Autosomal recessive malignant osteopetrosis

Autosomal recessive malignant osteopetrosis (also known as infantile malignant osteopetrosis, severe neonatal or infantile osteopetrosis, or Albers-Schönberg disease — infantile form) is a rare, life-threatening inherited bone disorder characterized by a failure of osteoclasts to properly resorb bone. This leads to a progressive, generalized increase in bone density (osteosclerosis) that paradoxically results in fragile bones prone to fracture. The abnormally dense bone encroaches on the bone marrow cavity, severely impairing blood cell production (bone marrow failure), which leads to anemia, thrombocytopenia, and increased susceptibility to infections. The overgrowth of bone also compresses cranial nerves, frequently causing blindness, deafness, and facial nerve palsy. Hepatosplenomegaly develops as the liver and spleen attempt to compensate for the failing bone marrow through extramedullary hematopoiesis. The disease typically presents in infancy, often within the first few months of life, with failure to thrive, recurrent infections, bruising, and visual impairment. Skeletal abnormalities include macrocephaly, frontal bossing, and characteristic radiographic findings of uniformly dense bones with loss of the normal medullary canal. Hypocalcemia may occur and can lead to seizures. Without treatment, the condition is usually fatal in early childhood due to bone marrow failure, severe infections, or hemorrhage. Several genes have been implicated, including TCIRG1 (the most commonly mutated, accounting for approximately 50% of cases), CLCN7, OSTM1, SNX10, TNFSF11 (RANKL), and TNFRSF11A (RANK). The only curative treatment currently available is hematopoietic stem cell transplantation (HSCT), which can restore normal osteoclast function if performed early in the disease course. However, outcomes depend on the underlying genetic defect; for example, patients with OSTM1 mutations often have a primary neurodegenerative component that does not respond to transplantation. Supportive care includes management of infections, transfusions for cytopenias, calcium and vitamin D supplementation, and ophthalmologic and neurologic monitoring. Interferon gamma-1b has been used as adjunctive therapy in some cases to enhance osteoclast function.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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