Familial expansile osteolysis (FEO) is characterized by focal regions of increased bone remodeling resembling those seen in adult PDB. There is increased activity of osteoclasts and osteoblasts leading to expansion, deformity and increased risk of fracture. Although PDB and FEO have histologic and phenotypic similarities, they are sufficiently different to be considered separate diseases. FEO begins in the second decade, tends to be more severe, and the bone lesions are predominantly peripheral. Pain is prominent with increased medullary expansion leading to deformity and increased risk of fracture. Many affected individuals have early onset deafness and loss of dentition. FEO has been mapped to the TNFRSF11A gene which encodes RANK, where two different tandem duplications in exon 1 encoding the signal peptide have beeen found in several families (Hughes et al., 2000). Signal peptide cleavage is defective, leading to intracel-lular accumulation of RANK and increased constitutive NF-kB activation. Expansile skeletal hyperphosphatasia (ESH) is similar to FEO (Whyte et al., 2000), and is associated with a similar tandem duplication in TNFRSF11A, suggesting that these diseases are allelic (Whyte and Hughes, 2002). The slight phenotypic differences may be related to other genetic factors.
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