Osteogenesis Imperfecta

Osteogenesis imperfecta (OI), or “brittle bone disease,” is a rare genetic connective tissue disorder characterized by severe bone fragility. Although OI is considered a single disease, OI includes over 16 genotypes and clinical phenotypes with differing symptom severity. Of these 16, types I–IV are the most common. Because of the rarity of OI, OI is considered an “orphan disease” in the United States. Diagnosis is made clinically, through history and examination, and is confirmed by radiologic findings and DNA analysis. While there is no definitive cure, treatment is supportive, usually involving bisphosphonates, and is focused on reducing pain, reducing fracture frequency, reducing bony deformity, and increasing ambulation. The prognosis is variable, depending on the OI type.

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Overview

Definition

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder characterized by impaired bone formation and severe bone fragility.

Epidemiology

  • Most common genetic cause of osteoporosis
  • Incidence:
    • Overall: 1 in 20,000 births
    • Type I: 1 in 15,000 to 1 in 20,000 births
    • Type II: 1 in 60,000 births
    • Types III and IV: unknown, very low
  • The distribution is similar worldwide.
  • Males and females are equally affected.

Etiology

  • Mutations in genes encoding collagen type 1 (COL1A1 and COL1A2): 
    • 90% of all cases
    • Classified as types I–IV 
  • Other mutations (10%):
    • Post-translational defects
    • 3-prolyl-hydroxylation complex defects
    • Other proteins involved in bone formation and homeostasis
Table: Major pathologic mutations, modes of inheritance, and phenotypes for OI types I-IV
Type IType IIType IIIType IV
Mutated geneCOL1A1, COL1A2 (collagen type 1 alpha 1 and 2 chains)COL1A1, COL1A2, and CRTAP (cartilage-associated protein)COL1A1, COL1A2 COL1A1, COL1A2
Inheritance modalityAutosomal dominantAutosomal dominant AND autosomal recessiveAutosomal dominantAutosomal dominant
DefectFrameshift mutations in collagen type 1 alpha 1 and 2 chains leading to decreased amounts of normal collagenDisrupted formation of the collagen triple helix structure, leading to little or no normal collagenMutations causing structural protein defects leading to severe pathologyMutations causing structural protein defects leading to minimal or mild pathology

Pathophysiology

  • Mutations in alpha 1 or alpha 2 chains of type 1 collagen:
    • Decreased amount of type 1 collagen (type I) 
    • Disruption of type 1 collagen triple helix (type II)
    • Structural protein defects of type 1 collagen (type III and IV)
  • Increased amounts of type III and IV collagen in bone tissue
  • Increased activity of osteoclasts and abnormal osteoblast differentiation
  • Poor deposition of hydroxyapatite crystals and paradoxic bone hypermineralization
  • Globally abnormal bone growth: decreased bone trabeculae and cortical thickness
  • Fractures with normal movement and very low-impact activities, with a normal healing process

Clinical Presentation

  • Variable severity
  • Type II die in utero or early infancy.
  • Present to a variable extent in types I, III, and IV:
    • Excess or atypical fractures
    • Short stature
    • Scoliosis
    • Basilar skull deformities (may cause nerve compression)
    • Blue sclerae
    • Hearing loss
    • Dentinogenesis imperfecta (opalescent teeth)
    • Increased laxity of ligaments
    • Wormian bones (small bones near cranial sutures)
    • Easy bruising
Table: Classification of OI (forms I-IV) based on inheritance pattern and clinical appearance
Type IType IIType IIIType IV
DescriptionNon-deforming with blue scleraePerinatally lethalProgressively deformingVariable with normal sclerae
SeverityMildPerinatal lethalSevereMild to moderate
Fractures< 100> 100> 100> 100
Bone deformityUncommonSevereModerate to severeMild to moderate
StatureNormal to mildly reducedSeverely reducedReducedVariable
Dentogenesis imperfectaVariableCommonCommonVariable
Color of scleraeBlueDark blueBlueNormal to gray
Hearing lossPresent in approximately 50%FrequentVariable

Diagnosis

History

  • History of fractures:
    • Multiple and recurrent fractures during very low-impact activities (e.g., diaper change)
    • Specific bone fractures:
      • Olecranon process
      • Transverse humerus
      • Diaphyseal humerus 
    • Fractures before or during birth
  • History of extra-skeletal symptoms:
    • Hearing loss
    • Easy bruising
  • Family history of the disease or findings suggestive of undiagnosed disease in relatives:
    • Family history of multiple fractures
    • Family history of extra-skeletal symptoms:
      • Hearing loss
      • Dentinogenesis imperfecta
    • Lack of family history does not rule out disease.
  • History of child abuse: important to rule out in cases of fractures

Physical examination

  • Skeletal findings:
    • Dentinogenesis imperfecta: translucent teeth with amber, blue, or gray coloration
    • Genu varum (bow legs): outward bowing at the knees 
    • Scoliosis
    • Loose joints
    • Limb deformity (particularly bowing of the femur)
  • Extra-skeletal findings:
    • Prolonged bleeding from injured areas
    • Easy bruising
    • Blue-colored sclera
    • Breathing problems/fatigue
    • Hypoacusia that can be conductive, sensorineural, or mixed (deficient ossification of the middle ear)
    • Muscle weakness
    • Short stature (more common in severe cases)

Laboratory testing

  • Bloodwork:
    • Usually normal
    • Alkaline phosphatase may be increased.
    • ↓ Markers of bone formation, ↑ markers of bone resorption
  • Urine: Hypercalciuria with normal renal function may be present.
  • Biopsy:
    • Collagen: In vitro fibroblast culturing shows abnormal organization/structure. 
    • Bone histology:
      • Shows disorganized bone structure
      • Decreased size and number of bony trabeculae
      • Increased osteoblasts and osteoclasts
  • Genetic studies:
    • No widely available commercial tests
    • Genomic DNA testing for mutations in COL1A1 and COL1A2
  • Prenatal testing:
    • Chorionic villus sampling
    • Amniocentesis

Imaging

  • Prenatal ultrasound: evidence of bony deformities
  • X-ray findings suggestive of OI:
    • Multiple fractures in various states of healing
    • Thin bone cortices and widened metaphysis 
    • Low bone density
    • Bowed femurs
    • “Wormian” bones
    • “Codfish” vertebrae
    • Saber shins
    • Coxa vara
    • Kyphoscoliosis
    • Platyspondyly
Table: Radiographic findings of OI (types I-IV)
Type IType IIType IIIType IV
Skull radiographic findingsIntra-sutural bonesUndermineralization; calcified areasIntra-sutural bonesIntra-sutural bones (sometimes)
Spine radiographic findingsBiconcave vertebrae (adults)Widened vertebral bodies (platyspondyly)Biconcave vertebrae; kyphoscoliosisBiconcave vertebrae
Extremity radiographic findingsThin corticesSeverely deformed femursFlared metaphyses, bowing, thin corticesThin cortices
Other radiographic findingsOsteopeniaSmall, beaded ribs (pathognomonic)Thin ribs, severe osteoporosisProtrusio acetabuli in a subset

Management

There is no definitive cure for OI.

Goals of therapy

  • Reduce pain
  • Reduce fractures
  • Reduce bone deformity
  • Increase ambulation/independence

Lifestyle modifications

  • Controlled weight carrying
  • Safe exercises to improve muscle and bone strength
  • Diet rich in calcium and vitamin D 
  • Avoidance of alcohol and caffeine
  • Steroids are contraindicated.
  • Avoidance of active or passive inhalation of cigarette smoke

Supportive management

  • Casts and splints
  • Braces 
  • Physical therapy
  • Implantation of rods in legs or arms
  • Dental workup
  • Hearing aids
  • Crowns for brittle teeth
  • Mobility aids (e.g., crutches, canes, wheelchairs, walkers)
  • Supplemental oxygen 
  • Genetic counseling for parents considering future pregnancies

Bisphosphonates (pamidronate)

  • Inhibit bone turnover/resorption
  • Have been shown to reduce fracture rates
  • Long-term effect on other skeletal symptoms (scoliosis, deformity) is unclear.

Surgical therapy

  • Fracture repair
  • Deformity correction

Prognosis

  • Severe functional limitation and decreased quality of life 
  • Type I cases can attain a full lifespan.
  • Type II cases die prenatally or within the 1st year of life.
  • Type III and IV cases require walking aids, but can attain household and community ambulation skills.

Differential Diagnosis

  • Child abuse: defined by the U.S. government as “any recent act or failure to act on the part of a parent or caretaker, which results in death, serious physical or emotional harm, sexual abuse or exploitation, or an act or failure to act which presents an imminent risk of serious harm.” Physically abused children may present with recurrent fractures and visits to the emergency department (ED). Old and recent signs of inflicted trauma are more indicative of the diagnosis of child abuse. 
  • Rickets: a disease of the growing bone caused by inadequate bone mineralization due to vitamin D deficiency. Rickets presents with recurrent fractures, limb deformities, increased alkaline phosphatase, and dental abnormalities in some cases, but does not display hearing loss and blue sclerae. 
  • Osteomalacia: a condition of decreased bone density in adults that tends to appear prior to the development of osteoporosis. Osteomalacia shows fractures and increased alkaline phosphatase, but no hearing loss or blue sclerae.
  • Paget’s disease of the bone: a disorder characterized by increased and abnormal remodeling of bone tissue that presents with fractures, bone deformity, bowing of long bones, increased alkaline phosphatase, and conductive hearing loss. However, 20% of cases are asymptomatic and diagnosis may be made incidentally as these patients are investigated for something else.

References

  1. Stankovits, L. M., M.D., & Lopyan, A.H., M.D., M.S. (2020). Genetic and metabolic conditions. Pediatric Clinics of North America, 67(1), 23-43. doi:http://dx.doi.org/10.1016/j.pcl.2019.09.005
  2. Marini, J. C. (2020). Osteogenesis imperfecta. In R. M. Kliegman MD, J. W. St Geme MD, N. J. Blum MD, Shah, Samir S., MD, MSCE, Tasker, Robert C., MBBS, MD & Wilson, Karen M., MD, MPH (Eds.), Nelson textbook of pediatrics (pp. 3736-3740.e1). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323529501007215
  3. Forlino, A., PhD., & Marini, J.C., Dr. (2016). Osteogenesis imperfecta. Lancet, The, 387(10028), 1657-1671. doi:http://dx.doi.org/10.1016/S0140-6736(15)00728-X
  4. Prockop, D. J., & Bateman, J. F. (2018). Heritable disorders of connective tissue. In J. L. Jameson, A. S. Fauci, D. L. Kasper, S. L. Hauser, D. L. Longo & J. Loscalzo (Eds.), Harrison’s principles of internal medicine, 20e (). New York, NY: McGraw-Hill Education. accessmedicine.mhmedical.com/content.aspx?aid=1160017759 
  5. Forlino, A., Cabral, W. A., Barnes, A. M., & Marini, J. C. (2011). New perspectives on osteogenesis imperfecta. Nature reviews. Endocrinology.
  6. Moscote-Salazar, L. R., Koller, O., Valenzuela, S., Narvaez-Rojas, A., Satyarthee, G. D., Mo-Carrascal, J., & Maraby, J. (2018). Neurosurgical Implications of Osteogenesis Imperfecta in a Child after Fall: Case Illustration. Journal of pediatric neurosciences, 13(4), 459–461.
  7. Dubowitz, H., & Lane, W. G. (2020). Abused and neglected children. In R. M. Kliegman MD et al., Nelson textbook of pediatrics (pp. 98-111.e1). https://www.clinicalkey.es/#!/content/3-s2.0-B978032352950100016X
  8. Greenbaum, L. A. (2020). Vitamin D deficiency (rickets) and excess. In R. M. Kliegman MD et al., Nelson textbook of pediatrics (pp. 375-385.e1). doi:http://dx.doi.org/10.1016/B978-0-323-52950-1.00064-X. Retrieved from https://www.clinicalkey.es/#!/content/3-s2.0-B978032352950100064X
  9. Ralston, S. H. (2020). Paget disease of bone. In L. Goldman MD, & A. I. Schafer MD (Eds.), Goldman-Cecil medicine (pp. 1623-1626.e2). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323532662002332
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  11. Niyibizi, C., Wang, S., Mi, Z. et al. (2004). Gene therapy approaches for osteogenesis imperfecta. Gene Ther 11, 408–416. https://doi.org/10.1038/sj.gt.3302199
  12. Steiner, R.D., Pepin, M.G., & Byers, P.H. (2005). Osteogenesis Imperfecta. Gene Reviews at GeneTests: Medical Genetics Information Resource.

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