Familial expansile osteolysis in a large Spanish kindred resulting from an insertion mutation in the TNFRSF11A gene

Familial expansile osteolysis (FEO) is a rare autosomal dominant disorder resembling Paget’s disease of bone (PDB), characterised by osteolytic lesions. These are mainly located in the long bones and spare the axial skeleton. Progressive osteoclastic resorption accompanied by medullar expansion leads to severe, painful, disabling deformity and a tendency to pathological fracture. Characteristically, FEO is accompanied by deafness and loss of dentition as a result of middle ear and jaw abnormalities, and biochemically serum alkaline phosphatase levels are variably raised.1–3 FEO cases present with appendicular lesions,4 while PDB patients tend to present with trunk and skull lesions.5 The FEO gene was mapped to 18q21.1-q22 by linkage to DNA markers6 and recently Hughes et al 5 have identified mutations in the gene encoding the receptor activator of nuclear factor-kappa-B (RANK, TNFRSF11A ) as a cause of FEO. They proceeded to identify two different heterozygous insertion mutations in exon 1 of the TNFRSF11A gene in affected members of four families with FEO or familial PDB. All mutations affected the signal peptide region of the RANK protein. Expression of recombinant forms of the mutant RANK proteins showed alterations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK mediated nuclear factor-kappa-B signalling in vitro, consistent with the presence of an activating mutation. Although PDB and FEO share some clinical features (bone resorption, deafness, and loss of dentition), linkage to 18q21.1-q22 is unusual in familial PDB and three other candidate loci have been described in PDB kindreds, indicating the genetic heterogeneity of this disease.7,8 There are some rare early onset PDB cases which show TNFRS11A mutations, but in the vast majority of cases, no mutation is found.9 Recently, Whyte et al 10,11 described a 15 base pair …