Osteogenesis imperfecta: Clinical features and diagnosis
- John F Beary, III, MD
John F Beary, III, MD
- Clinical Professor of Medicine
- University of Cincinnati
- Arkadi A Chines, MD
Arkadi A Chines, MD
- Clinical Professor of Medicine
- University of California, Los Angeles
Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with many phenotypic presentations. It is often called "brittle bone disease." Severely affected patients suffer multiple fractures with minimal or no trauma, and infants with the worst form of OI die in the perinatal period. Mild forms of OI may manifest with only premature osteoporosis or severe postmenopausal bone mineral loss.
The pathogenesis, clinical features, diagnosis, and differential diagnosis of OI are presented here. The management and prognosis of OI are discussed separately. (See "Osteogenesis imperfecta: Management and prognosis".)
The estimated incidence of OI is approximately 1 per 20,000 births . This qualifies it as an orphan disease, which is defined in the United States as a disease affecting 200,000 patients or less.
The cause of OI is established in most cases. In patients with identified molecular defects, OI is most commonly caused by mutations in genes encoding the alpha-1 and alpha-2 chains of type I collagen  or proteins involved in posttranslational modification of type I collagen. Type I collagen fibers are polymers of tropocollagen molecules, each of which is a triple helix that contains portions of one alpha 2 and two alpha 1 polypeptide chains. The composition of tropocollagen is shown in the figure (figure 1). Type I collagen is an important structural protein for bone, tendon, ligament, skin, and sclerae. Defective bone quality explains many clinical aspects of OI. (See "Bone physiology and biochemical markers of bone turnover", section on 'Bone formation'.)
Most patients with OI have an autosomal dominant mutation in COL1A1 (located at 17q21.31-q22) or COL1A2 (located at 7q22.1) that affects the structure of one of the two alpha chains of type I collagen. The severity of the clinical presentation depends upon the effect of the mutation (table 1 and table 2) [3-7]. As an example, mutations in COL1A1 or COL1A2 that lead to decreased amounts of normal collagen cause the mild phenotype seen in type I OI. In contrast, mutations that disrupt the formation of the normal type I collagen triple helix cause the lethal phenotype seen in type IIA OI. Other COL1A1 and COL1A2 mutations that result in structural protein defects cause moderate (type IV) and severe, but not lethal (type III), forms of OI.
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