Figure 1. Skin hyperextensibility
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Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Ehlers-Danlos syndrome (EDS), classic type is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility. It includes two previously designated subtypes (EDS type I and EDS type II) that are now recognized to form a continuum of clinical findings. The skin is smooth, velvety to the touch, and hyperelastic; i.e., it extends easily and snaps 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 delayed, 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. Less common findings include mitral and tricuspid valve prolapse, aortic root dilatation, and spontaneous rupture of large arteries.
Diagnosis/testing. The diagnosis of EDS, classic type is established by family history and clinical examination. Quantitative and qualitative studies of type V collagen chains are usually not useful in confirming a diagnosis. Approximately 50% of individuals with classic EDS have an identifiable mutation in COL5A1 or COL5A2, the genes encoding type V collagen. Sequence analysis of both genes and COL5A1 null allele testing are available on a clinical basis.
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. 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: acetylsalicylate; sports that strain joints.
Genetic counseling. EDS, classic type is inherited in an autosomal dominant manner. It is estimated that approximately 50% of affected individuals have inherited the disease-causing mutation from an affected parent, and approximately 50% of affected individuals have a de novo disease-causing mutation. Each child of an affected individual has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk may be possible for families in which the disease-causing mutation has been identified in an affected family member.
The diagnosis of Ehlers-Danlos syndrome (EDS), classic type is established by family history and clinical examination. Diagnostic criteria were developed by a medical advisory group in a conference (sponsored by the Ehlers-Danlos Foundation [USA] and the Ehlers-Danlos Support Group [UK]) at Villefranche in 1997 [Beighton et al 1998].
The combination of the first three major diagnostic criteria should have a high specificity for EDS, classic type. The presence of one or more minor criteria contributes to the diagnosis of EDS, classic type but is not sufficient to establish the diagnosis.
Figure 1. Skin hyperextensibility
Figure 1) should be tested at a neutral site (one not subjected to mechanical forces or scarring), such as the volar surface of the forearm. It is measured by pulling up the skin until resistance is felt. In young children, hyperextensibility of the skin is difficult to assess because of abundant subcutaneous fat.
Figure 2. Widened atrophic scars
Figure 2) (a manifestation of tissue fragility)
Figure 3. Passive flexion of thumbs to the forearm: manifestation of joint hypermobility
Figure 3) depends on age, gender, and family as well as ethnic backgrounds. Joint hypermobility in classic EDS 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).Positive family history
| 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.
Smooth, velvety skin
Molluscoid pseudotumors: fleshy, heaped-up lesions associated with scars over pressure points such as the elbows and knees
Subcutaneous spheroids: small, cyst-like, hard shot-like nodules, freely moveable in the subcutis over the bony prominences of the legs and arms. They occur in approximately one-third of affected individuals, are numerous, and feel like hard grains of rice. X-ray reveals an outer calcified layer with a translucent core. The spheroids represent subcutaneous fat globules that have lost their blood supply, becoming fibrosed and calcified.
Complications of joint hypermobility (e.g., sprains, dislocations/subluxations, pes planus)
Muscle hypotonia, delayed gross motor development
Easy bruising
Manifestations of tissue extensibility and fragility (e.g., hiatal hernia, anal prolapse in childhood, cervical insufficiency)
Surgical complications (postoperative hernias)
Electron microscopy of a skin biopsy in EDS, classic type often suggests disturbed collagen fibrillogenesis. A "cauliflower" deformity of collagen fibrils is characteristic [Hausser & Anton-Lamprecht 1994]. However, these findings are not specific for EDS and thus not diagnostic. Furthermore, ultrastructural changes, usually most pronounced in the central parts of the reticular dermis, may be missed if the skin biopsy is not full thickness.
Biochemical testing on cultured dermal fibroblasts:
Type V collagen. The chains of type V collagen are synthesized by cultured fibroblasts. However, type V collagen is synthesized by fibroblasts at low levels, so that alterations in electrophoretic mobility are poorly reproducible, making this an ineffective method for routine diagnostic evaluation.
Type I collagen. Rarely, an abnormal electrophoretic pattern for type I collagen is detected because of a non-glycine substitution in the COL1A1 gene coding for the proα1(I) collagen chain of type I collagen [Nuytinck et al 2000].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genes. The genes encoding type V collagen, COL5A1 and COL5A2, are known to be associated with the classic form of Ehlers-Danlos syndrome.
A COL1A1 gene mutation, Arg134Cys, has been identified in two unrelated individuals with classic EDS [Nuytinck et al 2000]; however, mutations in COL1A1 are not major causes of classic EDS.
Other loci. In approximately 50% of affected families, the disease-causing mutation is in COL5A1 or COL5A2; other loci are unknown.
Clinical testing. Molecular genetic testing for classic EDS is complicated by the large number of exons in the coding sequences (66 in the COL5A1 gene and 52 in the COL5A2 gene) and the wide distribution of mutations.
Sequence analysis. Approximately 50% of individuals with classic EDS have an identifiable mutation in the COL5A1 or COL5A2 gene.
Table 2 summarizes molecular genetic testing for this disorder.
| Gene Symbol | Proportion of EDS, Classic Type Attributed to Mutations in This Gene | Test Method | Mutations Detected | Test Availability |
|---|---|---|---|---|
| COL5A1 | 46% 1 | Sequence analysis | Sequence variants | Clinical
 |
| COL5A2 | 4% 1 |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To confirm the diagnosis in a proband
Biochemical testing on cultured dermal fibroblasts
Sequence analysis of COL5A1 and COL5A2
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.
No other phenotypes are associated with mutations in COL5A1 and COL5A2.
Ehlers-Danlos syndrome (EDS) is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and 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 classic EDS in particular. Skin extends easily and snaps back after release (unlike lax, redundant skin, as in cutis laxa).
The skin is smooth and velvety 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 delayed, and stretching of scars after apparently successful primary wound healing is characteristic. Scars become wide, with a "cigarette-paper"-like or papyraceous appearance.
Other dermatologic features in classic EDS:
Molluscoid pseudotumors (see Clinical Diagnosis)
Subcutaneous spheroids (see Clinical Diagnosis)
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; and localized swelling may also occur
Chillblains: cold injuries, characterized by a red swollen skin that is tender, 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 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 classic EDS 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. Fatigue and muscle cramps are relatively frequent. CSF leak has rarely been reported to cause postural hypotension and headache in individuals with classic EDS [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 classic EDS.
Mitral valve prolapse and, less frequently, tricuspid valve prolapse may occur. Stringent criteria should be used for the diagnosis of mitral valve prolapse.
Aortic root dilatation may be more common than previously thought [Wenstrup et al 2002].
Spontaneous rupture of large arteries, along with intracranial aneurysms and arteriovenous fistulae, may occur in the rare individual with a severe form of classic EDS.
Pregnancy in a woman with classic EDS bears risk for the newborn as well as for the mother. As a whole, these complications are more frequent than in the normal population; however, it is difficult to quantitate the incidence of each complication in affected individuals because no good studies exist:
Premature rupture of the membranes (if the pregnancy is affected) and prematurity are common, 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.
In affected women, tearing of the perineal skin by forceps and, after delivery, extension of episiotomy incisions and prolapse of the uterus and/or bladder may occur.
The number of individuals described with mutations in COL5A1 or COL5A2 is relatively small. Although there can be some variability in severity of the phenotype, no genotype/phenotype correlations have emerged to date. In particular, no difference in severity is noted in individuals with a COL5A1 null mutation as compared to individuals with a structural mutation or those in whom no mutation can be detected.
Inter- and intrafamilial variability can be great.
Individuals with a non-functional (i.e., null) COL5A1 allele can have very mild classic EDS, while other family members may have severe classic EDS [Malfait & De Paepe 2005].
Anticipation is not observed.
As a result of the 1997 Villefranche conference on EDS [Beighton et al 1998], the former EDS type I and type II are now reclassified as EDS, classic type.
The prevalence of EDS type I has been estimated to be 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.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Other forms of Ehlers-Danlos syndrome (EDS) should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation. The disorders in which clinical findings overlap with the classic type of EDS include the following:
Ehlers-Danlos syndrome, hypermobility type (EDS type III). In this form, joint hypermobility is the primary manifestation. The skin is often soft or velvety and may be mildly hyperextensible. Subluxations and dislocations are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint disease is common. Chronic pain, distinct from that associated with acute dislocations or advanced osteoarthritis, is a serious complication of the condition and can be both physically and psychologically disabling. Easy bruising is common, but atrophic scarring is more characteristic of the classic type of EDS. Joint hypermobility is the primary clinical manifestation. Skin abnormalities, such as variable skin hyperextensibility and smooth velvety skin, are found; but the presence of atrophic scars in individuals with joint hypermobility suggests the diagnosis of classic EDS.
The diagnosis of EDS, hypermobility type is based entirely on clinical evaluation and family history. In most individuals with EDS, hypermobility type, the causative gene is unknown and unmapped [Malfait et al 2006a]. Haploinsufficiency of TNXB (the gene encoding tenascin X) and heterozygosity for missense mutations in TNXB have been associated with EDS, hypermobility type in a small subset of affected individuals (see Tenascin X deficiency) [Zweers et al 2003, Zweers et al 2005]. A single occurrence of a COL3A1 mutation in a family thought to have EDS, hypermobility type has been reported. Inheritance is autosomal dominant.
Tenascin X deficiency. Homozygous mutations have been identified in TNXB in individuals with an autosomal recessive EDS phenotype characterized by mild joint hypermobility, skin hyperextensibility, and easy bruising but without atrophic scarring [Schalkwijk et al 2001, Lindor & Bristow 2005]. Heterozygotes for the same mutation, especially females, appear to have an EDS hypermobility phenotype.
Familial joint hypermobility syndrome, and other syndromes in which hypermobility is found, share hypermobility of the joints with classic EDS; but the absence of skin hyperextensibility and atrophic scarring excludes the diagnosis of classic EDS.
Ehlers-Danlos syndrome, vascular type (EDS type IV) is characterized by thin, translucent skin; easy bruising; characteristic facial appearance; and arterial, intestinal, and/or uterine fragility. Affected individuals are at risk for arterial rupture, aneurysm, and/or dissection; gastrointestinal perforation or rupture; and uterine rupture during pregnancy. One-fourth of individuals with EDS, vascular type experience a significant medical problem by age 20 years and more than 80% by age 40 years. The median age of death is 48 years.
The diagnosis of EDS, vascular type is based on clinical findings and confirmed by biochemical and/or molecular genetic testing. Biochemical studies in affected individuals demonstrate abnormal electrophoretic mobility and abnormal efficiency of secretion of type III procollagen by cultured dermal fibroblasts. Molecular genetic testing is used to identify mutations in the COL3A1 gene. Inheritance is autosomal dominant.
Ehlers-Danlos syndrome, progeroid form is a rare autosomal recessive disorder characterized by progeroid appearance with wrinkled facies, curly and fine hair, scanty eyebrows and eyelashes, and periodontitis, in addition to typical signs of EDS. It is caused by homozygous mutations in B4GALT7, the gene encoding beta-1,4-galactosyltransferase 7.
Ehlers-Danlos syndrome, kyphoscoliotic form (previously known as EDS type VI) is a generalized connective tissue disorder characterized by kyphoscoliosis, joint laxity, muscle hypotonia, and, in some individuals, fragility of the ocular globe. Intelligence is normal; life span may be normal, but affected individuals are at risk for rupture of medium-sized arteries and respiratory compromise if kyphoscoliosis is severe.
EDS, kyphoscoliotic form is caused by deficient activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1: lysyl hydroxylase 1). The diagnosis of EDS, kyphoscoliotic form relies on the demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by HPLC, a highly sensitive and specific test. Assay of lysyl hydroxylase enzyme activity in skin fibroblasts is also available. Molecular genetic testing of the PLOD1 gene, which encodes the enzyme lysyl hydroxylase 1, is available. Inheritance is autosomal recessive.
Ehlers-Danlos syndrome, arthrochalasia type (previously called type VIIA & B) is distinguished by congenital bilateral hip dislocation and severe joint hypermobility. Tissue fragility (including atrophic scars) and skin hyperextensibility are usually present; severity ranges from mild to severe. It is caused by mutations in COL1A1 or COL1A2 leading to the deletion of exon 6 of the mRNA coding for the α1 chain (EDS VIIA) or the α2 chain (EDS VIIB) of type I collagen, respectively. Inheritance is autosomal dominant.
Ehlers-Danlos syndrome, dermatosparaxis type (previously called EDS type VIIC) is characterized by extreme skin fragility, laxity, and a sagging, redundant appearance. Other distinct features are delayed closure of the fontanels, characteristic facies, edema of the eyelids, blue sclerae, umbilical hernia, short fingers, and short stature. The disorder is caused by deficient activity of procollagen-N-proteinase, the enzyme that excises the N-terminal propeptide in procollagen types I, II, and III [Malfait et al 2005]. Inheritance is autosomal recessive.
Ehlers-Danlos syndrome, cardiac valvular form is characterized by joint hypermobility, skin hyperextensibility, and sometimes atrophic scarring, as well as cardiac valvular defects. Total absence of the proα2(I) chains of type I collagen as a result of homozygous or compound heterozygous mutations in the COL1A2 gene is causative [Schwarze et al 2004, Malfait et al 2006b]. Inheritance is autosomal recessive.
Classic-like Ehlers-Danlos syndrome with propensity for arterial rupture is reminiscent of classic EDS, with skin hyperextensibility, easy bruising, and atrophic scarring, and propensity for arterial rupture in adulthood [Author, personal observation]. Arginine-to-cysteine mutations in COL1A1, the gene encoding the proα1(I) chain of type I collagen, have recently been identified in a series of adults with this disorder. Inheritance is autosomal dominant [Malfait et al 2007].
Ehlers-Danlos syndrome and periventricular nodular heterotopia. Mutations in the FLNA gene have been identified in a limited number of individuals with periventricular nodular heterotopia (a neuronal migration disorder characterized by seizures and conglomerates of neural cells around the lateral ventricles of the brain) and features of EDS [Gómez-Garre et al 2006]. See X-linked Periventricular Heterotopia.
Classic EDS shows limited overlap with other connective tissue disorders, including variants of the following; these disorders are differentiated by other distinctive clinical features:
Marfan syndrome has a broad continuum of clinical manifestations involving the ocular, skeletal, and cardiovascular systems. Lens dislocation, seen in approximately 60%, is a hallmark feature. Myopia, retinal detachment, glaucoma, and early cataract formation are seen. Bone overgrowth leads to long extremities and pectus deformity (excavatum or carinatum) and joint laxity; scoliosis is common. Cardiovascular manifestations include dilatation of the aorta, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, triscuspid valve prolapse, and enlargement of the proximal pulmonary artery. Marfan syndrome is a clinical diagnosis based on family history and the observation of characteristic findings in multiple organ systems. Diagnostic criteria have been established. Molecular genetic testing of the FBN1 gene is clinically available. Inheritance is autosomal dominant.
Occipital horn syndrome (OHS) (see ATP7A-related copper transport disorders) is characterized by "occipital horns," distinctive wedge-shaped calcifications at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. Occipital horns may be clinically palpable or observed on skull radiographs. Individuals with OHS also have lax skin and joints, bladder diverticula, inguinal hernias, and vascular tortuosity. There is no particular ease of bruising or fragility of the skin. Serum copper concentration and serum ceruloplasmin concentration are low. Molecular genetic testing of ATP7A is clinically available. Inheritance is X-linked.
Hyperelastic skin should also be distinguished from that observed in the cutis laxa syndromes and De Barsy syndrome, in which the redundant skin hangs in loose folds and only returns very slowly to its former position. In these syndromes, the skin is not fragile; and wound healing is normal.
For a detailed review of complications and management, see Wenstrup & Hoechstetter [2004].
To establish the extent of disease in an individual diagnosed with Ehlers-Danlos syndrome (EDS), classic type, the following evaluations are recommended:
Clinical examination of the skin with assessment of skin hyperextensibility, atrophic scars and bruises, and other manifestations of classic EDS
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 for individuals under age ten years
Evaluation of clotting factors if severe easy bruising is present
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.
For recommendations on treatment of joint laxity and dislocations, see EDS, Hypermobility Type. (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.
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.
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. No strict guidelines exist regarding recommended dose during the third trimester of pregnancy.
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.)
Yearly echocardiogram is warranted if an abnormality such as aortic dilatation or mitral valve prolapse is present.
Monitoring of pregnant women for preterm labor is warranted during the third trimester when the risk of premature rupture of the membranes is increased.
Follow-up of women throughout pregnancy and in the postpartum period is recommended because of the increased risk of skin lacerations, postpartum hemorrhages, and prolapse of the uterus and/or bladder.
The following should be avoided:
Sports with heavy joint strain (contact sports, fighting sports, football, running)
Acetylsalicylate (aspirin)
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Ehlers-Danlos syndrome (EDS), classic type is inherited in an autosomal dominant manner.
Parents of a proband
It is estimated that approximately 50% of affected individuals have inherited the disease-causing mutation from an affected parent and approximately 50% of affected individuals have a de novo disease-causing mutation.
The parents of a proband with an apparent de novo mutation 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.
Note: Although approximately 50% of individuals diagnosed with classic EDS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members.
Sibs of a proband
The risk to sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
Although no instances of germline mosaicism have been reported, it remains a theoretical possibility in a minority of cases.
Offspring of a proband. Each child of an individual with classic EDS has a 50% chance of inheriting the mutation.
Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is found to be affected or to have a disease-causing mutation, his/her family members are at risk.
Prediction of phenotype. Because of intrafamilial clinical variability, it is not possible to predict the phenotype in family members who have inherited a disease-causing mutation.
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation; however, the frequency of parental mosaicism is unknown. Additional explanations, including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption, could also be explored.
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for conditions which (like classic EDS) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| COL5A1 | 9q34.2-q34.3 | Collagen alpha-1(V) chain |
| COL5A2 | 2q31 | Collagen alpha-2(V) chain |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 120190 | COLLAGEN, TYPE V, ALPHA-2; COL5A2 |
| 120215 | COLLAGEN, TYPE V, ALPHA-1; COL5A1 |
| 130000 | EHLERS-DANLOS SYNDROME, TYPE I |
| 130010 | EHLERS-DANLOS SYNDROME, TYPE II |
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| COL5A1 | 1289 (MIM No. 120215) | COL5A1 |
| COL5A2 | 1290 (MIM No. 120190) | COL5A2 |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
COL5A1
Normal allelic variants. See Table 3. The COL5A1 cDNA comprises 66 exons distributed over more than 150 kb of genomic DNA.
Pathologic allelic variants. See Table 3. Several types of mutations have been identified in both COL5A1 and COL5A2:
The most common types of molecular defect lead to haploinsufficiency for the COL5A1 mRNA. In approximately 40% of individuals with classic EDS, nonsense or frameshift mutations are responsible for a non-functional COL5A1 allele [Wenstrup et al 2000, Schwarze et al 2000, Schwarze et al 2001, Malfait et al 2005]. Nonsense, frameshift, or splice-site mutations that introduce a premature termination codon are usually responsible for this non-functional COL5A1 allele. A variety of mechanisms lead to nonsense-mediated decay of the mutation-bearing mRNA or to failure of the chains to associate. The predicted consequence is synthesis of approximately half the amount of normal type V collagen.
Structural mutations in COL5A1, which exert a dominant-negative effect, have been demonstrated in approximately ten to 15 individuals with classic EDS. In a small proportion of individuals, a mutation affects the structural integrity of type V collagen, resulting in the production of a functionally defective type V collagen protein (dominant-negative mutation). These structural mutations are most commonly splice-site mutations that result in exon skipping [Burrows et al 1998, Malfait et al 2005] and a few point mutations that result in the substitution for glycine in the triple-helical region of the collagen molecule [Giunta & Steinmann 2000, Malfait et al 2005]. A unique point mutation in the COL5A1 gene that changes a highly conserved cysteine residue to a serine in the C-terminal propeptide of the α1(V) collagen chain has also been identified (p.Cys1639Ser). In contrast to other disorders characterized by mutations in the fibrillar collagen genes, remarkably few mutations resulting from the substitution of a glycine by a bulkier amino acid have been found.
A p.Gly530Ser substitution in the amino-terminal propeptide of the α1(V) chain may be disease-modifying when present in the heterozygous state and disease-causing in the homozygous state [Giunta & Steinmann 2000, Giunta et al 2002].
| Class of Variant Allele | DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequence |
|---|---|---|---|
| Pathologic or disease-modifying 1 | c.1588G>A | p.Gly530Ser | NM_000093.3NP_000084.3 |
| Pathogenic | c.4916G>C | p.Cys1639Ser |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).
1. May be disease-modifying when present in the heterozygous state and disease-causing in the homozygous state [Giunta & Steinmann 2000, Giunta et al 2002]
Normal gene product. Collagen α1 (V) chain (type V collagen chains). Type V collagen is a quantitatively minor fibrillar collagen that is widely distributed in a variety of tissues. It is present mainly 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 very large amino-terminal propeptide. Recent data indicate that type V collagen controls collagen fibril assembly in several tissues [Wenstrup et al 2004].
Abnormal gene product. Missense mutations in the triple helical domain of the α1(V) or α2(V) chains are likely to have dominant-negative activity; i.e., the mutant forms can interfere with the utilization of the normal protein derived from the normal allele. Diminished amounts, caused by premature termination of codons in the COL5A1 gene or mRNA product, may alter normal collagen fibrillogenesis.
COL5A2
Normal allelic variants. The COL5A2 cDNA comprises 51 exons distributed over 67 kb.
Pathologic allelic variants. Structural mutations in the COL5A2 gene have been demonstrated in few individuals with classic EDS. These structural mutations are most commonly splice-site mutations that result in exon skipping [Michalickova et al 1998, Malfait et al 2005] and one point mutation that results in a substitution for glycine in the triple helical region of the collagen molecule [Richards et al 1998].
Normal gene product. Collagen α2(V) chains (type V collagen chains). Type V collagen is a quantitatively minor fibrillar collagen that is widely distributed in a variety of tissues. It is present mainly 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 very large amino-terminal propeptide.
Abnormal gene product. Missense mutations in the triple helical domain of the α1(V) or α2(V) chains are likely to have dominant-negative activity; that is, the mutant forms can interfere with the utilization of the normal protein derived from the normal allele.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Association Francaise des Syndrome d'Ehlers Danlos
34 rue Léon Joulin
37 000 Tours
France
Email: m.h.boucand@wanadoo.fr
www.afsed.com
Canadian Ehlers-Danlos Association
88 De Rose Avenue
Bolton ON L7E 1AB
Canada
Phone: 905-951-7559
Fax: 905-761-7567
Email: ceda@rogers.com
www.ehlersdanlos.ca
Ehlers-Danlos National Foundation
3200 Wilshire Boulevard
Suite 1601 South Tower
Los Angeles CA 90010
Phone: 800-956-2902; 213-368-3800
Fax: 213-427-0057
Email: staff@ednf.org
www.ednf.org
Ehlers-Danlos Support Group
PO Box 337
Aldershot Surrey GU12 6WZ
United Kingdom
Phone: 01252 690940
Email: director@ehlers-danlos.org
www.ehlers-danlos.org
National Library of Medicine Genetics Home Reference
Ehlers-Danlos syndrome
Medline Plus
Ehler-Danlos Syndrome
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
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 to live Web site
29 October 2003 (ca) Review posted to live Web site
20 June 2003 (rw, ad) Original submission
