Genetics, pathogenesis and complications of osteopetrosis

Human osteopetrosis is a rare genetic disorder caused by osteoclast failure, which ranges widely in severity. In the most severe forms, deficient bone resorption prevents enlargement of bone cavities, impairing development of bone marrow, leading to hematological failure. Closure of bone foramina causes cranial nerve compression with visual and hearing deterioration. Patients also present with osteosclerosis, short stature, malformations and brittle bones. This form is fatal in infancy, has an autosomal recessive inheritance and is cured with hematopoietic stem cell transplantation, with a rate of success <50% and unsatisfactory rescue of growth and visual deterioration. It relies on loss-of-function mutations of various genes, including the TCIRG1 gene, encoding for the a3 subunit of the H+ATPase and accounting for >50% of cases, the ClCN7 and the OSTM1 genes, which have closely related function and account for approximately 10% of cases, also presenting with neurodegeneration. Further genes are implicated in rare forms with various severities and association with other syndromes and, recently, the RANKL gene has been found to be mutated in a subset of patients lacking osteoclasts. Autosomal recessive osteopetrosis may also have intermediate severity, with a small number of cases due to loss-of-function mutations of the CAII or the PLEKHM1 genes. Dominant negative mutations of the ClCN7 gene cause the so-called Albers-Schönberg disease, which represents the most frequent and heterogeneous form of osteopetrosis, ranging from asymptomatic to intermediate/severe, thus suggesting additional genetic/environmental determinants affecting penetrance. Importantly, recent work has demonstrated that osteoblasts may also contribute to the pathogenesis of the disease, either because they are affected by intrinsic defects, or because their activity may be enhanced by deregulated osteoclasts abundantly present in most forms. Therapy is presently unsatisfactory and effort is necessary to unravel the gene defects yet unrecognized and identify new treatments to improve symptoms and save life.