Osteogenesis Imperfecta - Pediatrics

Introduction

A hereditary condition resulting from a decrease in the amount of normal Type I collagen
Pathophysiology
- can result from
  - decreased collagen secretion
  - production of abnormal collagen
- leads to insufficient osteoid production
  - physeal osteoblasts cannot form sufficient osteoid
  - periosteal osteoblasts cannot form sufficient osteoid and therefore cannot remodel normally
Genetics
- 90% have an identifiable genetic mutation
  - COL 1A1 and COL 1A2
    - causes abnormal collagen cross-linking via a glycine substitution in the procollagen molecule
- autosomal dominant and autosomal recessive forms
  - milder autosomal dominant forms (Types I and IV)
  - severe autosomal recessive forms (Types II and III)
- CRTAP and LEPRE1 genes associated with severe, lethal forms of OI not associated with primary structural defect of type I collagen
Orthopaedic manifestations
- bone fragility and fractures
  - fractures heal in normal fashion initially but the bone does not remodel
  - can lead to progressive bowing
- ligamentous laxity
- short stature
- scoliosis
- codfish vertebrae (compression fx)
- basilar invagination
- olecranon apophyseal avulsion fx
- coxa vara (10%)
- congenital anterolateral radial head dislocations
Non-Orthopaedic manifestations
- blue sclera
- dysmorphic, triangle shaped facies
- hearing loss
  - 50% of adults with OI
  - may be conductive, sensorial and mixed
- brownish opalescent teeth (dentinogenesis imperfecta)
  - alteration in dentin
  - brown/blue teeth, soft, translucent, prone to cavities
  - affects primary teeth > secondary teeth
- wormian skull bones (puzzle piece intrasutural skull bones)
- hypermetabolism
  - increased risk of malignant hyperthermia
  - hyperhidrosis, tachycardia, tachypnoea, heat intolerance
- thin skin prone to subcutaneous hemorrhage
- cardiovascular
  - mitral valve prolapse
  - aortic regurgitation

Anatomy

Type I collagen is the most important structural protein of bone, skin, tendon, dentin, sclera
triple helix structure
- two alpha-1 chains coded by genes COL1A1
- one alpha-2 chain coded by gene COL1A2
- triple helix structure is possible because of glycine at every 3rd amino acid residue
  - genetic mutations alter triple helix by substitution of glycine with another amino acid

Classification

Sillence originally classified into four types
- however most likely a continuum of disease
- additional types have been added
- 90% of patients can be grouped into the Sillence Type I and IV

Sillence Classification of Osteogenesis Imperfecta (simplified)
Type	Inheritence	Sclerae	Features
Type I	Autosomal dominant, quantitative disorder in collagen	blue	Mildest form. Presents at preschool age (tarda). Hearing deficit in 50%. Divided into type A and B based on tooth involvement
Type II	Autosomal recessive, qualitative disorder in collagen	blue	Lethal in perinatal period
Type III	Autosomal recessive, qualitative disorder in collagen	normal	Fractures at birth. Progressively short stature. Most severe survivable form
Type IV	Autosomal dominant, qualitative disorder in collagen	normal	Moderate severity. Bowing bones and vertebral fractures are common. Hearing normal. Divided into type A and B based on tooth involvement
Type V, VI, VII have been added to the original classification system (these have no Type I collagen mutation but have abnormal bone on microscopy and a similar phenotype)
Type V	Autosomal dominant		Hypertrophic callus after fracture. Congenital anterolateral radial head dislocation. Ossification of IOM between radius and ulna and tibia and fibula
Type VI			Moderate severity. Similar to type IV
Type VII	Autosomal recessive		Associated with rhizomelia and coxa vara

Presentation

Symptoms
- mild cases
  - multiple fractures during childhood
- severe cases
  - present with fractures at birth and can be fatal
  - number of fractures typically decreases as patient ages and usually stops after puberty
- basilar invagination
  - presents with apnea, altered consciousness, ataxia, or myelopathy
  - usually in third or fourth decade of life, but can be as early as teenage years
Physical exam
- multiple fractures leads to
  - saber shin appearance of tibia
  - bowing of long bones
- trendelenburg gait
  - if coxa vara present

Imaging

Radiographs
- thin cortices
- generalized osteopenia
- saber shins
- skull radiographs reveal wormian bones
- coxa vara

Evaluation

Labroratory
- mildly elevated ALP
Histology
- increased diameter of haversion canals and osteocyte lacunae
- replicated cement lines
- increased number of osteoblasts and osteoclasts
- decreased number of trabeculae
- decreased cortical thickness
Diagnosis
- diagnosis is based on family history associated with typical radiographic and clinical features
- Labs
  - no commercially available diagnostic test due to variety of genetic mutations
  - laboratory values are typically within normal range
- possible methods diagnosis include
  - skull radiographs to look for wormian bones
  - fibroblast culturing to analyze type I collagen (positive in 80% of type IV)
    - can be used for confirmation of diagnosis in equivocal cases
  - biopsy
    - collagen analysis of a punch biopsy
    - iliac crest biopsy which shows a decrease in cortical widths and cancellous bone volume, with increased bone remodeling.

Treatment of Fractures

Fracture prevention
- early bracing
  - indicated to decrease deformity and lessen fractures
- bisphosphonates
  - indicated in most cases of OI to reduce fracture rate, pain, improve ambulation
    - marked improvement in pain at 1-6wk after initiation
  - inhibits osteoclasts
    - increases cortical diameter 88%
    - increases cancellous bone volume 46%
  - does not affect development of scoliosis
  - chronic use causes horizontal metaphyseal bands seen on radiographs
    - growth arrest lines
  - maintain bisphosphonate-free period around the time of IM rodding
    - interferes with osteotomy healing >> fracture healing
- growth hormone
- bone marrow transplantation
  - has been used with some success
Fracture treatment
- nonoperative
  - observation
    - indications
      - indicated if child is <2 years (treat as child without OI)
- operative
  - fixation with telescoping rods
    - indications
      - consider in patients > 2 years
      - allow continued growth
  - fixation with load sharing device
    - indications
      - consider in patients > 2 years
      - fracture with deformity beyond accepted tolerances after closed reduction

Treatment of Long Bone Bowing Deformities

Operative
- realignment osteotomy with rod fixation (Sofield-Miller procedure)
  - indications
    - severe deformity to reduce fracture rates
  - techniques include
    - nontelescopic devices (Rush rods, Williams rods)
    - telescopic devices (Sheffield rod, Bailey-Dubow rod, Fassier-Duval rod)

Treatment of Scoliosis

Vital capacity drops to 40% of expected for a 60° curve
Nonoperative
- observation
  - indications
    - if curve is <45 °
- bracing is ineffective and not recommended
  - because of fragility of ribs
Operative
- posterior spinal fusion
  - indications
    - for curves > 45 ° in mild forms and > 35 ° in severe forms
  - technique
    - challenging due to fragility of bones
    - use allograft instead of iliac crest autograft due to paucity of bone
    - ASF only indicated in very young children to prevent crankshaft
    - associated with a large blood loss

Treatment of Basilar Invagination

Operative
- decompression and posterior fusion
  - indications
    - radiographic features of invagination and cord compression with physical exam findings of myelopathy
  - techniques
    - resection of bony compression via transoral approach