Osteogenesis Imperfecta

Osteogenesis imperfecta (OI), ou "doença dos ossos frágeis", é uma doença genética rara do tecido conjuntivo caracterizada por uma fragilidade óssea grave. Embora a OI seja considerada uma única doença, inclui mais de 16 genótipos e fenótipos clínicos com diferentes graus de gravidade dos sintomas. Destes 16, os tipos I-IV são os mais comuns. Devido à raridade da OI, esta é considerada uma "doença órfã" nos Estados Unidos. O diagnóstico é feito clinicamente, através da história e do exame objetivo, e é confirmado com achados imagiológicos e análise do DNA. Embora não haja uma cura definitiva, o tratamento é de suporte, geralmente envolvendo bisfosfonatos, e foca-se na redução da dor, redução da frequência de fraturas, redução da deformidade óssea e aumento da deambulação. O prognóstico é variável, dependendo do tipo de OI.

Última atualização: Jan 10, 2023

Responsibilidade editorial: Stanley Oiseth, Lindsay Jones, Evelin Maza

Descrição Geral

Definição

Osteogenesis imperfecta (OI) é uma doença hereditária do tecido conjuntivo caracterizada por défices na formação óssea e fragilidade óssea grave.

Epidemiologia

  • 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.

Etiologia

  • 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 I Type II Type III Type IV
Mutated gene COL1A1, COL1A2 (collagen type 1 alpha 1 and 2 chains) COL1A1, COL1A2, and CRTAP (cartilage-associated protein) COL1A1, COL1A2 COL1A1, COL1A2
Inheritance modality Autosomal dominant Autosomal dominant AND autosomal recessive Autosomal dominant Autosomal dominant
Defect Frameshift mutations in collagen type 1 alpha 1 and 2 chains leading to decreased amounts of normal collagen Disrupted formation of the collagen triple helix structure, leading to little or no normal collagen Mutations causing structural protein defects leading to severe pathology Mutations causing structural protein defects leading to minimal or mild pathology

Fisiopatologia

  • 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

Apresentação Clínica

  • 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 I Type II Type III Type IV
Description Non-deforming with blue sclerae Perinatally lethal Progressively deforming Variable with normal sclerae
Severity Mild Perinatal lethal Severe Mild to moderate
Fractures < 100 > 100 > 100 > 100
Bone deformity Uncommon Severe Moderate to severe Mild to moderate
Stature Normal to mildly reduced Severely reduced Reduced Variable
Dentogenesis imperfecta Variable Common Common Variable
Color of sclerae Blue Dark blue Blue Normal to gray
Hearing loss Present in approximately 50% Frequent Variable

Diagnóstico

História

  • 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

Exame físico

  • 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)

Exames laboratoriais

  • 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

Imagiologia

  • 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 I Type II Type III Type IV
Skull radiographic findings Intra-sutural bones Undermineralization; calcified areas Intra-sutural bones Intra-sutural bones (sometimes)
Spine radiographic findings Biconcave vertebrae (adults) Widened vertebral bodies (platyspondyly) Biconcave vertebrae; kyphoscoliosis Biconcave vertebrae
Extremity radiographic findings Thin cortices Severely deformed femurs Flared metaphyses, bowing, thin cortices Thin cortices
Other radiographic findings Osteopenia Small, beaded ribs (pathognomonic) Thin ribs, severe osteoporosis Protrusio acetabuli in a subset

Tratamento

Não há cura definitiva para a OI.

Objetivos da terapêutica

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

Alterações do estilo de vida

  • 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

Terapêutica de suporte

  • 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

Bisfosfonatos (pamidronato)

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

Terapêutica cirúrgica

  • Fracture repair
  • Deformity correction

Prognóstico

  • 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.

Diagnóstico diferencial

  • 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.

Referências

  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
  10. Marini, J.C. (2004). Osteogenesis imperfecta: Comprehensive management. Adv Pediatr. 1988;35:391-426. PMID: 3055864.
  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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