What are the features and management of osteogenesis imperfecta?

Features and Management of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heterogeneous family of genetic disorders characterized primarily by bone fragility and fractures, along with variable extraskeletal manifestations including blue sclerae, dentinogenesis imperfecta, hearing loss, and skeletal deformities. 1

Key Clinical Features

Primary Skeletal Features

• Fragile bones prone to fractures - the hallmark feature of all OI types
• Transverse fractures occurring in the shafts of long bones
• Demineralized bones/osteopenia on radiographs
• Skeletal deformities (especially in more severe types)
• Scoliosis and/or kyphosis
• Wormian bones of the skull

Common Extraskeletal Features

• Blue sclerae - particularly prominent in OI type I
• Dentinogenesis imperfecta (DI) - hypoplastic, translucent, carious, late-erupting, or discolored teeth
• Hearing impairment due to otosclerosis
• Poor linear growth/short stature (variable by type)
• Macrocephaly with triangular-shaped face
• Hyperextensible joints
• Easy bruisability
• Inguinal and/or umbilical hernias 1

Classification of OI

OI is classified into multiple types based on clinical features and genetic basis:

1. OI Type I:

   • Mildest form
   • Fractures with little or no deformity
   • Blue sclerae
   • Normal stature
   • Hearing loss
   • Autosomal dominant inheritance 1

2. OI Type II:

   • Lethal perinatal form
   • Undermineralized skull
   • Beaded ribs
   • Compressed femurs
   • Long bone deformity
   • Platyspondyly
   • Autosomal dominant inheritance 1

3. OI Type III:

   • Progressively deforming bones
   • Moderate deformity at birth
   • Variable sclerae hue
   • Very short stature
   • Dentinogenesis imperfecta
   • Autosomal dominant or recessive inheritance 1

4. OI Type IV:

   • Normal sclerae
   • Mild/moderate bone deformity with fractures
   • Variable short stature
   • Dentinogenesis imperfecta
   • Some hearing loss
   • Autosomal dominant inheritance 1

5. OI Types V-VII: Additional variants with specific features such as calcification of interosseous membrane, hyperplastic callus formation, or congenital fractures 1

Genetic Basis

• Most commonly caused by heterozygous mutations in COL1A1 and COL1A2 genes that encode type I collagen
• Many cases involve de novo mutations with no family history
• Phenotypic expression varies widely, even within families sharing the same mutation
• Some types involve reduced collagen production (milder), while others involve structural alterations (more severe)
• Additional genes have been implicated in rarer forms of OI 1, 2

Diagnosis

Diagnosis is based on:

1. Clinical features - fracture history, physical examination findings
2. Family history - though many cases have no family history due to de novo mutations
3. Radiographic findings - osteopenia, fractures, skeletal deformities
4. Genetic testing - molecular analysis of COL1A1/COL1A2 and other genes
5. Biochemical testing - collagen analysis from skin fibroblasts 1

Important diagnostic considerations:

• Blue sclerae can occur in normal infants before 12 months of age
• OI types IV, V, and VI with normal sclerae may present only with fractures
• Differentiation from child abuse is critical in infants with unexplained fractures 1

Management Approach

Management requires a multidisciplinary team including:

• Pediatrician/endocrinologist
• Orthopedic surgeon
• Rehabilitation specialist
• Physiotherapist
• Occupational therapist
• Dentist
• Geneticist
• Social worker/psychologist 3

Medical Treatment

Bisphosphonate therapy is the mainstay of medical treatment for OI and has been shown to decrease bone pain, enhance well-being, improve muscle strength and mobility, and decrease fracture incidence. 3

Benefits include:

• Inhibition of bone resorption
• Facilitation of bone formation
• Pain reduction
• Improved mobility 2

Surgical Treatment

Surgical interventions focus on:

• Internal splinting of long bones
• Correction of deformities
• Pain reduction
• Ensuring healing without increasing deformities 2, 4

Rehabilitation

Physical and occupational therapy are crucial components:

• Timely remobilization after fractures
• Regular strengthening of muscles
• Improvement of mobility
• Prevention of muscle wasting
• Avoidance of bone resorption caused by immobilization 2

Emerging Therapies

Newer therapeutic approaches under investigation include:

• Sclerostin inhibition
• Transforming growth factor-β inhibition
• Smart intramedullary rods (composed of nitinol shape-memory alloy)
• Bone marrow transplantation to increase osteoblast density
• Gene-targeted therapies 5, 6, 4

Important Clinical Considerations

1. Differential diagnosis: OI must be distinguished from child abuse in cases of unexplained fractures in infants. Child abuse is more common than OI, but children with OI can also be abused. 1

2. Variable expression: The severity of OI can vary greatly, even within families with the same mutation.

3. Monitoring: Regular assessment of bone density, growth, mobility, and hearing is essential for optimal management.

4. Lifelong management: While some types of OI may improve after puberty, most require ongoing care throughout life.