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  • 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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Questions (1)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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