Overview
Definition
Osteogenesis imperfecta (OI) is an inherited connective tissue disorder characterized by impaired bone formation and severe bone fragility.
Epidemiology
- Most common genetic cause of osteoporosis
- Incidence:
- Overall: 1 in 20,000 births
- Type I: 1 in 15,000 to 1 in 20,000 births
- Type II: 1 in 60,000 births
- Types III and IV: unknown, very low
- The distribution is similar worldwide.
- Males and females are equally affected.
Etiology
- Mutations in genes encoding collagen type 1 (COL1A1 and COL1A2):
- 90% of all cases
- Classified as types I–IV
- Other mutations (10%):
- Post-translational defects
- 3-prolyl-hydroxylation complex defects
- Other proteins involved in bone formation and homeostasis
| Type I | Type II | Type III | Type IV | |
|---|---|---|---|---|
| Mutated gene | COL1A1, COL1A2 (collagen type 1 alpha 1 and 2 chains) | COL1A1, COL1A2, and CRTAP (cartilage-associated protein) | COL1A1, COL1A2 | COL1A1, COL1A2 |
| Inheritance modality | Autosomal dominant | Autosomal dominant AND autosomal recessive | Autosomal dominant | Autosomal dominant |
| Defect | Frameshift mutations in collagen type 1 alpha 1 and 2 chains leading to decreased amounts of normal collagen | Disrupted formation of the collagen triple helix structure, leading to little or no normal collagen | Mutations causing structural protein defects leading to severe pathology | Mutations causing structural protein defects leading to minimal or mild pathology |
Pathophysiology
- Mutations in alpha 1 or alpha 2 chains of type 1 collagen:
- Decreased amount of type 1 collagen (type I)
- Disruption of type 1 collagen triple helix (type II)
- Structural protein defects of type 1 collagen (type III and IV)
- Increased amounts of type III and IV collagen in bone tissue
- Increased activity of osteoclasts and abnormal osteoblast differentiation
- Poor deposition of hydroxyapatite crystals and paradoxic bone hypermineralization
- Globally abnormal bone growth: decreased bone trabeculae and cortical thickness
- Fractures with normal movement and very low-impact activities, with a normal healing process
Clinical Presentation
- Variable severity
- Type II die in utero or early infancy.
- Present to a variable extent in types I, III, and IV:
- Excess or atypical fractures
- Short stature
- Scoliosis
- Basilar skull deformities (may cause nerve compression)
- Blue sclerae
- Hearing loss
- Dentinogenesis imperfecta (opalescent teeth)
- Increased laxity of ligaments
- Wormian bones (small bones near cranial sutures)
- Easy bruising
| Type I | Type II | Type III | Type IV | |
|---|---|---|---|---|
| Description | Non-deforming with blue sclerae | Perinatally lethal | Progressively deforming | Variable with normal sclerae |
| Severity | Mild | Perinatal lethal | Severe | Mild to moderate |
| Fractures | < 100 | > 100 | > 100 | > 100 |
| Bone deformity | Uncommon | Severe | Moderate to severe | Mild to moderate |
| Stature | Normal to mildly reduced | Severely reduced | Reduced | Variable |
| Dentogenesis imperfecta | Variable | Common | Common | Variable |
| Color of sclerae | Blue | Dark blue | Blue | Normal to gray |
| Hearing loss | Present in approximately 50% | — | Frequent | Variable |
Diagnosis
History
- History of fractures:
- Multiple and recurrent fractures during very low-impact activities (e.g., diaper change)
- Specific bone fractures:
- Olecranon process
- Transverse humerus
- Diaphyseal humerus
- Fractures before or during birth
- History of extra-skeletal symptoms:
- Hearing loss
- Easy bruising
- Family history of the disease or findings suggestive of undiagnosed disease in relatives:
- Family history of multiple fractures
- Family history of extra-skeletal symptoms:
- Hearing loss
- Dentinogenesis imperfecta
- Lack of family history does not rule out disease.
- History of child abuse: important to rule out in cases of fractures
Physical examination
- Skeletal findings:
- Dentinogenesis imperfecta: translucent teeth with amber, blue, or gray coloration
- Genu varum (bow legs): outward bowing at the knees
- Scoliosis
- Loose joints
- Limb deformity (particularly bowing of the femur)
- Extra-skeletal findings:
- Prolonged bleeding from injured areas
- Easy bruising
- Blue-colored sclera
- Breathing problems/fatigue
- Hypoacusia that can be conductive, sensorineural, or mixed (deficient ossification of the middle ear)
- Muscle weakness
- Short stature (more common in severe cases)
Blue-colored sclera associated with OI
Image: “Blue sclera” by the Department of Medical Oncology, Ankara University School of Medicine, 06300 Ankara, Turkey. License: CC BY 3.0.
Dentinogenesis imperfecta:
Image: “Anterior teeth showing brownish discoloring” by the Division of Oral Radiology, Department of Clinical Dentistry, Federal University of Ceará, Rua Alexandre Baraúna 949, 60430-160 Fortaleza, CE, Brazil. License: CC BY 3.0.
Anterior teeth show a brownish discoloration (upper dental arch (a), lower arch (b), and dental occlusion(c)).
Intraoral photograph showing yellowish discoloration and chipping of the dentition: A 4-year-old male child with OI (type IV)
Image: “Chipping of the dentition” by the Department of Oral Medicine and Radiology, AB Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore 575018, India. License: CC BY 3.0.
Infant with OI: Notice the deformity of the limbs, an indication of possible fractures during inspection.
Image: “Congenita A type of osteogenesis imperfecta” by the Maria Sklodowska Curie Clinical Emergency Hospital for Children, Bucharest, Romania. License: CC BY 2.0.
Laboratory testing
- Bloodwork:
- Usually normal
- Alkaline phosphatase may be increased.
- ↓ Markers of bone formation, ↑ markers of bone resorption
- Urine: Hypercalciuria with normal renal function may be present.
- Biopsy:
- Collagen: In vitro fibroblast culturing shows abnormal organization/structure.
- Bone histology:
- Shows disorganized bone structure
- Decreased size and number of bony trabeculae
- Increased osteoblasts and osteoclasts
- Genetic studies:
- No widely available commercial tests
- Genomic DNA testing for mutations in COL1A1 and COL1A2
- Prenatal testing:
- Chorionic villus sampling
- Amniocentesis
Imaging
- Prenatal ultrasound: evidence of bony deformities
- X-ray findings suggestive of OI:
- Multiple fractures in various states of healing
- Thin bone cortices and widened metaphysis
- Low bone density
- Bowed femurs
- “Wormian” bones
- “Codfish” vertebrae
- Saber shins
- Coxa vara
- Kyphoscoliosis
- Platyspondyly
| Type I | Type II | Type III | Type IV | |
|---|---|---|---|---|
| Skull radiographic findings | Intra-sutural bones | Undermineralization; calcified areas | Intra-sutural bones | Intra-sutural bones (sometimes) |
| Spine radiographic findings | Biconcave vertebrae (adults) | Widened vertebral bodies (platyspondyly) | Biconcave vertebrae; kyphoscoliosis | Biconcave vertebrae |
| Extremity radiographic findings | Thin cortices | Severely deformed femurs | Flared metaphyses, bowing, thin cortices | Thin cortices |
| Other radiographic findings | Osteopenia | Small, beaded ribs (pathognomonic) | Thin ribs, severe osteoporosis | Protrusio acetabuli in a subset |
Prenatal ultrasound diagnosing OI:
Image: “Prenatal ultrasound” by the Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institution, Johns Hopkins University, Baltimore, MD, USA. License: CC BY 2.5.
This prenatal ultrasound at 22 weeks’ gestation shows bowing of the femur (the crosshairs show the extremities of the femur).
Radiograph showing OI:
Image: “Fig. 260” by Bryant, Joseph D. License: Public domain.
periosteal dysplasia, almost complete absence of cortical bone, and numerous fractures
Chest radiograph showing long and narrow thorax (barrel-shaped chest) with anterior compression
Image: “Barrel-shaped chest” by the Department of Oral Medicine and Radiology, AB Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore 575018, India. License: CC BY 3.0.
Radiograph of the lower limbs showing bowing of the femur, with widening of the metaphases:
Image: “Bowing of the femur” by the Department of Oral Medicine and Radiology, AB Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore 575018, India. License: CC BY 3.0.
a 4-year-old boy with OI (type IV)
Radiograph showing a bowing tibia and fibula (saber shins):
Image: “Radiograph showing bowing tibia and fibula” by the Department of Oral Medicine and Radiology, AB Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore 575018, India. License: CC BY 3.0.
a 4-year-old boy with OI (type IV)
Biconcave deformities in the lower thoracic and lumbar vertebrae in a 15-year-old patient with OI (“codfish” vertebrae)
Image: “Osteogenesis imperfecta” by the 1st Department of Orthopaedic Surgery, School of Medicine, University of Athens, “Attikon” Hospital, Rimini 1 Haidari 12462, Athens, Greece. License: CC BY 2.0.Radiographs of a 19-year-old woman with OI: Fragile bones, short trunk, severe kyphoscoliosis, and platyspondyly are noticed.
Image: “Biconcavity deformities” by the Department of Endocrine and Metabolic Diseases, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China. License: CC BY 3.0.
Human skull with wormian bones in a 21-year-old man
Image: “Wormian bones” by E. Barclay-Smith. License: Public domain.
Management
There is no definitive cure for OI.
Goals of therapy
- Reduce pain
- Reduce fractures
- Reduce bone deformity
- Increase ambulation/independence
Lifestyle modifications
- Controlled weight carrying
- Safe exercises to improve muscle and bone strength
- Diet rich in calcium and vitamin D
- Avoidance of alcohol and caffeine
- Steroids are contraindicated.
- Avoidance of active or passive inhalation of cigarette smoke
Supportive management
- Casts and splints
- Braces
- Physical therapy
- Implantation of rods in legs or arms
- Dental workup
- Hearing aids
- Crowns for brittle teeth
- Mobility aids (e.g., crutches, canes, wheelchairs, walkers)
- Supplemental oxygen
- Genetic counseling for parents considering future pregnancies
Bisphosphonates (pamidronate)
- Inhibit bone turnover/resorption
- Have been shown to reduce fracture rates
- Long-term effect on other skeletal symptoms (scoliosis, deformity) is unclear.
Surgical therapy
- Fracture repair
- Deformity correction
Prognosis
- Severe functional limitation and decreased quality of life
- Type I cases can attain a full lifespan.
- Type II cases die prenatally or within the 1st year of life.
- Type III and IV cases require walking aids, but can attain household and community ambulation skills.
Differential Diagnosis
- Child abuse: defined by the U.S. government as “any recent act or failure to act on the part of a parent or caretaker, which results in death, serious physical or emotional harm, sexual abuse or exploitation, or an act or failure to act which presents an imminent risk of serious harm.” Physically abused children may present with recurrent fractures and visits to the emergency department (ED). Old and recent signs of inflicted trauma are more indicative of the diagnosis of child abuse.
- Rickets: a disease of the growing bone caused by inadequate bone mineralization due to vitamin D deficiency. Rickets presents with recurrent fractures, limb deformities, increased alkaline phosphatase, and dental abnormalities in some cases, but does not display hearing loss and blue sclerae.
- Osteomalacia: a condition of decreased bone density in adults that tends to appear prior to the development of osteoporosis. Osteomalacia shows fractures and increased alkaline phosphatase, but no hearing loss or blue sclerae.
- Paget’s disease of the bone: a disorder characterized by increased and abnormal remodeling of bone tissue that presents with fractures, bone deformity, bowing of long bones, increased alkaline phosphatase, and conductive hearing loss. However, 20% of cases are asymptomatic and diagnosis may be made incidentally as these patients are investigated for something else.
References
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- Niyibizi, C., Wang, S., Mi, Z. et al. (2004). Gene therapy approaches for osteogenesis imperfecta. Gene Ther 11, 408–416. https://doi.org/10.1038/sj.gt.3302199
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