Introduction:

• It is a heterogenous group of disorders characterized by increased bone density due to defect in osteoclast differentiation and function.

Epidemiology:

• Rare disorder
• Autosomal recessive- 1 in 2,50,000 births
• Autosomal dominant- 5 in 1,00,000 population

Pathogenesis:

• Defect in osteoclast functioning due to various mutations
• Increased bone density paradoxically weakens the bones, leading to fractures and osteomyelitis.

Classification (Genes affected in bracket):

• Autosomal recessive osteopetrosis:
  • Classic (TCIRG)
  • Neuropathic (CLCN7, OSTM1)
    • Often have retinal atrophy
    • Osteopetrosis associated with renal tubular acidosis (Carbonic anhydrase II)
    • Associated with developmental delay, intracranial calcification
• X Linked osteopetrosis, lymphedema, anhidroticectodermal dysplasia and immunodeficiency (IKBKG)
• Intermediate osteopetrosis (CLCN7, PLEKHM I)
• Autosomal dominant osteopetrosis/Albers- Schonberg disease (CLCN7)

Clinical Features (varying range of severity is noted from asymptomatic to very severe forms):

• Bone marrow suppression- Symptoms due to pancytopenia
• Skeletal deformities
  • Skull changes
    • Macrocephaly
    • Frontal bossing
    • Choanalatresia
    • Hydrocephalus
    • Narrowing of nerve foramina (Cranial nerve compression- II, VII and VIII)- Blindness, deafness, facial palsy
• Dental abnormalities- Tooth eruption defects and dental caries
• Short stature
• Extramedullary hematopoiesis leading to hepatosplenomegaly
• Hypocalcemia leading to tetanic seizures

Investigations:

• Hemogram- Pancytopenia
• X-Ray/ CT scan
  • Increased bone density, diffuse and focal sclerosis of varying severity
  • Modelling defects at metaphysis (Erlenmeyer Flask deformity)
  • Bone in bone appearance particularly in vertebrae and phalanges
  • Focal sclerosis of the skull base, pelvis and vertebral end plates- “Sandwich” vertebrae/ “rugger jersey” spine.
  • Pathological fractures
  • Osteomyelitis
• S. Creatinine kinase B- Increased
• S. Tartrate resistant acid phosphatase- Increased
• BM biopsy
• Genetic testing for gene defects

Prognosis:

• Severe infantile forms: If untreated die within 1^st decade of life due to bone marrow suppression.
• Adult forms- Normal life expectancy

Differential Diagnosis:

• Fluorosis
• Beryllium, lead, bismuth poisoning
• Myelofibrosis
• Paget’s disease
• Malignancies- Lymphoma, osteoblasticsecondaries

Treatment:

• Supportive care:
  • Orthopedic management of fractures
  • Calcium and vitamin D for hypocalcemic seizures
  • Transfusion support for marrow failure
  • Surgical decompression of optic nerve
  • Dental surveillance and hygiene
• Hematopoietic stem cell transplantation
  • Reserved for severe forms of disease, as it is associated with high morbidity and mortality
  • Better outcomes with transplants if done before 3 months of age
• Interferon Gamma-1b can be used as bridge till HSCT is done