Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that presents with a wide clinical phenotype spectrum: from perinatal lethality and severe deformities to very mild forms without fractures. Most cases of OI are due to autosomal dominant mutations of the type I collagen genes. A multidisciplinary approach with rehabilitation, orthopedic surgery, and consideration of medical therapy with bisphosphonates underpins current management. Greater understanding of the pathogenesis of OI may lead to novel, therapeutic approaches to help improve clinical symptoms of children with OI in the future.
Key points
- •
Osteogenesis imperfecta (OI) is the most common cause of primary osteoporosis in children and presents with variable severity.
- •
Ninety percent of cases of OI are due to autosomal dominant mutations of type 1 collagen genes, but new genes involved with post-translational collagen modification have been recently implicated in rare recessive forms.
- •
Management of children with moderate to severe OI involves physiotherapy, rehabilitation, orthopedic surgery, and consideration of bisphosphonate treatment.
- •
Fracture management emphasizes minimizing time and extent of immobilization to minimize secondary disuse osteoporosis. Surgical management of long bone fractures and deformities includes intramedullary fixation devices.
- •
Bisphosphonate therapy can increase bone mineral density and decrease bone pain and fracture incidence. The optimal treatment regimen and duration is unknown.
Osteogenesis imperfecta (OI) is a term used to describe a group of inherited connective tissue conditions that are characterized by increased bone fragility and low bone mass. With an estimated prevalence of 1 in 12,000 to 15, 000 children, it has a broad clinical phenotype, ranging in severity from perinatal lethality to mild clinical forms without fractures. Wormian bones are present in the skull in approximately 60% of patients ( Fig. 1 ). Other clinical characteristics such as blue sclera, dental abnormalities, skin hyperlaxity, and joint hypermobility are heterogeneous in presentation even in affected members of the same family.
Most of the cases are associated with mutations in 1 of 2 genes that encode the alpha chains of collagen type I (COL1A1 and COL1A2). Over the past 10 years, multiple additional genes involved with post-translational modification of type 1 collagen, bone cell signaling, or regulation of bone matrix homeostasis have been identified, expanding the genetic spectrum of OI.
Classification of osteogenesis imperfecta
The Sillence classification, published in 1979, was the first systemic classification of OI phenotype, divided based on clinical and radiographic criteria. Patients were classified as having mild nondeforming (type I), moderate (type IV), severe progressively deforming (type III), or perinatal lethal (type II) OI. With increased awareness of the genetic complexity of OI and the phenotypic variability arising from mutations at single loci, there is ongoing debate about the optimal method to categorize patients. Tables 1 and 2 outline the current known genetic mutations associated with OI. Careful analysis of the inheritance pattern and clinical phenotype can help guide genetic testing.
| Gene | Condition | Disease Mechanism | Skeletal Phenotype | Associated Features |
|---|---|---|---|---|
| COL1A1 | OI type I | Decreased type I collagen production | Mild | Nondeforming, most fractures prepubertal, presenile deafness, aortic regurgitation |
| COL1A1 COL1A2 | OI type II | Abnormal type 1 collagen production | Lethal | Multiple rib, long bone and vertebral fractures, pulmonary hypoplasia, central nervous system malformations and hemorrhages |
| OI type III | Abnormal type 1 collagen production | Severe | Triangular facies, short stature, severe long bone deformities, elongated vertebral pedicles, “popcorn” appearance of metaphyses and epiphyses, decreased ability to ambulate | |
| OI type IV | Abnormal type 1 collagen production | Moderate | Short stature, may have long bone bowing, scoliosis, and joint laxity | |
| IFITM5 | OI type V | Dysregulation of collagen mineralization | Moderate | Calcification of forearm intraosseous membrane, radial head dislocation, hyperplastic callous formation |
| Gene | Condition | Disease Mechanism | Skeletal Phenotype | Associated Features |
|---|---|---|---|---|
| SERPINF1 | OI type VI | Mineralization defect | Moderate to severe | Healthy at birth with subsequent progressively severe deformities. Undermineralization and “fish-scale” pattern on iliac crest biopsies |
| CRTAP | OI type VII | Collagen 3-hydroxylation defect | Severe to lethal | Rhizomelia, neonatal fractures, popcorn metaphyses, short stature |
| LEPRE1 | OI type VIII | Collagen 3-hydroxylation defect | Severe to lethal | Rhizomelia, popcorn metaphyses, short stature |
| PPIB | OI type IX | Collagen 3-hydroxylation defect | Severe | Short stature |
| SERPINH1 | OI type X | Chaperone defect | Severe | Renal stones |
| FKBP10 | OI type XI | Chaperone defect | Moderate to severe | Contractures |
| BMP1 | OI type XII | Defective collagen processing | Severe | Hyperextensibility |
| SP7 | Unclassified | Impaired osteoblast differentiation | Moderate | Delayed tooth eruption |
| WNT1 | Unclassified | Impaired osteoblast function | Moderate to severe | Central nervous system malformations |
Autosomal Dominant Osteogenesis Imperfecta
Autosomal dominant mutations in COL1A1 or COL1A2 account for approximately 90% cases of OI (see Table 1 ). Type I OI arises from a quantitative defect in collagen production due to a silenced allele of the COL1A1 gene. Usually as a result of a premature stop codon within the gene, these mutations lead to half of the normal amount of protein production. The structure of the type 1 collagen protein that is produced is normal. Type 1 OI presents with fractures, typically before puberty, and is nondeforming. With the completion of growth the incidence of fractures decreases.
In comparison, type II, III, and IV OI are a result of structural defects in type I collagen due to missense mutations in either the COL1A1 or COL1A2 gene. The most common mutations, involving substitution of glycine by a larger amino acid, disrupt the triple helix assembly of collagen, impairing its function and interactions with the extracellular matrix. Depending on the helical location of a mutation and the resultant instability of the protein, the clinical phenotype can range from lethal to mildly deforming.
Type II OI is the most severe form of OI and newborns do not generally survive past the perinatal period. Infants present with multiple intrauterine fractures and severe long bone deformities. Pulmonary hypoplasia with multiple rib fractures or central nervous malformations usually result in death. Type III OI is the most severe, nonlethal form and is characterized by history of multiple fractures from infancy, severe long bone deformities, and significant short stature. Children have typical triangular facies from a relatively large skull with underdeveloped facial bones. Multiple vertebral compression fractures cause severe scoliosis, kyphosis, and rib cage deformity. Distortion of the growth plates with partial calcification of cartilage can lead to a popcorn appearance of epiphyses. Ambulation is often limited either to a wheelchair or with aids. Type IV OI, although not as severe as type III, can present with some long limb bowing, vertebral fractures, and relative short stature. Most children are ambulatory, although may need walking aids.
Individuals with type V OI exhibit specific clinical features including calcification of the forearm intraosseous membrane, radiodense metaphyseal bands at growth plates of long bones, and development of hyperplastic callus after trauma. There is an 85% incidence of radial head dislocation. Genetic mutations in the gene encoding interferon-induced transmembrane protein 5 (IFITM5) were discovered in 2012 to be the causative defect. Although IFITM5 appears to play a role in bone ossification, the mechanism by which it regulates collagen mineralization is not known.
Autosomal Recessive Osteogenesis Imperfecta
The autosomal recessive forms of OI are rare conditions and account for approximately 2% to 5% of cases. Mutations have been discovered in critical elements involved in type I collagen secretion and post-translation modification (collagen 3-hydroxylation and chaperone defects) as well as signaling and transcription factors involved in osteoblast function (see Table 2 ). Although the autosomal recessive forms are uncommon, the discovery of multiple new genes responsible for OI has shed light onto new mechanistic pathways and possible therapeutic approaches.
Classification of osteogenesis imperfecta
The Sillence classification, published in 1979, was the first systemic classification of OI phenotype, divided based on clinical and radiographic criteria. Patients were classified as having mild nondeforming (type I), moderate (type IV), severe progressively deforming (type III), or perinatal lethal (type II) OI. With increased awareness of the genetic complexity of OI and the phenotypic variability arising from mutations at single loci, there is ongoing debate about the optimal method to categorize patients. Tables 1 and 2 outline the current known genetic mutations associated with OI. Careful analysis of the inheritance pattern and clinical phenotype can help guide genetic testing.
| Gene | Condition | Disease Mechanism | Skeletal Phenotype | Associated Features |
|---|---|---|---|---|
| COL1A1 | OI type I | Decreased type I collagen production | Mild | Nondeforming, most fractures prepubertal, presenile deafness, aortic regurgitation |
| COL1A1 COL1A2 | OI type II | Abnormal type 1 collagen production | Lethal | Multiple rib, long bone and vertebral fractures, pulmonary hypoplasia, central nervous system malformations and hemorrhages |
| OI type III | Abnormal type 1 collagen production | Severe | Triangular facies, short stature, severe long bone deformities, elongated vertebral pedicles, “popcorn” appearance of metaphyses and epiphyses, decreased ability to ambulate | |
| OI type IV | Abnormal type 1 collagen production | Moderate | Short stature, may have long bone bowing, scoliosis, and joint laxity | |
| IFITM5 | OI type V | Dysregulation of collagen mineralization | Moderate | Calcification of forearm intraosseous membrane, radial head dislocation, hyperplastic callous formation |
| Gene | Condition | Disease Mechanism | Skeletal Phenotype | Associated Features |
|---|---|---|---|---|
| SERPINF1 | OI type VI | Mineralization defect | Moderate to severe | Healthy at birth with subsequent progressively severe deformities. Undermineralization and “fish-scale” pattern on iliac crest biopsies |
| CRTAP | OI type VII | Collagen 3-hydroxylation defect | Severe to lethal | Rhizomelia, neonatal fractures, popcorn metaphyses, short stature |
| LEPRE1 | OI type VIII | Collagen 3-hydroxylation defect | Severe to lethal | Rhizomelia, popcorn metaphyses, short stature |
| PPIB | OI type IX | Collagen 3-hydroxylation defect | Severe | Short stature |
| SERPINH1 | OI type X | Chaperone defect | Severe | Renal stones |
| FKBP10 | OI type XI | Chaperone defect | Moderate to severe | Contractures |
| BMP1 | OI type XII | Defective collagen processing | Severe | Hyperextensibility |
| SP7 | Unclassified | Impaired osteoblast differentiation | Moderate | Delayed tooth eruption |
| WNT1 | Unclassified | Impaired osteoblast function | Moderate to severe | Central nervous system malformations |
Autosomal Dominant Osteogenesis Imperfecta
Autosomal dominant mutations in COL1A1 or COL1A2 account for approximately 90% cases of OI (see Table 1 ). Type I OI arises from a quantitative defect in collagen production due to a silenced allele of the COL1A1 gene. Usually as a result of a premature stop codon within the gene, these mutations lead to half of the normal amount of protein production. The structure of the type 1 collagen protein that is produced is normal. Type 1 OI presents with fractures, typically before puberty, and is nondeforming. With the completion of growth the incidence of fractures decreases.
In comparison, type II, III, and IV OI are a result of structural defects in type I collagen due to missense mutations in either the COL1A1 or COL1A2 gene. The most common mutations, involving substitution of glycine by a larger amino acid, disrupt the triple helix assembly of collagen, impairing its function and interactions with the extracellular matrix. Depending on the helical location of a mutation and the resultant instability of the protein, the clinical phenotype can range from lethal to mildly deforming.
Type II OI is the most severe form of OI and newborns do not generally survive past the perinatal period. Infants present with multiple intrauterine fractures and severe long bone deformities. Pulmonary hypoplasia with multiple rib fractures or central nervous malformations usually result in death. Type III OI is the most severe, nonlethal form and is characterized by history of multiple fractures from infancy, severe long bone deformities, and significant short stature. Children have typical triangular facies from a relatively large skull with underdeveloped facial bones. Multiple vertebral compression fractures cause severe scoliosis, kyphosis, and rib cage deformity. Distortion of the growth plates with partial calcification of cartilage can lead to a popcorn appearance of epiphyses. Ambulation is often limited either to a wheelchair or with aids. Type IV OI, although not as severe as type III, can present with some long limb bowing, vertebral fractures, and relative short stature. Most children are ambulatory, although may need walking aids.
Individuals with type V OI exhibit specific clinical features including calcification of the forearm intraosseous membrane, radiodense metaphyseal bands at growth plates of long bones, and development of hyperplastic callus after trauma. There is an 85% incidence of radial head dislocation. Genetic mutations in the gene encoding interferon-induced transmembrane protein 5 (IFITM5) were discovered in 2012 to be the causative defect. Although IFITM5 appears to play a role in bone ossification, the mechanism by which it regulates collagen mineralization is not known.
Autosomal Recessive Osteogenesis Imperfecta
The autosomal recessive forms of OI are rare conditions and account for approximately 2% to 5% of cases. Mutations have been discovered in critical elements involved in type I collagen secretion and post-translation modification (collagen 3-hydroxylation and chaperone defects) as well as signaling and transcription factors involved in osteoblast function (see Table 2 ). Although the autosomal recessive forms are uncommon, the discovery of multiple new genes responsible for OI has shed light onto new mechanistic pathways and possible therapeutic approaches.
Extraskeletal clinical features of osteogenesis imperfecta
Hearing Loss
The hearing loss, a mixture of conductive and sensorineural deficiency, is generally progressive, with 50% of adults with OI having hearing loss by 50 years of age ( Box 1 ). The prevalence of hearing difficulties in children with OI is around 5%.
-
Hearing loss
-
Dental abnormalities
- •
Dentinogenesis imperfecta
- •
Malocclusion
- •
-
Blue/grey sclera
-
Connective tissue features
- •
Joint hyperextensibility
- •
-
Hypercalcuria
-
Cardiovascular involvement
- •
Aortic root dilatation
- •
-
Neurological features
- •
Macrocephaly
- •
Hydrocephalus
- •
Basilar invagination
- •
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
