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Osteogenesis imperfecta (OI) is a genetic connective tissue disorder affecting primarily bones and soft tissues, characterized by bone fragility and susceptibility to bone fractures.
- Clinical severity is widely varied and dependent in part on the genetic etiology.
- Typical symptoms can include recurrent fractures, bone and/or spine deformities, short stature, blue or grey sclerae (occurring in approximately 80% of cases), dentinogenesis imperfecta (DI; occurring in approximately 40% of cases), and joint hypermobility.
1 in 10,000 births
- The majority of cases (∼85%) are due to autosomal dominant mutations in the genes encoding type I collagen, COL1A1 and COL1A2.
- Traditionally, OI has been classified due to clinical presentation, as initially described by Sillence. However, in the last decade, new dominant and recessive forms caused by mutations in several different genes have been described, which has altered the classification of OI. Modified classification typing is noted in parentheses below:
- Type I (classic nondeforming OI with blue sclerae): usually normal stature, fractures infrequent, and usually in prepubertal years. No bowing of long bones. Blue sclerae. Early hypoacusia common.
- Type II (perinatally lethal OI): death usually in perinatal period due to pulmonary hypoplasia. Intrauterine fractures, shortened long bones, and blue sclerae are common.
- Type III (progressively deforming OI): severely shortened stature, severe deformities of long bones, prevalent vertebral fractures, scoliosis, chest deformities. Characteristic triangular face.
- Type IV (common variable OI with normal sclerae): DI common, short stature, bowing of long bones, vertebral fractures, scoliosis, and joint laxity. Patients are usually ambulatory. Sclerae are usually normal hue.
- Other clinical forms of OI
- OI with calcification in interosseous membranes (type V): autosomal dominant mutations of IFITM5 gene. Patients can develop hyperplastic calluses in long bones after fracture causing tender, firm swellings over bones. Blue sclerae and DI not common.
- Type VI: rare form of recessive OI due to mutations in SERPINF1 gene causing severe matrix mineralization defect. No blue sclerae, DI, or wormian bones. Rhizomelic shortening of extremities.
- Type VII: recessive mutation of CRTAP gene causing rhizomelia, early fractures, and osteopenia
- Type VIII: absence or severe deficiency of prolyl 3-hydroxylase activity due to mutations in the LEPRE1 gene
- Type IX: moderate to severe OI caused by defects in the PPIB gene
- Type X and XI: chaperone defects caused by SERPINH1 or FKBP10 mutations. Type XI due to FKBP10 mutations can cause progressively deforming OI or Bruck syndrome.
- Mutations in COL1A1 or COL1A2 cause altered triple-helical collagen structure leading to abnormal collagen fibrils.
- Procollagen molecules more susceptible to proteolytic degradation
- Collagen fibrils are disorganized
- Abnormal osteoid formation
- Decrease in osteoid seams
- Recessive OI is caused by defects in genes whose products interact with type I collagen leading to many of the same cellular features, although the precise pathomechanisms are as yet incompletely understood.
- Osteoblasts: increased osteoblast cellularity; however, reduction in differentiated cells capable of making mineralized matrix
- Decreased bone formation during remodeling
- Osteoclasts: increased osteoclast number to remove defective matrix
- Growth retardation: Disruption of balance between bone formation and resorption is more pronounced during periods of rapid linear growth (i.e., childhood, puberty).
- Failure of normal maturation of procollagen to type 1 collagen and failure of normal collagen cross-linking
- Abnormality of collagen production and organization