Ehlers-Danlos Syndrome, Arthrochalasia Type, 1

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A number sign (#) is used with this entry because of evidence that Ehlers-Danlos syndrome arthrochalasia type 1 (EDSARTH1) is caused by heterozygous mutation in the COL1A1 (120150) on chromosome 17q21.

Several forms of osteogenesis imperfecta (see, e.g., OI1, 166200) are also caused by mutation in the COL1A1 gene.

Description

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).

Genetic Heterogeneity of Arthrochalasia-type Ehlers-Danlos Syndrome

See EDSARTH2 (617821), caused by mutation in the COL1A2 gene (120160).

Clinical Features

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 3rd 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).

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.

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 (EDSARTH2; 617821), but less severe than those present in EDS VIIC (EDSDERMS; 225410). 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.

Molecular Genetics

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 affected members of 6 unrelated families with EDS type VIIB (617821), 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.

Nomenclature

Halila et al. (1986) referred to the enzymatic form of EDS VII as type VIIA and to the autosomal dominant form as type VIIB.

Nusgens et al. (1992) referred to the 2 structural defects of procollagen polypeptides as EDS VIIA and EDS VIIB for the COL1A1 and COL1A2 defects, respectively. They used the designation EDS VIIC for the autosomal recessive enzymatic form (225410).