The most severe form of osteopetrosis is the congenital malignant form, which is inherited as an autosomal recessive disorder. Children usually present with recurrent infections and episodes of hypocalcemia, small medullary cavities that lead to and pancytopenia. Neurologic manifestations including retinal and brain degeneration are present. Death usually occurs in infancy or early childhood, and most patients die of the complications of anemia, bleeding, or infection.
Autosomal dominant osteopetrosis is milder, although 60% to 80% of patients have clinical manifestations. Onset is usually in adolescence. Radiographs of the spine show a “sandwich vertebra” that is diagnostic. A bone-in-bone appearance is often seen at the iliac wings. Fractures occur in about 80% of patients, with the femur most commonly involved. Hearing and visual loss occur in less than 5% of patients.
The hallmark of congenital malignant osteopetrosis is the complete failure of normal osteoclast activity. Defective osteoclastic bone resorption in the presence of normal osteoblastic bone formation results in an extreme excess of mineralized bone that encroaches on the intramedullary spaces. This leads to excessive extramedullary hematopoiesis with severe hepatosplenomegaly and a resultant anemia, thrombocytopenia, and white blood cell abnormalities. Osteoclastic dysfunction, together with loss of the medullary cavities and thickened bones, leads to encroachment on the cranial nerve foramina and neurologic complications, including optic atrophy, blindness, deafness, and any of the cranial nerve palsies. Cerebral atrophy and hydrocephalus have also been reported.
Most of the genes involved with human osteopetrosis are associated with the control of osteoclast intra- and extracellular pH. Genes the control pH include (1) the enzyme carbonic anhydrase (CAII), which catalyzes the hydration of CO2 to H2CO3 and provides a source of hydrogen ions; (2) the α3 subunit of the vacuolar H+-ATPase of the ruffled border; (3) the ruffled border Cl− (ClCN7); (4) the ostm1 protein (OSTM1) association with Cl− transport; and (5) plehkm1 protein (PLEHKM1) involved in vesicle trafficking and acidification. This impairment of acidification results in osteoclast inability to resorb both organic and inorganic matrix. Most patients with osteopetrosis have a normal or increased number of osteoclasts that display no major morphologic defects but are unable to form a ruffled border, which is required for bone resorption. A few patients with osteopetrosis lack osteoclasts and likely have a defect in osteoclastogenic signaling, which in some patients is a result of mutations of the RANKL gene.
Osteoclasts are required during growth for modeling bones and enlarging the medullary cavity, in remodeling to replace woven with lamellar bone, and to remove damaged bone. The abnormalities in the medullary cavity result in hematologic manifestations. Optic and auditory nerve entrapment cause visual and auditory defects. Persistence of calcified cartilage because of decreased resorption and inability to resorb and repair microdamage results in an abnormal skeleton that is prone to fracture.
Stem cell transplants are used to treat severe osteopetrosis. The age of transplantation is critical in determining outcome; transplantation before age 6 months is associated with better preservation of vision. Prenatal diagnosis and stem cell infusion before birth may present the best approach for a rescue in humans. Nonskeletal manifestations such as retinal atrophy and neurodegeneration may not be corrected with stem cell transplants in all genetic types of osteopetrosis.
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