about Osteopetrosis
Malignant Infantile Osteopetrosis (MIOP)
Synonyms of Osteopetrosis
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Albers-Schonberg disease
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marble bone disease
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osteosclerosis fragilis generalisata
Subdivisions of Osteopetrosis
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osteopetrosis, autosomal dominant; adult type (ADO)
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osteopetrosis, autosomal recessive; malignant infantile type (ARO)
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osteopetrosis, intermediate autosomal (IAO)
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osteopetrosis, X-linked recessive (XLO)
Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth. Symptoms and severity can vary greatly, ranging from neonatal onset with life-threatening complications (such as bone marrow failure) to the incidental finding of osteopetrosis on X-ray. Depending on severity and age of onset, features may include fractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. In rare cases, there may be neurological impairment or involvement of other body systems.
Osteopetrosis may be caused by mutations in at least 10 genes. Inheritance can be autosomal recessive, autosomal dominant, or X-linked recessive with the most severe forms being autosomal recessive. Management depends on the specific symptoms and severity and may include vitamin D supplements, various medications, and/or surgery. Adult osteopetrosis requires no treatment by itself, but complications may require intervention.
The various types of osteopetrosis are caused by genetic mutations in one of at least ten genes. There is nothing a parent can do before, during or after a pregnancy to cause osteopetrosis in a child.
The genes associated with osteopetrosis are involved in the development and/or function of osteoclasts, cells that break down bone tissue when old bone is being replaced by new bone (bone remodeling). This process is necessary to keep bones strong and healthy. Mutations in these genes can lead to abnormal osteoclasts, or having too few osteoclasts. If this happens, old bone cannot be broken down as new bone is formed, so bones become too dense and prone to breaking.
Osteopetrosis, Autosomal Recessive;
Malignant Infantile Type
​The most severe type of osteopetrosis, malignant infantile type, is apparent from birth, and if left untreated, can lead to death in the first decade of life. Symptoms vary depending on the exact gene change (mutation). Affected individuals may have an abnormally large head (macrocephaly). They may also have hydrocephalus, characterized by inhibition of the normal flow of cerebrospinal fluid (CSF) within and abnormal widening (dilatation) of the cerebral spaces of the brain (ventricles), causing accumulation of CSF in the skull and potentially increased pressure on brain tissue. Symptoms that affect the eyes may include wasting away (atrophy) of the retina, eyes that appear widely spaced (hypertelorism), eyes that protrude from their orbits (exophthalmos), cross-eyes (strabismus), involuntary rhythmic movements of the eyes (nystagmus), and blindness.
Other symptoms associated with malignant infantile type of osteopetrosis include hearing loss, abnormally small jaw (micrognathia), chronic inflammation of the mucous membranes in the nose (rhinitis), eating difficulties and/or growth retardation. Some affected individuals experience delays in acquiring skills that require the coordination of muscles and voluntary movements (delayed psychomotor development). Some affected individuals may experience delayed tooth development or severe dental caries. In addition, abnormal enlargement of the liver and spleen (hepatosplenomegaly); abnormal hardening of some bones (osteosclerosis); fractures, usually of the ribs and long bones; inflammation of the lumbar vertebrae (osteomyelitis); increased density of the cranial bones (cranial hyperostosis) leading to nerve compression; and/or increased pressure inside the skull may also occur. Patients can also present with seizures due to low levels of calcium in the blood. Symptoms of severe neurodegeneration can manifest in rare variants of malignant infantile osteopetrosis.
Some affected individuals with the malignant infantile type of osteopetrosis may also experience consequences of reduced bone marrow space: marked deficiency of all types of blood cells (pancytopenia), the formation and development of blood cells outside the bone marrow, as in the spleen and liver (extramedullary hematopoiesis), and the occurrence of myeloid tissue in extramedullary sites (myeloid metaplasia). This may lead to frequent infections such as pneumonia and urinary tract infections. Affected individuals may also
experience low levels of iron in red blood cells (anemia), due to both reduced bone marrow space and increased destruction of red blood cells due to an enlarged spleen. Of note, hematological defects usually present before neurological ones.
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Approximately eight to 40 children are born in the United States each year with the malignant infantile type of osteopetrosis. In the general population, one in every 250,000 individuals is born with this form of osteopetrosis. Higher rates have been found in specific regions of Costa Rica, the Middle East, Sweden and Russia. Males and females are affected in equal numbers.
At present, the only established cure for autosomal recessive malignant infantile osteopetrosis is hematopoietic stem cell transplantation (HSCT) for specific cases. This allows the restoration of bone resorption by donor-derived osteoclasts.