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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 transplantatio
      • 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
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
 

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(OBQ05.220) A 12-year-old girl presents with a history of numerous long bone fractures in the past. Examination reveals normal-appearing sclera, and the dentin abnormality shown in Figure A. A radiograph of her lower extremities is shown in Figure B. The patient’s disorder is the result of which of the following? Review Topic

QID: 1106
FIGURES:
1

Vitamin D deficiency

12%

(96/790)

2

Abnormal osteoclast function

2%

(12/790)

3

Qualitative defect of type I collagen synthesis

79%

(623/790)

4

Mutated fibroblast growth factor receptor

2%

(14/790)

5

Defective N-Ac-Gal-6 sulfate sulfatase enzyme

4%

(35/790)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3
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(OBQ10.265) Which of the following pediatric congenital disorders is caused by a glycine substitution in the procollagen molecule? Review Topic

QID: 3316
1

Scurvy

7%

(143/2057)

2

Osteogenesis imperfecta

80%

(1654/2057)

3

Fibrous dysplasia

6%

(116/2057)

4

Diastrophic dysplasia

4%

(81/2057)

5

Ochronosis (alkaptonuria)

3%

(54/2057)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

(OBQ11.207) A 12-year-old girl has been diagnosed with a severe form of osteogenesis imperfecta that has resulted in thin bones and multiple fractures. She now presents for follow-up of scoliosis which was noticed by her mother 1 year ago. She has no back pain and is neurologically intact. Radiographs show a 42-degree right thoracic curve, which has increased from 31-degree from her previous radiographs taken 9 months earlier. What is the most appropriate management for her spinal deformity? Review Topic

QID: 3630
1

Observation alone with serial radiographic and clinical monitoring.

4%

(96/2176)

2

Posterior spinal fusion with instrumentation

65%

(1414/2176)

3

Anterior spinal fusion with instrumentation

3%

(60/2176)

4

Fixation with telescoping rods

6%

(124/2176)

5

Custom-molded bracing with serial radiographic and clinical monitoring.

22%

(472/2176)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

(OBQ08.263) An adolescent male with a known genetic mutation of COL1A1 presents to the emergency department with symptoms of unsteady gait and difficulty with buttoning his shirt. On physical exam, when the patient holds his fingers extended and adducted, the small finger spontaneously abducts. Snapping of the patient's distal phalanx of the middle finger leads to spontaneous flexion of the other fingers. What is the most likely cause of the patient's symptoms? Review Topic

QID: 649
1

Basilar invagination

47%

(446/946)

2

C6 cervical disc foraminal herniation

6%

(56/946)

3

Atlantoaxial instability

40%

(375/946)

4

Ossification of the posterior longitudinal ligament (OPLL)

6%

(58/946)

5

Epidural abscess

1%

(8/946)

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

(OBQ11.216) A 10-year-old girl has bilateral knee radiographs as shown in Figure A. Which of the following conditions is most likely present? Review Topic

QID: 3639
FIGURES:
1

Osteogenesis imperfecta (OI)

73%

(1595/2188)

2

Ellis-van Creveld (EVC) syndrome/chondroectodermal dysplasia

14%

(299/2188)

3

Marfan syndrome

2%

(40/2188)

4

Caffey disease

9%

(202/2188)

5

Juvenile idiopathic arthritis (JIA)

2%

(47/2188)

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

(OBQ06.205) A mutation in the COL1A1 and COL1A2 genes is associated with all of the following manifestations EXCEPT: Review Topic

QID: 216
1

Basilar invagination

7%

(99/1421)

2

Webbed neck

65%

(929/1421)

3

Olecranon apophyseal avulsion fractures

12%

(164/1421)

4

Scoliosis

5%

(68/1421)

5

Discoloration of sclerae

10%

(148/1421)

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PREFERRED RESPONSE 2

(OBQ04.263) A child has a genetic disorder of the COL1A1 gene resulting in a decreased production of functional type I collagen. Which of the following radiographs is MOST consistent with his condition? Review Topic

QID: 1368
FIGURES:
1

Figure A

6%

(77/1186)

2

Figure B

4%

(53/1186)

3

Figure C

4%

(44/1186)

4

Figure D

80%

(948/1186)

5

Figure E

5%

(56/1186)

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PREFERRED RESPONSE 4

(OBQ09.68) Type I collagen defects are responsible for the clinical manifestations of osteogenesis imperfecta. Mutation of what gene or genes are most responsible for this? Review Topic

QID: 2881
1

FGFR3

3%

(45/1479)

2

FGFR2

3%

(43/1479)

3

COMP

2%

(27/1479)

4

COL1A1/COL1A2

90%

(1337/1479)

5

Fibrillin

2%

(23/1479)

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PREFERRED RESPONSE 4
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