Case Presentation
A 4-year-old male child presented to the pediatric orthopedic outpatient department with a history of recurrent long bone fractures since infancy. His most recent injury—a transverse fracture of the left femoral shaft—occurred after a minor fall while walking. The child’s past history revealed more than five fracture events, all due to trivial trauma. There were associated complaints of dental discoloration and early tooth loss. Developmental milestones were normal, but his height and weight were below the 3rd percentile.
On examination, he had blue sclerae, a triangular facies, and bowing of the lower limbs. Dental evaluation revealed dentinogenesis imperfecta. There were no signs of bruising or other indications of child abuse. Audiometric evaluation showed mild conductive hearing loss. Skeletal survey demonstrated generalized osteopenia, multiple healed fractures with callus formation, and signs of previous rodding procedures. Genetic testing revealed a pathogenic variant in the COL1A1 gene, confirming a diagnosis of Osteogenesis Imperfecta Type I.
Introduction
Osteogenesis Imperfecta (OI), commonly known as “brittle bone disease,” is a rare group of genetic connective tissue disorders characterized primarily by bone fragility. The hallmark of OI is a predisposition to fractures with minimal or no trauma. In addition to skeletal manifestations, OI can affect the teeth, eyes, ears, skin, and joints due to the widespread presence of type I collagen in connective tissues.
The incidence of OI ranges from 1 in 15,000 to 1 in 20,000 live births. Its clinical spectrum varies widely, from perinatal lethality to nearly asymptomatic adults with a mild phenotype. Accurate diagnosis and classification are essential for guiding treatment, preventing complications, and offering genetic counseling.
Etiology and Genetic Basis
OI results from mutations that affect the biosynthesis or structure of type I collagen, a major structural protein in bone and other connective tissues. Over 90% of cases are associated with mutations in the COL1A1 and COL1A2 genes located on chromosomes 17 and 7, respectively. These genes encode the pro-alpha1 and pro-alpha2 chains of type I collagen.
Depending on the nature of the mutation, the result may be:
- Quantitative defect (haploinsufficiency): Reduced production of normal collagen (e.g., Type I OI).
- Qualitative defect (dominant-negative mutation): Structurally abnormal collagen that disrupts triple helix formation (e.g., Type II OI).
In addition, more than ten rare genes are implicated in autosomal recessive or X-linked forms (e.g., CRTAP, LEPRE1, PPIB, IFITM5, WNT1, SERPINF1), typically producing more severe phenotypes due to abnormalities in collagen modification, folding, or secretion.
Classification of Osteogenesis Imperfecta
The Sillence classification, based on clinical severity and inheritance pattern, remains the most widely used:
- Type I – Mild, non-deforming with blue sclerae; normal lifespan.
- Type II – Perinatal lethal; multiple fractures in utero.
- Type III – Severe, progressively deforming with short stature and multiple fractures.
- Type IV – Moderate severity with normal sclerae; variable prognosis.
- Type V – Distinct histological features; hypertrophic callus formation.
- Types VI to XV – Newly identified, with specific genetic mutations and phenotypes.
Pathophysiology
Type I collagen comprises two α1 chains and one α2 chain forming a stable triple helix. Mutations in COL1A1 or COL1A2 result in defective or deficient collagen molecules. This affects the mineralization and tensile strength of bones, leading to:
- Decreased bone density
- Impaired bone architecture
- Altered collagen fibril morphology
- Increased bone fragility
Non-skeletal tissues are also affected. In the eye, thin sclerae appear blue due to underlying choroid visibility. In the inner ear, abnormal ossicles can lead to conductive hearing loss. In teeth, abnormal dentin forms the basis of dentinogenesis imperfecta.
Clinical Features
Symptoms vary widely but may include:
Musculoskeletal
- Recurrent fractures from minimal trauma
- Bowed limbs
- Scoliosis or kyphosis
- Joint laxity
- Muscle weakness
Extraskeletal
- Blue sclerae (especially in Type I)
- Dentinogenesis imperfecta (opalescent, brittle teeth)
- Hearing loss (conductive or sensorineural)
- Short stature
- Triangular face
- Wormian bones in skull radiographs
In severe cases, respiratory complications from thoracic deformity can be life-threatening.
Diagnosis
Diagnosis is based on a combination of clinical findings, radiological features, and genetic testing.
Clinical Evaluation
- Family history of fractures
- Blue sclerae, dental anomalies
- Delayed fracture healing or deformities
Radiographic Features
- Osteopenia
- Thin cortical bone
- Multiple fractures with varying healing stages
- Wormian bones in skull
- Codfish vertebrae
Bone Mineral Density (BMD)
- Assessed by Dual-Energy X-ray Absorptiometry (DEXA)
Genetic Testing
- COL1A1/COL1A2 sequencing
- Whole-exome sequencing for rarer forms
Biochemical Tests
- Collagen analysis from cultured fibroblasts (rarely used now)
Differential Diagnosis
Conditions that can mimic OI include:
- Non-accidental injury (child abuse)
- Rickets (vitamin D deficiency or inherited)
- Hypophosphatasia
- Ehlers-Danlos syndrome
- Marfan syndrome
- Osteopetrosis
- Bruck syndrome
Distinguishing OI from child abuse is critical, especially in infants and toddlers with multiple fractures and no trauma history.
Management
There is no definitive cure, but a multidisciplinary approach improves outcomes.
1. Pharmacological Treatment
- Bisphosphonates (e.g., intravenous pamidronate, zoledronate): Inhibit osteoclast activity, increase BMD, reduce fracture rate.
- Calcium and Vitamin D: Support bone metabolism.
- Denosumab: Off-label use in severe cases, particularly in non-responders to bisphosphonates.
- Teriparatide: Approved in adults but not routinely used in children due to concerns over growth plate effects.
2. Orthopedic Management
- Fracture care and immobilization
- Intramedullary rodding (e.g., telescopic rods) to stabilize long bones and prevent deformity
- Spinal surgery in severe scoliosis
3. Physical and Occupational Therapy
- Encourages mobility, muscle strengthening, and independence
- Avoids immobilization-related complications
4. Hearing and Dental Care
- Regular audiometric assessments
- Hearing aids or implants as needed
- Dental crowns, implants, and preventive care for dentinogenesis imperfecta
5. Genetic Counseling
- Essential for affected families
- Prenatal diagnosis possible via chorionic villus sampling or amniocentesis
Complications
- Recurrent fractures and bone deformities
- Severe scoliosis and thoracic insufficiency
- Chronic pain and reduced mobility
- Respiratory failure (in severe types)
- Early-onset osteoarthritis
- Psychosocial impacts: anxiety, depression, social isolation
- Reduced life expectancy in severe types (e.g., Type II or III)
Newer and Emerging Therapies
1. Gene Therapy
- Experimental approaches using CRISPR/Cas9 to correct defective collagen genes.
- Viral and non-viral vectors under investigation.
2. Stem Cell Therapy
- Prenatal and postnatal infusion of mesenchymal stem cells to improve collagen production.
- Early-phase clinical trials show promise.
3. Anti-sclerostin Therapy (e.g., Romosozumab)
- Stimulates bone formation; approved in postmenopausal osteoporosis.
- Studies in OI are ongoing.
4. RNA Interference
- Silencing of mutant alleles using RNAi technology may prevent dominant-negative collagen effects.
5. Enzyme Replacement Therapy
- Particularly relevant in recessive OI forms with processing enzyme deficiencies.
Prognosis
Prognosis depends on the type and severity of OI:
- Type I: Normal lifespan with good function
- Type II: Perinatal death
- Type III and IV: Variable; with appropriate treatment, patients may achieve mobility and function, though skeletal deformities persist
Early diagnosis, proactive management, and support systems can significantly enhance life expectancy and quality of life.
Conclusion
Osteogenesis Imperfecta represents a spectrum of connective tissue disorders with significant genetic and clinical heterogeneity. Advances in molecular genetics have revolutionized diagnosis and expanded the understanding of its pathophysiology. While current management is primarily supportive, emerging therapies targeting the genetic root of the disease offer hope for more effective interventions in the near future. A patient-centered, multidisciplinary approach remains the cornerstone of care in this lifelong disorder.