EDS VIIB
EDS7B, INCLUDED
EDS VII, MUTANT PROCOLLAGEN TYPE EDS VIIB, INCLUDED
ARTHROCHALASIS MULTIPLEX CONGENITA
EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE
EDS VIIA
EDS7A
EDS type VII is distinguished from the 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). ... EDS type VII is distinguished from the 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). 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.'
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) ... 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. Cole et al. (1986) reported a 3-month-old girl with type VII EDS. She was born with bilateral dislocation of the hips and knees and mildly hyperelastic skin. At 4 years 7 months, her face had a chubby appearance due to laxity of facial tissues. Height was at the third centile, which was thought to be due in part to progressive right thoracolumbar scoliosis. She also had a large inguinal hernia. Collagen fibrils in the skin were irregular in outline and varied widely in diameter. Studies of her collagen showed a deletion of 24 amino acids (positions 136-159) from the pro-alpha-1(I) protein. The deleted segment normally contains the small globular region of the NH2-propeptide, the procollagen N-proteinase cleavage site, the NH2-telopeptide, and the first triplet of the helix of the alpha-1(I) collagen chain. Loss of the procollagen N-proteinase cleavage site accounted for the persistence of NH2-propeptide despite normal activity of N-proteinase. Collagen production by mutant fibroblasts was doubled, possibly due to reduced feedback inhibition by NH2-propeptide. Neither parent had the deletion, indicating a de novo event in the child. The deleted peptide corresponded precisely to the sequence coded by exon 6 of the normal pro-alpha-1(I) gene (Chu et al., 1984). Viljoen et al. (1987) reported a 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 girl with EDS VIIA born of a 23-year-old Caucasian father and a 31-year-old mother of Japanese origin. She presented at birth with large fontanels, a small umbilical hernia, joint laxity, contractures of the digits of both hands, short femurs, and pendulous skin folds. Radiographs demonstrated bilateral hip dislocation. At the age of 5 months, patent and bulging fontanels with prominent frontal bossing were noted. She had a small chin, deep blue sclerae, a narrow chest with mild pectus excavatum, and a large umbilical hernia. Her large joints were hypermobile. Genetic analysis identified a heterozygous mutation in the COL1A1 gene (120150.0057) that resulted in the skipping of exon 6. 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. Based on the clinical features of 5 additional affected families, Byers et al. (1997) concluded that fractures should be considered part of the phenotype of EDS VII. Giunta et al. (2008) reported a 12-month-old girl who was noted at birth to have bilateral hip dislocation, subluxations of the shoulders, elbows, and knees, arthrogryposis of the hands and feet, clubfoot, and hypotonia. Other features included short stature, frontal bossing, hypertelorism, depressed nasal bridge, macrostomia, bluish sclerae, Moderate pectus excavatum, umbilical hernia, and velvety skin. Skin biopsy showed highly irregular collagen fibrils with variable diameters. The changes were more pronounced than those observed in EDS VIIB, but less severe than those present in EDS VIIC. Genetic analysis identified a heterozygous mutation in the COL1A1 gene (120150.0066), confirming EDS VIIA. Giunta et al. (2008) emphasized the importance of examining the collagen fibril ultrastructure for accurate diagnosis.
In a girl with EDS VIIA reported by Cole et al., 1986), Weil et al. (1989) identified a de novo heterozygous mutation in the COL1A1 gene that resulted in the skipping of exon 6 (120150.0026). The deleted peptides ... In a girl with EDS VIIA reported by Cole et al., 1986), Weil et al. (1989) identified a de novo heterozygous mutation in the COL1A1 gene that resulted in the skipping of exon 6 (120150.0026). The deleted peptides included those encoding the N-proteinase cleavage site necessary for proper collagen processing. D'Alessio et al. (1991) identified the same COL1A1 mutation in another child with EDS VIIA. 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 a patient 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 type VIIB, Byers et al. (1997) identified heterozygous mutations in the COL1A2 gene (see, e.g., 120160.0042) that resulted in the skipping of exon 6. Some patients had fractures, consistent with alterations in mineral deposition on collagen fibrils in bony tissues. A patient with EDS VIIA had a more severe phenotype compared to those with EDS VIIB, and electron microscopy indicated a more severe disruption of collagen fibrils in EDS VIIA compared to EDS VIIB. Byers et al. (1997) noted that collagen I contains 2 COL1A1 chains and 1 COL1A2 chain; thus, mutations in the COL1A1 gene would affect 3/4 of the collagen molecules, whereas mutations in the COL1A2 gene would affect only half.