Panostotic Expansile Bone Disease With Massive Jaw Tumor Formation and a Novel Mutation in the Signal Peptide of RANK |
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| Authors: | Anne L Schafer Steven Mumm Ivan El‐Sayed William H McAlister Andrew E Horvai Andrea M Tom Edward C Hsiao Frederick V Schaefer Michael T Collins Mark S Anderson Michael P Whyte Dolores M Shoback |
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| Affiliation: | 1. Department of Medicine, University of California, San Francisco, CA, USA;2. Endocrine Research Unit, Department of Veterans Affairs Medical Center, San Francisco, CA, USA;3. Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA;4. Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes‐Jewish Hospital, St. Louis, MO, USA;5. Department of Otolaryngology, University of California, San Francisco, CA, USA;6. Mallinckrodt Institute of Radiology, Washington University School of Medicine at St. Louis Children's Hospital, St. Louis, MO, USA;7. Department of Pathology, University of California, San Francisco, CA, USA;8. Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA, USA;9. Center for Genetic Testing at Saint Francis, Tulsa, OK, USA;10. National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA |
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| Abstract: | Precise regulation of bone resorption is critical for skeletal homeostasis. We report a 32‐year‐old man with a panostotic expansile bone disease and a massive hemorrhagic mandibular tumor. Originally from Mexico, he was deaf at birth and became bow‐legged during childhood. There was no family history of skeletal disease. Puberty occurred normally, but during adolescence he experienced difficulty straightening his limbs, sustained multiple fractures, and developed a bony tumor on his chin. By age 18 years, all limbs were misshapen. The mandibular mass grew and protruded from the oral cavity, extending to the level of the lower ribs. Other bony defects included a similar maxillary mass and serpentine limbs. Upon referral at age 27 years, biochemical studies showed serum alkaline phosphatase of 1760 U/L (Nl: 29‐111) and other elevated bone turnover markers. Radiography of the limbs showed medullary expansion and cortical thinning with severe bowing. Although the jaw tumors were initially deemed inoperable, mandibular mass excision and staged partial maxillectomy were eventually performed. Tumor histopathology showed curvilinear trabeculae of woven bone on a background of hypocellular fibrous tissue. Fibrous dysplasia of bone was suspected, but there was no mutation in codon 201 of GNAS in samples from blood or tumor. His clinical and radiographic findings, elevated serum markers, and disorganized bone morphology suggested amplified receptor activator of NF‐κB (RANK) signaling, even though his disorder differed from conditions with known constitutive activation of RANK signaling (eg, familial expansile osteolysis). We found a unique 12‐base pair duplication in the signal peptide of TNFRSF11A, the gene that encodes RANK. No exon or splice site mutations were found in the genes encoding RANK ligand or osteoprotegerin. Alendronate followed by pamidronate therapies substantially decreased his serum alkaline phosphatase activity. This unique patient expands the phenotypes and genetic basis of the mendelian disorders of RANK signaling activation. © 2014 American Society for Bone and Mineral Research. |
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| Keywords: | PANOSTOTIC EXPANSILE BONE DISEASE OSTEOCLASTS RANK SIGNALING OSTEOPROTEGERIN |
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