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Tumor-induced osteomalacia in association with PTEN-negative Cowden syndrome

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Abstract

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic condition in which phosphaturic mesenchymal tumors (PMTs) secrete high levels of fibroblast growth factor 23 (FGF23) into the circulation. This results in renal phosphate wasting, hypophosphatemia, muscle weakness, bone pain, and pathological fractures. Recent studies suggest that fibronectin-fibroblast growth factor receptor 1 (FN1-FGFR1) translocations may be a driver of tumorigenesis. We present a patient with TIO who also exhibited clinical findings suggestive of Cowden syndrome (CS), a rare autosomal dominant disorder characterized by numerous benign hamartomas, as well as an increased risk for multiple malignancies, such as thyroid cancer. While CS is a clinical diagnosis, most, but not all, harbor a mutation in the tumor suppressor gene PTEN. Genetic testing revealed a somatic FN1-FGFR1 translocation in the FGF23-producing tumor causing TIO; however, a germline PTEN mutation was not identified. To our knowledge, this is the first reported case of concurrent TIO and CS.

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References

  1. Chong WH, Molinolo AA, Chen CC, Collins MT (2011) Tumor-induced osteomalacia. Endocr Relat Cancer 18(3):R53–R77. https://doi.org/10.1530/ERC-11-0006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bhattacharyya N, Chong WH, Gafni RI, Collins MT (2012) Fibroblast growth factor 23: state of the field and future directions. Trends Endocrinol Metab 23(12):610–618. https://doi.org/10.1016/j.tem.2012.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lee JC, Jeng YM, Su SY, Wu CT, Tsai KS, Lee CH, Lin CY, Carter JM, Huang JW, Chen SH, Shih SR, Mariño-Enríquez A, Chen CC, Folpe AL, Chang YL, Liang CW (2015) Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour. J Pathol 235(4):539–545. https://doi.org/10.1002/path.4465

    Article  CAS  PubMed  Google Scholar 

  4. Lee JC, Su SY, Changou CA, Yang RS, Tsai KS, Collins MT, Orwoll ES, Lin CY, Chen SH, Shih SR, Lee CH, Oda Y, Billings SD, Li CF, Nielsen GP, Konishi E, Petersson F, Carpenter TO, Sittampalam K, Huang HY, Folpe AL (2016) Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. Mod Pathol 29(11):1335–1346. https://doi.org/10.1038/modpathol.2016.137

    Article  CAS  PubMed  Google Scholar 

  5. Pilarski R (2009) Cowden syndrome: a critical review of the clinical literature. J Genet Couns 18(1):13–27. https://doi.org/10.1007/s10897-008-9187-7

    Article  PubMed  Google Scholar 

  6. Pilarski R, Eng C (2004) Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 41(5):323–326. https://doi.org/10.1136/jmg.2004.018036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bale SJ, Amos CI, Parry DM, Bale AE (1991) Relationship between head circumference and height in normal adults and in the nevoid basal cell carcinoma syndrome and neurofibromatosis type I. Am J Med Genet 40(2):206–210. https://doi.org/10.1002/ajmg.1320400217

    Article  CAS  PubMed  Google Scholar 

  8. Chong WH, Andreopoulou P, Chen CC, Reynolds J, Guthrie L, Kelly M, Gafni RI, Bhattacharyya N, Boyce AM, El -Maouche D, Crespo DO, Sherry R, Chang R, Wodajo FM, Kletter GB, Dwyer A, Collins MT (2013) Tumor localization and biochemical response to cure in tumor-induced osteomalacia. J Bone Miner Res 28(6):1386–1398. https://doi.org/10.1002/jbmr.1881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gallo LH, Nelson KN, Meyer AN, Donoghue DJ (2015) Functions of fibroblast growth factor receptors in cancer defined by novel translocations and mutations. Cytokine Growth Factor Rev 26(4):425–449. https://doi.org/10.1016/j.cytogfr.2015.03.003

    Article  CAS  PubMed  Google Scholar 

  10. Collins, M., et al. (2015) Striking response of tumor-induced osteomalacia to the FGFR inhibitor NVP-BGJ398 American Society of Bone and Mineral Research Annual Meeting Seattle. WA.(pp. LB-SA0035 and SA0035)

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Acknowledgements

The authors would like to thank Reinhard Ebner, Joseph Cheng, Claire Tzou and Dale Whitley of CytoTest Inc. (Rockville, MD) for their technical support and assistance.

Funding

This research was supported in part by the Intramural Research Program of the NIH, NIDCR. This research was made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH by the Doris Duke Charitable Foundation (grant no. 2014194), the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, and other private donors (for a complete list, visit the foundation website at http://www.fnih.org).

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Authors and Affiliations

  1. Section on Skeletal Disorders and Mineral Homeostasis, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    J. A. Berglund, R. I. Gafni, D. El-Maouche, L. C. Guthrie & M. T. Collins

  2. Musculoskeletal Tumor Surgery, Virginia Cancer Specialists, Fairfax, VA, USA

    F. Wodajo

  3. Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    E. W. Cowen

  4. Nuclear Medicine, Radiology and Imaging Sciences, Hatfield Clinical Research Center, National Institutes of Health, Bethesda, MD, USA

    R. Chang & C. C. Chen

  5. Department of Pathology, University of California San Diego, San Diego, CA, USA

    A. A. Molinolo

Authors
  1. J. A. Berglund
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  2. R. I. Gafni
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  3. F. Wodajo
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  4. E. W. Cowen
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  5. D. El-Maouche
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  6. R. Chang
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  7. C. C. Chen
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  8. L. C. Guthrie
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  9. A. A. Molinolo
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  10. M. T. Collins
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Corresponding author

Correspondence to M. T. Collins.

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Berglund, J.A., Gafni, R.I., Wodajo, F. et al. Tumor-induced osteomalacia in association with PTEN-negative Cowden syndrome. Osteoporos Int 29, 993–997 (2018). https://doi.org/10.1007/s00198-017-4372-x

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  • DOI: https://doi.org/10.1007/s00198-017-4372-x

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