Osteopetrosis
Osteopetrosis is a rare group of inherited disorders characterized by a marked increase in bone density. It is also known as marble bone disease or Albers-Schönberg disease. Osteopetrosis can be inherited in an autosomal dominant (AD), autosomal recessive (AR), or X-linked recessive manner. The incidence of the disease is estimated to be approximately 1 case per 250, 000 individuals.
Clinical presentation of osteopetrosis is highly variable, ranging from asymptomatic to fatal in infancy. Based on age and clinical presentation, there are 3 main types: AR infantile, AR intermediate, and AD adult. Infantile osteopetrosis is a rare, life-threatening condition. Patients present during the first few months of life with fractures, osteomyelitis, macrocephaly, frontal bossing, short stature and mastoid and paranasal sinus malformations. Sclerosis of bone causes bone marrow failure, pancytopenia and hepatosplenomegaly due to extramedullary hematopoiesis.
Patients with intermediate osteopetrosis are often asymptomatic at birth, but present during childhood with frequent fractures, osteomyelitis, anemia, tooth eruption defects, and optic nerve compression. Patients with the adult form of osteopetrosis usually present in late adolescence or adulthood with complications confined mainly to the skeletal system. Bone marrow function is usually not compromised.
Normally, osteoclast-mediated bone resorption is well matched with osteoblast-mediated bone formation. Osteoblasts produce factors such as RANKL and M-CSF that regulate osteoclast formation and activity. Osteoclasts are believed to produce multiple factors that regulate osteoblast function and activity.
Osteopetrosis is caused by defects in the differentiation or function of osteoclasts. A number of mutations have been identified. Osteoclast-rich osteopetrosis is most often caused by mutations in genes coding for proteins involved in the acidification process which is necessary for bone resorption. Sixty percent of patients with severe autosomal recessive osteopetrosis have a mutation in the osteoclast specific proton pump subunit TCIRG1. Mutations in the CLCN7 gene, that encodes for the osteoclast-specific chloride channel, and carbonic anhydrase II have also been described. Mutations in nuclear factor kappa B ligand (RANKL) result in a rare osteoclast-poor form of osteopetrosis.
Osteopetrosis is usually diagnosed on the basis of clinical and radiological findings. Abnormal laboratory tests include increased levels of serum CK-BB isoenzyme and tartrate-resistant acid phosphatase (TRAP). These enzymes are released from osteoclasts. The usefulness of bone turnover markers such as C-telopeptide and procollagen type 1 N-terminal has not been proven. Genetic testing can be used to confirm the diagnosis and subtype in most patients. Subtyping is important for patient management since subtypes have different prognoses.
