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Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO; see this term), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis; see this term). Classic ARO is characterized by fractures, short stature, compressive neuropathies, hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. The presence of primary neurodegeneration, intellectual deficit, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO (see this term). Osteopetrosis is caused by failure of osteoclast development or function, and mutations in at least ten genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation and should be confirmed by gene testing where applicable. Once the diagnosis of a primary osteopetrotic condition is made, it is important to distinguish between different subtypes. Correct diagnosis is essential for predicting and understanding the natural history of the disease, providing specific treatments where available, and offering adapted counseling regarding recurrence risks and prenatal diagnosis for severe forms. Alternative diagnoses include fluorosis; beryllium, lead and bismuth poisoning; myelofibrosis; Paget`s disease (sclerosing form); and malignancies (lymphoma, osteoblastic cancer metastases) (see these terms). Treatment of osteopetrotic conditions is largely symptomatic, although hematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure, and currently offers the best chance of longer-term survival for patients in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a consequence of bone marrow suppression. Life expectancy in the adult-onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy. |