summary Osteogenesis Imperfecta is a common congenital disorder caused by a mutation in COL1A1 or COL1A2 genes resulting in abnormal collagen cross-linking and overall decrease in type 1 collagen. Patients present with fragility fractures, scoliosis, hearing loss, and cardiovascular abnormalities. Diagnosis is made based on family history associated with typical radiographic and clinical features. No commercially available diagnostic test exists due to the variety of genetic mutations. Treatment is a multidisciplinary approach for fracture prevention with bisphosphonates, fracture management when present, and realignment osteotomies for long bone deformities. Etiology 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 dominant forms (Types II and III) autosomal recessive forms (Type VI, VII) 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 most common first presenting sign 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 Inheritance Sclera 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 dominant Qualitative disorder in collagen Blue Lethal in perinatal period Type III Autosomal dominant Qualitative disorder in collagen Normal Most severe survivable form Fractures at birth. Progressively short stature. 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 Sillence Classification modification (Types V-VII added) These 3 types of OI have no Type I collagen mutation but have abnormal bone on microscopy and a similar phenotype Type V Congenital anterolateral radial head dislocation Hypertrophic callus after a fracture Ossification of IOM between radius and ulna and tibia and fibula Autosomal Dominant Type VI Moderate severity Similar to type IV Autosomal recessive Type VII Associated with rhizomelia and coxa vara Autosomal recessive 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