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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%) 
  • 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. 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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Questions (8)

(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%

(61/1542)

2

Posterior spinal fusion with instrumentation

67%

(1032/1542)

3

Anterior spinal fusion with instrumentation

4%

(54/1542)

4

Fixation with telescoping rods

5%

(82/1542)

5

Custom-molded bracing with serial radiographic and clinical monitoring.

20%

(306/1542)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

Children with severe forms of osteogenesis imperfecta and progressive scoliosis should be treated with posterior spinal fusion with instrumentation when the curve exceeds 35 degrees.

Spinal deformity is common in children with osteogenesis imperfecta, particularly in severe forms. Curves develop early and generally progress. Bracing is not indicated due to the complications associated with the brace on the soft bones of the rib cage. In the patient with severe disease with thin bones and numerous fractures, posterior correction and fusion is indicated, and should be done early when the curve is greater than 35 degrees. In the patient with mild disease and thick bones surgery is indicated when the curve is greater than 45 degrees.

Burnei et al review the diagnosis and treatment of OI. They report that medical treatment with bisphosphonates, even in patients younger than age 2 years, have become widely accepted in the symptomatic treatment of OI. They report alendronate has a proven beneficial effect, demonstrating a decrease in fracture frequency and improvement of vertebral bone density and quality of life.

Janus et al. retrospectively studied 20 children who underwent halo gravity traction and posterior spine instrumentation for scoliosis. They emphasize that correction and stabilization of the scoliotic spine in osteogenesis imperfecta is difficult, primarily due to implant pull-out due to the poor bone quality. With their technique, they found an overall improved sitting balance and an increased functional ability in 7 of 20 patients after surgery. They conclude that although partial loss of correction seems inevitable, operative stabilization is possible.

Pan et al. emphasize the surgical treatment of scoliosis in patients with osteogenesis imperfecta is difficult due to poor bone quality, which often leads to breakage of bones, dislodgement of implants, and late loss of correction. They found the usage of pedicle screw and a 3-rod fixation technique, together with cyclic intravenous bisphosphonate administration and halo-gravity traction preoperatively, contributed to improved outcomes.

Illustration A shows the sequential radiographs before and after surgical treatment of one patient from the Janus et al study. Image A,B and C is prior to surgery. Image D is immediately postoperative, and Image E and F are at 2 years. Notice in Image E and F the alignment of the spine is maintained without loss of correction despite the pull-out of the distal hook due to the fracture of the lamina.

Incorrect Answers:
Answer 1: Due to the progressive nature of scoliosis in children with OI, this patient should be treated with surgery.
Answer 3: Due to the pulmonary compromise associated with OI, an anterior approach is less favorable than a posterior approach.
Answer 4: A Growing rod construct is not required at age 11 and likely would be complicated in an osteopenic patient. Telescoping rods are utilizing for long bone deformity such as in the humerus or femur.
Answer 5: Bracing is minimally effective and associated with complications, and therefore, is not indicated in children with osteogenesis imperfecta and scoliosis.

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(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%

(1451/1980)

2

Ellis-van Creveld (EVC) syndrome/chondroectodermal dysplasia

13%

(261/1980)

3

Marfan syndrome

2%

(39/1980)

4

Caffey disease

9%

(186/1980)

5

Juvenile idiopathic arthritis (JIA)

2%

(40/1980)

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

The AP radiograph of the knee shows dense parallel bands in distal femoral and proximal tibial and fibular metaphyses. This radiographic finding is associated with long-term bisphosphonate use, and from the options provided, bisphosphonate administration is most appropriately prescribed in the setting of OI.

Poyrazoglu et al reviewed 35 patients with OI that were given pamidronate on 3 consecutive days every 3 to 4 months. They found that bone mineral density increased and fracture rate decreased in children and infants with OI during pamidronate treatment.

Onwuneme et al present a case report and discuss the radiographic findings of parallel dense metaphyseal lines in two children treated with cyclical intravenous pamidronate. It has been found that the number of lines correspond to the number of pamidronate treatments received and the separation of the lines was determined by the age of the child and the rate of growth of the bone imaged.

Namazi presents a Level 5 editorial on an article authored by Bajpai et al. Bajpai et al conducted a study on 20 OI patients and found that pamidronate treatment led to an increase in bone mineral density (BMD) Z score and a decrease in fracture rate.

Illustration A and B demonstrates an OI patient with history of multiple fractures and horizontal parallel metaphyseal lines from chronic pamidronate therapy.

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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

8%

(139/1846)

2

Osteogenesis imperfecta

80%

(1476/1846)

3

Fibrous dysplasia

6%

(106/1846)

4

Diastrophic dysplasia

4%

(72/1846)

5

Ochronosis (alkaptonuria)

3%

(48/1846)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

Osteogenesis imperfecta (OI) is caused by a defect in Type I collagen (COL1A1 and COL1A2) that causes abnormal cross-linking via a glycine substitution in the procollagen molecule. This defect leads to decreased collagen secretion, bone fragility, “wormian” bones, short stature, scoliosis, tooth defects, hearing defects, and ligamentous laxity.

The article by Cole explains that OI includes a wide spectrum of disease and has various inheritance patterns (autosomal dominant or autosomal recessive). Fibrous dysplasia is caused by a germ line defect in the Gsa protein. Scurvy is caused by a vitamin C deficiency that causes a decrease in chondroitin sulfate synthesis and subsequent defect in intracellular hydroxylation of collagen peptides. Diastrophic dysplasia is caused by a mutation of a gene coding for a sulfate transport protein. Ochronosis (alkaptonuria) is caused by a defect in the homogentisic acid oxidase system.


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(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%

(43/1309)

2

FGFR2

3%

(36/1309)

3

COMP

2%

(20/1309)

4

COL1A1/COL1A2

91%

(1188/1309)

5

Fibrillin

2%

(20/1309)

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

Pathological manifestions of osteogenesis imperfecta (OI) occur because of abnormal collagen type I. Clinical manifestions include multiple fractures, blue sclera, and scoliosis. The genes responsible for collagen synthesis are COL1A1/COL1A2 and many mutations have been characterized which result in OI. Quantitative collagen defects result in the milder OI form whereas qualitative collagen defects result in more severe clinical manifestations.


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(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

48%

(369/768)

2

C6 cervical disc foraminal herniation

7%

(57/768)

3

Atlantoaxial instability

37%

(284/768)

4

Ossification of the posterior longitudinal ligament (OPLL)

7%

(50/768)

5

Epidural abscess

1%

(7/768)

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PREFERRED RESPONSE 1

The clinical presentation is consistent for symptoms of myelopathy in a patient with Osteogenesis imperfecta (OI). Basilar invagination is the most likely cause.

Osteogenesis imperfecta (OI) is a genetic disease resulting from mutations in type I collagen genes causing bone fragility and deformities (including wormian bone appearance). Patients with osteogenesis imperfecta are known to develop basilar invagination, defined as a protrusion of the odontoid process into the foramen magnum. Basilar invagination is commonly seen with Klippel-Feil syndrome, occipitocervical synostosis, achondroplasia, osteogenesis imperfecta, Morquio syndrome, and spondyloepiphyseal dysplasia.

Kovero et al evaluated skull base anatomy in 54 patient with OI (type I, III, and IV) and 108 controls. They found 22.2% of the OI group had basilar invagination while none of the controls did. Screening radiographs are recommended in this group along with MRI in those whose films suggest the possibility of basilar invagination. Surgical decompression and fusion is recommended in those with neurologic symptoms. In patients with severe OI, an open door maxillotomy may be required (Le Fort I osteotomy of the maxilla combined with a midline split of the soft palate and maxilla).

Illutrations A and B are CT and MRI images, respectively, that demonstrate basilar invagination with associated central canal stenosis.

Incorrect Answers:
Answer 2: Cervical disc foraminal herniation is not associated with Osteogenesis imperfecta (OI) and would not cause myelopathy.
Answer 3: Atlantoaxial instability is often associated with Down's syndrome but is not commonly associated with Osteogenesis imperfecta (OI).
Answer 4: OPLL is not associated with Osteogenesis imperfecta (OI).
Answer 5: Epidural abscess is not commonly associated with Osteogenesis imperfecta (OI).

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(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%

(101/1362)

2

Webbed neck

65%

(884/1362)

3

Olecranon apophyseal avulsion fractures

12%

(159/1362)

4

Scoliosis

5%

(65/1362)

5

Discoloration of sclerae

10%

(140/1362)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

A mutation in the COL1A1 and COL1A2 genes results in a weakened organic bone matrix (qualitative defect in Type I collagen) and is the underlying cause of Osteogenesis Imperfecta (OI). Quantitative defects in Type I collagen result in less severe forms of OI.

Kocher et al reviews the various orthopaedic conditions associated with osteogenesis imperfecta. These conditions include bone bowing, multiple fractures, olecranon apophyseal fractures, dentinogenesis imperfecta resulting in brownish opalescent teeth, hearing loss, blue sclerae , joint hyperlaxity, basilar invagination, severe scoliosis, and wormian skull bones.

Cole et al discusses how the discovery of the collagen mutation in OI (COL1A1 and COL1A2 genes) can serve as a template to discover the genetic etiologies for other connective tissue disorders.

Illustration A shows basilar invagination with the tip of the odontoid and anterior arch of atlas are well above Chamberlain line (white line) and the clivus canal angle is <150° (yellow line).
Illustration B shows blue sclerae associated with OI.
Illustration C shows an olecranon apophyseal avulsion fracture and its postoperative fixation is shown in Illustration D.
Illustration E demonstrates the scoliosis associated with OI.

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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%

(89/770)

2

Abnormal osteoclast function

2%

(13/770)

3

Qualitative defect of type I collagen synthesis

80%

(617/770)

4

Mutated fibroblast growth factor receptor

2%

(13/770)

5

Defective N-Ac-Gal-6 sulfate sulfatase enzyme

4%

(33/770)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

The question stem is describing a patient with osteogenesis imperfecta Type IV, which is caused by a qualitative defect in the synthesis of Type I collagen. Inherited or spontaneous genetic mutations of genes COL1A1 and COL1A2 are known to be the basic anomaly that alters the collagen synthesis and structure. The quantitative disorders of type I collagen are associated with milder forms of OI (Type I), whereas the qualitative disorders are associated with more severe phenotypes (Types II, III and IV). Moderate clinical severity with white sclera and dentinogenesis imperfecta, shown in Figure A, are classically associated with Type IV OI. Figure B demonstrated lower extremity bowing and malunion, characteristic of OI.

In their review article, Baitner et al describe the major osteochondrodysplasias, define their causes and clinical manifestations, and discuss the underlying molecular defects as well as the anatomical aspects of these disorders.

Incorrect Answers:
1-Vitamin D deficiency is associated with Rickets, of which there are many types. It presents with a variety of symptoms including genu varum, increased fracture risk, and bone pain.
2-Abnormal osteoclast function is associated with osteopetrosis, and excessive bone accumulation and fragility.
4-Mutated FGFR is associated with achondroplasia.
5-Defective N-Ac-Gal-6 sulfatase enzyme is associated with Morquio Syndrome.


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(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

7%

(75/1149)

2

Figure B

4%

(50/1149)

3

Figure C

3%

(40/1149)

4

Figure D

80%

(924/1149)

5

Figure E

5%

(54/1149)

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

Figure D depicts a telescoping rod in the right femur and bowing of the left femur with coxa vara; a common finding in osteogenesis imperfecta (OI). OI is a genetic defect which results in abnormal type I collagen with subsequent fragility fractures.

Figure A shows dysplastic clavicles, characteristic of cleidocranial dysplasia. Figure B is a hand radiograph showing dense bone and obliterated medullary canals, suggesting osteopetrosis. Figure C shows epiphyseal abnormalities found in multiple epiphyseal dysplasia (MED) or spondyloepiphyseal dysplasia (SED). Figure E depicts squared iliac wings and horizontal acetabuli, characteristic of achondroplasia.

Cole et al provide an overview of OI and non-skeletal manifestations including blue sclera and long bone bowing (Illustrations A and B). There were initially four, but now seven types of OI based on severity and inheritance (see Review Topic).

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