Alternative titles; symbols
SNOMEDCT: 83470009; ORPHA: 287; DO: 14720;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q34.3 | Ehlers-Danlos syndrome, classic type, 1 | 130000 | Autosomal dominant | 3 | COL5A1 | 120215 |
A number sign (#) is used with this entry because Ehlers-Danlos syndrome classic type 1 (EDSCL1) is caused by heterozygous mutation in the collagen alpha-1(V) gene (COL5A1; 120215) on chromosome 9q34.
Rarely, specific mutations in the COL1A1 gene (e.g., R134C, 120150.0059) cause classic EDS.
The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The main features of classic Ehlers-Danlos syndrome are loose-jointedness and fragile, bruisable skin that heals with peculiar 'cigarette-paper' scars (Beighton, 1993).
Genetic Heterogeneity of Classic Ehlers-Danlos Syndrome
See EDSCL2 (130010), caused by mutation in the COL5A2 gene (120190) on chromosome 2q32.
Classification of Ehlers-Danlos Syndrome
The current OMIM classification of Ehlers-Danlos syndromes is based on a 2017 international classification described by Malfait et al. (2017), which recognizes 13 EDS subtypes: classic, classic-like (606408, 618000), cardiac-valvular (225320), vascular (130050), hypermobile (130020), arthrochalasia (130060, 617821), dermatosparaxis (225410), kyphoscoliotic (225400, 614557), spondylodysplastic (130070, 615349), musculocontractural (601776, 615539), myopathic (616471), periodontal (130080, 617174), and brittle cornea syndrome (229200, 614170). This classification is a revision of the 'Villefranche classification' reported by Beighton et al. (1998), which was widely used in the literature and in OMIM. For a description of the Villefranche classification, see HISTORY.
In an early classification of EDS, the designations EDS I and EDS II were used for severe and mild forms of classic EDS, respectively. EDS I was characterized by marked skin involvement and generalized, gross joint laxity, with musculoskeletal deformity and diverse orthopedic complications. Prematurity occurred in approximately 50% of cases. Internal complications such as aortic and bowel rupture were occasionally present. EDS II had all the stigmata of EDS I, but to a minor degree (summary by Steinmann et al., 2002). Both were considered to be forms of classic EDS.
Graf (1965) reported a brother and sister with Ehlers-Danlos syndrome who developed 'spontaneous' carotid-cavernous fistula. Internal complications included rupture of large vessels, hiatus hernia, spontaneous rupture of the bowel, and diverticula of the bowel. Retinal detachment has been observed (Pemberton et al., 1966). Schofield et al. (1970) reported brother and sister in their 60s who suffered spontaneous rupture of the colon. They had joint laxity, and both bruised easily and sustained many lacerations from minor trauma. The father of the 2 sibs and the son of the brother may have been affected.
Barabas (1966) concluded that most persons with EDS are born prematurely due to premature rupture of fetal membranes.
Patients with urinary tract infection and other problems related to bladder diverticulum were reported by Eadie and Wilkins (1967) and by Zalis and Roberts (1967). Cuckow et al. (1994) described a 4-year-old boy with huge bladder diverticula complicating type I EDS.
Friedman and Harrod (1982) described a severe form of EDS. The mother died of dissecting aneurysm of the aorta. Autopsy also showed myxomatous changes in the mitral and tricuspid valves with redundancy of cusps and chordae. Both mother and son had large hernias, positional foot deformities, abnormal thoracic shape, asthma, and severe eczematoid dermatitis. In an 18-year-old girl with EDS, Mishra et al. (1992) demonstrated aneurysm of the membranous ventricular septum as well as mitral valve prolapse. The patient had had lumbosacral fusion for recurrent spondylolisthesis.
In a large Azerbaijanian village (population about 6,000), Kozlova et al. (1984) observed a kindred with 92 persons affected with EDS I. One patient, whose affected parents were cousins, was judged to be homozygous.
The minimal diagnostic features for EDS I used in the study of Wenstrup et al. (1996) were autosomal dominant inheritance, generalized joint laxity, hyperextensible skin with doughy and velvety texture, and the presence of widened atrophic scars. The criterion used to distinguish EDS II from EDS I was the absence of widened atrophic scars in EDS II.
De Felice et al. (2001) studied 4 patients with EDS II and 8 patients with EDS III (130020), the hypermobile type. They concluded that absence of the inferior labial frenulum and the lingual frenulum are characteristics of EDS. Absence of the inferior labial frenulum showed 100% sensitivity and 99.4% specificity; absence of the lingual frenulum showed 71.4% sensitivity and 100% specificity.
Wenstrup et al. (2002) performed a prospective cohort study on 71 consecutive EDS patients. Twenty of 71, or 28%, had aortic root dilatation defined as greater than 2 standard deviations above population-based norms. Fourteen of 42 individuals with the classic form of EDS (types I and II) and 6 of 29 individuals with the hypermobility form (EDS III) had aortic root dilatation, with no gender differences. Wenstrup et al. (2002) concluded that aortic root dilatation is a common finding in EDS. However, rates of progression and complication were unknown.
Nordschow and Marsolais (1969) could demonstrate no abnormality of shrinkage temperature thermograms of tendon collagen from a hypermobile joint of an EDS patient. They supported the suggestion of Wechsler and Fisher (1964) that the defect concerns the amount of collagen produced. Varadi and Hall (1965) concluded that elastin is normal.
Borck et al. (2010) reported a 42-year-old German man with EDS and spontaneous rupture of his left common iliac artery, who was negative for mutation in COL3A1 but was found instead to carry a de novo heterozygous nonsense mutation (120215.0012) in the COL5A1 gene. The patient had a history of recurrent inguinal hernias and easy bruising since childhood; hypertension had been diagnosed 2 years earlier. Physical examination revealed pigmented scars over bony prominences, molluscoid pseudotumors at elbows and knees, skin hyperextensibility, as well as varicose veins, all consistent with EDS. He had no articular hypermobility or history of joint dislocation, no ophthalmologic involvement, and no kyphoscoliosis or periodontitis. His parents were unaffected and did not carry the mutation; however, his daughter and son, who had smooth skin with a history of easy bruising, which had raised the suspicion of child abuse by schools and social authorities, were also heterozygous for the mutation. Borck et al. (2010) stated that this was the first report of a patient with COL5A1 mutation-positive EDS and rupture of a large artery, suggesting that arterial rupture might be a rare complication of classic EDS.
Skin like that in EDS has been observed with a fibrinolytic defect (134900).
Deodhar and Woolf (1994) suggested that patients with Ehlers-Danlos syndrome are at unusual risk for postmenopausal osteoporosis.
Voermans et al. (2009) performed a cross-sectional study on the presence of neuromuscular symptoms in 40 patients with various forms of EDS. Ten patients each were analyzed with classic EDS, vascular EDS (130050), hypermobility EDS (130020), and TNX-deficient EDS (606408). Overall, those with classic EDS and TNX-deficient EDS reported the most neuromuscular involvement, with muscle weakness, hypotonia, myalgia, easy fatigability, and intermittent paresthesias, although patients in all groups reported these features. Physical examination showed mild to moderate muscle weakness (85%) and reduction of vibration sense (60%) across all groups. Nerve conduction studies demonstrated axonal polyneuropathy in 5 (13%) of 39 patients. Needle electromyography showed myopathic EMG features in 9 (26%) and a mixed neurogenic-myopathic pattern in 21 (60%) of 35 patients. Muscle ultrasound showed increased echo intensity in 19 (48%) and atrophy in 20 (50%) of 40 patients. Mild myopathic features were seen on muscle biopsy of 5 (28%) of 18 patients. Patients with the hypermobility type EDS caused by TNXB haploinsufficiency were least affected. Voermans et al. (2009) postulated that abnormalities in muscle or nerve extracellular matrix may underlie these findings.
Castori et al. (2010) observed that patients with EDS reported high levels of chronic pain.
Classic EDS is an autosomal dominant disorder (Wenstrup et al., 1996; De Paepe et al., 1997).
Scarbrough et al. (1984) described what they considered to be EDS II in a 14-year-old male with an unbalanced t(6;13). The karyotype was designated as 45,XY,-6,-13,+der(6),t(6;13)(q27;q11). The patient was monosomic for 13pter-q11 and for a small part of 6q27 (the most distal segment of 6q). Joint hypermobility, velvety skin, several well-healed, parchment-like scars over both shins, and mild propensity for bruising were described. The patient had serious neuropsychiatric problems.
Using an intragenic simple sequence repeat polymorphism of the COL5A1 gene (120215) as a linkage marker, Loughlin et al. (1995) showed linkage to EDS II; maximum lod = 8.3 at theta = 0.00 in a single large pedigree. The COL5A1 gene is located on 9q34.2-q34.3.
Greenspan et al. (1995) used 3-prime untranslated region RFLPs to exclude the COL5A1 gene as a candidate in families with Ehlers-Danlos syndrome type II. The reason for inconsistency with the findings of Loughlin et al. (1995) may be the genetic heterogeneity of EDS II.
In a 3-generation family with features of Ehlers-Danlos syndrome types I and II, Burrows et al. (1996) observed tight linkage to the COL5A1 gene (120215) on chromosome 9q34; a lod score of 4.07 at zero recombinations located on 9q34.2-q34.3.
Greenspan et al. (1995) used 3-prime untranslated region RFLPs to exclude the COL5A1 gene as a candidate in families with Ehlers-Danlos syndrome type II. The reason for inconsistency with the findings of Loughlin et al. (1995) may be the genetic heterogeneity of EDS II.
In a 3-generation family with features of Ehlers-Danlos syndrome types I and II, Burrows et al. (1996) observed tight linkage to the COL5A1 gene (120215) on chromosome 9q34; a lod score of 4.07 at zero recombination was calculated. The variation in expression in this family suggested that EDS types I and II are allelic, and the linkage data supported the hypothesis that a mutation in COL5A1 can cause both phenotypes. was calculated. The variation in expression in this family suggested that EDS types I and II are allelic, and the linkage data supported the hypothesis that a mutation in COL5A1 can cause both phenotypes.
Wenstrup et al. (1996) reported 2 families in which EDS I cosegregated with the gene encoding the pro-alpha-1(V) collagen chains (COL5A1). In 2 other families with EDS I, linkage was excluded from both the COL5A1 and the COL5A2 loci.
In a large Azerbaijanian family with typical clinical manifestations of EDS I, Sokolov et al. (1991) excluded linkage with 3 collagen genes: COL1A1 (120150), COL1A2 (120160), and COL3A1 (120180). At least in this family, the mutation appeared not to lie in any of these genes.
Wenstrup et al. (1996) demonstrated that affected individuals in one of the EDS I COL5A1-linked families were heterozygous for a 4-bp deletion in intron 65 which led to a 234-bp deletion of exon 65 in the processed mRNA for pro-alpha-1(V) chains (120215.0002). Wenstrup et al. (1996) noted that the fact that EDS II has been reported to be linked to COL5A1 is indicative that EDS types I and II constitute a clinical and molecular spectrum. They concluded that EDS I and EDS II are genetically heterogeneous. They were unable to distinguish clinically between the COL5A1-linked and unlinked families.
In 2 unrelated patients with classic EDS I, Nuytinck et al. (2000) identified a heterozygous missense mutation in the COL1A1 gene (120150.0059).
Malfait et al. (2005) studied fibroblast cultures from 48 patients with classic EDS for the presence of type V collagen defects. Forty-two (88%) were heterozygous for an expressed polymorphic variant of COL5A1, and cDNA from 18 (43%) expressed only 1 COL5A1 allele. In total, 17 mutations leading to a premature stop codon and 5 structural mutations were identified in the COL5A1 and COL5A2 genes. In 3 patients with a positive COL5A1 null-allele test, no mutation was found. Overall, in 25 of the 48 patients (52%), an abnormality in type V collagen was confirmed. Variability in severity of the phenotype was observed, but no significant genotype-phenotype correlations were found. The relatively low mutation detection rate suggested that other genes are involved in classic EDS. Malfait et al. (2005) excluded COL1A1, COL1A2 (120160), and DCN (125255) as major candidate genes for classic EDS, since they could find no causal mutation in these genes in a number of patients who tested negative for COL5A1 and COL5A2.
Pallotta et al. (2004) described a 2-generation family with EDS in which 2 children exhibited features suggestive of EDS I and their mother exhibited features more suggestive of EDS IV (130050), i.e., she had thin nose and thin lips, thin translucent skin with prominent vasculature, and acroosteolysis. No mutation was identified in the COL3A1 gene (120180), but a deletion mutation was detected in the COL5A1 gene (120215.0011) in all 3 affected family members. The molecular diagnosis allowed the investigators to categorize the family into the classic form of EDS, which is associated with a good long-term prognosis.
Symoens et al. (2012) analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations, and 7 were COL5A1 null-alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null-allele, whereas one-third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra- and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring, and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, indicating that this is the major, if not the only, cause of classic EDS.
Reviews
Molecular defects in collagen in the several forms of EDS were surveyed by Prockop and Kivirikko (1984).
Associations Pending Confirmation
For discussion of a possible association between a complex multisystem disorder with connective tissue abnormalities reminiscent of Ehlers-Danlos syndrome and variation in the LAMA5 gene, see 601033.0002.
Barabas (1967) suggested the existence of 3 distinct types of the Ehlers-Danlos syndrome. In the classic type, the patients are born prematurely because of premature rupture of fetal membranes, and have severe skin and joint involvement but no varicose veins or arterial ruptures. A second (mild or 'varicose') group is not born prematurely and, although varicose veins are severe, the skin and joint manifestations are not. In a third ('arterial') group, bruising, including spontaneous ecchymoses during menstruation, is a paramount sign. Skin is soft and transparent but not very extensible, and joint hypermobility is limited to the hands. Severe and unexplained abdominal pain is a feature. Repeated arterial ruptures occur in these patients.
According to the original Beighton classification (Beighton, 1970), EDS I is the severe form of classic Ehlers-Danlos syndrome and EDS II is the mild form.
According to the classification used by McKusick (1972): EDS I, or gravis type, is the severe classic form. EDS II (130010), or mitis type, is the mild classic form. EDS III (130020) is the benign hypermobility form. EDS IV (130050) is the arterial, ecchymotic or Sack form. EDS V (see 314400) was a possible X-linked form. EDS VI (225400) is the form due to deficiency of lysyl hydroxylase. EDS VII (225410) is the form due to deficiency of procollagen protease. EDS VIII (130080) is the form with accompanying periodontitis. EDS IX (304150) is the form with occipital horns. EDS X (225310) is the form with a possible fibronectin defect. EDS XI (147900) is the familial joint instability syndrome.
Steinmann et al. (2002) noted that EDS IX (EDS9) and EDS XI (EDS11) have been reclassified as occipital horn syndrome and familial joint hypermobility syndrome, respectively, and that the existence of EDS V (EDS5), EDS VIII (EDS8), and EDS X (EDS10) as distinct entities is questionable.
In the Villefranche classification of EDS (Beighton et al., 1998), 6 main descriptive types were substituted for earlier types numbered with Roman numerals: classic type (EDS I and EDS II, 130010), hypermobility type (EDS III, 130020), vascular type (EDS IV, 130050), kyphoscoliosis type (EDS VI, 225400), arthrochalasia type (EDS VIIA and VIIB, 130060), and dermatosparaxis type (EDS VIIC, 225410). Six other forms were listed, including a category of 'unspecified forms.' Major and minor diagnostic criteria were defined for each type and complemented whenever possible with laboratory findings.
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