EHLERS-DANLOS SYNDROME, VASCULAR TYPE
EHLERS-DANLOS SYNDROME, SACK-BARABAS TYPE
EHLERS-DANLOS SYNDROME, ARTERIAL TYPE
EDS IV
EHLERS-DANLOS SYNDROME, ECCHYMOTIC TYPE
EDS4
Ehlers-Danlos syndrome type 4
Ehlers-Danlos syndrome type IV
Sack-Barabas syndrome
EDS type 4
Ehlers-Danlos syndrome type IV is an autosomal dominant disorder characterized by the joint and dermal manifestations as in other forms of the syndrome but also by proneness to spontaneous rupture of bowel and large arteries.
Beighton ... Ehlers-Danlos syndrome type IV is an autosomal dominant disorder characterized by the joint and dermal manifestations as in other forms of the syndrome but also by proneness to spontaneous rupture of bowel and large arteries. Beighton et al. (1998) reported on a revised nosology of the Ehlers-Danlos syndromes, designated the Villefranche classification. Major and minor diagnostic criteria were defined for each type and complemented whenever possible with laboratory findings. Six main descriptive types were substituted for earlier types numbered with Roman numerals: classic type (EDS I and II), hypermobility type (EDS III), vascular type (EDS IV), kyphoscoliosis type (EDS VI), arthrochalasia type (EDS VIIA and VIIB), and dermatosparaxis type (EDS VIIC). Six other forms were listed, including a category of 'unspecified forms.'
Steinmann et al. (1989) suggested that determination of serum levels of procollagen type III aminopropeptide is a simple test for diagnosis and might be especially helpful in making the diagnosis in children.
Johnson et al. (1995) ... Steinmann et al. (1989) suggested that determination of serum levels of procollagen type III aminopropeptide is a simple test for diagnosis and might be especially helpful in making the diagnosis in children. Johnson et al. (1995) were successful in demonstrating mutations in all 13 patients with typical or acrogeric EDS IV using denaturing gradient gel electrophoresis (DGGE) in the study of PCR-amplified cDNA from the C-terminal domain of type III collagen. Autio et al. (1997) pictured the characteristic facial appearance, as well as the thin transparent skin over the anterior aspect of the chest and upper arms, of an EDS IV patient. They suggested B-mode ultrasonic techniques, in place of skin biopsy, as a useful noninvasive method for demonstrating thin skin. In addition, they concluded that the measurement of procollagen propeptides in body fluids is a valuable noninvasive method helpful in the diagnosis and classification of EDS. They confirmed the diagnosis of EDS IV in a patient by measuring type III amino-terminal procollagen propeptide levels in the skin interstitial fluid, i.e., suction blister fluid (SBF), and serum and the type I amino-terminal procollagen propeptide level in SBF. The serum concentration of the type III propeptide has been shown to be abnormally low or in the low normal range in EDS IV patients and well-correlated with the ability of the patient's cultured fibroblasts to secrete type III procollagen. In the patient reported, the serum concentration of the type III propeptide was low; however, the elimination of the type III propeptide molecule from the serum is a constant process and may be altered by factors such as abnormal liver function. Thus, the concentration of the type III propeptide in the SBF more accurately reflects an individual's synthesis of type III collagen. This value was abnormally low in the reported patient. In turn, the concentration of the type I propeptide in the SBF was normal. Pepin et al. (2000) reviewed the clinical and family histories and the medical and surgical complications of 220 index patients with biochemically confirmed Ehlers-Danlos syndrome type IV and 199 of their affected relatives. They identified the underlying COL3A1 mutation in 135 index patients. Complications were rare in childhood; 25% of the index patients had a first complication by the age of 20 years, and more than 80% had at least 1 complication by the age of 40. The calculated median survival of the entire cohort was 48 years. Most deaths resulted from arterial rupture. Bowel rupture, which often involved the sigmoid colon, accounted for about one-quarter of complications but rarely led to death. Complications of pregnancy led to death in 12 of the 81 women who became pregnant. The types of complications were not associated with specific mutations in COL3A1. The authors urged that the diagnosis of EDS IV be considered in young people who come to medical attention because of uterine rupture during pregnancy or arterial or visceral rupture.
The malignant form of EDS (type IV) owes its bad reputation to a proneness to spontaneous rupture of bowel or large arteries. Paradoxically, other manifestations are less dramatic than in some other forms of EDS. For example, joint ... The malignant form of EDS (type IV) owes its bad reputation to a proneness to spontaneous rupture of bowel or large arteries. Paradoxically, other manifestations are less dramatic than in some other forms of EDS. For example, joint hypermobility may be confined largely to the fingers and whereas the skin is strikingly thin and translucent, it is only mildly hyperextensible. Bruisability, however, is very striking; indeed, 'ecchymotic type' is a synonym for type IV. Superti-Furga et al. (1988) provided the first description of a mutation in the COL3A1 gene in type IV EDS. The proband was 22 years old; his father was affected with the same disorder and had died at age 34 years. He had been hospitalized for bleeding in the anterior abdominal wall and retroperitoneally following minor trauma. He went into cardiac arrest; open-chest cardiac massage resulted in avulsion of the heart from the superior vena cava with massive intrathoracic bleeding and death. Type III procollagen is stored in dermal fibroblasts which show markedly dilated endoplasmic reticulum. Byers et al. (1979) emphasized the heterogeneity of EDS IV. Of 2 patients only 1 showed dilated endoplasmic reticulum. Probably a defect in type III collagen is a common feature. One of their patients showed keloid formation, a seemingly paradoxical feature that I also have observed in this disorder. One patient had had spontaneous pneumothorax as well as spontaneous rupture of the bowel. Pope et al. (1980) reported an apparent dominant form of EDS IV (in father and daughter). The acrogeric appearance of the skin of the hands was particularly striking in the 37-year-old father. A third patient (their patient 1) had severe acrogeric EDS IV. At age 7 she had been presented at the Section of Dermatology of the Royal Society of Medicine (Morris, 1957). At age 25 she suffered spontaneous rupture of the splenic artery and 3 years later had rupture of a left renal artery aneurysm. At age 29 she showed the typical facies and hand changes of acrogeria. The skin over the nose and ears was tight like that in scleroderma. Acroosteolysis was present. Chemical studies showed striking deficiency of type III collagen in all 3 cases. See 120180.0015. In an 18-year-old girl whom they considered to have EDS I, De Paepe et al. (1987) found large, irregular collagen fibers by light microscopy of skin biopsies, with the same finding in the affected father. Electron microscopy showed variation in the diameter and shape of collagen fibrils as well as slight dilatation of the rough endoplasmic reticulum of fibroblasts in father and daughter. In both instances, the findings in the unaffected mother were normal. Synthesis of type III collagen was reduced to 50% of normal in the father and daughter. The patient had perhaps a greater tendency to bruising than do many EDS I patients. The abnormality in type III collagen suggested the diagnosis of EDS IV. Fox et al. (1988) described a man who developed a spontaneous pulsating tinnitus in his left ear at the age of 20.5 years; he discovered accidentally that this noise could be stopped by firm pressure over the left side of the neck. Left-sided periorbital swelling, reddening of the conjunctiva, and ocular pain developed 6 months later, with left-sided pulsatile proptosis and a loud vascular bruit over the left orbit. Signs of EDS IV included thin nose and lips, hyperextensible joints, lax or thin skin with prominent venous markings, and small linear telangiectases on the trunk. There was a history of rectal bleeding attributed to multiple colonic diverticula. The patient was found to have a deficiency of type III collagen. The carotid-cavernous fistula was closed by means of a balloon catheter. Fox et al. (1988) referred to 5 previously reported cases of the Ehlers-Danlos syndrome presenting as spontaneous carotid-cavernous fistula. In a group of 14 families, Rudd et al. (1983) identified 20 women with EDS IV. The diagnosis was confirmed in at least 1 member of each family by demonstration of reduced production of type III collagen by dermal fibroblasts in vitro. Of the 20 women, 10 had been pregnant and 5 had died of pregnancy-related complications. The overall risk of death in each pregnancy was 25% in this series. Pregnancy-related complications included rupture of bowel, aorta, vena cava or uterus, vaginal laceration, and postpartum uterine hemorrhage. Nine of the families had 29 affected persons in an autosomal dominant pedigree pattern; the remaining 5 families had a single case. Pope and Nicholls (1983) took a less pessimistic view of pregnancy in EDS IV. Byard et al. (1990) ascribed the 'sudden infant death syndrome' in a previously healthy 5-month-old female infant to type IV Ehlers-Danlos syndrome leading to spontaneous subarachnoid hemorrhage. The skin and aorta at postmortem showed a deficiency of type III collagen. There was no parental consanguinity and no family history of EDS, and both parents were aged 25. There were no gross features of EDS IV and the diagnosis was based exclusively on the finding that type III collagen in aorta and skin was reduced. Sherry et al. (1992) described a 16-year-old boy with EDS IV who developed a hepatoportal fistula 9 days after sigmoid colectomy and colostomy were performed for spontaneous rupture of the colon. The fistula was successfully occluded angiographically with a transcatheter coil In 2 patients with inherited EDS IV, Superti-Furga et al. (1992) demonstrated evidence of microangiopathy of skin capillaries with microbleedings, microaneurysms, and increased transcapillary diffusion. In a series of 10 patients, Lewkonia and Pope (1985) found several with peripheral joint contractures and 3 who had acroosteolysis involving both fingers and toes. The simulation of chronic inflammatory joint disease was pointed out. Newton and Carpenter (1959) also reported acroosteolysis in EDS but it is not clear that the mother and daughter that they reported had type IV. They pointed out that the dislocation of the thumbs and other fingers may contribute to the simulation of rheumatoid arthritis. Yost et al. (1995) described a 27-year-old man with EDS type IV who had recurrent and eventually fatal pulmonary hemorrhages. This had apparently not been previously described. North et al. (1995) reviewed the cerebral vascular complications in 202 individuals with molecularly confirmed type IV Ehlers Danlos syndrome. Of these, 19 individuals had cerebral vascular complications which included intracranial aneurysms, spontaneous carotid cavernous sinus fistulas, and dissection of cervical arteries. The mean age at presentation of the cerebral vascular complication was 28.3 years ranging from 17 to 48. Phan et al. (1998) described a 39-year-old man with known EDS IV who presented with massive spontaneous hemothorax due to ruptured internal mammary artery aneurysm. He had first presented in his twenties with right renal infarction; 3 years later he underwent partial left nephrectomy for left renal infarction, and an aneurysm of the left renal artery was excised and the artery replaced. In addition to joint hypermobility, he had elastosis perforans serpiginosa. Emergency anterolateral thoracotomy for ligation of an abnormally fragile left internal mammary artery proximal to the aneurysm and drainage of an extensive hemothorax was accomplished successfully and postoperative recovery was uneventful. Commenting on the report of Pepin et al. (2000), Barabas (2000) stated that in his experience, teenage boys are at high risk for arterial rupture, which is often fatal. He suggested that this may be because during the prepubertal growth spurt the defective collagen is further weakened. He stated further that patients who undergo surgery are prone to arterial rupture in the postoperative period. Pepin et al. (2000) had commented that preexisting aneurysms are only occasionally documented in patients who have arterial ruptures. Barabas (2000) suggested that this is because the patients with EDS type IV do not have true aneurysms. Aneurysms, if present, follow arterial tears and are walled-in hematomas or pseudoaneurysms. Barabas (2000) also drew attention to the danger of varicose vein surgery in unrecognized cases of EDS type IV, since the extreme fragility of all blood vessels can lead to loss of a limb or even loss of life. Kroes et al. (2003) described a mother and son with EDS type IV and unusual congenital anomalies. The mother had amniotic band-like constrictions on one hand, a unilateral clubfoot, and macrocephaly owing to normal-pressure hydrocephalus; the son had esophageal atresia and hydrocephalus. The family was also anomalous in that protein analysis of collagen III in cultured fibroblasts of the mother showed no abnormalities; however, DNA analysis of the COL3A1 gene revealed a pathogenic mutation (120180.0031) in both the mother and the son. The relationship between the COL3A1 mutation and the congenital anomalies was not clear. The experience emphasized the importance of performing both collagen protein analysis and DNA analysis of COL3A1. In 16 patients with EDS type IV and 16 age-, gender-, and blood pressure-matched controls, Boutouyrie et al. (2004) measured circumferential wall stress in an elastic (common carotid) and a muscular (radial) artery. In the carotid artery, steady circumferential wall stress was 43% higher in EDS patients than in controls, pulsatile circumferential wall stress was 22% higher, and carotid intima-media thickness was 32% lower (p less than 0.001 for all findings). Carotid internal diameter and radial artery parameters were not significantly different between the 2 groups. Boutouyrie et al. (2004) concluded that the abnormally low intima-media thickness of elastic arteries in EDS IV patients generates higher wall stress, which may increase the risk of arterial dissection and rupture. Germain and Herrera-Guzman (2004) provided an extensive review of EDS IV.
Schwarze et al. (2001) studied 4 patients with EDS IV who presented with vascular aneurysm or rupture and were found to be haploinsufficient for a COL3A1 allele. They noted that in contrast to the severe phenotype in these ... Schwarze et al. (2001) studied 4 patients with EDS IV who presented with vascular aneurysm or rupture and were found to be haploinsufficient for a COL3A1 allele. They noted that in contrast to the severe phenotype in these patients, mice that are haploinsufficient for COL3A1 have no identified phenotype and individuals with null mutations in the dominant protein of a tissue, i.e., COL1A1 and COL2A1, have milder phenotypes than those caused by mutations that alter protein sequence. Schwarze et al. (2001) suggested that the major effect of many of these dominant mutations in the 'minor' collagen genes may be expressed through protein deficiency rather than through incorporation of structurally altered molecules into fibrils. Plancke et al. (2009) reported a 10-year-old French girl, born of consanguineous parents, with EDS type IV who was found to carry a homozygous truncating mutation in the COL3A1 gene (479dupT; 120180.0034). The patient's unaffected parents were each heterozygous for the mutation, suggesting autosomal recessive inheritance. The mutation was shown to result in nonsense-mediated decay. The lack of phenotype in the parents was discussed by Plancke et al. (2009) in light of the study by Schwarze et al. (2001), who reported a severe phenotype resulting from haploinsufficiency for COL3A1 due to truncating mutations. Plancke et al. (2009) noted that heterozygous Col3a1-null mice have no phenotype (Liu et al., 1997), similar to the parents of their French patient. Plancke et al. (2009) also noted that the nonsense-mediated mRNA process is inefficient and, in the cases of Schwarze et al. (2001), could have resulted in the production of a small amount of protein with dominant-negative effects. Leistritz et al. (2011) reviewed the clinical and family histories of medical complications in 54 individuals from 19 families with COL3A1-null mutations. Compared with individuals with missense or exon-skipping mutations, they found that life span was extended, the age of first complication was delayed by almost 15 years, and major complications were limited to vascular events. Families were ascertained after a complication in a single individual, but only 28% of relatives, some of whom had reached their seventies or eighties without incident, had a complication and only 30% had minor clinical features of vascular Ehlers-Danlos syndrome type IV. Leistritz et al. (2011) concluded that null mutations of COL3A1 have reduced penetrance compared with missense and splicing mutations, and the phenotype seems to be limited almost entirely to vascular events.
Superti-Furga and Steinmann (1988) and Superti-Furga et al. (1986, 1988) showed that a patient with severe, dominantly inherited EDS IV had a deletion of 3.3 kb in the triple-helical coding domain of 1 of the 2 genes for ... Superti-Furga and Steinmann (1988) and Superti-Furga et al. (1986, 1988) showed that a patient with severe, dominantly inherited EDS IV had a deletion of 3.3 kb in the triple-helical coding domain of 1 of the 2 genes for the pro-alpha-chains of type III collagen. His cultured skin fibroblasts contained equal amounts of normal length mRNA and of mRNA shortened by approximately 600 bases, and synthesized both normal and shortened procollagen chains. In procollagen molecules containing 1 or more shortened chains, a triple helix was formed with a length of only about 780 amino acids. The mutant procollagen molecules had decreased thermal stability, were less efficiently secreted, and were not normally processed. This was the first description of the molecular lesion in the COL3A1 gene in a case of EDS type IV. In affected members of the family reported by Fox et al. (1988), Richards et al. (1992) described a gly847-to-glu mutation of the COL3A1 gene (120180.0014). This family included an unaffected member who was mosaic for the mutation. Kontusaari et al. (1992) described mosaicism for a mutation in the COL3A1 gene in the asymptomatic mother of a patient with EDS type IV (120180.0015). Milewicz et al. (1993) found heterozygosity for a 2-kb deletion in the COL3A1 gene in a severely affected teenaged girl whose asymptomatic father was mosaic for the same deletion. Milewicz et al. (1993) gave a useful summary of the numerous autosomal dominant or X-linked recessive disorders in which this phenomenon has been observed. Gilchrist et al. (1999) identified a gly571-to-ser substitution in the triple helical domain of the products of one COL3A1 allele (120180.0026) in a large family with a milder phenotype than that typically associated with EDS IV. Clinical presentation in some of the affected members occurred at a later age than usual. Longevity was longer than that seen in many families, and there was less pregnancy-associated morbidity or mortality than that found in some families. The authors suggested that some clinical aspects of EDS IV may be related to the nature of the mutation and its effect on the behavior of the protein. Palmeri et al. (2003) characterized 7 members of a family with EDS IV. The index patient, a young woman with an acrogeric face, suffered chronic muscle pain and cramps, Achilles tendon retraction, finger flexion contractures, and seizures. The mother had similar features and had experienced an ischemic stroke at the age of 43 years. A gly883-to-val mutation in the COL3A1 gene (120180.0033) was identified in both. Angiography of the cerebral vessels in the mother revealed coiling on both internal carotids in the extracranial tract, which mimicked fibromuscular dysplasia as reported by Schievink and Limburg (1989). The phenotypically normal maternal grandmother was found to be mosaic for this mutation. The maternal grandfather and a maternal aunt each had an abdominal aortic aneurysm, the rupture of which was the cause of death in the latter at 40 years of age; the aneurysm in the grandfather was presumably an incidental finding, with a cause different from the vascular disease that the other members of the family inherited from the mosaic maternal grandmother. - Ehlers-Danlos Syndrome Type IV Variant Kontusaari et al. (1990) studied a 37-year-old female captain in the U. S. Air Force who had a family history of sudden death due to rupture of thoracic or abdominal aortic aneurysms. She had mild hyperextensibility of joints and apparent arachnodactyly, with a hand-to-height ratio of 10.9% (upper limit of normal). She had a tendency to bruise easily, and the surgeon who had previously removed her appendix noted that her tissues seemed friable and bled easily, with the loss of 1 liter of blood during that operation. She had no history of joint dislocations, her skin had normal texture without unusual extensibility, and she did not have subluxation of the lens on slit-lamp examination. Analysis of the COL31A gene revealed heterozygosity for a missense mutation (G619R; 120180.0002) that was also found in pathology specimens from her mother and a maternal aunt, who died at age 34 years and 55 years, respectively, of aortic aneurysms. In a 34-year-old man with a history of thin skin and easy bruisability, who died of massive intrathoracic and intraabdominal hemorrhage, Kontusaari et al. (1990) identified heterozygosity for a splice site mutation in the COL3A1 gene (120180.0004). At autopsy, no distinct aneurysm or bleeding point was identified, but microscopic sections of aorta revealed an apparent decrease in and disorganization of elastic fibers, and all the abdominal soft tissues appeared to be unusually friable. The proband's father and 1 brother had died of rupture of abdominal and thoracic aneurysms, respectively.
Diagnostic criteria and standardized nomenclature for the Ehlers-Danlos syndromes (EDSs) were suggested by a medical advisory group in a conference sponsored by the Ehlers-Danlos National Foundation (US) and the Ehlers-Danlos Support Group (UK) at Villefranche in 1997 [Beighton et al 1998]. ...
DiagnosisClinical DiagnosisDiagnostic criteria and standardized nomenclature for the Ehlers-Danlos syndromes (EDSs) were suggested by a medical advisory group in a conference sponsored by the Ehlers-Danlos National Foundation (US) and the Ehlers-Danlos Support Group (UK) at Villefranche in 1997 [Beighton et al 1998]. Diagnostic criteria for Ehlers-Danlos syndrome type IV (EDS type IV) are modified here to reflect the authors' experience. The combination of any two of the major diagnostic criteria should have a high specificity for EDS type IV; DNA testing is strongly recommended to confirm the diagnosis. The presence of two or more minor criteria should lead to consideration of the diagnosis of EDS type IV but is not sufficient to establish the diagnosis.Major diagnostic criteria for EDS type IV include:Arterial ruptureIntestinal ruptureUterine rupture during pregnancyFamily history of EDS type IVMinor diagnostic criteria for EDS type IV include:Thin, translucent skin (especially noticeable on the chest/abdomen)Characteristic facial appearance (thin lips and philtrum, small chin, thin nose, large eyes)Acrogeria (an aged appearance to the extremities, particularly the hands)Arteriovenous carotid-cavernous sinus fistulaHypermobility of small jointsTendon/muscle ruptureEarly-onset varicose veinsPneumothorax/pneumohemothoraxEasy bruising (spontaneous or with minimal trauma)Chronic joint subluxations/dislocationsCongenital dislocation of the hipsTalipes equinovarus (clubfoot)Gingival recessionTestingBiochemical (protein-based) testing. Biochemical testing for EDS type IV requires cultured dermal fibroblasts. Proteins synthesized by these cells are biosynthetically labeled with radio-labeled proline, and assessed by sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The amount of type III procollagen synthesized, the quantity secreted into the medium, and the electrophoretic mobility of the constituent chains are assessed. Analysis of type III procollagen synthesized by cultured cells can identify abnormalities in synthesis and mobility of type III collagen chains. Such testing remains a valuable resource to confirm mRNA and protein consequences when a unique sequence variant is identified and to look for protein abnormalities in an individual with convincing phenotype but an apparently normal sequence of COL3A1. Rare small multiexonic deletions not detected by deletion/duplication analysis (e.g., MLPA) may be identified using cDNA sequencing.Molecular Genetic TestingGene. COL3A1 is the only gene in which mutations are known to cause EDS type IV.Clinical testingSequence analysis. Direct sequence analysis of the coding regions and adjacent splice sites of COL3A1 using DNA extracted from a blood sample or other source of genomic DNA identifies a mutation in over 95% of individuals with EDS type IV. 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. About 4% of identified mutations lead to mRNA instability or to failure of chain association in the products of the mutant allele [Schwarze et al 2001, Leistritz et al 2010]. Deletion/duplication analysis can identify exon and multiexon COL3A1 deletions if the target exons are in the amplification set. About 2% of all individuals with EDS type IV have a genomic deletion. We have confirmed that although found by other methods, these could be detected by deletion/duplication analysis such as MLPA. The low frequency of genomic deletions is consistent with the failure to detect a deletion after routine screening (by MLPA) of approximately 100 specimens submitted for COL3A1 clinical sequencing studies [Boston University School of Medicine - Human Genetics DNA Diagnostic Laboratory genetic counselors, personal communication]. One 3.5-Mb contiguous gene deletion that includes COL3A1 was identified by MLPA [Meienberg et al 2010]. Table 1. Summary of Molecular Genetic Testing of EDS Type IVView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCOL3A1Sequence analysisSequence variants 2>95%ClinicalDeletion / duplication analysis 3Exonic or whole gene-deletions~2% 41. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.4. Genomic deletions are rare, although splice site mutations that lead to exon skipping are frequently seen. The majority of exon-skipping events have been confirmed by cDNA amplification and sequencing. MLPA should be effective in detecting single- or multiple-exon deletion events if the target exon is in the MLPA set.Interpretation of test resultsFor issues to consider in interpretation of sequence analysis results, click here.For issues related to the value of protein-based testing see Biochemical (protein-based) testing.Testing StrategyTo confirm/establish the diagnosis in a probandSequence analysis of COL3A1 confirms the clinical diagnosis of EDS type IV over 95% of the time. Sequence analysis identifies variants of unknown significance, the role of which may be defined by biochemical (protein-based) testing.Deletion/duplication analysis. If a mutation is not detected on sequence analysis of genomic DNA, deletion/duplication analysis may be indicated, particularly in instances when sequencing does not identify heterozygous sequence variants and the phenotype is compelling. To date, such deletions are rare (<2%) in COL3A1. Biochemical (protein-based) testing. Testing of type III procollagen synthesized by cultured cells from a skin biopsy is the recommended assay when a mutation is not identified by sequence analysis or when a sequence variant of unknown clinical significance is found. Such testing may confirm mRNA and protein consequences of a variant of unknown significance or may identify a type III collagen protein abnormality, indicating that the mutation was missed as a result of a technical problem (e.g., mutation is masked by location under a primer or presence of a multiexonic deletion). Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersEhlers-Danlos syndrome, hypermobility type (EDS type III). A single report of a family with clinical features of EDS type III and a COL3A1 mutation typically associated with the EDS type IV (NM_000090.3:c.2410G>A (p.Gly804Ser) or Gly637Ser in the triple helical domain) [Narcisi et al 1994] led to the suspicion of a causative relationship between COL3A1 mutations and EDS type III; however, neither biochemical studies of collagen synthesis nor COL3A1 genomic DNA sequence analysis have identified a type III collagen defect in any other individuals with the clinical diagnosis of EDS type 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 described with familial aortic aneurysm, but clinically more consistent with EDS type IV, and in another family with aortic aneurysm. In spite of this report, existence of a subset of individuals with a COL3A1 mutation giving rise to the phenotype of familial aortic aneurysm in the absence of other findings of EDS type IV seems unlikely [Author, personal observation].
A retrospective review of the health history of more than 400 individuals with Ehlers-Danlos syndrome (EDS) type IV 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. ...
Natural HistoryA retrospective review of the health history of more than 400 individuals with Ehlers-Danlos syndrome (EDS) type IV 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. As of 2010, more than 500 COL3A1 mutations have been identified by molecular testing in the authors’ laboratory and almost 200 others have been reported. Within this group a subpopulation of 3%-4% have haploinsufficiency mutations. Review of clinical histories of the COL3A1 probands and family members reveals a 15-year delay in onset of complications, similarly improved life expectancy, and paucity of both obstetric and bowel complications [Leistritz et al 2010]. Children. Approximately 12% of neonates with EDS type IV have clubfoot, and 3% have congenital dislocation of the hips. Rare infants have evidence of amniotic bands including a small number with limb deficiencies. In childhood, inguinal hernia, pneumothorax, and recurrent joint dislocation or subluxation are described. Affected individuals often have a lifelong history of easy bruising. Most children with EDS type IV have few major complications; and, in families with a negative family history, the disorder is often unrecognized in childhood.Adults. Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with missense and exon-skipping mutations of COL3A1. Such complications are dramatic and often unexpected, presenting as sudden death, stroke and its neurologic 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 in this group. Individuals with haploinsufficiency mutations may present with arterial events (none yet are described with bowel-or pregnancy-related catastrophes); the average age of first event in this group is 37 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, or may occur spontaneously. The sites of arterial rupture are the thorax and abdomen (50%), head and neck (25%), and extremities (25%). The clinical presentation depends on the location of the arterial event.Rupture of the gastrointestinal (GI) tract occurs in about 25% of affected individuals with missense mutations. To date, such GI events have not been documented in the families with haploinsufficiency mutations. The majority of GI perforations occur in the sigmoid colon. Ruptures 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. Surgical re-anastomosis can generally be accomplished. 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].Keratoconus [Kuming & Joffe 1977], periodontal disease, and venous varicosities have been reported [Tsipouras et al 1986]. Pregnancy for women with EDS type IV has as much as a 12% risk for death from peripartum arterial rupture or uterine rupture [Pepin et al 2000].
To date, the only clear genotype-phenotype correlations are the 15-year delay in onset of complications, decreased penetrance, and increased life expectancy in individuals with haploinsufficiency mutations, and the higher frequency of acrogeria in individuals with mutations that alter the carboxyl-terminal quarter of the triple helical domain of the chains of type III procollagen [Leistritz et al 2010]. ...
Genotype-Phenotype CorrelationsTo date, the only clear genotype-phenotype correlations are the 15-year delay in onset of complications, decreased penetrance, and increased life expectancy in individuals with haploinsufficiency mutations, and the higher frequency of acrogeria in individuals with mutations that alter the carboxyl-terminal quarter of the triple helical domain of the chains of type III procollagen [Leistritz et al 2010].
Other forms of Ehlers-Danlos syndrome (EDS) should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation who have normal collagen III biochemical studies or genetic analysis of COL3A1. The disorders in which clinical findings overlap with EDS type IV include the following:...
Differential DiagnosisOther forms of Ehlers-Danlos syndrome (EDS) should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation who have normal collagen III biochemical studies or genetic analysis of COL3A1. The disorders in which clinical findings overlap with EDS type IV 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. More than half of individuals with EDS, classic type, have an identifiable mutation in COL5A1 or COL5A2.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 PLOD1, which encodes lysyl hydroxylase 1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1). The diagnosis of EDS, kyphoscoliotic form relies on the demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by high pressure liquid chromatography (HPLC) and identification of a mutation in PLOD1.Ehlers-Danlos syndrome VIII (periodontal form) is a rare disorder including features of the classic type 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 in addition to the six identified genes (see Thoracic Aortic Aneurysms and Aortic Dissections). Loeys-Dietz syndrome (LDS) is an autosomal dominant disorder characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus). Approximately 75% of affected individuals have LDS type I with craniofacial manifestations (ocular hypertelorism, bifid uvula/cleft palate, craniosynostosis); approximately 25% have LDS type II with cutaneous manifestations (velvety and translucent skin; easy bruising; widened, atrophic scars). LDSI and LDSII form a clinical continuum. The natural history of LDS is characterized by aggressive arterial aneurysms (mean age at death 26.1 years) and high incidence of pregnancy-related complications including death and uterine rupture. The diagnosis of LDS is based on characteristic clinical findings in the proband and family members and molecular genetic testing of TGFBR1 and TGFBR2, the only two genes in which causative mutations have been found. 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 PKD1 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. EDS type IV 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 on 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 type IV.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
Currently, no consensus exists regarding the appropriate extent of evaluation at the time of initial diagnosis. ...
ManagementEvaluations Following Initial DiagnosisCurrently, no consensus exists regarding the appropriate extent of evaluation at the time of initial diagnosis. Approach to a vascular evaluation depends on the age of the individual and the circumstances in which the diagnosis is made. Because of the risk of asymptomatic aneurysm/dissection, initial visualization of the arterial tree is commonly undertaken; the approach employed varies by region and by institution (see Surveillance). No gastrointestinal factors are known to increase the risk of bowel rupture, thus negating the need for initial invasive GI evaluation. Treatment of ManifestationsSurgical intervention may be life-saving in the face of bowel rupture, arterial rupture, or organ rupture (e.g., the uterus in pregnancy). When surgery is required for treatment, it is appropriate to target the approach and minimize surgical exploration because of the risk of inadvertent damage to other tissues [Oderich et al 2005]. In general, surgical procedures are more likely to be successful when the treating physician is aware of the diagnosis of EDS type IV and its associated tissue fragility. Prompt surgical intervention of bowel rupture is essential to limit the extent of infection and facilitate early restoration of bowel continuity. Death from bowel rupture is uncommon because intervention is generally effective. Bowel continuity can be restored successfully in most instances, usually three to six months after the initial surgery. The recurrence of bowel tears proximal to the original site and the risk of complications resulting from repeat surgery have led some to recommend partial colectomy to reduce the risk of 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 [Fuchs & Fishman 2004].Affected individuals should be instructed to seek immediate medical attention for sudden, unexplained pain.A MedicAlert® bracelet should be worn.SurveillanceThe use of surveillance of the arterial tree assumes that effective interventions will decrease the risk of arterial dissection or rupture and prolong life. At a time when an open surgical approach was the only alternative, the benefit of surveillance could not be established. As endovascular approaches to management of aneurysms and dissection become more available, intervention is considered earlier and surveillance is seen to have greater benefit. There are, however, no published data that assess the efficacy of screening strategies to identify the regions in the arterial vasculature at highest risk; conversely, there are examples in which regions of concern in the arterial vasculature failed to progress and arterial rupture occurred at other more distant sites. Thus, the benefit of controlled studies cannot be overemphasized. If undertaken, the noninvasive imaging such as sonography, MR or CT angiography with or without venous contrast has been documented to identify aneurysms, dissections, and vascular ruptures. Conventional arterial angiography (with contrast injection) should be discouraged because it has been associated with added de novo complications [Zilocchi et al 2007]. Arterial tear/dissection may result at the site of entry of the catheter; furthermore, injection pressure may lead to arterial aneurysms. Arteriography is currently best used as part of a planned interventional procedure, such as coil embolization or stenting of bleeding arteries. Agents/Circumstances to AvoidTrauma. Because of inherent tissue fragility, it is prudent for individuals with EDS type IV to avoid collision sports (e.g., football), heavy lifting, and weight training. Of note, no evidence suggests that moderate recreational exercise is detrimental.Elective surgery. Increased tissue fragility results in a higher risk of surgical complications; thus, elective surgery for individuals with EDS type IV 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 and at sites of high pressure injection, arteriograms are not recommended and the use of CTA, MRA, and ultrasonography should be considered for routine surveillance.Routine colonoscopy should be avoided because of the risks of bowel perforation by the instrument and secondary to insufflation. Routine colonoscopy for cancer screening should be replaced with noninvasive measures. Virtual colonoscopy, which also involves insufflation, may have similar complications. In the face of a family history of cancer, standard or emerging strategies of surveillance may be of benefit.Evaluation of Relatives at RiskThe genetic status of at-risk relatives can be clarified by molecular genetic testing if the disease-causing mutation in the family is known. For those found to have the family-specific mutation, management is the same as for individuals identified through clinical findings.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management It is prudent to follow pregnant women with EDS type IV in a high-risk obstetrical program. It is not known if elective caesarian section decreases the risk of mortality and vaginal and cervical tears and these benefits outweigh the associated morbidity. Educating the pregnant woman as to possible complications and the need for close monitoring is recommended.Therapies Under InvestigationA recently published clinical trial of the efficacy of a cardioselective β-blocker with β-2 agonist vasodilatory properties (celiprolol) in reducing risk of arterial rupture or dissection concluded that there was a benefit: a reduced number of arterial events (rupture or dissection, fatal or not) was reported in the treatment group. Although the study was directed to measure benefit in individuals with EDS type IV, randomization to treatment or control group was undertaken prior to mutation characterization. The treated and untreated groups with mutations differed in size and age distribution so that it is difficult to determine if there is a measurable benefit [Ong et al 2010].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Ehlers-Danlos Syndrome Type IV: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCOL3A12q32.2Collagen alpha-1(III) chainDatabase of osteogenesis imperfecta and type III collagen mutationsCOL3A1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Ehlers-Danlos Syndrome Type IV (View All in OMIM) View in own window 120180COLLAGEN, TYPE III, ALPHA-1; COL3A1 130050EHLERS-DANLOS SYNDROME, TYPE IV, AUTOSOMAL DOMINANTNormal allelic variants. The COL3A1 cDNA comprises 51 exons distributed over 44 kb of genomic DNA (reference sequence NM_000090.3). The Database of Human Type I and Type III Collagen Mutations (www.le.ac.uk/genetics/collagen) provides a list of known variants.Pathologic allelic variants. More than 600 mutations in COL3A1 that result in a disease-causing phenotype have been identified. The majority of identified mutations 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. 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, Leistritz et al 2010]. The consequence is synthesis of about one half the amount of normal type III procollagen. (See Database of Human Type I and Type III Collagen Mutations.)In the analysis to date of the mutations identified in COL3A1, at least two classes of mutations — substitutions of glycine in the triple helical domain by alanine and introduction of premature termination codons — are underrepresented (in terms of the predicted frequency) among individuals with clinical features of EDS type IV. Thus, some mutations in COL3A1 may not produce an EDS, vascular type phenotype. It is unclear if individuals with these classes of mutations have limited phenotypes and present at later ages or if there is a molecular explanation for the absence of certain mutation types. Normal gene product. COL3A1 encodes the proα1(III) chain 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 1,466 amino acids in length.Abnormal gene product. Mutations of COL3A1 typically result in a structural alteration of type III collagen that leads to intracellular storage and impaired secretion of collagen chains.