Osteogenesis imperfecta (OI), also known as Brittle Bone Disease, is characterized by frequent bone fractures after little or no trauma and, in its more severe forms, can lead to bone deformity, disability, or even death. At least 90% of all cases of OI, which occurs at an estimated frequency of 1:10,000 births, are believed to be associated with autosomal dominant loss-of-function mutations in either of the two genes coding for type I collagen, COL1A1 and COL1A2 (1). Early diagnosis of OI is important, since preventive and therapeutic measures, including bisphosphonate treatment, can minimize the number of bone fractures and reduce the extent of bone deformity. However, the milder (and more common) forms of OI (also known as OI Tarda) may be difficult to diagnose in infants. Biochemical studies on type I collagen from cultured skin cells can confirm most cases of OI, but require a skin biopsy and typically take two months. This delay in diagnosis can be problematic, since non-traumatic fractures in infants can be misinterpreted as a sign of child abuse, and may force a separation of infants and parents until a diagnosis of OI can be confirmed. Child abuse has been reported in 24 out of 10,000 children under the age of three and is thus much more common than OI (2).
Genetic testing for OI-associated loss-of-function mutations in COL1A1 and COL1A2 can diagnose OI with a sensitivity similar to that of biochemical testing, but in as little as two to three weeks and based on a single blood draw.
Types and Causes of OI
Classification of OI into different types is mostly based on severity of the phenotype, which can range from perinatal death to premature osteoporosis without any fractures (3). The classification system most widely used today is based on clinical, radiographic, and histological information (4-7) and distinguishes between type I (mild), type II (perinatally lethal), type III (severe and deforming), and types IV-VII (moderately severe and moderately deforming). An earlier grouping system distinguished between OI Congenita, with fractures occurring in utero or at birth, and OI Tarda, with the first fracture occurring after birth.
| Type of OI | Bone fragility | Bone Deformity | Mutation in | Effect of Mutation | Inheritance Pattern |
| I | mild | none | type I collagen | null mutation | autosomal dominant |
| II | lethal | type I collagen | dominant negative | autosomal dominant | |
| III | severe | severe | type I collagen | dominant negative | autosomal dominant* |
| IV | moderate | moderate | type I collagen | dominant negative | autosomal dominant |
| V | moderate | moderate | unknown | unknown | autosomal dominant |
| VI | moderate | moderate | unknown | unknown | unknown |
| VII | moderate | moderate | unknown | unknown | autosomal recessive |
* Autosomal recessive in rare cases
Type I OI
Type I OI is the mildest type of OI and is caused by mutations in COL1A1 or COL1A2. Typically, these mutations are null mutations, i.e., the mutated gene does not give rise to an alpha chain that can be assembled into a triple helix. Therefore, null mutations reduce the overall quantity of type I collagen in bone and cause mild OI due to haploinsufficiency.
Types II-IV OI
Types II-IV are caused by mutations in COL1A1 or COL1A2 that lead to synthesis of a mutated alpha chain still able to form a triple helix.
However, the triple helix containing the mutant alpha chain is structurally compromised, as is the collagen fibril containing the mutant triple helix. Thus, the mutations associated with types II-IV OI reduce the quality of the type I collagen in bone. These mutations have a dominant negative effect, since co-polymerization of normal and mutated triple helices into collagen fibrils results in the formation of a poorly organized protein matrix, affecting mineral deposition into the bone and reducing its tensile strength (8).
Types V-VII OI
Types V-VII are caused by mutations in other, as yet unidentified genes (5-7)
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The main characteristic of OI is bone fragility: Individuals can suffer from tens to hundreds of bone fractures during their lifetimes. Fractures are generally more frequent before puberty and beyond middle age, due to the protective effect of sex hormones on bones. OI is also associated with premature osteoporosis.
OI has been classified into seven types based on clinical, radiological, and histological criteria (4-7). However, the borders between these groupings are blurred, since OI presents with an essentially continuous spectrum of severity. Defining characteristics for a given type of OI may not always be present or may be shared by different types, and the same mutations can lead to different types of OI in different individuals (9). In general, mild to moderate OI is much more common than severe OI.
Type I OI is the mildest type of OI and is caused by mutations in COL1A1 or COL1A2. Typically, these mutations are null mutations, i.e., the mutated gene does not give rise to an alpha chain that can be assembled into a triple helix. Therefore, null mutations reduce the overall quantity of type I collagen in bone and cause mild OI due to haploinsufficiency.
Types II-IV OI
Types II-IV are caused by mutations in COL1A1 or COL1A2 that lead to synthesis of a mutated alpha chain still able to form a triple helix.
However, the triple helix containing the mutant alpha chain is structurally compromised, as is the collagen fibril containing the mutant triple helix. Thus, the mutations associated with types II-IV OI reduce the quality of the type I collagen in bone. These mutations have a dominant negative effect, since co-polymerization of normal and mutated triple helices into collagen fibrils results in the formation of a poorly organized protein matrix, affecting mineral deposition into the bone and reducing its tensile strength (8).
Types V-VII OI
Types V-VII are caused by mutations in other, as yet unidentified genes (5-7)
If you want to learn more about:
- Role of Type I Collagen in Osteogenesis please click here.
- Null Mutations in Type I Collagen Genes please click here.
- Dominant Negative Mutations in Type I Collagen Genes please click here.
Clinical Presentation of OI
The main characteristic of OI is bone fragility: Individuals can suffer from tens to hundreds of bone fractures during their lifetimes. Fractures are generally more frequent before puberty and beyond middle age, due to the protective effect of sex hormones on bones. OI is also associated with premature osteoporosis.
OI has been classified into seven types based on clinical, radiological, and histological criteria (4-7). However, the borders between these groupings are blurred, since OI presents with an essentially continuous spectrum of severity. Defining characteristics for a given type of OI may not always be present or may be shared by different types, and the same mutations can lead to different types of OI in different individuals (9). In general, mild to moderate OI is much more common than severe OI.
Typical Clinical Presentation of OI Types I through VII
| Type of OI | Bone deformity | Stature | Scleral Hue | Often Associated With | |
| Hearing Loss | DI | ||||
| I | no | normal | blue | yes | no |
| II | severe | / | dark | / | / |
| III | severe | very short | grey | yes | yes |
| IV | moderate | short | no | no | yes |
| V | moderate | short | no | no | no |
| VI | |||||
| VII | |||||
Type I OI is the mildest and most common form of OI. Bones are fragile and may break after minimal trauma but are usually not deformed, and subjects often attain normal stature. Subjects with type I OI often, but not always, have blue sclera, mild joint hypermobility, and increased bruising. By adolescence or early adulthood, about 50% of patients will be affected by functional hearing loss. Rarely, type I OI is accompanied by dentinogenesis imperfecta (DI), which is characterized by discolored and brittle teeth.
Type II OI is the most severe form of OI and accounts for about 5% of all cases of OI (10, 11). Bone fractures often occur in utero, bones are severely deformed, and infants are either stillborn or unlikely to survive infancy.
Type III OI is the most severe form of OI that is compatible with survival past infancy and accounts for about 20% of all cases of OI (10, 11). This type of OI is also known as the Progressive Deforming Type, since bones are not only highly fragile, but also tend to become deformed over time due to tension from attached muscles or angulated healing of fractures. Patients with type III OI may experience hundreds of fractures over their lifetime, often starting in utero, and usually remain very short in stature. Defining characteristics are a triangular face and disproportionately short legs, a disproportionately wide arm span, and a disproportionately big cranium. Severe early hearing loss is common, as is DI, and a scleral hue may be present. Without aggressive intervention, individuals with type III OI often become wheelchair bound.
Type IV OI may be more severe than type I but is usually milder than type III. Bone fractures are frequent, but bone deformity is generally mild to moderate. Subjects are often short of stature and may suffer from DI or hearing loss. A scleral hue may be present.
Based on histological findings, about 8% of OI type IV have been reclassified into separate categories, types V through VII (1). Patients in this group typically have white sclera and do not suffer from DI.
OI is suspected from fractures without or with minimal trauma. The more severe forms of OI (types II and III) can usually be confirmed through radiographic examination of the bones and measurements of body proportions. Milder forms of OI (types I and IV-VII) may be more difficult to diagnose, especially in infants. Many of the characteristic signs of OI – such as hearing loss, short stature, and DI – only become apparent over time. In addition, scleral hue, originally considered one of the defining hallmarks of type I OI, is common in all babies up to 18 months of age.
A diagnosis of OI can be confirmed through biochemical analysis of the type I collagen produced by cultured skin fibroblasts from the patient. OI-associated mutations in COL1A1 or COL1A2 lead either to a reduction in the amount of type I collagen produced or to a change in its electrophoretic mobility. Since biochemical testing requires expansion of fibroblast cultures in vitro, it usually takes about two months.
Diagnosis of OI can also be achieved through genetic testing for mutations in COL1A1 or COL1A2. Genetic testing requires less time than biochemical testing and detects a similar proportion (about 90%) of all cases of OI (2). In one study, genetic testing detected all cases of type-I-collagen related OI (10).
Apart from treatment of fractures as necessary, management of OI is largely preventive, involving such measures as correct positioning and supporting of the infant and muscle strengthening. Thus, it is critical to diagnose OI as early as possible. In severe cases of OI (type II and III), orthopedic intervention may be necessary, such as bracing or surgical insertion of rods along bones.
Recently, treatment with bisphosphonates such as pamidronate has been shown to increase bone mass and to decrease bone pain and frequency of fractures (12-14). However, the long-term effects of bisphosponate treatment, which may compromise bone quality over time, are not known yet (15). Use of growth hormone to correct OI-associated short stature is also under investigation (1).
In the future, it may be possible to convert severe forms of OI into type I OI by using targeted gene therapy to insert a null mutation into the COL1Agene harboring the OI-associated mutation (16).
At least 90% of all cases of OI, or all cases categorized as type I-IV, are believed to be associated with mutations in COL1A1 or COL1A2. By contrast, OI types V-VII appear to be due to mutations in other, as yet unidentified genes.
Most OI-associated mutations in COL1A1 and COL1A2 are autosomal dominant. In rare cases of type III OI, mutations in COL1A1 have been shown to be autosomal recessive (17). About 50% of OI occurs in families without a history for the disease (18). Up to 20% of apparently sporadic mutations may be due to parental mosaicism (19). In these cases, a somatic mutation in a type I collagen gene occurred during embryonic development of the parent, and the cell harboring the mutation gave rise to germline as well as somatic cells. Mosaic individuals themselves typically show either a mild or no OI phenotype (20), but the recurrence rate of OI in children of mosaic carriers may be as high as 50%. Therefore, genetic testing for OI at birth is advised for siblings of children with OI.
Of note, mutations in COL1A1 and COL1A2 are also associated with other phenotypes, such as Ehlers-Danlos Syndrome type VII, atypical Marfans Syndrome, and idiopathic osteoporosis.
The Osteogenesis Imperfecta Evaluation detects mutations in COL1A1 and COL1A2, the genes coding for type I collagen, and can identify about 90% of all cases of OI. Genetic testing can confirm a diagnosis of OI faster than currently used biochemical methods and may complement biochemical studies in establishing a firm diagnosis. This is especially important in infants, where non-traumatic fractures due to OI can be misinterpreted as signs of child abuse, potentially forcing a lengthy separation of infant and parents. Prompt diagnosis of OI is also important in infants with a family history of OI, so that preventive measures to minimize bone fractures can be taken without delay.
Type II OI is the most severe form of OI and accounts for about 5% of all cases of OI (10, 11). Bone fractures often occur in utero, bones are severely deformed, and infants are either stillborn or unlikely to survive infancy.
Type III OI is the most severe form of OI that is compatible with survival past infancy and accounts for about 20% of all cases of OI (10, 11). This type of OI is also known as the Progressive Deforming Type, since bones are not only highly fragile, but also tend to become deformed over time due to tension from attached muscles or angulated healing of fractures. Patients with type III OI may experience hundreds of fractures over their lifetime, often starting in utero, and usually remain very short in stature. Defining characteristics are a triangular face and disproportionately short legs, a disproportionately wide arm span, and a disproportionately big cranium. Severe early hearing loss is common, as is DI, and a scleral hue may be present. Without aggressive intervention, individuals with type III OI often become wheelchair bound.
Type IV OI may be more severe than type I but is usually milder than type III. Bone fractures are frequent, but bone deformity is generally mild to moderate. Subjects are often short of stature and may suffer from DI or hearing loss. A scleral hue may be present.
Based on histological findings, about 8% of OI type IV have been reclassified into separate categories, types V through VII (1). Patients in this group typically have white sclera and do not suffer from DI.
Diagnosis of OI
OI is suspected from fractures without or with minimal trauma. The more severe forms of OI (types II and III) can usually be confirmed through radiographic examination of the bones and measurements of body proportions. Milder forms of OI (types I and IV-VII) may be more difficult to diagnose, especially in infants. Many of the characteristic signs of OI – such as hearing loss, short stature, and DI – only become apparent over time. In addition, scleral hue, originally considered one of the defining hallmarks of type I OI, is common in all babies up to 18 months of age.
A diagnosis of OI can be confirmed through biochemical analysis of the type I collagen produced by cultured skin fibroblasts from the patient. OI-associated mutations in COL1A1 or COL1A2 lead either to a reduction in the amount of type I collagen produced or to a change in its electrophoretic mobility. Since biochemical testing requires expansion of fibroblast cultures in vitro, it usually takes about two months.
Diagnosis of OI can also be achieved through genetic testing for mutations in COL1A1 or COL1A2. Genetic testing requires less time than biochemical testing and detects a similar proportion (about 90%) of all cases of OI (2). In one study, genetic testing detected all cases of type-I-collagen related OI (10).
Treatment of OI
Apart from treatment of fractures as necessary, management of OI is largely preventive, involving such measures as correct positioning and supporting of the infant and muscle strengthening. Thus, it is critical to diagnose OI as early as possible. In severe cases of OI (type II and III), orthopedic intervention may be necessary, such as bracing or surgical insertion of rods along bones.
Recently, treatment with bisphosphonates such as pamidronate has been shown to increase bone mass and to decrease bone pain and frequency of fractures (12-14). However, the long-term effects of bisphosponate treatment, which may compromise bone quality over time, are not known yet (15). Use of growth hormone to correct OI-associated short stature is also under investigation (1).
In the future, it may be possible to convert severe forms of OI into type I OI by using targeted gene therapy to insert a null mutation into the COL1Agene harboring the OI-associated mutation (16).
Genetics of OI
At least 90% of all cases of OI, or all cases categorized as type I-IV, are believed to be associated with mutations in COL1A1 or COL1A2. By contrast, OI types V-VII appear to be due to mutations in other, as yet unidentified genes.
Most OI-associated mutations in COL1A1 and COL1A2 are autosomal dominant. In rare cases of type III OI, mutations in COL1A1 have been shown to be autosomal recessive (17). About 50% of OI occurs in families without a history for the disease (18). Up to 20% of apparently sporadic mutations may be due to parental mosaicism (19). In these cases, a somatic mutation in a type I collagen gene occurred during embryonic development of the parent, and the cell harboring the mutation gave rise to germline as well as somatic cells. Mosaic individuals themselves typically show either a mild or no OI phenotype (20), but the recurrence rate of OI in children of mosaic carriers may be as high as 50%. Therefore, genetic testing for OI at birth is advised for siblings of children with OI.
Of note, mutations in COL1A1 and COL1A2 are also associated with other phenotypes, such as Ehlers-Danlos Syndrome type VII, atypical Marfans Syndrome, and idiopathic osteoporosis.
Genetic Testing for OI
The Osteogenesis Imperfecta Evaluation detects mutations in COL1A1 and COL1A2, the genes coding for type I collagen, and can identify about 90% of all cases of OI. Genetic testing can confirm a diagnosis of OI faster than currently used biochemical methods and may complement biochemical studies in establishing a firm diagnosis. This is especially important in infants, where non-traumatic fractures due to OI can be misinterpreted as signs of child abuse, potentially forcing a lengthy separation of infant and parents. Prompt diagnosis of OI is also important in infants with a family history of OI, so that preventive measures to minimize bone fractures can be taken without delay.
How Is Genetic Testing for OI Performed?
DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of COL1A1 and COL1A2 are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a complete, detailed result report is sent to the patient’s physician.
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References
1. Rauch F, Glorieux FH (2004) Osteogenesis imperfecta. Lancet 363:1377-85.
Link to PubMed
2. Marlowe A, Pepin MG, Byers PH (2002) Testing for osteogenesis imperfecta in cases of suspected non-accidental injury. J Med Genet 39:382-6.
Link to PubMed
3. Shapiro JR, Stover ML, Burn VE, McKinstry MB, et al (1992) An osteopenic nonfracture syndrome with features of mild osteogenesis imperfecta associated with the substitution of a cysteine for glycine at triple helix position 43 in the pro alpha 1(I) chain of type I collagen. J Clin Invest 89:567-73.
Link to PubMed
4. Sillence DO, Senn A, Danks DM (1979) Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 16:101-16.
Link to PubMed
5. Glorieux FH, Rauch F, Plotkin H, Ward L, et al (2000) Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 15:1650-8.
Link to PubMed
6. Glorieux FH, Ward LM, Rauch F, Lalic L, et al. (2002) Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 17:30-8.
Link to PubMed
7. Ward LM, Rauch F, Travers R, Chabot G, et al (2002) Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone 31:12-8.
Link to PubMed
8. Cohen-Solal L, Zylberberg L, Sangalli A, Gomez Lira M, et al (1994) Substitution of an aspartic acid for glycine 700 in the alpha 2(I) chain of type I collagen in a recurrent lethal type II osteogenesis imperfecta dramatically affects the mineralization of bone. J Biol Chem 269:14751-8.
Link to PubMed
9. Zolezzi F, Valli M, Clementi M, Mammi I, et al (1997) Mutation producing alternative splicing of exon 26 in the COL1A2 gene causes type IV osteogenesis imperfecta with intrafamilial clinical variability. Am J Med Genet 71:366-70.
Link to PubMed
10. Ward LM, Lalic L, Roughley PJ, Glorieux FH (2001) Thirty-three novel COL1A1 and COL1A2 mutations in patients with osteogenesis imperfecta types I-IV. Hum Mutat 17:434.
Link to PubMed
11. Ries-Levavi L, Ish-Shalom T, Frydman M, Lev D, et al (2004) Genetic and biochemical analyses of Israeli osteogenesis imperfecta patients. Hum Mutat 23:399-400.
Link to PubMed
12. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, et al (1998) Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 339:947-52.
Link to PubMed
13. Plotkin H, Rauch F, Bishop NJ, Montpetit K, et al (2000) Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age. J Clin Endocrinol Metab 85:1846-50.
Link to PubMed
14. Astrom E, Soderhall S (2002) Beneficial effect of long term intravenous bisphosphonate treatment of osteogenesis imperfecta. Arch Dis Child 86:356-64.
Link to PubMed
15. Marini JC (2003) Do bisphosphonates make children's bones better or brittle? N Engl J Med 349:423-6.
Link to PubMed
16. Chamberlain JR, Schwarze U, Wang PR, Hirata RK, et al (2004) Gene targeting in stem cells from individuals with osteogenesis imperfecta. Science 303:1198-201.
Link to PubMed
17. Pihlajaniemi T, Dickson LA, Pope FM, Korhonen VR, et al (1984) Osteogenesis imperfecta: cloning of a pro-alpha 2(I) collagen gene with a frameshift mutation. J Biol Chem 259:12941-4.
Link to PubMed
18. Blumsohn A, McAllion SJ, Paterson CR (2001) Excess paternal age in apparently sporadic osteogenesis imperfecta. Am J Med Genet 100:280-6.
Link to PubMed
19. Lund AM, Nicholls AC, Schwartz M, Skovby F (1997) Parental mosaicism and autosomal dominant mutations causing structural abnormalities of collagen I are frequent in families with osteogenesis imperfecta type III/IV. Acta Paediatr 86:711-8.
Link to PubMed
20. Cabral WA, Marini JC (2004) High proportion of mutant osteoblasts is compatible with normal skeletal function in mosaic carriers of osteogenesis imperfecta. Am J Hum Genet 74:752-60.
Link to PubMed
1. Rauch F, Glorieux FH (2004) Osteogenesis imperfecta. Lancet 363:1377-85.
Link to PubMed
2. Marlowe A, Pepin MG, Byers PH (2002) Testing for osteogenesis imperfecta in cases of suspected non-accidental injury. J Med Genet 39:382-6.
Link to PubMed
3. Shapiro JR, Stover ML, Burn VE, McKinstry MB, et al (1992) An osteopenic nonfracture syndrome with features of mild osteogenesis imperfecta associated with the substitution of a cysteine for glycine at triple helix position 43 in the pro alpha 1(I) chain of type I collagen. J Clin Invest 89:567-73.
Link to PubMed
4. Sillence DO, Senn A, Danks DM (1979) Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 16:101-16.
Link to PubMed
5. Glorieux FH, Rauch F, Plotkin H, Ward L, et al (2000) Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 15:1650-8.
Link to PubMed
6. Glorieux FH, Ward LM, Rauch F, Lalic L, et al. (2002) Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 17:30-8.
Link to PubMed
7. Ward LM, Rauch F, Travers R, Chabot G, et al (2002) Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone 31:12-8.
Link to PubMed
8. Cohen-Solal L, Zylberberg L, Sangalli A, Gomez Lira M, et al (1994) Substitution of an aspartic acid for glycine 700 in the alpha 2(I) chain of type I collagen in a recurrent lethal type II osteogenesis imperfecta dramatically affects the mineralization of bone. J Biol Chem 269:14751-8.
Link to PubMed
9. Zolezzi F, Valli M, Clementi M, Mammi I, et al (1997) Mutation producing alternative splicing of exon 26 in the COL1A2 gene causes type IV osteogenesis imperfecta with intrafamilial clinical variability. Am J Med Genet 71:366-70.
Link to PubMed
10. Ward LM, Lalic L, Roughley PJ, Glorieux FH (2001) Thirty-three novel COL1A1 and COL1A2 mutations in patients with osteogenesis imperfecta types I-IV. Hum Mutat 17:434.
Link to PubMed
11. Ries-Levavi L, Ish-Shalom T, Frydman M, Lev D, et al (2004) Genetic and biochemical analyses of Israeli osteogenesis imperfecta patients. Hum Mutat 23:399-400.
Link to PubMed
12. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, et al (1998) Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 339:947-52.
Link to PubMed
13. Plotkin H, Rauch F, Bishop NJ, Montpetit K, et al (2000) Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age. J Clin Endocrinol Metab 85:1846-50.
Link to PubMed
14. Astrom E, Soderhall S (2002) Beneficial effect of long term intravenous bisphosphonate treatment of osteogenesis imperfecta. Arch Dis Child 86:356-64.
Link to PubMed
15. Marini JC (2003) Do bisphosphonates make children's bones better or brittle? N Engl J Med 349:423-6.
Link to PubMed
16. Chamberlain JR, Schwarze U, Wang PR, Hirata RK, et al (2004) Gene targeting in stem cells from individuals with osteogenesis imperfecta. Science 303:1198-201.
Link to PubMed
17. Pihlajaniemi T, Dickson LA, Pope FM, Korhonen VR, et al (1984) Osteogenesis imperfecta: cloning of a pro-alpha 2(I) collagen gene with a frameshift mutation. J Biol Chem 259:12941-4.
Link to PubMed
18. Blumsohn A, McAllion SJ, Paterson CR (2001) Excess paternal age in apparently sporadic osteogenesis imperfecta. Am J Med Genet 100:280-6.
Link to PubMed
19. Lund AM, Nicholls AC, Schwartz M, Skovby F (1997) Parental mosaicism and autosomal dominant mutations causing structural abnormalities of collagen I are frequent in families with osteogenesis imperfecta type III/IV. Acta Paediatr 86:711-8.
Link to PubMed
20. Cabral WA, Marini JC (2004) High proportion of mutant osteoblasts is compatible with normal skeletal function in mosaic carriers of osteogenesis imperfecta. Am J Hum Genet 74:752-60.
Link to PubMed
