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.
Dominant Osteopetrosis Type I
Dominant Autosomal Osteopetrosis Type II (Albers-Schonberg Disease; Autosomal Dominant Marble Bones; Osteosclerosis
Mild Autosomal Osteopetrosis (Osteopetrosis Renal Tubular Acidosis; Osteopetrosis Resulting from Carbonic
Anhydrase II Deficiency)
Autosomal Recessive Osteopetrosis (Malignant Osteopetrosis; Autosomal Recessive Marble Bones; Autosomal
Recessive Albers-Schonberg Disease)
1:100,000-500,000 live births for the autosomal
dominant form and 1:200,000 live births for the autosomal recessive form.
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.
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.
Based on radiographic findings and laboratory
investigations revealing low serum calcium and elevated serum phosphate and
alkaline phosphatase concentrations.
Different forms of osteopetrosis have been
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, ...