OVERWIEV
● Osteogenesis Imperfecta (OI) is connective tissue disease
● Decreased mechanical resistance of bone due to defects in collagen metabolism
● Recurrent fractures and progressive skeletal deformities
● Reduction in the amount of normal COL1A1 or COL1A2 genes or its replacement with a poorly functioning mutant collagen
● Other clinical features, may include blue or gray sclerae, dentinogenesis imperfecta, progressive hearing loss, easy bruising, unstable and lax joints, and muscular weakness
ETIOLOGY
90% result from autosomal dominant mutations in
● COL1A1 (on chromosome 17)
● COL1A2 (on chromosome 7)
which encode the α1 and α2 chains of type 1 procollagen, causes abnormal collagen cross-linking via a glycine substitution in the procollagen molecule
Quantitative Defects (Haploinsufficiency):
● Seen in Type 1 OI
● The collagen produced is structurally normal, but the amount is insufficient
● Milder phenotype.
Qualitative Defects (Structural Abnormalities):
● Seen in Types II, III, and IV OI
● Point mutations result in the production of structurally abnormal collagen
● Impaired triple-helix formation and more severe clinical phenotypes
Autosomal Dominant (Classic): Most common. Associated with COL1A1/COL1A2 mutations.
Autosomal Recessive: Identified in more severe or lethal phenotypes. These mutations often affect genes responsible for:
● Post-translational modification (e.g., CRAP, LEPRE1, PPIB).
● Chaperone functions and folding (e.g., SERPINH1, FKBP10).
● Osteoblast differentiation and signaling (e.g., SP7, WNT1).
● Bone mineralization (e.g., IFITM5 - Note: This is an autosomal dominant form leading to hypertrophic callus).
CLASSIFICATION
● Clinical gold standard Sillence Classification
● originally 4 types
Later on added Cole modifications (type V , VI , VII)
These 3 types of OI have no Type I collagen mutation but have abnormal bone on microscopy and a similar phenotype
TYPE | INHERITANCE | SCLAREA | KEY CLİNİCAL FEATURES |
Type I | Autosomal Dominant | Blue | Mildest form; presents at preschool age (tarda). 50% have hearing deficit. Subdivided into A and B based on dentinogenesis imperfecta (tooth involvement). |
Type II | Autosomal Recessive | Blue | Lethal in the perinatal period. |
Type III | Autosomal Recessive | Normal | Most severe survivable form. Fractures present at birth; progressively short stature and severe limb deformities. |
Type IV | Autosomal Dominant | Normal | Moderate severity. Common findings include bowing of long bones and vertebral fractures. Hearing is usually normal. Subdivided (A/B) by tooth involvement. |
Type V | - | - | Characterized by hypertrophic callus formation after fractures and ossification of the interosseous membranes (IOM) in the forearm and leg. |
Type VI | - | - | Moderate severity, clinically similar to Type IV. |
Type VII | - | - | Associated with rhizomelia (shortening of proximal limb segments) and coxa vara. |
● Shapiro modification of the Looser classification
● Stronger prognostic indicator
OI Congenita
■ most severe form
■ fractures occur in utero or at birth
OI Tarda
■ fractures begin after the neonatal period
Class | Fracture Timing | Radiological Findings |
Congenita A | Fractures present at birth | Bone is radiologically abnormal |
Congenita B | Fractures present at birth | Bone is radiologically normal |
Tarda A | First fracture occurs before or at walking stage | Bones are narrow and osteopenic |
Tarda B | First fracture occurs after walking | Bone is radiologically normal |
CLINICAL PRESENTATION
Skeletal Manifestations:
● Recurrent fractures from minimal or no trauma
Fractures often involve the long bones (femur and humerus)
Can occur in utero, during birth, or during daily activities
Frequency typically decreases after puberty
● Progressive Deformities, Recurrent fractures and the "wax-like" quality of the bone lead to:
Lower Extremity: Anterolateral bowing of the femur and anterior bowing of the tibia saber ‘shin’
Upper Extremity: Radial head dislocation and bowing of the forearm.
Spine: Scoliosis and kyphosis (common in Types III and IV), and vertebral compression fractures (codfish vertebrae).
● Growth retardation is a hallmark of severe forms (Type III). Proportional or disproportional short stature is common.
● Craniofacial: Macrocephaly, triangular facies, and frontal bossing.
Extra-Skeletal Manifestations (Systemic Findings):
● Blue Sclerae
● Dentinogenesis Imperfecta (DI)
● Hearing Loss
● Ligamentous Laxity
● Easy bruising and thin, translucent skin due to capillary fragility and abnormal dermal collagen.
● Basilar Invagination
In severe cases (Type III/IV),
the skull base can settle onto the cervical spine, potentially causing brainstem compression.
presents with apnea, altered consciousness, ataxia, or myelopathy
● Aortic or mitral valve regurgitation may develop in adulthood
● Radiological Evaluation
● Long bones of the limbs short and wide with thin cortices
● Diaphyses as wide as the metaphyses
● Numerous fractures in various stages of healing
● Popcorn calcifications
Seen primarily in Type III
Scalloped, radiolucent areas with sclerotic margins at the ends of long bones (growth plates), representing disordered mineralization
● Codfish Vertebrae
Biconcave vertebral bodies caused by the pressure of the intervertebral discs on the weakened bone
● Wormian Bones
The presence of more than 10 Wormian bones is highly suggestive of OI
● Shepherd’s Crook Deformity
Severe varus deformity of the proximal femur, common in Types III and IV, which significantly impairs ambulation
● Protrusio Acetabuli
● Zebra stripe sign
cyclic bisphosphonate treatment
Laboratory and Genetic Evaluation
● No single commercially available diagnostic test
● Alkaline phosphatase levels may be mildly elevated
DIFFERENTIAL DIAGNOSES
● Congenital hypophosphatasia
● Achondroplasia
● Pyknodysostosis
● Diffuse osteopenia in the early stages of leukemia
● Idiopathic juvenile osteoporosis
● Child abuse or battered child syndrome
TREATMENT/MANAGEMENT
1. General Approach
● Mild Disease
Primarily focused on fracture management
avoid contact sports.
● Moderate to Severe
Requires comprehensive rehabilitation
orthopedic intervention for fractures and scoliosis
● Severe Disease
Often necessitates intramedullary rodding
osteotomies to correct long-bone bowing
2. Medical Therapy
● Bisphosphonates
Intravenous pamidronate / oral alendronate
reduce bone resorption, increase bone mineral density , and improve ambulatory status
maintain bisphosphonate-free period around the time of IM rodding
■ interferes with osteotomy healing >> fracture healing
● Investigational Treatments
Gene therapy, cell transplantation, and monoclonal antibodies (e.g., romosozumab or TGFβ inhibitors)
not yet in routine clinical use.
3. Orthopedic Management
The primary goal is to optimize function and prevent/correct deformity.
● Surgical Techniques
Sofield–Millar procedure (multiple osteotomies with internal fixation).
● Intramedullary Rodding: Prophylactic rodding is recommended for recurrent long-bone fractures
Telescoping Rods: (e.g., Fassier–Duval) Grow with the child to provide continuous support.
Non-telescoping Rods: (e.g., Rush nails, Williams rods) Fixed-length options used depending on bone size.
● Spine Care: Continuous monitoring for scoliosis, kyphosis, and basilar invagination
PROGNOSIS
The prognosis for Osteogenesis Imperfecta is highly variable and depends on several key clinical indicators:
● Classification Systems
The Shapiro classification
● Ambulatory Predictors
The age at which the first long bone fracture occurs
● Survival Factors
severity and location of fractures
● Developmental Milestones
independent sitting or standing by age 12 is a strong indicator of ultimate walking ability
● Early Milestones
independent sitting or standing by 12 months of age are highly likely to successfully ambulate later in life
REFERENCES
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