OSTEOGENESIS IMPERFECTA (OI)
Definition
- Also referred to as “brittle bone disease.”
- Rare hereditary connective tissue disorder (~1 case per 200,000 live births).
- Marked variability in clinical presentation:
- Moderate to severe forms often present in infancy (fractures with little/no trauma).
- Mild forms may only appear later (adulthood) with premature osteoporosis.
Etiology & Genetic Background
- ~90% of cases: Autosomal dominant germline mutations in type I collagen genes—COL1A1 and COL1A2.
- Collagen type I is crucial for normal bones, sclerae, tendons, ligaments, teeth, and skin.
- Disease can result from abnormal structure or reduced production of type I collagen.
- Mutations in other collagen-related genes (e.g., encoding cartilage-associated proteins) found in a minority of OI patients.
- Intra-familial variability: Patients with the same mutation may have different severities (involving other genetic or environmental factors).
Key Clinical Features
- Recurrent bone fractures (often minimal or no trauma).
- Blue sclerae (translucent sclera revealing underlying uveal tissue).
- Opalescent teeth (dentinogenesis imperfecta) → teeth appear grayish or bluish, may be fragile.
- Easy bruising of tissues.
- Basilar skull deformities with possible neurological complications.
- Hearing loss (due to fracture of ossicles or inner ear involvement).
- Ligament laxity with hypermobility.
Clinical Subtypes
- Type I OI (Mild)
- Typically mild manifestations:
- Infrequent fractures (long bones, ribs).
- Normal stature, possible premature osteoporosis.
- Mild scoliosis can occur.
- Blue sclerae.
- Teeth: normal appearance or opalescent.
- Early-onset hearing loss is common.
- Often related to a COL1A1 allele deletion → normal collagen structure but reduced overall production.
- Typically mild manifestations:
- Type II OI (Lethal Perinatal)
- Multiple severe fractures in utero or at birth.
- Typically fatal shortly after delivery (respiratory failure).
- Types III, IV, V, VI, VII, and VIII
- Severe bone fragility with frequent fractures and limb deformities.
- Progressive skeletal deformities:
- Bowed long bones, scoliosis, short stature.
- Basilar skull changes → possible nerve compression.
- Hearing loss if ossicles are affected.
- Joint hypermobility can be present.
- Type III: progressive deforming form leading to wheelchair use.
- Type IV: somewhat less growth retardation vs. Type III; may have normal sclera.
- Type V: “Congenital brittle bones with redundant callus;” no dentinogenesis imperfecta.
- Type VI: “Congenital brittle bones with mineralization defect;” accumulation of osteoid in bone tissue.
- Type VII: Rare, recessive, with rhizomelia (shortening near proximal limb segments).
- Type VIII: Recessive, prolyl 3-hydroxylase 1 deficiency → severely undermineralized bone matrix.
Laboratory Findings
- Calcium, phosphorus, PTH often normal in typical OI.
- Hypercalciuria may occur, correlates with disease severity.
- Bone markers:
- Formation markers (bone-specific alkaline phosphatase, osteocalcin, collagen propeptides) may be low in severe disease (impaired osteoblast function).
- Resorption markers (urinary hydroxyproline, N/C-telopeptide crosslinks) may be high, reflecting increased collagen breakdown.
- Bone biopsy typically not necessary; if done, may show:
- Disorganized bone architecture.
- High turnover with decreased cortical width, trabecular number, and cancellous bone volume.
Differential Diagnosis
- Rickets (various forms).
- Child abuse (non-accidental fractures).
- Idiopathic juvenile osteoporosis.
- Hypophosphatasia (tissue-nonspecific alkaline phosphatase deficiency).
- Juvenile Paget disease.
- Fibrous dysplasia, Ehlers-Danlos syndrome, Menkes disease, Cole-Carpenter syndrome.
Diagnosis
- Clinical diagnosis: Recurrent fractures, blue sclerae, family history, dentinogenesis imperfecta, hearing loss.
- Genetic testing: Mutational analysis of COL1A1 and COL1A2.
- Skeletal radiographs: May reveal osteopenia, thin cortices, multiple fractures in different healing stages.
Treatment & Management
- Team approach: Genetics, orthopedics, neurology, physical/occupational therapy, dental, ENT, psychology, endocrinology.
- Goals:
- Reduce fracture frequency.
- Maximize mobility and independence.
- Prevent/managing deformities (e.g., scoliosis).
- Control pain.
- Monitoring:
- Bone mineral density (BMD) with DXA.
- Frequency of fractures.
- Hearing tests, dental evaluations.
- For Type III OI → annual echocardiogram (to detect aortic root dilation/valvular issues).
- Pharmacologic therapy:
- Bisphosphonates (e.g., pamidronate, alendronate) → shown to increase BMD, decrease fractures, and improve mobility.
- Monitor for any “mineralization defect” OI types (e.g., Type VI) where bisphosphonates may be less effective or contraindicated.
- Other treatments under investigation: growth hormone, gene therapy, bone marrow transplant.
- Prognosis:
- Type I: Normal life expectancy; mild disease.
- More severe forms: Shortened lifespan, linked to thoracic deformities and related complications.
- Skilled orthopedic interventions and bracing may reduce complications and improve quality of life.