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Snapshot
  • A 9-month-old boy is seen by his pediatrician for failure to thrive and for growth retardation. He has experienced multiple long bone fractures since birth. His mother has recently noticed that he has been bruising and bleeding more easily than usual. He has also developed chronic nasal stuffiness.
Introduction
  • Clinical definition
    • metabolic bone disease caused by defective osteoclastic resorption of immature bone
    • osteopetrosis is also known as marble bone disease
      • "osteopetrosis" translates to "stone bone" in Greek
  • Epidemiology
    • incidence
      • rare condition
      • estimated incidence 1 per 100,000-500,000 births
    • demographics
      • malignant infantile variant (autosomal recessive) presents in infancy
      • intermediate variant (autosomal recessive) presents in childhood
      • benign adult-onset variant (autosomal dominant) presents in late adolescence
  • Etiology
    • normal bone-remodeling cycle
      • healthy bone formation relies on an appropriate dynamic balance between osteoblast-mediated formation and osteoclast-mediated resorption
        • osteoblasts synthesize bone matrix
        • osteoclasts acidify and degrade bone matrix to allow for new bone formation
    • pathophysiology of osteopetrosis
      • osteoclasts are unable to adequately acidify bone matrix
        • autosomal recessive forms caused by proton pump, chloride channel, or carbonic anhydrase II dysfunction 
        • autosomal dominant form caused by chloride channel dysfunction
      • impaired bone resorption leads to overly dense bone that is more likely to fracture
  • Associated conditions
    • pancytopenia
      • due to bone marrow encroachment
    • cranial nerve palsy
      • due to overgrowth of skull foramina
    • low back pain
      • increased risk of spondylolysis
    • long bone fractures
      • low-energy fractures 
      • often accompanied by malunion or non-union due to impaired bone healing
    • mandible osteomyelitis
      • due to abnormal vascular supply to the mandible
    • nasal congestion
      • due to sinus malformations
  • Prognosis
    • natural history of the disease
      • autosomal recessive forms
        • malignant infantile variant 
          • fatal in infancy
        • intermediate variant
          • patients can live to adulthood but lifespan is often shortened
      • autosomal dominant form
        • normal lifespan with otherwise good health
Presentation
  • Autosomal recessive forms are frequently symptomatic
    • symptoms
      • multiple long bone fractures
        • lower extremity > upper extremity > axial skeleton
      • cranial nerve palsies
        • optic nerve > auditory nerve > trigeminal nerve > facial nerve
      • pancytopenia
        • severe anemia
        • easy bleeding and bruising
        • frequent infections
      • mandible osteomyeltis
        • due to abnormal vascular supply to the mandible
      • nasal congestion
        • due to sinus malformations
      • failure to thrive
      • growth retardation
    • physical exam
      • macrocephaly
      • hepatosplenomegaly
        • due to compensatory extramedullary hematopoeisis
      • poor dentition
  • Autosomal dominant form
    • symptoms
      • frequently asymptomatic and diagnosed after a low energy pathologic fracture
      • anemia
      • early-onset osteoarthritis
    • physical exam
      • normal
Imaging
  • Radiographs
    • recommended views
      • multiple views of any bone of interest
    • findings
      • generalized osteosclerosis
        • bones may appear uniformly dense and sclerotic
          • "rugger jersey spine" or "sandwich vertebrae"
        • constriction of the diaphysis with metaphyseal flaring
          • "Erlenmeyer flask deformity"
      • loss of medullary canal diameter
      • bone-in-bone appearance
        • "endobone" 
      • evidence of prior fractures
Studies
  • Serum labs
    • pancytopenia
      • due to bone marrow encroachment
    • increased acid phosphatase
      • due to increased release from defective osteoclasts
    • low to normal calcium levels
    • increased parathyroid hormone
      • secondary hyperparathyroid hormone
    • normal to increased alkaline phosphatase
Differential
  • McCune-Albright syndrome 
    • distinguishing factor
      • presents with polyostotic fibrous dysplastic lesions, endocrinopathy, and cafe-au-lait spots
  • Achondroplasia 
    • distinguishing factor
      • presents with shortened stature, macrocephaly, shortened extremities, and normal lifespan
Treatment
  • Medical management
    • bone marrow transplant
      • indication
        • autosomal recessive forms
      • purpose
        • normal donor cells can provide normal osteoclast functioning
    • high-dose calcitriol
      • indication
        • autosomal recessive forms
      • purpose
        • stimulate dormant osteoclasts to increase bone resorption
Complications
  • Malunion or nonunion of fractured bones
  • Refracture
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