reported in two families [Chesneau et al 2021, Micale et al 2021].
- If the parents appear to be unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of a very mild phenotype in an undiagnosed heterozygous parent and of parental germline mosaicism.
Offspring of a proband. Each child of an individual with cEDS has a 50% chance of inheriting the pathogenic variant.
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.
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.
Prenatal Testing and Preimplantation Genetic Testing
Once the cEDS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. However, the severity, specific manifestations, and progression of cEDS are variable and cannot be predicted based on family history or the presence of a pathogenic variant identified on prenatal testing.
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.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
- Ehlers-Danlos Society - EuropeUnited KingdomPhone: +44 203 887 6132
- Ehlers-Danlos Support UKUnited KingdomPhone: 0208 736 5604; 0800 9078518
- The Ehlers-Danlos SocietyPhone: 410-670-7577
- MedlinePlus
- DICE EDS and HSD Global Registry
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
![Table Icon](/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif)
Table A.
Classic Ehlers-Danlos Syndrome: Genes and Databases
![Table Icon](/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif)
Table B.
OMIM Entries for Classic Ehlers-Danlos Syndrome (View All in OMIM)
Molecular Pathogenesis
COL1A1 encodes the pro-α1 chains of type I collagen, whose triple helix comprises two α1 chains and one α2 chain. Type I collagen is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis, and tendon.
COL5A1 and COL5A2 encode the pro-α1 and the pro-α2 chain of type V collagen, respectively. Type V collagen is a minor fibril-forming collagen that is mainly present as [α1(V)]2 α2(V) heterotrimers in skin, bone, and tendon. It forms heterotypic fibrils with type I collagen and regulates the diameter of those fibrils, presumably through its partially retained amino-terminal propeptide. The pathogenic mechanism underlying classic Ehlers-Danlos syndrome (cEDS) is hypothesized to be "functional" haploinsufficiency of type V collagen, caused either by loss of expression of one COL5A1 allele, inefficient trafficking of mutated protein through the endoplasmic reticulum, or impaired incorporation of mutated α chains into type V collagen heterotrimers. Given its important regulatory role during the formation of heterotypic type I/V collagen fibrils, reduced availability of type V collagen is expected to negatively impact interactions with other extracellular matrix (ECM) components and hence compromises the general organization of the ECM [Symoens et al 2012].
![Table Icon](/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif)
Table 8.
Classic Ehlers-Danlos Syndrome: Gene-Specific Mechanism of Disease Causation
COL1A1-specific laboratory technical considerations. Although most pathogenic variants in COL1A1 cause osteogenesis imperfecta, the specific missense variant c.934C>T causes cEDS.
![Table Icon](/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif)
Table 9.
Pathogenic Variants Referenced in This GeneReview by Gene
Chapter Notes
Author Notes
The Malfait Lab (Center for Medical Genetics Ghent [CMGG] at Ghent University Hospital and Department for Biomolecular Medicine at Ghent University, Belgium) performs integrative translational research on Ehlers-Danlos syndromes (EDS). CMGG at Ghent University Hospital, in which the Malfait Lab is embedded, has a strong reputation as an internationally recognized center of expertise for research, diagnostics, and clinical management related to a range of hereditary connective tissue disorders (CTD), including, among others, EDS.
At the Malfait Lab, PI Prof Fransiska Malfait, MD, PhD, and Postdoctoral Fellow Delfien Syx, PhD, lead studies in the following areas of interest:
- Unraveling the molecular basis of hereditary CTD, with a special focus on EDS and other hypermobility-related disorders, and studying their natural history and genotype-phenotype correlations;
- Elucidating molecular and physiologic mechanisms underlying hereditary CTD pathogenesis, using an integrated approach of in vitro and in vivo techniques, on tissue samples of humans and animal models (zebra fish, mice);
- Studying prevalence, nature, and pathophysiologic mechanisms of pain in individuals with EDS and in relevant animal models.
Fransiska Malfait (eb.tnegu@tiaflam.aksisnarf) is actively involved in clinical research regarding individuals with EDS. Prof Malfait would be happy to communicate with persons who have any questions regarding diagnosis of EDS or other considerations.
Prof Malfait is also interested in hearing from clinicians treating families affected by EDS in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Dr Sofie Symoens (eb.tnegu@sneomys.eifos) to inquire about cEDS-related variants of uncertain significance.
Acknowledgments
This work is supported by the Research Foundation Flanders (12Q5920N to D.S.; 1842318N & 3G041519 to F.M.), Ghent University (GOA019-21 to F.M.), Association française des syndromes d'Ehlers-Danlos (AFSED), The Ehlers-Danlos Society, Zebrapad VZW. The authors wish to thank the International Consortium on the Ehlers-Danlos Syndromes for their contribution.
Author History
Anne De Paepe, MD, PhD; Ghent University Hospital (2003-2024)
Fransiska Malfait, MD, PhD (2003-present)
Sofie Symoens, PhD
Delfien Syx, PhD
Richard Wenstrup, MD; Cincinnati Children's Hospital Medical Center (2003-2024)
Revision History
- 1 February 2024 (sw) Comprehensive update posted live
- 26 July 2018 (ha) Comprehensive update posted live
- 18 August 2011 (me) Comprehensive update posted live
- 24 July 2008 (me) Comprehensive update posted live
- 10 April 2006 (me) Comprehensive update posted live
- 29 October 2003 (ca) Review posted live
- 20 June 2003 (rw, ad) Original submission
References
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]
Literature Cited
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Initial Posting: May 29, 2007; Last Update: February 1, 2024.
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Malfait F, Symoens S, Syx D. Classic Ehlers-Danlos Syndrome. 2007 May 29 [Updated 2024 Feb 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.