Familial expansile osteolysis (excessive RANK effect) in a 5-generation American kindred

Familial expansile osteolysis (FEO) in a 5-generation American kindred [FEO_(Am)] is an autosomal dominant skeletal disorder, with somewhat variable expressivity, caused by an 18-bp tandem duplication (84dup18) in exon 1 of the TNFRSF11A gene which encodes RANK (receptor activator of nuclear factorκB). The TNFRSF11A mutation enhances NF-κB action (thereby promoting osteoclast formation, differentiation, and activity) because it extends the signal-peptide of RANK leading to intracellular trapping of this member of the tumor necrosis factor receptor superfamily. Our 30 years' experience with FEO involves 8 affected individuals. FEO_(Am) usually results in deafness in childhood due to degeneration of middle ear ossicles, and often engenders expansile osteolysis of a single major limb bone beginning during early adult life. Premature loss of dentition from destruction of teeth is a less common feature. Generalized osteopenia is a fourth, important, newly recognized manifestation. However, exceptional individuals may never have symptoms of FEO. Most, but not all, FEO_(Am) patients develop deafness involving dysplasia of the incus during early childhood as well as 1 (rarely 2) expansile lytic lesions within 1 major limb bone during adolescence or young adult life. Subsequently, recurrent fracture and deformity is possible, but intractable bone pain has occurred in only 1 individual. Coarse trabeculae throughout most extremity bones and generalized osteopenia in adult life indicate that FEO_(Am) is a metabolic bone disease. Elevation in biochemical markers of skeletal remodeling almost always, but not invariably, precedes expansile osteolysis. Perhaps, trauma with microfracture sometimes incites the osteoclastmediated skeletal destruction. In 1 teenage boy, resorption at the enamel-cementum junction coincided with orthodontic banding and destroyed his entire dentition. Histopathology of osteolytic defects in FEO_(Am) is consistent with Paget disease of bone (PDB). Eroded areas of fibrous trabeculae have foci of numerous, enlarged, giant cells with many nuclei, some nestled in Howship lacunae and appearing like PDB osteoclasts. Biochemical and occasionally symptomatic and radiographic improvement follows synthetic salmon or human calcitonin therapy, but the aminobisphosphonate compound, alendronate, corrects elevated markers of skeletal remodeling and produces radiographic healing that can be sustained despite cessation of treatment.