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Subsequently, genetically altered mice revealed physiologic roles for these proteins in bone biology. However, full appreciation of their significance for the human skeleton came from clinical characterization of several extremely rare, heritable disorders followed by discovery of their genetic bases. Familial expansile osteolysis (FEO) is an autosomal dominant disorder featuring constitutive activation of RANK due to an 18\u2010bp tandem duplication in its gene (<jats:italic>TNFRSF11A<\/jats:italic>). A similar, 27\u2010bp duplication causes what has been called a familial form of early\u2010onset Paget's disease of bone (PDB2). Expansile skeletal hyperphosphatasia (ESH) is allelic to FEO and PDB2 and involves a 15\u2010bp tandem duplication in <jats:italic>TNFRSF11A<\/jats:italic>. Autosomal recessive inheritance of deactivating mutations of the gene encoding OPG (<jats:italic>TNFRSF11B<\/jats:italic>) causes most cases of juvenile Paget disease. These disorders feature high bone turnover, deafness during early childhood, \u201cidiopathic external lysis\u201d of adult teeth, and sometimes focal lesions in appendicular bones that mimic active PDB. Biochemical markers indicate rapid skeletal remodeling. In FEO, osteolysis progresses to fat\u2010filled bone rather than to osteosclerosis. Antiresorptive therapy with bisphosphonates can be effective for each disorder.<\/jats:bold> <\/jats:p>","DOI":"10.1196\/annals.1346.016","type":"journal-article","created":{"date-parts":[[2006,7,10]],"date-time":"2006-07-10T18:13:44Z","timestamp":1152555224000},"page":"143-164","source":"Crossref","is-referenced-by-count":87,"title":["Paget's Disease of Bone and Genetic Disorders of RANKL\/OPG\/RANK\/NF\u2010\u03baB Signaling"],"prefix":"10.1111","volume":"1068","author":[{"given":"MICHAEL P.","family":"WHYTE","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,5,30]]},"reference":[{"key":"e_1_2_7_2_2","first-page":"243","article-title":"Paracrine regulation of osteoclast formation and activity: milestones in discovery","volume":"4","author":"Martin T.J.","year":"2004","journal-title":"J. Musculoskel. Neuron. 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