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Osteogenesis Imperfecta

Holden Heitner

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History

Many different names in the past

Ekman-Lobstein, Vrolik, and glass-bone disease

The condition has been found in ancient Egyptian mummy from 1000BC
Norse king Ivar the Boneless is suggested to have had it
Earliest study was in 1788 with Swede Olof Ekman

described the condition in his doctoral thesis

Lobstein dealt with affected adults in 1833
Vrolik studied in the 1850s
It wasn’t until 1897 with Martin Benno Schmidt the idea that the adult and newborn forms were the same

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OI Collagen

Mutations in either COL1A1 or COL1A2 are translated into collagen α-chains with abnormal structure, which delay folding of the heterotrimer and result in excess post-translational modification of the collagen helical region. Mutant procollagen chains unable to incorporate into heterotrimers are retrotranslocated into the cytosol and degraded by the ERAD pathway (1); fully misfolded heterotrimers with structural defects generate supramolecular aggregates that are eliminated by autophagy (2); mutant molecules with triple helical mutations are degraded through an unidentified pathway (3). Finally, abnormal procollagen can be secreted, processed and incorporated in the extracellular matrix (4). The secreted mutant collagen affects fibril structure and interactions of noncollagenous proteins with matrix, as well as matrix mineralization and osteoblast development and cell–cell and cell–matrix crosstalk. The overall result is bone deformity and fragility, although the relative importance of various contributions is under investigation. Abbreviations: ERAD, endoplasmic reticulum-associated proteasomal degradation; NCP, noncollagenous proteins.

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Overview

A hereditary condition resulting from a decrease in the amount of normal Type I collagen

Can be due to

Decreased collagen secretion
Production of abnormal collagen

Causes to insufficient osteoid production

Physical blasts cannot form sufficient osteoid
Periosteal osteoblasts cannot form sufficient osteoid and therefore cannot remodel normally

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Genetics

90% are identifiable genetic mutation

COL1a1 or COL1a2

Causes abnormal crosslinking via glycine substitution in the procollagen molecule

Can be both autosomal recessive and autosomal dominant
Can be severe or mild (tarda form)

Incidence estimated to be 1/20,000 live births

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Pathophysiology

Deficiency of Type I collagen

Due to AA substitution of glycine to bulkier AA in the collagen triple helix structure

Cause steric hindrance that creates a bulge in the complex

Body may respond by hydrolyzing the improper collagen structure
If not destroyed the improper collagen interferes with the relationship between collagen fibrils and hydroxyapatite crystals

Causing bone form to be altered and brittle

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Differential

Child abuse

Multiple fractures in different stages of healing

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Differential

Rickets

Slow growth, bone deformities, elevated alk phos, defective bone mineralization
Characteristic radiograph findings increased width of epiphyseal plate, irregular hazy margins of distal metaphysis, and marginal metaphyseal overgrowth

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Differential

Osteomalacia

Adults with bone pain, insufficiency fractures, inc alk phos, but no hearing loss nor blue sclera
Radiographic finding of reduced bone density, narrow lines of radiolucency at cortical margins, loss of distinct trabeculae in vertebral bodies

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OI Orthopaedic manifestations

Bone fragility and fractures

Fractures heal in normal fashion initially but bones don’t remodel
Can lead to progressive bowing

Ligamentous laxity
Short stature
Scoliosis
Codfish vertebrae (compression fracture)
Basilar invagination
Olecranon apophyseal avulsion fracture

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Non-Orthopaedic manifestations

Blue sclera
Hearing loss
Brownish opalescent teeth (dentinogensis imperfecta)
Wormian skull bones
Increased risk of malignant hyperthermia

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Sillence Classification of Osteogenesis Imperfecta (simplified)
Type	Inheritence	Sclerae	Features
Type I	Autosomal dominant	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	blue	Lethal in perinatal period
Type III	Autosomal recessive	normal	Fractures at birth. Progressively short stature. Most severe survivable form
Type IV	Autosomal dominant	normal	Moderate severity. Bowing bones and vertebral fractures are common. Hearing normal. Divided into type A and B based on tooth involvement

However most likely a continuum and there are addtionally types with 90% of patients being able to be grouped into the Sillence I-IV types

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Symptoms

Mild cases

Multiple childhood fractures

Severe cases

Present with fractures at birth

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 in teenage years

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Physical Exam

Multiple fractures lead to

Saber shin appearance of tibia
Bowing of long bones

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Imaging

Radiographs

Thin cortices
Generalized osteopenia
Sabershins
Skull radiographs revealing wormian bones

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Histology

Increased diameter of haversian canals and osteocyte lacunae
Replicated cement lines
Increased number of osteoblasts and osteoclasts
Decreased number of trabeculae
Decreased cortical thickness

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Diagnosis

Diagnosis is based on family history associated with typical radiograph findings
No commercially available diagnostic test due to variety of genetic mutations
Lab values are usually within normal ranges

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Diagnosis

Possible methods

Skull radiograph for wormian bones
Fibroblast culturing to analyze type 1 collagen (positive in 80% of type IV)

Can be used for confirmation of diagnosis in equivocal cases

Punch biopsy for collagen analysis
Iliac crest biopsy that shows decrease in cortical widths and cancellous bone volume with increased bone remodeling

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Treatment of fractures

Prevention

Early bracing is indicated to decrease deformity and lessen fractures
Bisphosphonates

Indicated in most cases to reduce fracture rate and pain
Function to increase cortical thickness by inhibit osteoclasts
Doesn’t affect development of scoliosis
Chronic use causes horizontal metaphyseal bands seen on radiograph

Experimental

Growth Hormone

To stimulate bone formation

Bone marrow transplant

Been used with some success

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Physiotherapy

Used to strengthen muscles
improve motility while minimizing fracture risk
Often involved hydrotherapy and use of support cushions to improve posture
Children often develop fear of trying new ways of moving due to fear of pain

this can make physiotherapy difficult in young children

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Fracture Treatment

Nonoperative

Observation if the child is <2 (same as child without OI)

Operative

Fixation with telescoping rods

Indicated in patients >2
Allows continued growth

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Treatment of long bone bowing deformities

Operative

Realignment of osteotomy with rod fixation

Indicated for severe deformity to reduce fracture rates

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Treatment of Scoliosis in OI

Nonoperative

Observe if curve <45 degrees
Bracing isn’t effective

Operative

Posterior spinal fusion

Indicated for curves >45 degrees in mild forms and >35 degrees in severe forms

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Treatment of Basilar Invagination

Operative

Decompression and posterior fusion

Indicated for radiographic features and cord compression with physical exam findings of myelopathy

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Prognosis

Dependent upon the type

Mild OI Type I

Typically have a few childhood fractures with no long bone deformity and normal life expectancy

Moderate to severe Type II-IV

Have increased risk of premature death in both childhood and adult life compared to general population

May be related to immobility and thoracic deformities

Increases risk of severe pulmonary infections and loss of lung function

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Work Cited

http://en.wikipedia.org/wiki/Osteogenesis_imperfecta#Pathophysiology

http://www.orthobullets.com/pediatrics/4102/osteogenesis-imperfecta

http://www.medpath.info/MainContent/Skeletal/Bone_02.html

http://emedicine.medscape.com/article/947588-overview

http://orthoinfo.aaos.org/topic.cfm?topic=a00051

http://www.nlm.nih.gov/medlineplus/osteogenesisimperfecta.html

http://www.niams.nih.gov/Health_Info/Bone/Osteogenesis_Imperfecta/osteogenesis_imperfecta_ff.asp