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Heterogenous genetic disorder resulting in increased bone mass as a consequence of defective bone resorption. Depending on the mode of inheritance, its course can be either uniformly fatal with pancytopenia, recurrent pathologic fractures, blindness, and other neurologic symptoms, or it can exist in a much milder form with later manifestation and favorable prognosis.

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Dominant Osteopetrosis Type I

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Dominant Autosomal Osteopetrosis Type II (Albers-Schonberg Disease; Autosomal Dominant Marble Bones; Osteosclerosis Fragilis Generalisata)

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Mild Autosomal Osteopetrosis (Osteopetrosis Renal Tubular Acidosis; Osteopetrosis Resulting from Carbonic Anhydrase II Deficiency)

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Autosomal Recessive Osteopetrosis (Malignant Osteopetrosis; Autosomal Recessive Marble Bones; Autosomal Recessive Albers-Schonberg Disease)

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1:100,000-500,000 live births for the autosomal dominant form and 1:200,000 live births for the autosomal recessive form.

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Exists in both autosomal recessive form (infantile or malignant osteopetrosis) and autosomal dominant form (benign osteopetrosis). The responsible mutations have been mapped to several gene loci: for the autosomal recessive form they are 16p13 (chloride channel 7 gene), 11q13.4-q13.5 (T-cell immunoregulator 1 gene), and 6q21 (spontaneous mouse gray lethal mutation). For the autosomal dominant form, the gene has also been mapped to 11q12-13 and to 16p13 (chloride channel 7 gene). The frequency of the two forms is about equal.

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On the one hand, the increased skeletal mass is the result of defective bone resorption, which is caused by failure of the (morphologically and numerically normal) osteoclasts to resorb the calcified cartilage during bone development. On the other hand, bone formation and enchondral ossification continue. This combination results in the typical dense radiologic appearance of the sclerotic bones. The microscopic finding of persistent primary spongiosa, which consists of calcified cartilage bars within the sclerotic bone, is considered pathognomonic. This process can occupy the majority of the medullary cavity and thereby affect bone marrow function and lead to extramedullary hematopoiesis with hepatosplenomegaly. The increased fragility of the bones is caused by deficient remodeling presenting as an inability to replace the woven bone by lamellar, mechanically more competent bone.

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Based on radiographic findings and laboratory investigations revealing low serum calcium and elevated serum phosphate and alkaline phosphatase concentrations.

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Different forms of osteopetrosis have been described.

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Autosomal Recessive or Malignant or Infantile Osteopetrosis: Symptoms may be present in fetal life (with risk of stillbirth and spontaneous abortion) or manifest in early infancy. Initial presenting symptoms are failure to thrive with growth retardation and a chronically stuffed nose. Later on, the most common signs are predisposition to pathologic fractures, macrocephaly, progressive blindness and deafness, and hepatosplenomegaly. Hematologic complications are present in more than 70% of these infants and are caused by marked reduction in the volume of bone marrow cavities throughout the body, resulting in severe anemia, thrombocytopenia, and leukoerythroblastosis. Hypersplenism may occur and lead to thrombocytopenia, leukopenia, and hemolytic anemia as a result of extracorpuscular destruction. High levels of fetal hemoglobin (HbF) are possible. Deafness, ...

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