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Ehlers-Danlos Syndrome, Classic Type

 

Ehlers-Danlos Syndrome, Classical Type. Includes: Ehlers-Danlos Syndrome Type I, Ehlers-Danlos Syndrome Type II]

Summary

 

Disease characteristics.  Classic Ehlers-Danlos syndrome (EDS) is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility that 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 valve prolapse 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 the COL5A1 or COL5A2gene, the genes encoding type V collagen. Sequence analysis is available on a research basis only. COL5A1 null allele testing detects a "null" COL5A1allele in approximately 30% of individuals with classic EDS and is available on a clinical basis.

Management.  Children with EDS classic type who have hypotonia and delayed motor development benefit from a physiotherapeutic program. Non-weight-bearing muscular exercise promotes muscular development and coordination. Individuals with muscle hypotonia and joint instability with chronic pain may need to adapt their lifestyles accordingly. Dermal wounds are closed without tension, preferably in two layers. Deep stitches are applied generously, while cutaneous stitches are left in place twice as long as usual with fixation of adjacent skin to prevent scar stretching. Anti-inflammatory drugs may alleviate joint pain. Cardiovascular problems are treated in a standard manner. Close monitoring is recommended throughout pregnancy, especially during the third trimester, and post partum. Ascorbic acid (vitamin C) may reduce bruising. 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 active times. Individuals are advised to avoid acetylsalicylate and sports with heavy joint strain. Individuals with mitral valve regurgitation require antibiotic prophylaxis for bacterial endocarditis. Follow-up echocardiogram is performed yearly when aortic dilatation or mitral valve prolapse is present.

Genetic counseling.  EDS classic type is inherited in an autosomal dominant manner. It is estimated that approximately 50% of affected individuals have inherited the mutant gene from an affected parent, and about 50% of affected individuals have a new disease-causing mutation. Each child of an individual with classic EDS has a 50% chance of inheriting the mutation. Prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member.

Diagnosis

 

Clinical Diagnosis

 

The diagnosis of 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 the classic type of EDS but is not sufficient to establish the diagnosis.

Major diagnostic criteria for the classic type of EDS:

   · Skin hyperextensibilty. Skin hyperextensibility 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.

   · Widened atrophic scars (a manifestation of tissue fragility)

   · Joint hypermobility.  Joint hypermobility depends on age, gender, and family and ethnic backgrounds. Joint hypermobility in classic EDS is general, affecting both large and small joints. It is usually noted when a child starts to walk. It should be assessed using the Beighton scale [Beighton 1988], the most widely accepted grading system for the objective semi-quantification of joint hypermobility (see Table 1).

   · Positive family history <!--[endif]-->

Minor diagnostic criteria for the classic type of EDS:

• 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 about 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)

   

Testing

 

Ultrastructural studies of classic EDS by electron microscopy often suggest disturbed collagen fibrillogenesis. A "cauliflower" deformity of collagen fibrils is characteristic [Hausser & Anton-Lamprecht 1994]. However, these findings are not specific for EDS and therefore 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. The chains of type V collagen are synthesized by cultured fibroblasts. However, type V collagen is synthesized by fibroblasts at low levels, so that quantitation and evaluation of alterations in electrophoretic mobilities are poorly reproducible, making this an ineffective method for routine diagnostic evaluation. Rarely, an abnormal electrophoretic pattern for type I collagen is detected because of a non-glycine substitution in the COL1A1 gene coding for the pro<!--[endif]-->1(I) collagen chain of type I collagen [Nuytinck et al 2000].

Molecular Genetic Testing

 

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work; listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. â€”ED.

Genes.  The genes encoding type V collagen, COL5A1 and COL5A2, are known to be associated with the classic form of Ehlers-Danlos syndrome.

Although a COL1A1 gene mutation, R134C, has been identified in two unrelated individuals with classic EDS [Nuytinck et al 2000], mutations in COL1A1 are not a major cause of classic EDS.

Other loci.  In about 50% of families, the mutant gene is COL5A1 or COL5A2; other loci are unknown.

Molecular genetic testing: Clinical use

• Confirmatory diagnostic testing

   

Molecular genetic testing: Clinical method.  Molecular genetic testing for classic EDS is complicated by the large number of exons in the coding sequences (66 in the COL5A1gene and 52 in the COL5A2 gene) and the wide distribution of mutations. Several types of mutations have been identified in both COL5A1 and COL5A2, including exon-skipping mutations, mutations that result in substitutions for glycine, mutations in the region that controls chain assembly, and mutations that result in mRNA instability ("null" mutations).

   ·  COL5A1 "null" allele testing.  Polymorphic markers in the expressed region of the genomic DNA may be used to determine if both COL5A1alleles have stable transcripts. Initially, testing determines if the individual is heterozygous for one of several COL5A1 polymorphic exonic markers in genomic DNA. Then, COL5A1 cDNA is tested to determine if both alleles are present. If only one of the two COL5A1alleles is present in cDNA, it is assumed that the absent allele is "null." COL5A1 "null" allele testing requires cultured fibroblasts, as it examines both genomic DNA and cDNA. It does not identify mutations within the COL5A1 gene. COL5A1 null allele testing detects a "null" COL5A1allele in approximately 30% of individuals with classic EDS.

Molecular genetic testing: Research

   ·  Sequence analysis.  Approximately 50% of individuals with classic EDS have an identifiable mutation in the COL5A1 or COL5A2gene. Sequence analysis is currently available on a research basis only.

Table 2 summarizes molecular genetic testing for this disorder.

Genetically Related (Allelic) Disorders

 

No other phenotypes are associated with mutations in COL5A1 and COL5A2.

Clinical Description

 

Natural History

 

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

     

  • Subcutaneous spheroids

     

  • Piezogenic papules: small, painful, reversible herniations of underlying adipose tissue globules through the fascia into the dermis, such as on medial and lateral aspects of the feet upon standing

     

  • Elastosis perforans serpiginosa: a rare skin condition of unknown etiology characterized by skin-colored to erythematous keratotic papules, some enlarging outwards in serpiginous or arcuate configurations, leaving slightly atrophic centers

     

  • Acrocyanosis: a painless disorder caused by constriction or narrowing of the small blood vessels in the skin, affecting mainly the hands in which the affected areas turn blue and become cold and sweaty 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

   

• Inguinal and umbilical hernia

   

• Hiatal and incisional hernia

   

• Recurrent rectal prolapse in early childhood

   

Joints

• Complications of joint hypermobility, such as 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 suffer from 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, Martens et al 2005 ; De Coster, van den Berghe et al 2005].

   

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 the classic type of 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 woman. 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, as no good studies exist.

• Premature rupture of the membranes (if the fetus is affected) and prematurity are common. In the severe (gravis) form of classic EDS, prematurity occurs in approximately 50% of cases; in the mild (mitis) form, prematurity does not occur more frequently than normal.

   

• 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 the affected woman, extension of episiotomy incisions, tearing of the perineal skin by forceps, and prolapse of the uterus and/or bladder may occur after delivery.

   

Genotype-Phenotype Correlations

 

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 so far. In particular, no difference in severity is noted in individuals with a COL5A1 null mutation as compared to individuals with a structural mutation or to those in whom no mutation can be detected.

Penetrance

 

Inter- and intrafamilial variability can be great. Individuals with a non-functional COL5A1 allele can have very mild classic EDS, while other family members may have severe classic EDS [Malfait & De Paepe 2005].

Anticipation

 

Anticipation is not observed.

Nomenclature

 

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 the "classic subtype" of EDS.

Prevalence

 

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 therefore go undetected.

Differential Diagnosis

 

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 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, Hakim et al 2006]. Haploinsufficiency of TNXB and heterozygosity for missense mutations in TNXB, the gene encoding tenascin X, have been associated with EDS, hypermobility type in a small subset of affected individuals (see below) [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 [Narcisi et al 1994]. Inheritance is autosomal dominant. <!--[endif]-->

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 with classic EDS hypermobility of the joints, but the absence of skin hyperextensibility and atrophic scarring excludes the diagnosis of classic EDS.

Ehlers-Danlos syndrome, vascular type (also known as EDS 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 eye lashes, and periodontitis, in addition to typical signs of EDS. It is caused by homozygous mutations in <!--[endif]-->4GALT7, the gene encoding galactosyltransferase I.

Ehlers-Danlos syndrome, kyphoscoliotic type (previously known as EDS 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 upon 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 PLOD1gene that encodes the enzyme lysyl hydroxylase 1 is available. Inheritance is autosomal recessive.

Ehlers-Danlos syndrome, arthrochalasia type (previously called type VII A & B) is distinguished by severe joint hypermobility at birth and congenital bilateral hip dislocation. 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 skipping of either an amino acid change or deletion of all or part of exon 6, of the mRNA coding for one of the <!--[endif]-->1 chains (EDS VIIA) or the <!--[endif]-->2 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 and skin laxity, but the skin has 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, and cardiac valvular defects. Total absence of the pro<!--[endif]-->2(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, Symoens et al 2006]. 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 with propensity for arterial rupture at adult age [author, personal observation]. Arginine-to-cysteine mutations in COL1A1, the gene encoding the pro<!--[endif]-->1(I) chain of type I collagen, have recently been identified in a series of adults with this disorder. Inheritance is autosomal dominant.

Classic EDS shows limited overlap with other connective tissue disorders, including variants of the following, but 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 about 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 upon family history and the observation of characteristic findings in multiple organ systems. Diagnostic criteria have been established. Molecular genetic testing of the FBN1gene is possible. Inheritance is autosomal dominant.

   ·  Occipital horn syndrome (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. A multiplex protocol of targeted mutation analysis, mutation scanning, and sequence analysis detects mutations in ATP7A in more than 95% of affected individuals. 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.

Management

 

For a detailed review of complications and management, see Wenstrup & Hoechstetter et al (2004).

Evaluations at Initial Diagnosis to Establish Extent of the Disease

 

• Good clinical inspection 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 those under the age of ten years

   

• Evaluation of clotting factors if severe easy bruising is present

   

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.

   

• 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.

   

• Careful follow-up is recommended throughout pregnancy and post partum. Monitoring is warranted during the third trimester when the risk of premature rupture of the membranes is increased.

   

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. No strict recommendations exist regarding third-trimester dose. In general, 2 grams per day is recommended for adults, with proportionally reduced doses for children; however, there is no limitation.

Prevention of Secondary Complications

 

• Very young children with pronounced skin fragility can wear protection in the form of 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 active times.

   

• Individuals with mitral valve regurgitation require antibiotic prophylaxis for bacterial endocarditis, following the usual prescribed regimens.

   

Surveillance

 

• If no abnormalities are found on echocardiogram in an adult, a follow-up echocardiogram is not necessary. (Because longitudinal data on progression of aortic dilation are not available, specific recommendations for follow-up in individuals with a normal aortic diameter are not available.)

   

• If an abnormality such as aortic dilatation or mitral valve prolapse is found on echocardiogram, follow-up echocardiogram should be performed once a year.

   

Agents/Circumstances to Avoid

 

• Sports with heavy joint strain (contact sports,fighting sports, football)

   

• Acetylsalicylate

   

Therapies Under Investigation

 

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

<!--[endif]-->Genetic Counseling

 

<!--[endif]-->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. â€”ED.

<!--[endif]-->Mode of Inheritance

 

Ehlers-Danlos syndrome, classic type is inherited in an autosomal dominant manner.

<!--[endif]-->Risk to Family Members

 

Parents of a proband

• It is estimated that approximately 50% of affected individuals have inherited the mutant gene from an affected parent, and about 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 about 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 upon 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.  The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected, his/her family members are at risk.

<!--[endif]-->Related Genetic Counseling Issues

 

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 clinical evidence of the disorder, it is likely that the proband has a de novo mutation, but the frequency of parental mosaicism is not yet known. Additional explanations including alternate paternity or undisclosed adoption could also be explored.

Family planning.  The optimal time for determination of genetic risk is before pregnancy.

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 DNA Banking for a list of laboratories offering this service.

Prenatal Testing

 

<!--[endif]-->No laboratories offering molecular genetic testing for prenatal diagnosis for classic EDS are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which linkage has been established or the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing, see <!--[endif]--> .

Requests for prenatal testing for conditions such as classic EDS that 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, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see <!--[endif]--> .

<!--[endif]-->Molecular Genetics

 

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. â€”ED.

COL5A1

Normal allelic variants: The COL5A1 cDNA comprises 66 exons distributed over more than 150 kb of genomic DNA.

Pathologic allelic variants:

• The most common types of molecular defect lead to haploinsufficiency for the COL5A1 mRNA. In approximately one-third 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 about half the amount of normal type V collagen.
  
  <!--[endif]-->

   

• Structural mutations in the 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 [Nicholls et al 1996 , Wenstrup et al 1996 , De Paepe et al 1997 , 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 <!--[endif]-->1(V) collagen chain has also been identified [De Paepe et al 1997]. In contrast to other disorders characterized by mutations in the fibrillar collagen genes, remarkably few mutations have been found that result from the substitution of a glycine by a bulkier amino acid.

   

• A G530S substitution located in the amino-terminal propeptide of the <!--[endif]-->1(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].

   

Normal gene product: Collagen <!--[endif]-->1 (V) chain (type V collagen chains). Type V collagen is a quantitatively minor fibrillar collagen that is widely distributed in a variety of tissues. In skin, bone,and tendon, it is present mainly as [<!--[endif]-->1(V)]₂ <!--[endif]-->2(V) heterotrimers. 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 <!--[endif]-->1(V) or <!--[endif]-->2(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 the substitution for glycine in the triple helical region of the collagen molecule [Richards et al 1998].

Normal gene product: Collagen <!--[endif]-->2(V) chains (type V collagen chains). Type V collagen is a quantitatively minor fibrillar collagen that is widely distributed in a variety of tissues. In skin, bone, and tendon, it is present mainly as [<!--[endif]-->1(V)]₂, <!--[endif]-->2(V) heterotrimers. 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 <!--[endif]-->1(V) or <!--[endif]-->2(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.

<!--[endif]-->Resources

 

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<!--[endif]-->   Resources Printable Copy <!--[endif]-->

References

 

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Literature Cited

 

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• <!--[endif]-->Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ (1998) Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National Foundation ( USA) and Ehlers-Danlos Support Group ( UK). Am J Med Genet 77:31-7 [Medline]

   

• <!--[endif]-->Burrows NP, Nicholls AC, Richards AJ, Luccarini C, Harrison JB, Yates JR, Pope FM (1998) A point mutation in an intronic branch site results in aberrant splicing of COL5A1 and in Ehlers-Danlos syndrome type II in two British families. Am J Hum Genet 63:390-8 [Medline]

   

• <!--[endif]-->Byers PH (2001) Disorders of collagen biosynthesis and structure. In: Scriver, Beaudet, Sly, Valle (eds) The Metabolic and Molecular Bases of Inherited Disease, 2 ed. Churchill Livingstone, Edinburgh, pp 1065-81

   

• <!--[endif]-->De Coster PJ, Martens LC, De Paepe A (2005) Oral health in prevalent types of Ehlers-Danlos syndromes. J Oral Pathol Med 34:298-307 [Medline]

   

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• <!--[endif]-->De Paepe A, Nuytinck L, Hausser I, Anton-Lamprecht I, Naeyaert JM (1997) Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II. Am J Hum Genet 60:547-54 [Medline]

   

• <!--[endif]-->Giunta C, Nuytinck L, Raghunath M, Hausser I, De Paepe A, Steinmann B (2002) Homozygous Gly530Ser substitution in COL5A1 causes mild classical Ehlers-Danlos syndrome. Am J Med Genet 109:284-90 [Medline]

   

• <!--[endif]-->Giunta C and Steinmann B (2000) Compound heterozygosity for a disease-causing G1489E [correction of G1489D] and disease-modifying G530S substitution in COL5A1 of a patient with the classical type of Ehlers-Danlos syndrome: an explanation of intrafamilial variability? Am J Med Genet 90:72-9 [Medline]

   

• <!--[endif]-->Hagberg C, Berglund B, Korpe L, Andersson-Norinder J (2004) Ehlers-Danlos Syndrome (EDS) focusing on oral symptoms: a questionnaire study. Orthod Craniofac Res 7:178-85 [Medline]

   

• <!--[endif]-->Hausser I and Anton-Lamprecht I (1994) Differential ultrastructural aberrations of collagen fibrils in Ehlers- Danlos syndrome types I-IV as a means of diagnostics and classification. Hum Genet 93:394-407 [Medline]

   

• <!--[endif]--> Lindor NM and Bristow J (2005) Tenascin-X deficiency in autosomal recessive Ehlers-Danlos syndrome. Am J Med Genet A 135:75-80 [Medline]

   

• <!--[endif]-->Malfait F, Coucke P, Symoens S, Loeys B, Nuytinck L, De Paepe A (2005) The molecular basis of classic Ehlers-Danlos syndrome: a comprehensive study of biochemical and molecular findings in 48 unrelated patients. Hum Mutat 25:28-37 [Medline]

   

• <!--[endif]-->Malfait F and De Paepe A (2005) Molecular genetics in classic Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet 139:17-23 [Medline]

   

• <!--[endif]-->Malfait F, Hakim AJ, De Paepe A, Grahame R (2006) The genetic basis of joint hypermobility syndromes. Rheumatology 45:502-7 [Medline]

   

• <!--[endif]-->Malfait F, Symoens S, Coucke P, Nunes L, De Almeida S, De Paepe A (2006) Total absence of the alpha2(I) chain of collagen type I is a rare cause of Ehlers-Danlos Syndrome hyermobility type. J Med Genet 43:e36 [Medline]

   

• <!--[endif]-->Michalickova K, Susic M, Willing MC, Wenstrup RJ, Cole WG (1998) Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce Ehlers-Danlos syndrome type I. Hum Mol Genet 7:249-55 [Medline]

   

• <!--[endif]-->Narcisi P, Richards AJ, Ferguson SD, Pope FM (1994) A family with Ehlers-Danlos syndrome type III/articular hypermobility syndrome has a glycine 637 to serine substitution in type III collagen. Hum Mol Genet 3:1617-20 [Medline]

   

• <!--[endif]-->Nicholls AC, Oliver JE, McCarron S, Harrison JB, Greenspan DS, Pope FM (1996) An exon skipping mutation of a type V collagen gene (COL5A1) in Ehlers-Danlos syndrome. J Med Genet 33:940-6 [Medline]

   

• <!--[endif]-->Nuytinck L, Freund M, Lagae L, Pierard GE, Hermanns-Le T, De Paepe A (2000) Classical Ehlers-Danlos syndrome caused by a mutation in type I collagen. Am J Hum Genet 66:1398-402 [Medline]

   

• <!--[endif]-->Richards AJ, Martin S, Nicholls AC, Harrison JB, Pope FM, Burrows NP (1998) A single base mutation in COL5A2 causes Ehlers-Danlos syndrome type II. J Med Genet 35:846-8 [Medline]

   

• <!--[endif]-->Schalkwijk J, Zweers MC, Steijlen PM, Dean WB, Taylor G, van Vlijmen IM, van Haren B, Miller WL, Bristow J (2001) A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. N Engl J Med 345:1167-75 [Medline]

   

• <!--[endif]-->Schievink WI, Gordon OK, Tourje J (2004) Connective tissue disorders with spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension: a prospective study. Neurosurgery 54:65-70 [Medline]

   

• <!--[endif]-->Schwarze U, Atkinson M, Hoffman GG, Greenspan DS, Byers PH (2000) Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II). Am J Hum Genet 66:1757-65 [Medline]

   

• <!--[endif]-->Schwarze U, Hata R, McKusick VA, Shinkai H, Hoyme HE, Pyeritz RE, Byers PH (2004) Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am J Hum Genet 74:917-30 [Medline]

   

• <!--[endif]-->Schwarze U, Schievink WI, Petty E, Jaff MR, Babovic-Vuksanovic D, Cherry KJ, Pepin M, Byers PH (2001) Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV. Am J Hum Genet 69:989-1001 [Medline]

   

• <!--[endif]-->Wenstrup RJ and Hoechstetter LB (2004) Ehlers-Danlos Syndromes. In: Cassidy SB, Allanson JE (eds) Management of Genetic Syndromes, 2 ed. John Wiley & Sons, NY, pp 211-24

   

• <!--[endif]-->Wenstrup RJ, Florer JB, Brunskill EW, Bell SM, Chervoneva I, Birk DE (2004) Type V collagen controls the initiation of collagen fibril assembly. J Biol Chem 279:53331-7 [Medline]

   

• <!--[endif]-->Wenstrup RJ, Florer JB, Willing MC, Giunta C, Steinmann B, Young F, Susic M, Cole WG (2000) COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS. Am J Hum Genet 66:1766-76 [Medline]

   

• <!--[endif]-->Wenstrup RJ, Langland GT, Willing MC, D'Souza VN, Cole WG (1996) A splice-junction mutation in the region of COL5A1 that codes for the carboxyl propeptide of pro alpha 1(V) chains results in the gravis form of the Ehlers-Danlos syndrome (type I). Hum Mol Genet 5:1733-6 [Medline]

   

• <!--[endif]-->Wenstrup RJ, Meyer RA, Lyle JS, Hoechstetter L, Rose PS, Levy HP, Francomano CA (2002) Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genet Med 4:112-7 [Medline]

   

• <!--[endif]-->Zweers MC, Bristow J, Steijlen PM, Dean WB, Hamel BC, Otero M, Kucharekova M, Boezeman JB, Schalkwijk J (2003) Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome. Am J Hum Genet 73:214-7 [Medline]

   

• <!--[endif]-->Zweers MC, Dean WB, van Kuppevelt TH, Bristow J, Schalkwijk J (2005) Elastic fiber abnormalities in hypermobility type Ehlers-Danlos syndrome patients with tenascin-X mutations. Clin Genet 67:330-4 [Medline]

   

<!--[endif]-->Author Information

 

Richard Wenstrup, MD
Division of Human Genetics
Cincinnati Children's Hospital Medical Center

Anne De Paepe, MD, PhD
Center for Medical Genetics
Ghent University Hospital

Revision History

 

• 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