A number sign (#) is used with this entry because of evidence that combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2) is caused by heterozygous mutation in the COL1A2 gene (120160) on chromosome 7q21.

Combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2) is an autosomal dominant generalized connective tissue disorder characterized by features of both osteogenesis imperfecta (bone fragility, long bone fractures, blue sclerae) and Ehlers-Danlos syndrome (joint hyperextensibility, soft and hyperextensible skin, abnormal wound healing, easy bruising, vascular fragility) (summary by Raff et al., 2000 and Malfait et al., 2013).

For a discussion of genetic heterogeneity of combined osteogenesis imperfecta and Ehlers-Danlos syndrome, see 619115.

Nathanson et al. (1997) described a 14-year-old boy and his 4-generation family who had a mixed osteogenesis imperfecta and Ehlers-Danlos syndrome phenotype. The proband had short stature, hypermobility and dislocation of large and small joints, blue sclerae, soft hyperextensible skin, decreased adipose tissue, and multiple fractures. He developed subacute bacterial endocarditis on a bicuspid aortic valve, requiring valve replacement surgery. The ascending aorta showed an abrupt transition in the proximal ascending aorta from normal to an area of disruption of elastin fibers with marked medial cystic necrosis and generalized mucomyxoid changes. Other affected family members were at or below the 5th centile in height and had blue sclerae, joint laxity, and/or fractures. The proband's sister had congenital dislocated hips requiring surgery.

Raff et al. (2000) described an 8-year-old boy with an OI and EDS phenotype. The boy was seen at 22 months of age because of a history of clubfeet and bilateral congenital hip dislocation. He had a prominent forehead with an anterior fontanel measuring 3x3 cm. His sclerae were blue-gray, and his teeth had an opalescent appearance. An umbilical hernia was present. He had generalized joint hypermobility but only mild hyperextensibility of the skin. He was neurologically normal and developmentally appropriate. At the age of 5 years, he had a normal gait but frequent dislocation of the left shoulder. His umbilical hernia was still evident and was eventually excised surgically. Generalized joint hypermobility, gray sclerae, and eroded dentition remained remarkable. At age 7 years, he sustained a fracture of the distal tibia. At age 8.5 years, he had an advanced bone age of 11.5 years. Bone density appeared normal.

Nicholls et al. (2001) reported a girl, born to first-cousin parents, with features of OIEDS. Marked ligamentous laxity and muscle hypertonia had first been noted at her premature (28 weeks' gestation) birth. Delayed ambulation was attributed to ligamentous laxity. At the age of 9 years she was of average height but showed marked generalized joint laxity, pes planus, and valgus heels leading to a secondary shortening of the Achilles tendon. Her skin was normal, her sclerae were pale blue, and there was dental overcrowding but no dentinogenesis imperfecta. There was a history of recurrent patellar dislocations and fractures of the skull, clavicle, fingers, and a toe following separate minimal traumas.

Malfait et al. (2013) reported a cohort of 7 patients with a clinical diagnosis of EDS who showed subtle signs of OI. The patients presented with severe joint hyperlaxity, soft and hyperextensible skin, abnormal wound healing, and easy bruising. Some had signs of vascular fragility, including an epidural hematoma with intraspinal hemorrhage following relatively mild trauma in a 5-year-old and a massive intracranial bleed in a newborn. Transmission electron microscopy, performed on one of the patients at age 37 years, showed lowered collagen fibril density in the dermis. Subtle signs of OI included blue sclerae, relatively short stature, and osteopenia or fractures. One patient had an atrial septal defect and another had aortic dilatation. The authors emphasized the importance of recognizing this phenotype for accurate genetic counseling, clinical management, and disease surveillance.

The transmission pattern of OIEDS2 in the family reported by Nathanson et al. (1997) was consistent with autosomal dominant inheritance.

In the affected proband of a 4-generation family segregating OIEDS, Nathanson et al. (1997) identified a heterozygous G-to-A transition in the fifth nucleotide of intron 9 of the COL1A2 gene, causing skipping of exon 9 (120160.0041). The shortened collagen chain disrupted the alignment of the 3 collagen chains forming the triple helix at exon 6, the site of N-proteinase procollagen cleavage and lysyl crosslinking.

In a patient with OIEDS2, Raff et al. (2000) identified a heterozygous 13.5-kb duplication involving 20 exons in the COL1A2 gene (120160.0043), resulting in an additional 477 amino acids in the triple helical domain.

In a girl, born of first-cousin parents, with an OIEDS phenotype, Nicholls et al. (2001) identified a homozygous splice site mutation in intron 46 of the COL1A2 gene (120160.0049). The mother was heterozygous for the mutation and showed some joint laxity; the father was not available for study. An older sister of the proband was found to be a carrier of the mutant allele.

Malfait et al. (2013) sequenced the COL1A1 and COL1A2 genes in 7 patients with OIEDS and identified heterozygous mutations in the most N-terminal part of the type I collagen helix (2 in COL1A1 and 5 in COL1A2) in all patients. Both mutations in COL1A1 were missense; of the 5 mutations in COL1A2, 3 were exon skipping (see, e.g., 120160.0056) and 2 were missense (see, e.g., 120160.0057). The mutations affected the rate of type I collagen N-propeptide cleavage and disturbed normal collagen fibrillogenesis.