Alternative titles; symbols
ORPHA: 1899; DO: 0080728;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q21.3 | Ehlers-Danlos syndrome, arthrochalasia type, 2 | 617821 | Autosomal dominant | 3 | COL1A2 | 120160 |
A number sign (#) is used with this entry because of evidence that Ehlers-Danlos syndrome arthrochalasia type 2 (EDSARTH2) is caused by heterozygous mutation in the COL1A2 (120160) gene on chromosome 7q21.
Several forms of osteogenesis imperfecta (see, e.g., OI1, 166200) are also caused by mutation in the COL1A2 gene.
Arthrochalasia-type EDS is distinguished from other types of EDS by the frequency of congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement (Byers et al., 1997; Giunta et al., 2008).
For a discussion of genetic heterogeneity of arthrochalasia-type EDS, see 130060.
Lichtenstein et al. (1973) reported a patient with arthrochalasis multiplex congenita, including short stature, small mandible, considerable hyperextensibility, and increased skin bruising. Although the patient was originally thought to have deficiency of procollagen proteinase, Steinmann et al. (1980) found evidence for a structural mutation in the alpha-2 polypeptide of type I collagen in this patient. Steinmann et al. (1980) postulated that the mutation rendered the procollagen resistant to the action of the peptidase that normally cleaves off the extra piece from the NH2-end. Since equal amounts of pro-N-alpha-2 and alpha-2 chains were produced, and the parents were unaffected, the patient's abnormality was presumed to represent a dominant mutation.
Eyre et al. (1985) and Steinmann et al. (1985) each reported a similar case of EDS VII.
Viljoen et al. (1987) reported a Xhosa family with EDS VII. The mother and her 4 children had generalized articular laxity, joint dislocations and subluxations, and wormian bones in the skull. The authors suggested that the last feature may be more common in EDS VII than previously realized.
Nicholls et al. (1991) reported a 29-year-old male with bilateral hip dislocation at birth and with other features of the Ehlers-Danlos syndrome type VIIB. The patient's affected daughter was born with bilateral hip dislocation, joint hyperflexibility, feet in the equinovarus position, and hyperextensible skin. This was 1 of the few observations of transmission of this disorder.
Carr et al. (1994) reported a 32-year-old woman with EDS VIIB confirmed by genetic analysis (120160.0032). She was born with bilateral hip dislocation, bilateral knee subluxation, and generalized joint hypermobility, as well as bilateral inguinal hernias and an umbilical hernia. Throughout her life, she had multiple fractures of the small bones of her hands and feet following moderate trauma. An affected brother was born with bilateral hip dislocation which led to subsequent osteoarthritis of the hips and total hip replacement at age 35. He also had marked swan neck deformities of his hands and had multiple fractures of the metacarpals, distal radius, distal ulnar, as well as a fracture of the patella and olecranon. Frequency of fractures reduced markedly after his teenage years. Both patients had a depressed nasal bridge. Electron microscopy of the proband's dermis, as well as deep fascia and hip joint capsule from the affected brother, showed that collagen fibrils in transverse section were nearly circular but with irregular margins. The history of frequent fractures found in this family was slightly atypical for type VIIB Ehlers-Danlos syndrome and suggested a phenotypic overlap with osteogenesis imperfecta.
Byers et al. (1997) reported a family in which 5 individuals spanning 3 generations had EDS VIIB confirmed by genetic analysis (120160.0042). The proband was a girl referred at age 9 months because of joint laxity and inability to sit unsupported. Her feet and wrists could be dorsiflexed 180 degrees, and her skin was soft and hyperextensible. Radiographs showed bilateral hip dislocations. Because bracing was unsuccessful in stabilizing her hips, she underwent, at 16 months, open reduction of both hips, capsular reefing, and varus osteostomies with casting and bracing. However, the procedures were not successful in preventing further dislocations. The child's father had bilateral hip dislocation identified at the age of 1 month; casting and bracing were not successful. Subluxation of the metacarpal phalangeal joint of 1 thumb, dislocation of the other, and subluxation of the first metatarsal joints were also present. A brother had bilateral congenital hip dislocation with unsuccessful correction and was of average height. This man had a son who was noted to have dislocated hips at 7 weeks of age together with dislocations of the right elbow, patellas, fingers, and toes. Radiographs of the paternal grandfather of the index case showed bilateral hip dislocations; he walked with difficulty, using crutches. No affected relatives had fractures, dental or hearing abnormalities, blue sclerae, poor wound healing, or hernias. However, based on the clinical features of 5 additional affected families and review of previously reported patients with mutations in COL1A2, Byers et al. (1997) concluded that fractures should be considered part of the phenotype of EDS VII.
The transmission pattern of EDS VIIB in 1 family reported by Byers et al. (1997) was consistent with autosomal dominant inheritance. The heterozygous mutations in the COL1A2 gene that were identified in 5 individuals with EDS VIIB by Byers et al. (1997) occurred de novo.
From studies of type I collagen in a patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2), Eyre et al. (1985) determined that 1 allele of the COL1A2 gene carried a de novo mutation (120160.0001) that resulted in deletion of 15 to 20 residues in the junction domain that spans the N-propeptidase cleavage site and the N-telopeptide cross-linking sequence.
In a patient with EDS VIIB reported by Steinmann et al. (1985) and Wirtz et al. (1987), Weil et al. (1988) identified a heterozygous mutation in the COL1A2 gene (120160.0002) that resulted in the skipping of exon 6 and elimination of the N-proteinase cleavage site necessary for proper collagen processing.
In a patient with EDS VIIB previously reported by Lichtenstein et al. (1973) and Steinmann et al. (1980), Weil et al. (1989) identified a de novo heterozygous mutation in the COL1A2 gene (120160.0003), resulting in the skipping of exon 6 and deletion of the cleavage site necessary for proper collagen processing. The expression of the alternative splicing in this patient was found to be temperature-dependent; cellular studies showed that missplicing was effectively abolished at 31 degrees C and gradually increased to 100% at 39 degrees C. This mutation is identical to that found in COL1A1 (120150.0026).
In a patient with EDS VIIB, Nicholls et al. (1991) identified a heterozygous mutation in the COL1A2 gene (120160.0021).
In an affected child from a Xhosa family with EDS VIIB previously described by Viljoen et al. (1987), Watson et al. (1992) identified a heterozygous mutation in the COL1A2 gene (120160.0021) that resulted in the skipping of exon 6.
In affected members of 6 unrelated families with EDS VIIB, Byers et al. (1997) identified heterozygosity for mutations in the COL1A2 gene (see, e.g., 120160.0042).
Byers, P. H., Duvic, M., Atkinson, M., Robinow, M., Smith, L. T., Krane, S. M., Greally, M. T., Ludman, M., Matalon, R., Pauker, S., Quanbeck, D., Schwarze, U. Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am. J. Med. Genet. 72: 94-105, 1997. [PubMed: 9295084] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19971003)72:1<94::aid-ajmg20>3.0.co;2-o]
Carr, A. J., Chiodo, A. A., Hilton, J. M. N., Chow, C. W., Hockey, A., Cole, W. G. The clinical features of Ehlers-Danlos syndrome type VIIB resulting from a base substitution at the splice acceptor site of intron 5 of the COL1A2 gene. J. Med. Genet. 31: 306-311, 1994. [PubMed: 8071956] [Full Text: https://doi.org/10.1136/jmg.31.4.306]
Eyre, D. R., Shapiro, F. D., Aldridge, J. F. A heterozygous collagen defect in a variant of the Ehlers-Danlos syndrome type VII. J. Biol. Chem. 260: 11322-11329, 1985. [PubMed: 2993307]
Giunta, C., Chambaz, C., Pedemonte, M., Scapolan, S., Steinmann, B. The arthrochalasia type of Ehlers-Danlos syndrome (EDS VIIA and VIIB): the diagnostic value of collagen fibril ultrastructure. (Letter) Am. J. Med. Genet. 146A: 1341-1346, 2008. [PubMed: 18409203] [Full Text: https://doi.org/10.1002/ajmg.a.32213]
Lichtenstein, J. R., Martin, G. R., Kohn, L. D., Byers, P. H., McKusick, V. A. Defect in conversion of procollagen to collagen in a form of Ehlers-Danlos syndrome. Science 182: 298-299, 1973. [PubMed: 4742738] [Full Text: https://doi.org/10.1126/science.182.4109.298]
Nicholls, A. C., Oliver, J., Renouf, D. V., McPheat, J., Palan, A., Pope, F. M. Ehlers-Danlos syndrome type VII: a single base change that causes exon skipping in the type I collagen alpha-2(I) chain. Hum. Genet. 87: 193-198, 1991. [PubMed: 1712342] [Full Text: https://doi.org/10.1007/BF00204180]
Steinmann, B., Rao, V. H., Gitzelmann, R. A structurally abnormal alpha-2(I) collagen chain in a further patient with the Ehlers-Danlos syndrome type VII. Ann. N.Y. Acad. Sci. 460: 506-509, 1985.
Steinmann, B., Tuderman, L., Peltonen, L., Martin, G. R., McKusick, V. A., Prockop, D. J. Evidence for a structural mutation of procollagen type I in a patient with the Ehlers-Danlos syndrome type VII. J. Biol. Chem. 255: 8887-8893, 1980. [PubMed: 6773953]
Viljoen, D., Goldblatt, J., Thompson, D., Beighton, P. Ehlers-Danlos syndrome: yet another type? Clin. Genet. 32: 196-201, 1987. [PubMed: 3621666] [Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb03354.x]
Watson, R. B., Wallis, G. A., Holmes, D. F., Viljoen, D., Byers, P. H., Kadler, K. E. Ehlers Danlos syndrome type VIIB: incomplete cleavage of abnormal type I procollagen by N-proteinase in vitro results in the formation of copolymers of collagen and partially cleaved pNcollagen that are near circular in cross-section. J. Biol. Chem. 267: 9093-9100, 1992. [PubMed: 1577745]
Weil, D., Bernard, M., Combates, N., Wirtz, M. K., Hollister, D., Steinmann, B., Ramirez, F. Identification of a mutation that causes exon skipping during collagen pre-mRNA splicing in an Ehlers-Danlos syndrome variant. J. Biol. Chem. 263: 8561-8564, 1988. [PubMed: 2454224]
Weil, D., D'Alessio, M., Ramirez, F., Steinmann, B., Wirtz, M. K., Glanville, R. W., Hollister, D. W. Temperature-dependent expression of a collagen splicing defect in the fibroblasts of a patient with Ehlers-Danlos syndrome type VII. J. Biol. Chem. 264: 16804-16809, 1989. [PubMed: 2777808]
Wirtz, M. K., Glanville, R. W., Steinmann, B., Rao, V. H., Hollister, D. W. Ehlers-Danlos syndrome type VIIB: deletion of 18 amino acids comprising the N-telopeptide region of a pro-alpha-2(I) chain. J. Biol. Chem. 262: 16376-16385, 1987. [PubMed: 3680255]