osteopetrosis (Albers-Schonberg disease)

Introduction

Bones are overly dense & defective.

Epidemiology

3 major types

• malignant infantile form
  • disease is apparent from birth
  • incidence is 1 in 1000,000-500,000 births
• intermediate form
  • less severe than the malignant infantile form
  • occurs in children < 10 years of age
• adultform:
  • adults 20-40 years (mild form)
  • prevalence: 1 in 20,000

Pathology

• osteoclasts deficient in number or function, resulting in defective resorption of immature bone
• all bones are affected
• bones are overly dense
• the skeleton is extremely heavy
• bones, although dense, are also weak
• overgrowth of bone may damage nerves & blood vessels, especially within the cranial vault
• leukopenia & dysfunctional leukocytes
• aplastic anemia (due to marrow failure)

Genetics

• malignant infantile form: autosomal recessive inheritance
  • associated with defects in ATP6V0A3/TCIRG1 gene
  • associated with defects in OSTM1 gene
  • associated with defects in TNFSF11 (type 2)
  • associated with defects in CLCN7 gene (type 4)
  • associated with defects in TNFRSF11A gene (type 7)
• intermediate form: autosomal recessive, autosomal dominant or sporadic
• adult form: autosomal dominant
  • type 1 associated with defects in LRP5
  • type 2 associated with defects in CLCN7 (most common form)
• large number of genetic abnormalities associated with osteopetrosis

Clinical manifestations

• malignant infantile form
  • anemia
  • frequent infections
  • no tooth eruption or inadequate tooth eruption from the gums
  • increased intracranial pressure
  • macrocephaly
  • failure to thrive
  • delays in psychomotor development
  • blindness, deafness, other brain disorders
  • 30% 10 year survival
• intermediate & adult forms
  • fractures
  • frequent infections
  • blindness, deafness, strokes
• autosomal dominant type 1 (OPTA1)
  • generalized osteosclerosis most pronounced in the cranial vault
  • patients are often asymptomatic, but some suffer from pain & hearing loss.
  • appears to be the only type of osteopetrosis not associated with an increased fracture rate
• autosomal dominant type 2
  • sclerosis, predominantly involving the spine, the pelvis & the skull base

Laboratory

• serum calcium low, value of 5.7 mg/dL (case report)
  • alkaline phosphatase in serum & serum phosphate normal in same case report
• bone biopsy
• hypogammaglobulinemia (type 7)

Radiology

• dense bones are found on X-rays (image)
• brain MRI, CT (image)

Complications

• adult form
  • fractures
  • cranial nerve compression
    • blindness, deafness, facial nerve paralysis

Management

• multidisciplinary team including
  • hematology
  • endocrinology
  • orthopedic surgery
• pharmaceutical agent
  • Actimmune (interferon gamma-1b)
    • only therapy specifically approved for osteopetrosis
    • both adult & pediatric patients may benefit
  • bone marrow transplantation can be curative
  • high-dose calcitriol
  • prednisone may improve anemia
• nutrition 4 physical therapy
• occupational therapy

Prognosis:

• infantile form: 30% 10 year survival
• intermediate form: generally normal life expectancy
• adult form: generally normal life expectancy

More general terms

• bone disease; osteopathia
• developmental disorder

Patient information

osteopetrosis patient information

Database

• OMIM: https://mirror.omim.org/entry/259700
• OMIM: https://mirror.omim.org/entry/259710
• OMIM: https://mirror.omim.org/entry/607634
• OMIM: https://mirror.omim.org/entry/612301
• OMIM: https://mirror.omim.org/entry/611490
• OMIM: https://mirror.omim.org/entry/166600