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Bone formation is stimulated when on the osteoblast surface a Wnt binds to low\u2010density lipoprotein receptor\u2010related protein 5 (LRP5) or 6 (LRP6), in turn coupled to a frizzled receptor. Sclerostin and dickkopf1 inhibit osteogenesis if either links selectively to the first \u03b2\u2010propeller of LRP5 or LRP6, thereby disassociating these cognate co\u2010receptors from the frizzled receptor. Sixteen heterozygous mutations identified since 2002 within\n                    <jats:italic>LRP5<\/jats:italic>\n                    and three heterozygous mutations identified since 2019 within\n                    <jats:italic>LRP6<\/jats:italic>\n                    prevent this binding of sclerostin or dickkopf1 and account for the exceptionally rare, but highly instructive, autosomal dominant disorders called LRP5 and LRP6 high bone mass (HBM). Herein, we characterize LRP6 HBM in the first large affected family. Their novel heterozygous\n                    <jats:italic>LRP6<\/jats:italic>\n                    missense mutation (c.719C&gt;T, p.Thr240Ile) was present in two middle\u2010aged sisters and three of their sons. They considered themselves healthy. Their broad jaw and torus palatinus developed during childhood and, contrary to the two previous reports of LRP6 HBM, the appearance of their adult dentition was unremarkable. Skeletal modeling, defined radiographically, supported classification as an endosteal hyperostosis. Areal bone mineral density (g\/cm\n                    <jats:sup>2<\/jats:sup>\n                    ) of the lumbar spine and total hip featured accelerated increases reaching\n                    <jats:italic>Z<\/jats:italic>\n                    \u2010scores of ~ +8 and +6, respectively, although biochemical markers of bone formation were normal. \u00a9 2023 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10717","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T08:38:21Z","timestamp":1673426301000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["<scp>LRP6<\/scp>\n                    High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of\n                    <scp>Low\u2010Density<\/scp>\n                    Lipoprotein\n                    <scp>Receptor\u2010Related<\/scp>\n                    Protein 6"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8755-8490","authenticated-orcid":false,"given":"Michael P","family":"Whyte","sequence":"first","affiliation":[{"name":"Division of Bone and Mineral Diseases, Department of Internal Medicine Washington University School of Medicine at Barnes\u2010Jewish Hospital  St. Louis MO USA"},{"name":"Center for Metabolic Bone Disease and Molecular Research Shriners Hospitals for Children \u2013 St. Louis  St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9267-4413","authenticated-orcid":false,"given":"Steven","family":"Mumm","sequence":"additional","affiliation":[{"name":"Division of Bone and Mineral Diseases, Department of Internal Medicine Washington University School of Medicine at Barnes\u2010Jewish Hospital  St. Louis MO USA"},{"name":"Center for Metabolic Bone Disease and Molecular Research Shriners Hospitals for Children \u2013 St. Louis  St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan C","family":"Baker","sequence":"additional","affiliation":[{"name":"Mallinckrodt Institute of Radiology, Musculoskeletal Section Washington University School of Medicine  St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Metabolic Bone Disease and Molecular Research Shriners Hospitals for Children \u2013 St. Louis  St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Homer","family":"Sedighi","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery Washington University School of Medicine at St. Louis Children's Hospital  St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenghui","family":"Duan","sequence":"additional","affiliation":[{"name":"Division of Bone and Mineral Diseases, Department of Internal Medicine Washington University School of Medicine at Barnes\u2010Jewish Hospital  St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4890-9400","authenticated-orcid":false,"given":"Tim","family":"Cundy","sequence":"additional","affiliation":[{"name":"Faculty of Medical &amp; 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