Endocrinol Metab.  2014 Jun;29(2):136-143. 10.3803/EnM.2014.29.2.136.

Diagnostic Modalities for FGF23-Producing Tumors in Patients with Tumor-Induced Osteomalacia

• Fukumoto S

• KMID: 2169418
• DOI: http://doi.org/10.3803/EnM.2014.29.2.136

Abstract

Fibroblast growth factor 23 (FGF23) is a hormone that is produced by osteocytes and regulates phosphate and vitamin D metabolism through binding to the Klotho-FGF receptor complex. Excessive actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia. Tumor-induced rickets/osteomalacia (TIO) is a paraneoplastic syndrome caused by overproduction of FGF23 from the responsible tumors. Because TIO is cured by complete resection of the causative tumors, it is of great clinical importance to locate these tumors. Several imaging methods including skeletal survey by magnetic resonance imaging and octreotide scintigraphy have been used to identify the tumors that cause TIO. However, none of these imaging studies indicate that the detected tumors are actually producing FGF23. Recently, systemic venous sampling was conducted for locating FGF23-producing tumor in suspected patients with TIO and demonstrated that this test might be beneficial to a subset of patient. Further studies with more patients are necessary to establish the clinical utility of venous sampling in patients with TIO.

Keyword

Fibroblast growth factor 23; Hypophosphatemia; 1,25-Dihydroxyvitamin D; Sampling

MeSH Terms

Fibroblast Growth Factors
Humans
Hypophosphatemia
Magnetic Resonance Imaging
Metabolism
Octreotide
Osteocytes
Osteomalacia*
Paraneoplastic Syndromes
Radionuclide Imaging
Vitamin D
Fibroblast Growth Factors
Octreotide
Vitamin D

Figure

• 

  Fig. 1 Changes in fibroblast growth factor 23 (FGF23) levels after removal of responsible tumors for tumor-induced rickets/osteomalacia (TIO). Responsible tumors for TIO were operated on day 0 and FGF23 levels were followed for up to 7 days. FGF23 was measured by an enzyme-linked immunosorbent assay that detects full-length FGF23 with a detection limit of 3 pg/mL (The horizontal line). The shaded area indicates the reference range for FGF23 (10 to 50 pg/mL). In six patients who were cured by the operation, FGF23 became undetectable in five patients within 2 days. In addition, FGF23 was below the lower limit of the reference range on day 2 in patient 8. FGF23 increased after the initial drop in patient 1 and 2, and hypophosphatemic osteomalacia was not cured in these patients.

• 

  Fig. 2 Fibroblast growth factor 23 (FGF23) levels obtained in venous sampling. FGF23 was high in patient's left external iliac vein and a tumor was found in the left femoral head. The unit of FGF23 is pg/mL.

Reference

1. ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000; 26:345–348. PMID: 11062477.

2. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A. 2001; 98:6500–6505. PMID: 11344269.

3. Fukumoto S, Martin TJ. Bone as an endocrine organ. Trends Endocrinol Metab. 2009; 20:230–236. PMID: 19546009.

4. Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet. 2004; 20:563–569. PMID: 15475116.

5. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004; 19:429–435. PMID: 15040831.

6. Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem. 2003; 278:37419–37426. PMID: 12874285.

7. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem. 2006; 281:6120–6123. PMID: 16436388.

8. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006; 444:770–774. PMID: 17086194.

9. Yamaoka K, Seino Y, Satomura K, Tanaka Y, Yabuuchi H, Haussler MR. Abnormal relationship between serum phosphate concentration and renal 25-hydroxycholecalciferol-1-alpha-hydroxylase activity in X-linked hypophosphatemic mice. Miner Electrolyte Metab. 1986; 12:194–198. PMID: 3724705.

10. The HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet. 1995; 11:130–136. PMID: 7550339.

11. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, Rios H, Drezner MK, Quarles LD, Bonewald LF, White KE. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006; 38:1310–1315. PMID: 17033621.

12. Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, Manor E, Buriakovsky S, Hadad Y, Goding J, Parvari R. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet. 2010; 86:273–278. PMID: 20137772.

13. Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U, Badenhoop K, Kaiser SM, Rittmaster RS, Shlossberg AH, Olivares JL, Loris C, Ramos FJ, Glorieux F, Vikkula M, Juppner H, Strom TM. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet. 2006; 38:1248–1250. PMID: 17033625.

14. Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet. 2010; 86:267–272. PMID: 20137773.

15. Benet-Pages A, Lorenz-Depiereux B, Zischka H, White KE, Econs MJ, Strom TM. FGF23 is processed by proprotein convertases but not by PHEX. Bone. 2004; 35:455–462. PMID: 15268897.

16. Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology. 2002; 143:3179–3182. PMID: 12130585.

17. White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. 2001; 60:2079–2086. PMID: 11737582.

18. Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res. 2007; 22:520–526. PMID: 17227222.

19. Hoffman WH, Jueppner HW, Deyoung BR, O'Dorisio MS, Given KS. Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am J Med Genet A. 2005; 134:233–236. PMID: 15742370.

20. Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, Bianco P, Gehron Robey P. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest. 2003; 112:683–692. PMID: 12952917.

21. Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, Bjerknes R. Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res. 2013; 28:1378–1385. PMID: 23325605.

22. Schouten BJ, Doogue MP, Soule SG, Hunt PJ. Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia. Ann Clin Biochem. 2009; 46(Pt 2):167–169. PMID: 19151167.

23. Shimizu Y, Tada Y, Yamauchi M, Okamoto T, Suzuki H, Ito N, Fukumoto S, Sugimoto T, Fujita T. Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: another form of FGF23-related hypophosphatemia. Bone. 2009; 45:814–816. PMID: 19555782.

24. Endo I, Fukumoto S, Ozono K, Namba N, Tanaka H, Inoue D, Minagawa M, Sugimoto T, Yamauchi M, Michigami T, Matsumoto T. Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients: proposal of diagnostic criteria using FGF23 measurement. Bone. 2008; 42:1235–1239. PMID: 18396126.

25. Schouten BJ, Hunt PJ, Livesey JH, Frampton CM, Soule SG. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol Metab. 2009; 94:2332–2337. PMID: 19366850.

26. Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY, Econs MJ, Inwards CY, Jan de Beur SM, Mentzel T, Montgomery E, Michal M, Miettinen M, Mills SE, Reith JD, O'Connell JX, Rosenberg AE, Rubin BP, Sweet DE, Vinh TN, Wold LE, Wehrli BM, White KE, Zaino RJ, Weiss SW. Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol. 2004; 28:1–30. PMID: 14707860.

27. Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, Oba K, Yang IM, Miyauchi A, Econs MJ, Lavigne J, Juppner H. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003; 348:1656–1663. PMID: 12711740.

28. Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab. 2002; 87:4957–4960. PMID: 12414858.

29. Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R, Jan De Beur SM, Schiavi SC, Kumar R. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest. 2003; 112:785–794. PMID: 12952927.

30. Carpenter TO, Ellis BK, Insogna KL, Philbrick WM, Sterpka J, Shimkets R. Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. J Clin Endocrinol Metab. 2005; 90:1012–1020. PMID: 15562028.

31. Rowe PS, Kumagai Y, Gutierrez G, Garrett IR, Blacher R, Rosen D, Cundy J, Navvab S, Chen D, Drezner MK, Quarles LD, Mundy GR. MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone. 2004; 34:303–319. PMID: 14962809.

32. Dupond JL, Mahammedi H, Prie D, Collin F, Gil H, Blagosklonov O, Ricbourg B, Meaux-Ruault N, Kantelip B. Oncogenic osteomalacia: diagnostic importance of fibroblast growth factor 23 and F-18 fluorodeoxyglucose PET/CT scan for the diagnosis and follow-up in one case. Bone. 2005; 36:375–378. PMID: 15777669.

33. Fukumoto S, Takeuchi Y, Nagano A, Fujita T. Diagnostic utility of magnetic resonance imaging skeletal survey in a patient with oncogenic osteomalacia. Bone. 1999; 25:375–377. PMID: 10495143.

34. Ishii A, Imanishi Y, Kobayashi K, Hashimoto J, Ueda T, Miyauchi A, Koyano HM, Kaji H, Saito T, Oba K, Komatsu Y, Kurajoh M, Nagata Y, Goto H, Wakasa K, Sugimoto T, Miki T, Inaba M, Nishizawa Y. The levels of somatostatin receptors in causative tumors of oncogenic osteomalacia are insufficient for their agonist to normalize serum phosphate levels. Calcif Tissue Int. 2010; 86:455–462. PMID: 20458578.

35. Jan de Beur SM, Streeten EA, Civelek AC, McCarthy EF, Uribe L, Marx SJ, Onobrakpeya O, Raisz LG, Watts NB, Sharon M, Levine MA. Localisation of mesenchymal tumours by somatostatin receptor imaging. Lancet. 2002; 359:761–763. PMID: 11888589.

36. Seufert J, Ebert K, Muller J, Eulert J, Hendrich C, Werner E, Schuuze N, Schulz G, Kenn W, Richtmann H, Palitzsch KD, Jakob F. Octreotide therapy for tumor-induced osteomalacia. N Engl J Med. 2001; 345:1883–1888. PMID: 11756579.

37. Takeuchi Y, Suzuki H, Ogura S, Imai R, Yamazaki Y, Yamashita T, Miyamoto Y, Okazaki H, Nakamura K, Nakahara K, Fukumoto S, Fujita T. Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia. J Clin Endocrinol Metab. 2004; 89:3979–3982. PMID: 15292336.

38. Ito N, Shimizu Y, Suzuki H, Saito T, Okamoto T, Hori M, Akahane M, Fukumoto S, Fujita T. Clinical utility of systemic venous sampling of FGF23 for identifying tumours responsible for tumour-induced osteomalacia. J Intern Med. 2010; 268:390–394. PMID: 20698924.

39. Andreopoulou P, Dumitrescu CE, Kelly MH, Brillante BA, Cutler Peck CM, Wodajo FM, Chang R, Collins MT. Selective venous catheterization for the localization of phosphaturic mesenchymal tumors. J Bone Miner Res. 2011; 26:1295–1302. PMID: 21611969.

40. Nasu T, Kurisu S, Matsuno S, Tatsumi K, Kakimoto T, Kobayashi M, Nakano Y, Wakasaki H, Furuta H, Nishi M, Sasaki H, Suzuki H, Ito N, Fukumoto S, Nanjo K. Tumor-induced hypophosphatemic osteomalacia diagnosed by the combinatory procedures of magnetic resonance imaging and venous sampling for FGF23. Intern Med. 2008; 47:957–961. PMID: 18480582.

41. Ogura E, Kageyama K, Fukumoto S, Yagihashi N, Fukuda Y, Kikuchi T, Masuda M, Suda T. Development of tumor-induced osteomalacia in a subcutaneous tumor, defined by venous blood sampling of fibroblast growth factor-23. Intern Med. 2008; 47:637–641. PMID: 18379151.

42. van Boekel G, Ruinemans-Koerts J, Joosten F, Dijkhuizen P, van Sorge A, de Boer H. Tumor producing fibroblast growth factor 23 localized by two-staged venous sampling. Eur J Endocrinol. 2008; 158:431–437. PMID: 18299479.

43. Westerberg PA, Olauson H, Toss G, Wikstrom B, Morales O, Linde T, Jonsson K, Ljunggren O, Larsson TE. Preoperative tumor localization by means of venous sampling for fibroblast growth factor-23 in a patient with tumor-induced osteomalacia. Endocr Pract. 2008; 14:362–367. PMID: 18463045.

44. Goetz R, Nakada Y, Hu MC, Kurosu H, Wang L, Nakatani T, Shi M, Eliseenkova AV, Razzaque MS, Moe OW, Kuro-o M, Mohammadi M. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci U S A. 2010; 107:407–412. PMID: 19966287.

45. Ranch D, Zhang MY, Portale AA, Perwad F. Fibroblast growth factor 23 regulates renal 1,25-dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice. J Bone Miner Res. 2011; 26:1883–1890. PMID: 21472778.

46. Yamazaki Y, Tamada T, Kasai N, Urakawa I, Aono Y, Hasegawa H, Fujita T, Kuroki R, Yamashita T, Fukumoto S, Shimada T. Anti-FGF23 neutralizing antibodies show the physiological role and structural features of FGF23. J Bone Miner Res. 2008; 23:1509–1518. PMID: 18442315.

47. Zhang MY, Ranch D, Pereira RC, Armbrecht HJ, Portale AA, Perwad F. Chronic inhibition of ERK1/2 signaling improves disordered bone and mineral metabolism in hypophosphatemic (Hyp) mice. Endocrinology. 2012; 153:1806–1816. PMID: 22334725.

48. Wohrle S, Henninger C, Bonny O, Thuery A, Beluch N, Hynes NE, Guagnano V, Sellers WR, Hofmann F, Kneissel M, Graus Porta D. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res. 2013; 28:899–911. PMID: 23129509.

49. Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, Kawakami T, Ito T, Zhang X, Humphrey J, Insogna KL, Peacock M. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014; 124:1587–1597. PMID: 24569459.