The classical features of autosomal recessive malignant osteopetrosis are fractures and visual impairment, which begins in early infancy or in foetal life. It results from the failure of osteoclasts to resorb immature bone. This leads to abnormal bone marrow cavity formation and to the clinical signs and symptoms of bone marrow failure. It is accompanied by hepatosplenomegaly due to compensatory extramedullary hematopoiesis. Impaired bone remodelling causes bony narrowing of the cranial nerve foramina, which results in cranial nerve (especially optic nerve) compression. Pathologically, there is a persistence of the primary spongiosa characterised by cores of calcified cartilage within bone. Abnormal remodelling of primary, woven bone to lamellar bone results in 'brittle' bone that is prone to fracture. Dental manifestations are delayed or failed tooth eruption. A rare form of the disease is associated with severe central nervous system dysfunction.
The disease is heterogeneous. Over 50% of cases are due to mutations in the TCIRG1 gene and another 10% are due to mutations in the CLCN7 gene. A small number of patients have been described with mutations in the OSTM1 gene.
