FGF23 and Syndromes of Abnormal Renal Phosphate Handling

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 728)


Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by 1,25(OH)2-vitamin D (1,25(OH)2D), dietary and circulating phosphate and possibly PTH. FGF23 was discovered as the humoral factor in tumors that causes hypophosphatemia and osteomalacia and through the identification of a mutant form of FGF23 that leads to autosomal dominant hypophosphatemic rickets (ADHR), a rare genetic disorder. FGF23 appears to be mainly secreted by osteocytes where its expression is up-regulated by 1,25(OH)2D and probably by increased serum phosphate levels. Its synthesis and secretion is reduced through yet unknown mechanisms that involve the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), dentin matrix protein 1 (DMP1) and ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Consequently, loss-of-function mutations in these genes underlie hypophosphatemic disorders that are either X-linked or autosomal recessive. Impaired O-glycosylation of FGF23 due to the lack of UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyl-transferase 3 (GALNT3) or due to certain homozygous FGF23 mutations results in reduced secretion of intact FGF23 and leads to familial hyperphosphatemic tumoral calcinosis. FGF23 acts through FGF-receptors and the coreceptor Klotho to reduce 1,25(OH)2D synthesis in the kidney and probably the synthesis of parathyroid hormone (PTH) by the parathyroid glands. It furthermore synergizes with PTH to increase renal phosphate excretion by reducing expression of the sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubules. Loss-of-function mutations in these two transporters lead to autosomal recessive Fanconi syndrome or to hereditary hypophosphatemic rickets with hypercalciuria, respectively.


FGF23 Level Hypophosphatemic Rickets Renal Phosphate Tumoral Calcinosis Autosomal Dominant Hypophosphatemic Rickets 
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  1. 1.
    Bianchine JW, Stambler AA, Harrison HE. Familial hypophosphatemic rickets showing autosomal dominant inheritance. Birth Defects Orig Artic Ser 1971; 7:287–295.PubMedGoogle Scholar
  2. 2.
    Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab 1997; 82:674–681.PubMedGoogle Scholar
  3. 3.
    Econs M, McEnery P, Lennon F et al. Autosomal dominant hypophosphatemic rickets is linked to chromosome 12p13. J Clin Invest 1997; 100:2653–2657.PubMedGoogle Scholar
  4. 4.
    ADHR Consortium T. White KE, Evans WE et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26:345–348.Google Scholar
  5. 5.
    Gribaa M, Younes M, Bouyacoub Y et al. An autosomal dominant hypophosphatemic rickets phenotype in a Tunisian family caused by a new FGF23 missense mutation. J Bone Miner Metab 2009; 28:111–115.PubMedGoogle Scholar
  6. 6.
    Kruse K, Woelfel D, Strom TM. Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation. Horm Res 2001; 55:305–308.PubMedGoogle Scholar
  7. 7.
    Burnett CH, Dent CE, Harper C et al. Vitamin D-resistant rickets. Analysis of twenty-four pedigrees with hereditary and sporadic cases. Am J Med 1964; 36:222–232.PubMedGoogle Scholar
  8. 8.
    Brownstein CA, Adler F, Nelson-Williams C et al. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci USA 2008; 105:3455–3460.PubMedGoogle Scholar
  9. 9.
    Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 2000; 277:494–498.PubMedGoogle Scholar
  10. 10.
    Burnett SM, Gunawardene SC, Bringhurst FR et al. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res 2006; 21:1187–1196.PubMedGoogle Scholar
  11. 11.
    Perwad F, Zhang MY, Tenenhouse HS et al. Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro. Am J Physiol Renal Physiol 2007; 293:F1577–F1583.PubMedGoogle Scholar
  12. 12.
    Nagano N, Miyata S, Abe M et al. Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats. Kidney Int 2006; 69:531–537.PubMedGoogle Scholar
  13. 13.
    Nishi H, Nii-Kono T, Nakanishi S et al. Intravenous calcitriol therapy increases serum concentrations of fibroblast growth factor-23 in dialysis patients with secondary hyperparathyroidism. Nephron Clin Pract 2005; 101:c94–c99.PubMedGoogle Scholar
  14. 14.
    Kolek OI, Hines ER, Jones MD et al. 1alpha,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 2005; 289:G1036–G1042.PubMedGoogle Scholar
  15. 15.
    Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 2008; 118:3820–3828.PubMedGoogle Scholar
  16. 16.
    Shimada T, Muto T, Urakawa I et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 2002; 143:3179–3182.PubMedGoogle Scholar
  17. 17.
    Kato K, Jeanneau C, Tarp MA et al. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem 2006; 281:18370–18377.PubMedGoogle Scholar
  18. 18.
    Frishberg Y, Ito N, Rinat C et al. Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. J Bone Miner Res 2007; 22:235–242.PubMedGoogle Scholar
  19. 19.
    Chefetz I, Kohno K, Izumi H et al. GALNT3, a gene associated with hyperphosphatemic familial tumoral calcinosis, is transcriptionally regulated by extracellular phosphate and modulates matrix metalloproteinase activity. Biochim Biophys Acta 2009; 1792:61–67.PubMedGoogle Scholar
  20. 20.
    White KE, Carn G, Lorenz-Depiereux B et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 2001; 60:2079–2086.PubMedGoogle Scholar
  21. 21.
    Ichikawa S, Imel EA, Kreiter ML et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 2007; 117:2684–2691.PubMedGoogle Scholar
  22. 22.
    Kuro-o M, Matsumura Y, Aizawa H et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390:45–51.PubMedGoogle Scholar
  23. 23.
    Bai X, Dinghong Q, Miao D et al. Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a Klotho-deficient phenotype. Am J Physiol Endocrinol Metab 2009; 296:E79–E88.PubMedGoogle Scholar
  24. 24.
    Kurosu H, Yamamoto M, Clark JD et al. Suppression of aging in mice by the hormone Klotho. Science 2005; 309:1829–1833.PubMedGoogle Scholar
  25. 25.
    Urakawa I, Yamazaki Y, Shimada T et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444:770–774.PubMedGoogle Scholar
  26. 26.
    Yamazaki Y, Tamada T, Kasai N et al. Anti-FGF23 neutralizing antibodies show the physiological role and structural features of FGF23. J Bone Miner Res 2008; 23:1509–1518.PubMedGoogle Scholar
  27. 27.
    Zhang X, Ibrahimi OA, Olsen SK et al. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 2006; 281:15694–15700.PubMedGoogle Scholar
  28. 28.
    Yu X, White KE. Fibroblast growth factor 23 and its receptors. Ther Apher Dial 2005; 9:308–312.PubMedGoogle Scholar
  29. 29.
    Yamashita T, Konishi M, Miyake A et al. Fibroblast growth factor (FGF)-23 inhibits renal phosphate reabsorption by activation of the mitogen-activated protein kinase pathway. J Biol Chem 2002; 277:28265–28270.PubMedGoogle Scholar
  30. 30.
    Liu S, Zhou J, Tang W et al. Pathogenic role of Fgf23 in Dmp1-null mice. Am J Physiol Endocrinol Metab 2008; 295:E254–E261.PubMedGoogle Scholar
  31. 31.
    Segawa H, Yamanaka S, Ohno Y et al. Correlation between hyperphosphatemia and type IINa-Pi cotransporter activity in klotho mice. Am J Physiol Renal Physiol 2007; 292:F769–F779.PubMedGoogle Scholar
  32. 32.
    Baum M, Schiavi S, Dwarakanath V et al. Effect of fibroblast growth factor-23 on phosphate transport in proximal tubules. Kidney Int 2005; 68:1148–1153.PubMedGoogle Scholar
  33. 33.
    Segawa H, Onitsuka A, Aranami F et al. Npt2a and Npt2c in Mice Play Distinct and Synergistic Roles in Inorganic Phosphate Metabolism and Skeletal Development. RENAL WEEK 2006, San Francisco, 2007; pp abstract SA-FC101.Google Scholar
  34. 34.
    Strom TM, Jüppner H. PHEX, FGF23, DMP1 and beyond. Curr Opin Nephrol Hypertens 2008; 17:357–362.PubMedGoogle Scholar
  35. 35.
    Liu S, Gupta A, Quarles LD. Emerging role of fibroblast growth factor 23 in a bone-kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization. Curr Opin Nephrol Hypertens 2007; 16:329–335.PubMedGoogle Scholar
  36. 36.
    Fukumoto S, Yamashita T. FGF23 is a hormone-regulating phosphate metabolism—unique biological characteristics of FGF23. Bone 2007; 40:1190–1195.PubMedGoogle Scholar
  37. 37.
    Farrow EG, Davis SI, Summers LJ et al. Initial FGF23-mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol 2009; 20:955–960.PubMedGoogle Scholar
  38. 38.
    Chang Q, Hoefs S, van der Kemp AW et al. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 2005; 310:490–493.PubMedGoogle Scholar
  39. 39.
    Cha SK, Hu MC, Kurosu H et al. Regulation of renal outer medullary potassium channel and renal K(+) excretion by Klotho. Mol Pharmacol 2009; 76:38–46.PubMedGoogle Scholar
  40. 40.
    Masuda H, Chikuda H, Suga T et al. Regulation of multiple ageing-like phenotypes by inducible klotho gene expression in klotho mutant mice. Mech Ageing Dev 2005; 126:1274–12783.PubMedGoogle Scholar
  41. 41.
    Donohue MM, Demay MB. Rickets in VDR null mice is secondary to decreased apoptosis of hypertrophic chondrocytes. Endocrinology 2002; 143:3691–3694.PubMedGoogle Scholar
  42. 42.
    Narchi H, El Jamil M, Kulaylat N. Symptomatic rickets in adolescence. Arch Dis Child 2001; 84:501–503.PubMedGoogle Scholar
  43. 43.
    Francis RM, Selby PL. Osteomalacia. Baillieres Clin Endocrinol Metab 1997; 11:145–163.PubMedGoogle Scholar
  44. 44.
    Econs MJ, Samsa GP, Monger M et al. X-Linked hypophosphatemic rickets: a disease often unknown to affected patients. Bone Miner 1994; 24:17–24.PubMedGoogle Scholar
  45. 45.
    Liang G, Katz LD, Insogna KL et al. Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice. Calcif Tissue Int 2009; 85:235–246.PubMedGoogle Scholar
  46. 46.
    DiMeglio LA, Econs MJ. Hypophosphatemic rickets. Rev Endocr Metab Disord 2001; 2:165–173.PubMedGoogle Scholar
  47. 47.
    Walton RJ, Bijvoet OL. Nomogram for derivation of renal threshold phosphate concentration. Lancet 1975; 2:309–310.PubMedGoogle Scholar
  48. 48.
    Brodehl J, Gellissen K, Weber HP. Postnatal development of tubular phosphate reabsorption. Clin Nephrol 1982; 17:163–171.PubMedGoogle Scholar
  49. 49.
    Alon U, Hellerstein S. Assessment and interpretation of the tubular threshold for phosphate in infants and children. Pediatr Nephrol 1994; 8:250–251.PubMedGoogle Scholar
  50. 50.
    Tieder M, Modai D, Samuel R et al. Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med 1985; 312:611–617.PubMedGoogle Scholar
  51. 51.
    Corut A, Senyigit A, Ugur SA et al. Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet 2006; 79:650–656.PubMedGoogle Scholar
  52. 52.
    Kremke B, Bergwitz C, Ahrens W et al. 2009 Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications. Exp Clin Endocrinol Diabetes 117:49–56.PubMedGoogle Scholar
  53. 53.
    Yamazaki Y, Okazaki R, Shibata M et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 2002; 87:4957–4960.PubMedGoogle Scholar
  54. 54.
    Jonsson KB, Zahradnik R, Larsson T et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 2003; 348:1656–1663.PubMedGoogle Scholar
  55. 55.
    Endo I, Fukumoto S, Ozono K et al. 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.PubMedGoogle Scholar
  56. 56.
    Imel EA, Peacock M, Pitukcheewanont P et al. Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia. J Clin Endocrinol Metab 2006; 91:2055–2061.PubMedGoogle Scholar
  57. 57.
    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.PubMedGoogle Scholar
  58. 58.
    Topaz O, Shurman DL, Bergman R et al. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet 2004; 36:579–581.PubMedGoogle Scholar
  59. 59.
    Ichikawa S, Guigonis V, Imel EA et al. Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations. J Clin Endocrinol Metab 2007; 92:1943–1947.PubMedGoogle Scholar
  60. 60.
    Larsson T, Yu X, Davis SI et al. A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis. J Clin Endocrinol Metab 2005; 90:2424–2427.PubMedGoogle Scholar
  61. 61.
    Geller JL, Khosravi A, Kelly MH et al. Cinacalcet in the management of tumor-induced osteomalacia. J Bone Miner Res 2007; 22:931–937.PubMedGoogle Scholar
  62. 62.
    Alon US, Levy-Olomucki R, Moore WV et al. Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol 2008; 3:658–664.PubMedGoogle Scholar
  63. 63.
    Seikaly MG, Baum M. Thiazide diuretics arrest the progression of nephrocalcinosis in children with X-linked hypophosphatemia. Pediatrics 2001; 108:E6.PubMedGoogle Scholar
  64. 64.
    Aono Y, Yamazaki Y, Yasutake J et al. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res 2009; 24:1879–1888.PubMedGoogle Scholar
  65. 65.
    Drezner MK. Tumor-induced osteomalacia. Rev Endocr Metab Disord 2001; 2:175–186.PubMedGoogle Scholar
  66. 66.
    Shimada T, Mizutani S, Muto T et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 2001; 98:6500–6505.PubMedGoogle Scholar
  67. 67.
    Carpenter TO, Ellis BK, Insogna KL et al. Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. J Clin Endocrinol Metab 2005; 90:1012–1020.PubMedGoogle Scholar
  68. 68.
    Rowe PS, de Zoysa PA, Dong R et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics 2000; 67:54–68.PubMedGoogle Scholar
  69. 69.
    Jan De Beur S, Finnegan R, Vassiliadis J et al. Tumors associated with oncogenic osteomalacia express genes important in bone and mineral metabolism. J Bone Miner Res 2002; 17:1102–1110.Google Scholar
  70. 70.
    Berndt T, Craig T, Bowe A et al. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest 2003; 112:785–794.PubMedGoogle Scholar
  71. 71.
    Nguyen BD, Wang EA. Indium-111 pentetreotide scintigraphy of mesenchymal tumor with oncogenic osteomalacia. Clin Nucl Med 1999; 24:130–131.PubMedGoogle Scholar
  72. 72.
    Dupond JL, Magy N, Mahammedi M et al. [Oncogenic osteomalacia: the role of the phosphatonins. Diagnostic usefulness of the Fibroblast Growth Factor 23 measurement in one patient]. Rev Med Interne 2005; 26:238–241.PubMedGoogle Scholar
  73. 73.
    Hesse E, Moessinger E, Rosenthal H et al. Oncogenic osteomalacia: exact tumor localization by coregistration of positron emission and computed tomography. J Bone Miner Res 2007; 22:158–162.PubMedGoogle Scholar
  74. 74.
    Takeuchi Y, Suzuki H, Ogura S et al. Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia. J Clin Endocrinol Metab 2004; 89:3979–3982.PubMedGoogle Scholar
  75. 75.
    Westerberg PA, Olauson H, Toss G et al. 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.PubMedGoogle Scholar
  76. 76.
    Nasu T, Kurisu S, Matsuno S et al. Tumor-induced hypophosphatemic osteomalacia diagnosed by the combinatory procedures of magnetic resonance imaging and venous sampling for FGF23. Intern Med 2008; 47:957–961.PubMedGoogle Scholar
  77. 77.
    van Boekel G, Ruinemans-Koerts J, Joosten F et al. Tumor producing fibroblast growth factor 23 localized by two-staged venous sampling. Eur J Endocrinol 2008; 158:431–437.PubMedGoogle Scholar
  78. 78.
    Parfitt AM, Kleerekoper M, Cruz C. Reduced phosphate reabsorption unrelated to parathyroid hormone after renal transplantation: implications for the pathogenesis of hyperparathyroidism in chronic renal failure. Miner Electrolyte Metab 1986; 12:356–362.PubMedGoogle Scholar
  79. 79.
    Levi M. Post-transplant hypophosphatemia. Kidney Int 59:2377–2387.Google Scholar
  80. 80.
    Bhan I, Shah A, Holmes J et al. Post-transplant hypophosphatemia: Tertiary “Hyper-Phosphatoninism”? Kidney Int 2006; 70:1486–1494.PubMedGoogle Scholar
  81. 81.
    Pande S, Ritter CS, Rothstein M et al. FGF-23 and sFRP-4 in chronic kidney disease and postrenal transplantation. Nephron Physiol 2006; 104:p23–p32.PubMedGoogle Scholar
  82. 82.
    Khosravi A, Cutler CM, Kelly MH et al. Determination of the elimination half-life of fibroblast growth factor-23. J Clin Endocrinol Metab 2007; 92:2374–2377.PubMedGoogle Scholar
  83. 83.
    Nordstrom H, Lennquist S, Lindell B et al. Hypophosphataemia in severe burns. Acta Chir Scand 1977; 143:395–399.PubMedGoogle Scholar
  84. 84.
    Dickerson RN, Gervasio JM, Sherman JJ et al. A comparison of renal phosphorus regulation in thermally injured and multiple trauma patients receiving specialized nutrition support. JPEN J Parenter Enteral Nutr 2001; 25:152–159.PubMedGoogle Scholar
  85. 85.
    Nafidi O, Lepage R, Lapointe RW et al. Hepatic resection-related hypophosphatemia is of renal origin as manifested by isolated hyperphosphaturia. Ann Surg 2007; 245:1000–1002.PubMedGoogle Scholar
  86. 86.
    Nafidi O, Lapointe RW, Lepage R et al. Mechanisms of renal phosphate loss in liver resection-associated hypophosphatemia. Ann Surg 2009; 249:824–827.PubMedGoogle Scholar
  87. 87.
    Salem RR, Tray K. Hepatic resection-related hypophosphatemia is of renal origin as manifested by isolated hyperphosphaturia. Ann Surg 2005; 241:343–348.PubMedGoogle Scholar
  88. 88.
    Albright F, Butler AM, Bloomberg E. Rickets resistant to vitamin D therapy Am J Dis Child 1937; 54 529–547.Google Scholar
  89. 89.
    Winters RW, Graham JB, Williams TF et al. A genetic study of familial hypophosphatemia and vitamin D resistant rickets with a review of the literature. Medicine (Baltimore) 1958; 37:97–142.Google Scholar
  90. 90.
    HYP-Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 1995; 11:130–136.Google Scholar
  91. 91.
    Sabbagh Y, Jones AO, Tenenhouse HS. PHEXdb, a locus-specific database for mutations causing X-linked hypophosphatemia. Hum Mutat 2000; 16:1–6.PubMedGoogle Scholar
  92. 92.
    Liu S, Guo R, Simpson LG et al. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem 2003; 278:37419–37426.PubMedGoogle Scholar
  93. 93.
    Sitara D, Razzaque MS, Hesse M et al. Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 2004; 23:421–432.PubMedGoogle Scholar
  94. 94.
    Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol 2007; 18:1637–1647.PubMedGoogle Scholar
  95. 95.
    Makras P, Hamdy NA, Kant SG et al. Normal growth and muscle dysfunction in X-linked hypophosphatemic rickets associated with a novel mutation in the PHEX gene. J Clin Endocrinol Metab 2008; 93:1386–1389.PubMedGoogle Scholar
  96. 96.
    Owen CJ, Habeb A, Pearce SH et al. Discordance for X-linked hypophosphataemic rickets in identical twin girls. Horm Res 2009; 71:237–244.PubMedGoogle Scholar
  97. 97.
    Rivkees SA, el-Hajj-Fuleihan G, Brown EM et al. Tertiary hyperparathyroidism during high phosphate therapy of familial hypophosphatemic rickets. J Clin Endocrinol Metab 1992; 75:1514–1518.PubMedGoogle Scholar
  98. 98.
    Seikaly MG, Brown R, Baum M. The effect of recombinant human growth hormone in children with X-linked hypophosphatemia. Pediatrics 1997; 100:879–884.PubMedGoogle Scholar
  99. 99.
    Lorenz-Depiereux B, Bastepe M, Benet-Pages A et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 2006; 38:1248–1250.PubMedGoogle Scholar
  100. 100.
    Feng JQ, Ward LM, Liu S et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006; 38:1310–1315.PubMedGoogle Scholar
  101. 101.
    Levy-Litan V, Hershkovitz E, Avizov L et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet 86:273–278.Google Scholar
  102. 102.
    Lorenz-Depiereux B, Schnabel D, Tiosano D et al. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet 86:267–272.Google Scholar
  103. 103.
    von Marschall Z, Fisher LW. Dentin matrix protein-1 isoforms promote differential cell attachment and migration. J Biol Chem 2008; 283:32730–32740.Google Scholar
  104. 104.
    Yuan B, Meudt J, Feng JO et al. 7B2 protein mediated inhibition of DMP1 cleavage in osteoblasts enhances FGF-23 production in hyp-mice. JBMR 2008; 23:s16 (abstract 1053).Google Scholar
  105. 105.
    Lu Y, Qin C, Xie Y et al. Studies of the DMP1 57-kDa functional domain both in vivo and in vitro. Cells Tissues Organs 2009; 189:175–185.PubMedGoogle Scholar
  106. 106.
    Terkeltaub R. Physiologic and pathologic functions of the NPP nucleotide pyrophosphatase/phosphodiesterase family focusing on NPP1 in calcification. Purinergic Signal 2006; 2:371–377.PubMedGoogle Scholar
  107. 107.
    Rutsch F, Vaingankar S, Johnson K et al. PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification. Am J Pathol 2001; 158:543–554.PubMedGoogle Scholar
  108. 108.
    Rutsch F, Ruf N, Vaingankar S et al. Mutations in ENPP1 are associated with “idiopathic” infantile arterial calcification. Nat Genet 2003; 34:379–381.PubMedGoogle Scholar
  109. 109.
    Ramjan KA, Roscioli T, Rutsch F et al. Generalized arterial calcification of infancy: treatment with bisphosphonates. Nat Clin Pract Endocrinol Metab 2009; 5:167–172.PubMedGoogle Scholar
  110. 110.
    Chodirker BN, Evans JA, Seargeant LE et al. Hyperphosphatemia in infantile hypophosphatasia: implications for carrier diagnosis and screening. Am J Hum Genet 1990; 46:280–285.PubMedGoogle Scholar
  111. 111.
    Jones A, Tzenova J, Frappier D et al. Hereditary hypophosphatemic rickets with hypercalciuria is not caused by mutations in the Na/Pi cotransporter NPT2 gene. J Am Soc Nephrol 2001; 12:507–514.PubMedGoogle Scholar
  112. 112.
    Tenenhouse HS, Econs MJ. Mendelian hypophosphatemias. In: Scriver CR, Beaudet AL, Valle D, Sly WS, Vogelstein B, Childs B, Kinzler KW, eds. The Metabolic and Molecular Bases of Inherited Diseases, 8th ed. McGraw-Hill, New York; 2001; pp 5039–5067.Google Scholar
  113. 113.
    Lorenz-Depiereux B, Benet-Pages A, Eckstein G et al. Hereditary Hypophosphatemic Rickets with Hypercalciuria Is Caused by Mutations in the Sodium-Phosphate Cotransporter Gene SLC34A3. Am J Hum Genet 2006; 78:193–201.PubMedGoogle Scholar
  114. 114.
    Bergwitz C, Roslin NM, Tieder M et al. SLC34A3 Mutations in Patients with Hereditary Hypophosphatemic Rickets with Hypercalciuria Predict a Key Role for the Sodium-Phosphate Cotransporter NaPi-IIc in Maintaining Phosphate Homeostasis. Am J Hum Genet 2006; 78:179–192.PubMedGoogle Scholar
  115. 115.
    Ichikawa S, Sorenson AH, Imel EA et al. Intronic Deletions in the SLC34A3 Gene Cause Hereditary Hypophosphatemic Rickets with Hypercalciuria. J Clin Endocrinol Metab 2006; 91:4022–4027.PubMedGoogle Scholar
  116. 16.
    Jaureguiberry G, Carpenter TO, Forman S et al. A novel missense mutation in SLC34A3 that causes hereditary hypophosphatemic rickets with hypercalciuria in humans identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc. Am J Physiol Renal Physiol 2008; 295:F371–F379.PubMedGoogle Scholar
  117. 17.
    Prie D, Huart V, Bakouh N et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med 2002; 347:983–991.PubMedGoogle Scholar
  118. 118.
    Lapointe JY, Tessier J, Paquette Y et al. NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak. Kidney Int 2006; 69:2261–2267.PubMedGoogle Scholar
  119. 119.
    Virkki LV, Forster IC, Hernando N et al. Functional characterization of two naturally occurring mutations in the human sodium-phosphate cotransporter type IIa. J Bone Miner Res 2003; 18:2135–2141.PubMedGoogle Scholar
  120. 120.
    Karim Z, Gerard B, Bakouh N et al. NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 2008; 359:1128–1135.PubMedGoogle Scholar
  121. 121.
    Bergwitz C, Bastepe M. NHERF1 Mutations and Responsiveness of Renal Parathyroid Hormone. NEJM 2008; 359:2615–2617.PubMedGoogle Scholar
  122. 122.
    Tieder M, Arie R, Modai D et al. Elevated serum 1,25-dihydroxyvitamin D concentrations in siblings with primary Fanconi’s syndrome. N Engl J Med 1988; 319:845–849.PubMedGoogle Scholar
  123. 123.
    Magen D, Berger L, Coady MJ et al. A loss-of-function mutation in NaPi-IIa and renal Fanconi’s syndrome. N Engl J Med 2010; 362:1102–1109.PubMedGoogle Scholar
  124. 124.
    Beck L, Karaplis AC, Amizuka N et al. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria and skeletal abnormalities. Proc Natl Acad Sci USA 1998; 95:5372–5377.PubMedGoogle Scholar
  125. 125.
    Iwaki T, Sandoval-Cooper MJ, Tenenhouse HS et al. A missense mutation in the sodium phosphate cotransporter Slc34a1 impairs phosphate homeostasis. J Am Soc Nephrol 2008; 19:1753–1762.PubMedGoogle Scholar
  126. 126.
    Beighton P, Cremin BJ, Kozlowski K. Osteoglophonic dwarfism. Pediatr Radiol 1980; 10:46–50.PubMedGoogle Scholar
  127. 127.
    Sklower Brooks S, Kassner G, Qazi Q et al. Osteoglophonic dysplasia: review and further delineation of the syndrome. Am J Med Genet 1996; 66:154–162.PubMedGoogle Scholar
  128. 128.
    White KE, Cabral JM, Davis SI et al. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet 2005; 76:361–367.PubMedGoogle Scholar
  129. 129.
    Farrow EG, Davis SI, Mooney SD et al. Extended mutational analyses of FGFR1 in osteoglophonic dysplasia. Am J Med Genet A 2006; 140:537–539.PubMedGoogle Scholar
  130. 130.
    Maroteaux P, Stanescu V, Stanescu R et al. Opsismodysplasia: a new type of chondrodysplasia with predominant involvement of the bones of the hand and the vertebrae. Am J Med Genet 1984; 19:171–182.PubMedGoogle Scholar
  131. 131.
    Zeger MD, Adkins D, Fordham LA et al. Hypophosphatemic rickets in opsismodysplasia. J Pediatr Endocrinol Metab 2007; 20:79–86.PubMedGoogle Scholar
  132. 132.
    Solomon LM, Fretzin DF, Dewald RL. The epidermal nevus syndrome. Arch Dermatol 1968; 97:273–285.PubMedGoogle Scholar
  133. 133.
    Gellis SS, Feingold M. Linear nevus sebaceous syndrome. Am J Dis Child 1970; 120:139–140.PubMedGoogle Scholar
  134. 134.
    Rogers M. Epidermal nevi and the epidermal nevus syndromes: a review of 233 cases. Pediatr Dermatol 1992; 9:342–344.PubMedGoogle Scholar
  135. 135.
    Menascu S, Donner EJ. Linear nevus sebaceous syndrome: case reports and review of the literature. Pediatr Neurol 2008; 38:207–210.PubMedGoogle Scholar
  136. 136.
    Hafner C, van Oers JM, Vogt T et al. Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi. J Clin Invest 2006; 116:2201–2207.PubMedGoogle Scholar
  137. 137.
    Skovby F, Svejgaard E, Moller J. Hypophosphatemic rickets in linear sebaceous nevus sequence. J Pediatr 1987; 111:855–857.PubMedGoogle Scholar
  138. 138.
    Zutt M, Strutz F, Happle R et al. Schimmelpenning-Feuerstein-Mims syndrome with hypophosphatemic rickets. Dermatology 2003; 207:72–76.PubMedGoogle Scholar
  139. 139.
    Hoffman WH, Jüppner HW, Deyoung BR et al. Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am J Med Genet A 2005; 134:233–236.PubMedGoogle Scholar
  140. 140.
    John M, Shah NS. Hypophosphatemic rickets with epidermal nevus syndrome. Indian Pediatr 2005; 42:611–612.PubMedGoogle Scholar
  141. 141.
    Hoffman WH, Jain A, Chen H et al. Matrix extracellular phosphoglycoprotein (MEPE) correlates with serum phosphorus prior to and during octreotide treatment and following excisional surgery in hypophosphatemic linear sebaceous nevus syndrome. Am J Med Genet A 2008; 146A:2164–2168.PubMedGoogle Scholar
  142. 142.
    Schwindinger WF, Francomano CA, Levine MA. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci USA 1992; 89:5152–5156.PubMedGoogle Scholar
  143. 143.
    Weinstein LS, Shenker A, Gejman PV et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. New Engl J Med 1991; 325:1688–1695.PubMedGoogle Scholar
  144. 144.
    Weinstein L, Yu S, Warner D et al. Endocrine Manifestations of Stimulatory G Protein alpha-Subunit Mutations and the Role of Genomic Imprinting. Endocr Rev 2001; 22:675–705PubMedGoogle Scholar
  145. 145.
    Yamamoto T, Miyamoto KI, Ozono K et al. Hypophosphatemic rickets accompanying McCune-Albright syndrome: evidence that a humoral factor causes hypophosphatemia. J Bone Miner Metab 2001; 19:287–295.PubMedGoogle Scholar
  146. 146.
    Riminucci M, Collins MT, Fedarko NS et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 2003; 112:683–692.PubMedGoogle Scholar
  147. 147.
    Collins MT, Chebli C, Jones J et al. Renal phosphate wasting in fibrous dysplasia of bone is part of a generalized renal tubular dysfunction similar to that seen in tumor-induced osteomalacia. J Bone Miner Res 2001; 16:806–813.PubMedGoogle Scholar
  148. 148.
    Kobayashi K, Imanishi Y, Koshiyama H et al. Expression of FGF23 is correlated with serum phosphate level in isolated fibrous dysplasia. Life Sci 2006; 78:2295–2301.PubMedGoogle Scholar
  149. 149.
    Brown WW, Jüppner H, Langman CB et al. Hypophosphatemia with elevations in serum fibroblast growth factor 23 in a child with Jansen’s metaphyseal chondrodysplasia. J Clin Endocrinol Metab 2009; 94:17–20.PubMedGoogle Scholar
  150. 150.
    Haviv YS, Silver J. Late onset oncogenic osteomalacia-associated with neurofibromatosis type II. Clin Nephrol 2000; 54:429–430.PubMedGoogle Scholar
  151. 151.
    Konishi K, Nakamura M, Yamakawa H et al. Hypophosphatemic osteomalacia in von Recklinghausen neurofibromatosis. Am J Med Sci 1991; 301:322–328.PubMedGoogle Scholar
  152. 152.
    Giard JM. Sur la calcifcation hibernale. Compes Rend Seanes Soc Biol So 1998; 34:1013–1015.Google Scholar
  153. 153.
    Duret MH. Tumeurs multiples et singulieres des bourses sereuses. Bull Mem Soc Ant Paris 1899; 74:725–731.Google Scholar
  154. 154.
    Sitara D, Kim S, Razzaque MS et al. Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. PLoS Genet 2008; 4:e1000154.PubMedGoogle Scholar
  155. 155.
    Martin A, David V, Laurence JS et al. Degradation of MEPE, DMP1 and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP. Endocrinology 2008; 149:1757–1772.PubMedGoogle Scholar
  156. 156.
    Ichikawa S, Lyles KW, Econs MJ. A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: evidence that the disorder is autosomal recessive. J Clin Endocrinol Metab 2005; 90:2420–2423.PubMedGoogle Scholar
  157. 157.
    Frishberg Y, Topaz O, Bergman R et al. Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders. J Mol Med 2005; 83:33–38.PubMedGoogle Scholar
  158. 158.
    Frishberg Y, Araya K, Rinat C et al. Sprecher E Hyperostosis-hyperphosphatemia syndrome caused by mutations in GALNT3 and associated with augmented processing of FGF-23. American Society of Nephrology, Philadelphia 2004; F–P0937.Google Scholar
  159. 159.
    Benet-Pages A, Orlik P, Strom TM et al. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet 2005; 14:385–390.PubMedGoogle Scholar
  160. 160.
    Masi L, Gozzini A, Carbonell S et al. A novel recessive mutation in fibroblast growth factor-23 (FGF23) causes a tumoral calcinosis. J Bone Miner Res 2005; p S128.Google Scholar
  161. 161.
    Garringer HJ, Malekpour M, Esteghamat F et al. Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis. Am J Physiol Endocrinol Metab 2008; 295:E929–E937.PubMedGoogle Scholar
  162. 162.
    Shimada T, Kakitani M, Yamazaki Y et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004; 113:561–568.PubMedGoogle Scholar
  163. 163.
    Hesse M, Fröhlich LF, Zeitz U et al. Ablation of vitamin D signaling rescues bone, mineral and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol 2007; 26:75–84.PubMedGoogle Scholar
  164. 164.
    Ichikawa S, Sorenson AH, Austin AM et al. Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression. Endocrinology 2009; 150:2543–2550.PubMedGoogle Scholar
  165. 165.
    Razzaque MS, Sitara D, Taguchi T et al. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J 2006; 20:720–722.PubMedGoogle Scholar
  166. 166.
    Ohnishi M, Nakatani T, Lanske B et al. Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase. Kidney Int 2009; 75:1166–1172.PubMedGoogle Scholar
  167. 167.
    Stubbs JR, Liu S, Tang W et al. Role of hyperphosphatemia and 1,25-dihydroxyvitamin d in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol 2007; 18:2116–2124.PubMedGoogle Scholar
  168. 168.
    Liu S, Zhou J, Tang W et al. Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab 2006; 291:E38–E49.PubMedGoogle Scholar
  169. 169.
    Yamaguchi T, Sugimoto T, Imai Y et al. Successful treatment of hyperphosphatemic tumoral calcinosis with long-term acetazolamide. Bone 1995; 16(4 Suppl):247S–250S.PubMedGoogle Scholar
  170. 170.
    Lufkin EG, Wilson DM, Smith LH et al. Phosphorus excretion in tumoral calcinosis: response to parathyroid hormone and acetazolamide. J Clin Endocrinol Metab 1980; 50:648–653.PubMedGoogle Scholar
  171. 171.
    Gowen M, Stroup GB, Dodds RA et al. Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J Clin Invest 2000; 105:1595–1604.PubMedGoogle Scholar
  172. 172.
    Bergwitz C, Banerjee S, Abu-Zahra H et al. Defective O-glycosylation due to a novel homozygous S129P mutation is associated with lack of fibroblast growth factor 23 secretion and tumoral calcinosis. J Clin Endocrinol Metab 2009; 94:4267–4274.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  1. 1.Endocrine UnitMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Pediatric Nephrology UnitMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

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