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COL1A1/2-Related Osteogenesis Imperfecta.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2005 Jan 28 [updated 2013 Feb 14].

Author information

Executive Director, Marshfield Clinic Research Foundation, Marshfield, Wisconsin
Legacy Center for Maternal Fetal Medicine, Portland, Oregon
Medical College of Wisconsin, Milwaukee, Wisconsin



COL1A1/2-related osteogenesis imperfecta (OI) is characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of COL1A1/2-related OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal dentition, normal stature, and normal life span. Fractures can occur in any bone, but are most common in the extremities. DI is characterized by gray or brown teeth that may appear translucent and wear down and break easily. COL1A1/2-related OI has been classified into four types (I, II, III, and IV) based on clinical presentation and radiographic findings. This classification system can be helpful in providing information about prognosis and management for a given individual. The four OI types are now referred to as follows: OI type I: classic non-deforming OI with blue sclerae. OI type II: perinatally lethal OI. OI type III: progressively deforming OI. OI type IV: common variable OI with normal sclerae.


The diagnosis of COL1A1/2-related OI is based on: Family history, a history of fractures, and characteristic physical findings; Radiographic findings (fractures of varying ages and stages of healing, wormian bones, "codfish" vertebrae, and osteopenia); and Molecular genetic testing of COL1A1 and COL1A2 and/or biochemical analysis of type 1 collagen. Biochemical testing (i.e., analysis of the structure and quantity of type I collagen synthesized in vitro by cultured dermal fibroblasts) detects abnormalities in 98% of individuals with historically classified OI type II, about 90% with OI type I, about 84% with OI type III, and about 84% with OI type IV. Molecular genetic testing of COL1A1 and COL1A2 detects abnormalities in more than 90% of individuals with historically classified OI types I, II, III, or IV.


Treatment of manifestations: Ideally, management is by a multidisciplinary team including specialists in the medical management of OI, orthopedics, rehabilitation medicine, pediatric dentistry, and otology/otolaryngology. Parents/other caregivers must practice safe handling techniques. Mainstays of treatment include: bracing of limbs; orthotics to stabilize lax joints; promotion of appropriate physical activity; muscle strengthening; pain management; and physical and occupational therapy to maximize bone stability, improve mobility, prevent contractures, and prevent head and spinal deformity. Mobility devices are used as needed. Fractures are treated with: intramedullary rodding when indicated to provide anatomic positioning of limbs; as short a period of immobility as is practical; small and lightweight casts; and physical therapy as soon as casts are removed. Progressive scoliosis in severe OI does not respond well to conservative or surgical management. Dental care strives to maintain both primary and permanent dentition, a functional bite or occlusion, optimal gingival health, and overall appearance. Conductive hearing loss may be improved with middle ear surgery; later-onset sensorineural hearing loss is treated in the same manner as it is when caused by other conditions. Prevention of secondary complications: During general anesthesia proper positioning on the operating room table and use of cushioning such as egg crate foam can help avoid fractures. Surveillance: Twice-yearly dental visits beginning in early childhood or even infancy for those with DI or at risk for DI. Hearing evaluation at three- to five-year intervals perhaps beginning as early as age five years until hearing loss is identified, then as indicated based on the nature and degree of hearing loss and associated interventions. Therapies under investigation: The role of treatment with bisphosphonates in changing the natural history of OI is incompletely understood. The Cochrane database contains a detailed meta-analysis of available data and as of the most recent update, bisphosphonate therapy did not appear to reduce fracture incidence but it did impact bone density and adult height. Oral alendronate treatment for two years in children with OI significantly decreased bone turnover and increased spine areal bone mineral density (BMD) but was not associated with improved fracture outcomes. Similarly, risedronate increased BMD and reduced first and recurrent clinical fractures in children with OI. Furthermore, human growth hormone therapy as an adjunct to bisphosphonate therapy correlated with improved linear growth and increased BMD.


COL1A1/2-related OI is inherited in an autosomal dominant manner. The proportion of cases caused by a de novo COL1A1 or COL1A2 mutation varies by the severity of disease: approximately 60% of cases of classic non-deforming OI with blue sclerae or common variable OI with normal sclerae, virtually 100% of perinatally lethal OI, and close to 100% of progressively deforming OI are de novo. Gonadal mosaicism may be present in 3%-5% of cases. Each child of an individual with a dominantly inherited form of COL1A1/2-related OI has a 50% chance of inheriting the mutation and of developing some manifestations of OI. Prenatal testing in at-risk pregnancies can be performed by molecular genetic testing if the COL1A1 or COL1A2 mutation has been identified in an affected relative. Ultrasound examination performed in a center with experience in diagnosing OI can be valuable in the prenatal diagnosis of the lethal form and most severe forms prior to 20 weeks' gestation; milder forms may be detected later in pregnancy if fractures or deformities occur.

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