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Osteogenesis imperfecta (OI) is a genetic disorder primarily affecting bones and connective tissues.
- Clinical severity variable and dependent in part on the nature of the molecular lesion
- Typical findings can include recurrent fracture, bone and/or spine deformities, short stature, blue or grey sclerae dentinogenesis imperfecta (DI), and joint hypermobility.
1 in 10,000 births
6 to 8:100,000 persons
- Most cases (~85%) are due to variants in genes encoding type I collagen, COL1A1, and COL1A2 inherited in an autosomal dominant manner
- Traditionally, OI has been classified by clinical severity. The Sillence criteria are the most widely used, and they have been modified to accommodate expansion of phenotypically or genotypically distinct forms of OI. (Note: A second classification system from the International Consortium of Skeletal Dysplasia [ICSD] is also used and indicated in parentheses in the list of types below when relevant):
- Type I (mild nondeforming OI): usually normal stature, fracture frequency is variable, and usually lessens after puberty. No bowing of long bones. Blue sclerae are frequent. Hearing loss is frequent, but hearing loss onset before adulthood is uncommon.
- Type II (perinatally lethal OI): death in perinatal period due to pulmonary hypoplasia; intrauterine fractures, shortened long bones, and blue sclerae 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): DI common, short stature, bowing of long bones, vertebral fractures, scoliosis, and joint laxity. Patients are usually ambulatory.
- Other clinical forms of OI
- Type V (OI with calcification of the interosseous membranes and/or hypertrophic callus): Patients frequently develop hyperplastic calluses in long bones after fracture causing tender, firm swellings over bones. Patients also will develop calcification in the interosseous membrane between the radius and ulna, which limits supination and pronation. Caused by variants in IFITM5 gene; inherited in an autosomal dominant manner
- Type VI: rhizomelic shortening of extremities with less prominent bowing than appreciated in other patients with moderate severity OI. Caused by variants in SERPINF1 gene and inherited in an autosomal recessive manner; bone histology with a characteristic lamellar fish-scale appearance
- Type VII/VIII/XI: moderate to lethal OI caused by variants in one of the three subunits of the prolyl hydroxylase enzyme encoded by CRTAP, P3H1, and PPIB genes and inherited in an autosomal recessive manner. These three OI types have a similar phenotype including prominent rhizomelic shortening, significant early fractures, and short stature.
- Type X and XI: moderate to severe OI, which has been mostly seen in consanguineous families; due to defects in chaperone proteins, caused by variants in the SERPINH1 or FKBP10 genes and inherited in an autosomal recessive manner
- Type XII: one case report with moderately severe disease from a consanguineous family; caused by homozygous deletion in the SP7 gene
- Type XIII: A few cases have been reported with generally severe disease; caused by variants in the BMP1 gene and inherited in an autosomal recessive manner
- Type XIV: described in several consanguineous families and appears to be of variable severity; caused by variants in the TMEM38B gene and inherited in an autosomal recessive manner
- Type XV: moderate severity OI caused by variants in the WNT1 gene; inherited in an autosomal recessive manner
- Type XVI: described in a handful of families with variable severity of OI and caused by deletions in the CREB3L1 gene. It is inherited in an autosomal recessive manner, but carriers can present with mild phenotype of blue sclerae and hypermobility.
- Type XVII: described cases of moderate severity with multiple fractures but normal stature; caused by variants in the SPARC gene and inherited in an autosomal recessive manner
- Truncating COL1A1 mutations cause haploinsufficiency of the α-1 peptide causing a quantitative collagen defect resulting in type I OI.
- Missense mutations in COL1A1 or COL1A2 alter triple-helical collagen structure leading to abnormal collagen fibrils and result in types II, III, or IV OI.
- Recessive OI is caused by defects in genes whose products interact with type I collagen in several different fashions including posttranslational modification, cellular trafficking and chaperone, mineralization, and cellular fate.
- 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
- The etiology of short stature is incompletely understood but is suggested to result from disruption of balance between bone formation and resorption, which is more pronounced during periods of rapid linear growth.
- Abnormality of procollagen I production, modification, and extracellular trafficking
- Defect of osteoblast development resulting in collagen I insufficiency