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Vascular Type|
Table 1. Molecular Genetic Testing of
EDS, Vascular Type
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Test Method
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Mutations Detected
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Mutation Detection Rate
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Test Availability
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cDNA or genomic DNA sequence analysis
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COL3A1 sequence alterations
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98-99%
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Clinical |
Interpretation of test results. For issues to consider in interpretation
of sequence analysis results, click here.
Testing Strategy for a Proband
Biochemical and direct genetic analysis are alternative and complementary
approaches to diagnosis and may be determined by the most readily available
clinical sample. The relative sensitivities of each are probably similar;
different classes of mutations are less easily recognized by
each.
- Protein-based studies may
be less sensitive for the identification of mutations that decrease production but
do not alter structure of type III procollagen.
- Genomic analysis misses
single or multiple exon deletions or allele deletion and identifies variants of
unknown significance, the role of which may be defined by study of proteins.
Genetically Related (Allelic) Disorders
· Ehlers-Danlos syndrome, hypermobility type (EDS III). A
single report of a family with clinical features of EDS III and a COL3A1mutation typically associated with the
vascular type of EDS (G637S) [Narcisi et al 1994] led to the suspicion of a causative
relationship between COL3A1mutations and EDS III; however, biochemical
studies of collagen synthesis have not identified a type III collagen defect in
other families with EDS III. Given the relatively young ages of most
individuals in the reported family and sparse history, reassessment is
warranted.
· Familial aortic aneurysm. A COL3A1 glycine
substitution mutation was identified in one family with familial aortic aneurysm [Kontusaari, Tromp, Kuivaniemi, Ladda et al 1990] and in
another family with aortic aneurysm [Kontusaari, Tromp, Kuivaniemi, Romanic et al 1990]. One of
the reported families likely had the vascular type of EDS that had gone
undetected prior to identification of the mutation. It is possible that the second
family with aortic aneurysm represents the milder end of a clinical spectrum
caused by mutations in the COL3A1 gene. However, studies of other families
with familial and nonfamilial aneurysm have
revealed no evidence of causative type III collagen mutations [Kuivaniemi et al 1993 , Tromp et al 1993].
Clinical Description
Natural History
A retrospective review of the health history of more than 400 individuals
with the vascular type of EDS confirmed by biochemical and/or molecular genetic testing delineated
the natural history of the disorder [Pepin et al 2000]. Among individuals ascertained as a result
of complications, 25% had experienced a significant medical complication by age
20 years and more than 80% by age 40 years. In a population ascertained on the
basis of major complications or clinical criteria alone, in which all had evidence
of abnormal type III procollagen production in cultured dermal fibroblasts, the
median age of death is 48 years.
About 12% of neonates with the vascular type of EDS have clubfoot and three
percent have congenital dislocation of the hips. In
childhood, inguinal hernia, pneumothorax, and recurrent joint dislocation or
subluxation are common. Affected individuals often have a lifelong
history of easy bruising. Keratoconus [Kuming & Joffe 1977], periodontal disease, and venous
varicosities have been reported [Tsipouras et al 1986]. Most children with the vascular type
of EDS have few complications and, in families with negative family history, the disease is often
unrecognized in childhood.
Vascular rupture or dissection and gastrointestinal perforation or organ
rupture are the presenting signs in 70% of adults with the vascular type of
EDS. Such complications are dramatic and unexpected, often presenting as sudden
death, stroke and its neurological sequelae, acute abdomen, retroperitoneal
bleeding, uterine rupture at delivery, and/or shock. The average age for the
first major arterial or gastrointestinal complication is 23 years.
Vascular complications include rupture, aneurysm, and/or dissection of major
or minor arteries. Arterial rupture may be preceded by aneurysm, arteriovenous
fistulae, or dissection, but also may occur spontaneously. The sites of
arterial rupture are the thorax and abdomen (50%), head and neck (25%), and
extremities (25%). Although uncommon, the vascular type of EDS is a cause of
stroke in young adults. The mean age of intracranial aneurysmal rupture,
spontaneous carotid-cavernous sinus fistula, and cervical artery aneurysm is 28
years [North et al 1995].
Rupture of the gastrointestinal tract occurs in about 25% of affected individuals. The majority of GI
perforations occur in the sigmoid colon. Rupture of the small bowel and stomach
have been reported, though infrequently. Bowel rupture is rarely lethal (3%) [Pepin et al 2000]. Recurrent bowel rupture proximal to the
first sigmoid tear is common.
Surgical intervention for bowel rupture is necessary and usually lifesaving.
Complications during and following surgery are related to tissue and vessel
friability, which result in recurrent arterial or bowel tears, fistulae, poor
wound healing, and suture dehiscence. Individuals who survive a first
complication may experience recurrent rupture. The timing and site of repeat
rupture cannot be predicted by the first event.
Rare complications include organ rupture that may involve the heart, with
ventricular rupture, the spleen, or the liver [Pepin et al 2000 , Ng & Muiesan 2005].
Pregnancy for women with the vascular type of EDS has as much as a 12% risk
for death from peripartum arterial rupture or uterine rupture [Pepin et al 2000].
Genotype-Phenotype Correlations
The majority (~2/3) of identified mutations result in substitution of other
amino acids for glycine residues in the [Gly-X-Y]343 triplets of the
triple helical domain. Most of the remaining mutations affect splice sites and usually result in exon skipping, but other more complex
outcomes can occur. A small number of mutations that lead to mRNA instability of
the products of the allele or to failure of chain association in
the trimer have been identified. The phenotypic effects of substitutions for
glycine and exon-skipping events are similar.
Individuals with COL3A1 null mutations may have a delay in the onset of
first symptoms. The number of families described with COL3A1 null mutations is small [Schwarze et al 2001].
The marked acrogeroid phenotype appears to reflect the presence of
mutations that alter sequences in the
carboxyl-terminal end of the type III collagen triple helix [Johnson et al 1995].
Penetrance
In families identified on the basis of clinical complications, penetrance of the vascular EDS phenotype appears to be close to 100%;
however, the age of detection of the phenotype may vary.
In the analysis of the mutations identified in the COL3A1 gene to this point, at least two classes of mutations — substitutions of glycine in
the triple helical domain by alanine and introduction of
premature termination codons — are under-represented among
individuals with vascular EDS. Thus, some mutations in COL3A1 may not produce a
vascular EDS phenotype.
Anticipation
Anticipation does not occur.
Nomenclature
The following terms have been used to describe the vascular type of EDS:
- Status dysvascularis:
introduced by Sack (1936), never used extensively
- Familial acrogeria: used by Gottron
(1940); probably included some individuals with vascular EDS
- Sack-Barabas syndrome or the Sack-Barabas type of Ehlers-Danlos syndrome: used after
Barabas (1967) introduced the disorder to the English language literature
Prevalence
Over the last 15 years, the authors have identified about 800 affected individuals in families in the
Because many families with the vascular type of EDS are identified only
after a severe complication or death, it is likely that individuals/families
with COL3A1 mutations with a mild phenotype 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 who have
normal collagen III biochemical studies. The disorders in which clinical
findings overlap with the vascular type of EDS include the following:
· Ehlers-Danlos syndrome, classic type is an autosomal dominant disorder
characterized by soft, doughy, stretchy skin, abnormal scars, and significant
large-joint hypermobility without accompanying blood vessel, bowel, or organ
rupture. The diagnosis is based on clinical and family history findings. Approximately
50% of individuals with EDS, classic type have an identifiable mutation in the COL5A1 or COL5A2gene.
· Ehlers-Danlos syndrome VI (kyphoscoliotic form) is an autosomal recessive disorder characterized
by progressive scoliosis, hypotonia, easy bruising and tissue fragility, and
fragility of the globe. Vascular rupture may be a feature of this type of EDS.
EDS, kyphoscoliotic form is caused by mutations in the PLOD1 gene, which encodes lysyl hydroxylase 1
(procollagen-lysine, 2-oxoglutarate 5-dioxygenase 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.
· Ehlers-Danlos syndrome VIII
(periodontal form) is a rare connective tissue disorder including features
of the classic type and the vascular type, but with the
additional findings of early periodontal friability. Recent studies suggest
that a gene for a variety of this type of EDS is
located on the short arm of chromosome 12.
· Isolated arterial aneurysm is usually NOT the result of
a type III collagen defect. Familial forms of arterial aneurysm have
been linked to at least three different loci.
· Loeys-Dietz syndrome is an autosomal dominant disorder
characterized by aneurysms that result from mutations in the genes TGFBR1 and TGFBR2,
encoding the TGF
receptor. The clinical presentation may be heterogeneous and include aneurysm
and rupture in the first year of life, craniofacial abnormalities, a
Marfan-like physical presentation, or familial aortic aneurysm. One group of individuals
has clinical features that overlap with vascular EDS. The diagnosis is made by sequence analysis of the two genes.
· Other
causes of arterial rupture include localized trauma and collagen vascular
disease.
· Polycystic kidney disease, autosomal dominant is
characterized by progressive cyst development and bilaterally enlarged
polycystic kidneys. Cysts also occur in liver, seminal vesicles, pancreas, and
arachnoid membrane. Non-cystic abnormalities include intracranial aneurysms and
dolichoectasias, dilatation of the aortic root and dissection of the thoracic
aorta, mitral valve prolapse, and abdominal wall hernias. The renal
manifestations of ADPKD include renal function abnormalities, hypertension,
renal pain, and renal insufficiency. ADPKD is caused by mutations in the PKD1 gene in 85% of affected individuals; in 15% of individuals,
mutations in PKD2 are causative. This
disorder should be considered in individuals with intracranial aneurysm.
· Marfan syndrome should be considered if the presenting
vascular complication is an aortic aneurysm or dissection. The vascular type of
EDS and Marfan syndrome can be distinguished relatively easily on physical
examination. Individuals with Marfan syndrome typically have dolichostenomelia
and arachnodactyly, lens dislocation, and dilatation or aneurysm of only the
aorta. Marfan syndrome is a clinical diagnosis based upon family history and the observation of
characteristic findings in multiple organ systems. It is caused by mutations in FBN1.
- Gastrointestinal entities to
be considered in individuals of any age with large or small bowel rupture
are perforated diverticulitis, irritable bowel disease, or inflamed
Meckel's diverticulum. Isolated gastrointestinal bleeding, as
seen in pseudoxanthoma elasticum and hereditary hemorrhagic telangectasia , is
not part of the usual presentation of EDS, vascular type.
Management
Evaluations
at Initial Diagnosis to Establish the Extent of Disease
Currently, no consensus exists regarding the extent of evaluation at the
time of initial diagnosis. Evaluation often depends on the circumstances in
which the diagnosis is made.
- If the diagnosis is
considered or made at the time of assessment for and surgical treatment of
bowel rupture, usually little additional assessment is necessary.
- If the diagnosis is made at
the time of arterial rupture, the remainder of the arterial tree is often
assessed by CAT or MRI in the process of identifying the site of
hemorrhage.
- For the asymptomatic adult
or child identified on the basis of family studies, it is not clear that
additional assessment is required. However, it has been suggested that a
noninvasive evaluation of the arterial tree could help to pinpoint
locations of future arterial tears. No data to assess this idea currently
exist.
Treatment of Manifestations
- When surgery is required
for the treatment of arterial or bowel complications or other health
problems, it is appropriate to minimize surgical exploration and
intervention [Oderich et al 2005]. In general, surgical procedures
are more likely to be successful when the treating physician is aware of
the diagnosis of the vascular type of EDS and its associated tissue
fragility.
- Prompt surgical
intervention of bowel rupture: bowel continuity can be restored successfully
in most instances either at the time of initial surgery or in a subsequent
repair of a colostomy.
- The recurrence of bowel
tears proximal to the original site and the risk of complications
resulting from repeat surgery have led some to recommend distal colectomy
to reduce the risk for recurrent bowel rupture. Some physicians and affected individuals consider total
colectomy as a prophylactic measure to avoid recurrent bowel complications
and the need for repeat surgery [Freeman et al 1996 , Fuchs & Fishman 2004].
- It is prudent to follow
pregnant women with the vascular type of EDS in a high-risk obstetrical
program. It is not known if the potential benefits of elective caesarian
section (decreasing the risk of mortality) outweigh the potential risks
(increasing morbidity). Educating the pregnant individual as to possible
complications and the need for close monitoring is recommended.
- Affected individuals should be
instructed to seek immediate medical attention for sudden unexplained
pain.
- A MedicAlert® bracelet should be worn.
Prevention of Primary Manifestations
No measures to prevent arterial vessel tears are known.
Treatment of hypertension, if present, is essential.
Surveillance
The necessity for periodic arterial screening is uncertain and can only be
determined by a detailed study. If such screening is undertaken, arteriograms are
not recommended because arterial tear/dissection may result at the site of
entry of the catheter; and injection pressure may lead to arterial aneurysms.
Preferable modes of surveillance include venous subtraction angiography and MRI
or CT scan without contrast material.
Agents/Circumstances to Avoid
· Trauma. Because of inherent tissue fragility, it is prudent for individuals with
the vascular type of EDS to minimize the risk of trauma by avoiding collision
sports (e.g., football), heavy lifting, and weight training. No evidence
suggesting that moderate recreational exercise is detrimental exists.
· Elective surgery. Increased
tissue fragility results in a higher risk of surgical complications; thus,
elective surgery for individuals with the vascular type of EDS is discouraged.
In general, avoidance of surgery in favor of more conservative management is
advised. For example, bleeding from a small vessel into a confined space is
often best treated conservatively.
· Arteriograms. Because
arterial tear/dissection may result at the site of entry of the catheter,
arteriograms are not recommended; injection pressure may lead to arterial
aneurysms.
Testing of Relatives At Risk
The genetic status of at-risk relatives should be clarified through clinical
evaluation and/or genetic testing. For those found to be affected, management is the same as for
individuals identified through clinical findings.
Therapies Under Investigation
A clinical trial of the effectiveness of -adrenergic
blockage for the reduction of risk of arterial rupture or dissection is
currently underway in
Search ClinicalTrials.gov
for access to information on clinical studies for a wide range of diseases and
conditions.
Genetic Counseling
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. —ED.
Mode
of Inheritance
The vascular type of EDS is inherited in an autosomal dominant manner.
Risk
to Family Members
Parents of a proband
- About 50% of affected individuals have inherited the COL3A1 mutation from an affected parent and about 50% of affected individuals have a de novo disease-causing mutation.
- Recommendations for the
evaluation of parents of a proband with an apparent de novo mutation include physical examination
and molecular genetic testing as
the rate of parental mosaicism in families with EDS IV is as
high as 20%.
- Parental somatic mosaicism for COL3A1 mutations that includes the germline has been documented in eleven
families in which affected individuals have been born to unaffected parents; mosaicism that is apparently limited to
the germline has been reported in two
families [Kontusaari et al 1992 , Richards et al 1992 , Milewicz et al 1993 , Byers et al 2003 , Palmeri et al 2003].
Note: Although many individuals diagnosed with the vascular
type of EDS have an affected parent, the family history may appear to be
negative because of failure to recognize the disorder in family members or
later onset of the disease in the affected parent.
Sibs of a proband
- The risk to the sibs
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%.
- If the parents are
clinically unaffected and/or the proband's disease-causing mutation cannot be
detected in DNA extracted from the leukocytes of
either parent, there remains a chance that one parent is mosaic in his or her germline. In this instance the
composite risk (which combines the risk of parental mosaicism and de novo mutation in the proband) is greater
than 0 but less than 7.8% [Byers et al 2003].
Offspring of a proband. Each child of an
individual with the vascular type of EDS has a 50% chance of inheriting the mutation and developing the disorder.
Other family members of a proband
- The risk to other family
members depends upon the status of the proband's parents.
- If a parent is found to be affected, his or her family members are
at risk.
Related
Genetic Counseling Issues
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, possible non-medical
explanations including alternate paternity 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.
Testing of at-risk asymptomatic individuals during childhood. In
the case of the vascular form of EDS, the benefits of testing individuals
during childhood include (1) elimination of concern for those children who do
not have the COL3A1 mutant allele identified and (2) improved
surveillance, awareness of treatment for potential complications, and appropriate
restriction of high-impact sports for those with the mutant allele.
Testing of apparently asymptomatic individuals during childhood for
disorders in which most of the complications occur in adulthood raises ethical
considerations. Consensus holds that individuals at risk for adult-onset
disorders should not be tested during childhood in the absence of symptoms if
the testing can have no positive consequences, such as intervention or improved
surveillance.The principal arguments against testing asymptomatic individuals
during childhood are that it removes their choice to know or not know this information,
it raises the possibility of stigmatization within the family and in other
social settings, and it could have serious educational and career implications [Bloch & Hayden 1990 , Harper & Clarke 1990]. (See also the National Society of
Genetic Counselors resolution on genetic testing of children and
the American Society of Human Genetics and
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
Biochemical
testing. Prenatal diagnosis is possible for fetuses at increased risk
in families in which the underlying biochemical abnormality of type III
collagen has been identified. Prenatal diagnosis using the
biochemical assay can only be performed on cultured cells obtained by chorionic
villus sampling (CVS) at about 10-12 weeks' gestation.
Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by
analysis of DNA extracted from fetal cells obtained by
amniocentesis usually performed at about 15-18 weeks' gestation or chorionic
villus sampling (CVS) at about 10-12 weeks' gestation. The disease-causing allele of an affected family member 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.
Preimplantation genetic diagnosis (PGD) may be available for families
in which the disease-causing mutation has been
identified in an affected family member. For laboratories
offering PGD, see 
.
Molecular Genetics
Information in the Molecular Genetics tables may differ from that in the
text; tables may contain more recent information. —ED.
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Molecular Genetics of Ehlers-Danlos Syndrome,
Vascular Type
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Gene Symbol
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Chromosomal Locus
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Protein Name
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COL3A1
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2q31
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Collagen proα 1(III)
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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.
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OMIM Entries for Ehlers-Danlos Syndrome,
Vascular Type
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Genomic Databases for Ehlers-Danlos Syndrome,
Vascular Type
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Gene Symbol
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Locus Specific
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Entrez Gene
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HGMD
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GeneCards
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GDB
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GenAtlas
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COL3A1
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For a
description of the genomic databases listed, click here.
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Normal allelic variants: The COL3A1 cDNA comprises 51 exons distributed over 44 kb of genomic DNA.
Pathologic allelic variants: Over 400 mutations in the COL3A1 gene that result in a disease-causing phenotype have been identified. The majority
of identified mutations are point mutations that result in single
amino acid substitutions for glycine in the GLY-X-Y repeat of the triple
helical region of the type III collagen molecule. About one-third of the known mutations occur at splice sites, and most result in exon skipping. A smaller number of splice mutations lead to the use of cryptic splice sites with partial exon exclusion or intron inclusion. The vast majority of
exon-skipping splice site mutations have been
identified at the 5' donor site with very few found at the 3' splice site [Schwarze et al 1997]. Several partial gene deletions have been reported as well. Less
common are mutations that create new chain termination codons and result in COL3A1 haploinsufficiency ("null"
mutations) [Schwarze et al 2001]. The consequence is synthesis of about
one-half the amount of normal type III procollagen. (See collagen
database of human type I and type III collagen mutations.)
Normal gene product: Collagen pro
1 (III) chain. The COL3A1gene encodes the chains of type III
procollagen, a major structural component of skin, blood vessels, and hollow
organs. The type III procollagen molecule is a homotrimer, with constituent
chains 1,467 amino acids in length.
Abnormal gene product: Mutations of the COL3A1 gene typically result in a structural
alteration of type III collagen that leads to intracellular storage and
impaired secretion of collagen chains.
Resources
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. -ED.
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References
Published Statements and Policies Regarding Genetic Testing
- American Society of Human
Genetics and
- National Society of Genetic
Counselors (1995) Resolution on prenatal and childhood testing for
adult-onset disorders.
Literature Cited
- Beighton
P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ (1998) Ehlers-Danlos
syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National
Foundation (
- Bloch
M and Hayden MR (1990) Opinion: predictive testing for
- Byers
PH, Pepin MG, Schwarze U, Gaulke LK (2003) Recurrence risk and asymptomatic
and symptomatic mosaicism in Ehlers-Danlos syndrome
(EDS) type IV. Am J Hum Genet 73S:206
- Freeman
RK, Swegle J, Sise MJ (1996) The surgical complications of Ehlers-Danlos
syndrome. Am Surg 62:869-73 [Medline]
- Fuchs
JR, Fishman SJ (2004) Management of spontaneous colonic perforation in
Ehlers-Danlos syndrome type IV. J Pediatr Surg 39:e1-3 [Medline]
- Harper
PS and Clarke A (1990) Should we test children for "adult"
genetic diseases? Lancet 335:1205-6 [Medline]
- Johnson
PH, Richards AJ, Lloyd JC, Pope FM, Hopkinson DA (1995) Efficient strategy
for the detection of mutations in acrogeric Ehlers- Danlos
syndrome type IV. Hum Mutat 6:336-42 [Medline]
- Kontusaari
S, Tromp G, Kuivaniemi H, Romanic AM, Prockop DJ (1990) A mutation in the gene for type III procollagen (COL3A1)
in a family with aortic aneurysms. J Clin Invest 86:1465-73 [Medline]
- Kontusaari
S, Tromp G, Kuivaniemi H, Ladda RL, Prockop DJ (1990) Inheritance of an RNA splicing mutation (G+ 1 IVS20) in
the type III procollagen gene (COL3A1) in a family having aortic
aneurysms and easy bruisability: phenotypic overlap between familial arterial aneurysms and
Ehlers-Danlos syndrome type IV. Am J Hum Genet 47:112-20 [Medline]
- Kontusaari
S, Tromp G, Kuivaniemi H, Stolle C, Pope FM, Prockop DJ (1992)
Substitution of aspartate for glycine 1018 in the type III procollagen
(COL3A1) gene causes type IV Ehlers-Danlos
syndrome: the mutated allele is present in most blood
leukocytes of the asymptomatic and mosaic mother. Am J Hum Genet 51:497-507 [Medline]
- Kuivaniemi
H, Prockop DJ, Wu Y, Madhatheri SL, Kleinert C, Earley JJ, Jokinen A,
Stolle C, Majamaa K, Myllyla VV, et al. (1993) Exclusion of mutations in the gene for type III collagen (COL3A1) as
a common cause of intracranial aneurysms or cervical artery dissections:
results from sequence analysis of the coding
sequences of type III collagen from 55 unrelated patients. Neurology 43:2652-8 [Medline]
- Kuming
BS and Joffe L (1977) Ehlers-Danlos syndrome associated with keratoconus.
A case report.
- Milewicz
DM, Witz AM, Smith AC, Manchester DK, Waldstein G, Byers PH (1993)
Parental somatic and germ-line mosaicism for a multiexon deletion with unusual endpoints in a
type III collagen (COL3A1) allele produces Ehlers-Danlos syndrome
type IV in the heterozygous offspring. Am J Hum
Genet 53:62-70 [Medline]
- Narcisi
P, Richards AJ,
-
- North
KN, Whiteman DA, Pepin MG, Byers PH (1995) Cerebrovascular complications
in Ehlers-Danlos syndrome type IV. Ann Neurol 38:960-4 [Medline]
- Oderich
GS, Panneton JM, Bower TC, Lindor NM, Cherry KJ, Noel AA, Kalra M,
Sullivan T, Gloviczki P (2005) The spectrum, management and clinical
outcome of Ehlers-Danlos syndrome type IV: a 30-year experience. J Vasc
Surg 42:98-106 [Medline]
- Palmeri
S, Mari F, Meloni I, Malandrini A, Ariani F, Villanova M, Pompilio A,
Schwarze U, Byers PH, Renieri A (2003) Neurological presentation of
Ehlers-Danlos syndrome type IV in a family with parental mosaicism. Clin Genet 63:510-5 [Medline]
- Pepin
M, Schwarze U, Superti-Furga A, Byers PH (2000) Clinical and genetic
features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J
Med 342:673-80 [Medline]
- Richards
AJ, Ward PN, Narcisi P, Nicholls AC, Lloyd JC, Pope FM (1992) A single
base mutation in the gene for type III collagen (COL3A1)
converts glycine 847 to glutamic acid in a family with Ehlers-Danlos
syndrome type IV. An unaffected family member is mosaic for the mutation. Hum Genet 89:414-8 [Medline]
- Schwarze
U, Goldstein JA, Byers PH (1997) Splicing defects in the COL3A1 gene:
marked preference for 5' (donor) spice-site mutations in patients with
exon-skipping mutations and Ehlers-Danlos syndrome
type IV. Am J Hum Genet 61:1276-86 [Medline]
- 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]
- Tromp
G, Wu Y, Prockop DJ, Madhatheri SL, Kleinert C, Earley JJ, Zhuang J,
Norrgard O, Darling RC, Abbott WM, et al. (1993) Sequencing of cDNA from 50 unrelated
patients reveals that mutations in the triple-helical domain of type III procollagen are an
infrequent cause of aortic aneurysms. J Clin Invest 91:2539-45 [Medline]
- Tsipouras
P, Byers PH, Schwartz RC, Chu ML, Weil D, Pepe G, Cassidy SB, Ramirez F
(1986) Ehlers-Danlos syndrome type IV: cosegregation of the phenotype to a COL3A1 allele of type III procollagen. Hum
Genet 74:41-6 [Medline]
Suggested
Readings
- Germain
DP and Herrera-Guzman Y (2004) Vascular Ehlers-Danlos syndrome. Ann
Genet 47:1-9 [Medline]
- Persikov
AV, Pillitteri RJ, Amin P, Schwarze U, Byers PH, Brodsky B (2004)
Stability related bias in residues replacing glycines within the collagen
triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders. Hum
Mutat 24:330-7 [Medline]
- Steinmann
B, Royce PM, Superti-Furga A (2002) The Ehlers-Danlos syndrome. In: Royce
PM, Steinmann B (eds) Connective Tissue and its Heritable Disorders.
Author Information
Revision History
- 7 June 2006 (me)
Comprehensive update posted to live Web site
- 25 January 2005 (cd) Revision:
change in availability of clinical testing
- 14 April 2004 (me)
Comprehensive update posted to live Web site
- 15 April 2002 (me)
Comprehensive update posted to live Web site
- 2 September 1999 (me)
Review posted to live Web site
- 6 April 1999 (mp) Original
submission
