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Hereditary hypophosphatemic rickets and tumor-induced osteomalacia

Steven J Scheinman, MD
Marc K Drezner, MD
Section Editors
Richard H Sterns, MD
Mitchell E Geffner, MD
Deputy Editor
Alison G Hoppin, MD


The term vitamin D-resistant rickets (VDRR) originally was used to describe a syndrome of hypophosphatemia and rickets (and/or osteomalacia) that resembled vitamin D deficiency but did not respond to vitamin D replacement or pharmacologic doses of vitamin D. Most of these cases were caused by renal phosphate wasting, leading to the alternate name of "phosphate diabetes." This disorder is now called hereditary hypophosphatemic rickets because the primary problem is now recognized to be phosphate wasting rather than true vitamin D resistance.

By contrast, true vitamin D resistance is characterized by hypocalcemia, as well as hypophosphatemia, and results from an inherited defect in the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D or in the calcitriol receptor that limits the interaction with 1,25-dihydroxyvitamin D. (See "Etiology and treatment of calcipenic rickets in children", section on 'Hereditary resistance to vitamin D' and "Etiology and treatment of calcipenic rickets in children", section on '1-alpha-hydroxylase deficiency'.)

Hereditary forms of hypophosphatemia or hypophosphatemic rickets include X-linked, autosomal dominant and autosomal recessive diseases, as well as hypophosphatemic rickets with hypercalciuria. The X-linked form is most common; the other forms are rare, with fewer than 100 reported cases. An acquired disorder, tumor-induced (or oncogenic) osteomalacia, has similar clinical manifestations to the familial syndromes. In addition to hypophosphatemia, these disorders all have normal serum levels of calcium and parathyroid hormone (PTH). Most of these disorders also have high circulating levels of fibroblast growth factor 23 (FGF23), a circulating hormone that causes renal phosphate-wasting and is a common final pathway (figure 1).

The etiology and treatment of hereditary hypophosphatemic rickets and tumor-induced osteomalacia will be reviewed here. The clinical manifestations and evaluation of rickets and osteomalacia are discussed separately. (See "Overview of rickets in children" and "Epidemiology and etiology of osteomalacia".)


X-linked hypophosphatemia (XLH) is a dominant disorder with a prevalence of approximately one case per 20,000 live births [1].

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Literature review current through: Sep 2017. | This topic last updated: Sep 26, 2017.
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  1. Alizadeh Naderi AS, Reilly RF. Hereditary disorders of renal phosphate wasting. Nat Rev Nephrol 2010; 6:657.
  2. Nesbitt T, Coffman TM, Griffiths R, Drezner MK. Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect. J Clin Invest 1992; 89:1453.
  3. Meyer RA Jr, Meyer MH, Gray RW. Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice. J Bone Miner Res 1989; 4:493.
  4. Xiao ZS, Crenshaw M, Guo R, et al. Intrinsic mineralization defect in Hyp mouse osteoblasts. Am J Physiol 1998; 275:E700.
  5. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nat Genet 1995; 11:130.
  6. Liu S, Guo R, Quarles LD. Cloning and characterization of the proximal murine Phex promoter. Endocrinology 2001; 142:3987.
  7. Yuan B, Takaiwa M, Clemens TL, et al. Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. J Clin Invest 2008; 118:722.
  8. Gaucher C, Walrant-Debray O, Nguyen TM, et al. PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. Hum Genet 2009; 125:401.
  9. Personal communication, Marc Drezner, MD.
  10. Christie PT, Harding B, Nesbit MA, et al. X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene. J Clin Endocrinol Metab 2001; 86:3840.
  11. Mumm S, Huskey M, Cajic A, et al. PHEX 3'-UTR c.*231A>G near the polyadenylation signal is a relatively common, mild, American mutation that masquerades as sporadic or X-linked recessive hypophosphatemic rickets. J Bone Miner Res 2015; 30:137.
  12. Benet-Pagès A, Lorenz-Depiereux B, Zischka H, et al. FGF23 is processed by proprotein convertases but not by PHEX. Bone 2004; 35:455.
  13. Razzaque MS, Lanske B. The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis. J Endocrinol 2007; 194:1.
  14. Ichikawa S, Gray AK, Bikorimana E, Econs MJ. Dosage effect of a Phex mutation in a murine model of X-linked hypophosphatemia. Calcif Tissue Int 2013; 93:155.
  15. 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.
  16. Feng JQ, Clinkenbeard EL, Yuan B, et al. Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone 2013; 54:213.
  17. Polisson RP, Martinez S, Khoury M, et al. Calcification of entheses associated with X-linked hypophosphatemic osteomalacia. N Engl J Med 1985; 313:1.
  18. Jehan F, Gaucher C, Nguyen TM, et al. Vitamin D receptor genotype in hypophosphatemic rickets as a predictor of growth and response to treatment. J Clin Endocrinol Metab 2008; 93:4672.
  19. Friedman NE, Lobaugh B, Drezner MK. Effects of calcitriol and phosphorus therapy on the growth of patients with X-linked hypophosphatemia. J Clin Endocrinol Metab 1993; 76:839.
  20. Alon US, Monzavi R, Lilien M, et al. Hypertension in hypophosphatemic rickets--role of secondary hyperparathyroidism. Pediatr Nephrol 2003; 18:155.
  21. Murthy AS. X-linked hypophosphatemic rickets and craniosynostosis. J Craniofac Surg 2009; 20:439.
  22. Nehgme R, Fahey JT, Smith C, Carpenter TO. Cardiovascular abnormalities in patients with X-linked hypophosphatemia. J Clin Endocrinol Metab 1997; 82:2450.
  23. Whyte MP, Schranck FW, Armamento-Villareal R. X-linked hypophosphatemia: a search for gender, race, anticipation, or parent of origin effects on disease expression in children. J Clin Endocrinol Metab 1996; 81:4075.
  24. Yuan B, Xing Y, Horst RL, Drezner MK. Evidence for abnormal translational regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase activity in the hyp-mouse. Endocrinology 2004; 145:3804.
  25. Marie PJ, Glorieux FH. Relation between hypomineralized periosteocytic lesions and bone mineralization in vitamin D-resistant rickets. Calcif Tissue Int 1983; 35:443.
  26. Glorieux FH, Marie PJ, Pettifor JM, Delvin EE. Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic vitamin D-resistant rickets. N Engl J Med 1980; 303:1023.
  27. 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.
  28. Raeder H, Shaw N, Netelenbos C, Bjerknes R. A case of X-linked hypophosphatemic rickets: complications and the therapeutic use of cinacalcet. Eur J Endocrinol 2008; 159 Suppl 1:S101.
  29. Geller JL, Khosravi A, Kelly MH, et al. Cinacalcet in the management of tumor-induced osteomalacia. J Bone Miner Res 2007; 22:931.
  30. 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.
  31. Wöhrle S, Henninger C, Bonny O, et al. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res 2013; 28:899.
  32. Whyte MP, Portale A, Imel E, et al. Burosumab (KRN23), a fully human anti-FGF23 monoclonal antibody for X-linked hypophosphatemia (XLH): final 64-week results of a randomized, open-label, phase 2 study of 52 children (meeting abstract). J Bone Miner Res 2017; 32.
  33. Imel E, Carpenter T, Gottesman GC, et al. . The effect of burosumab (KRN23), a fully human anti-FGF23 monoclonal antibody, on phosphate metabolism and rickets in 1 to 4-year-old children with X-linked hypophosphatemia (XLH). (Meeting abstract). J Bone Miner Res 2017; 32.
  34. Imel EA, Zhang X, Ruppe MD, et al. Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23. J Clin Endocrinol Metab 2015; 100:2565.
  35. Sullivan W, Carpenter T, Glorieux F, et al. A prospective trial of phosphate and 1,25-dihydroxyvitamin D3 therapy in symptomatic adults with X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 1992; 75:879.
  36. Verge CF, Cowell CT, Howard NJ, et al. Growth in children with X-linked hypophosphataemic rickets. Acta Paediatr Suppl 1993; 388:70.
  37. Personal communication, Michael Whyte, MD.
  38. Verge CF, Lam A, Simpson JM, et al. Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med 1991; 325:1843.
  39. Yuan B, Feng JQ, Bowman S, et al. Hexa-D-arginine treatment increases 7B2•PC2 activity in hyp-mouse osteoblasts and rescues the HYP phenotype. J Bone Miner Res 2013; 28:56.
  40. Connor J, Olear EA, Insogna KL, et al. Conventional Therapy in Adults With X-Linked Hypophosphatemia: Effects on Enthesopathy and Dental Disease. J Clin Endocrinol Metab 2015; 100:3625.
  41. Seikaly M, Browne R, Baum M. Nephrocalcinosis is associated with renal tubular acidosis in children with X-linked hypophosphatemia. Pediatrics 1996; 97:91.
  42. Alon U, Donaldson DL, Hellerstein S, et al. Metabolic and histologic investigation of the nature of nephrocalcinosis in children with hypophosphatemic rickets and in the Hyp mouse. J Pediatr 1992; 120:899.
  43. Tieder M, Blonder J, Strauss S, et al. Hyperoxaluria is not a cause of nephrocalcinosis in phosphate-treated patients with hereditary hypophosphatemic rickets. Nephron 1993; 64:526.
  44. Seikaly MG, Baum M. Thiazide diuretics arrest the progression of nephrocalcinosis in children with X-linked hypophosphatemia. Pediatrics 2001; 108:E6.
  45. Carpenter TO, Mitnick MA, Ellison A, et al. Nocturnal hyperparathyroidism: a frequent feature of X-linked hypophosphatemia. J Clin Endocrinol Metab 1994; 78:1378.
  46. Rivkees SA, el-Hajj-Fuleihan G, Brown EM, Crawford JD. Tertiary hyperparathyroidism during high phosphate therapy of familial hypophosphatemic rickets. J Clin Endocrinol Metab 1992; 75:1514.
  47. Knudtzon J, Halse J, Monn E, et al. Autonomous hyperparathyroidism in X-linked hypophosphataemia. Clin Endocrinol (Oxf) 1995; 42:199.
  48. Seikaly MG, Brown R, Baum M. The effect of recombinant human growth hormone in children with X-linked hypophosphatemia. Pediatrics 1997; 100:879.
  49. Baroncelli GI, Bertelloni S, Ceccarelli C, Saggese G. Effect of growth hormone treatment on final height, phosphate metabolism, and bone mineral density in children with X-linked hypophosphatemic rickets. J Pediatr 2001; 138:236.
  50. Haffner D, Nissel R, Wühl E, Mehls O. Effects of growth hormone treatment on body proportions and final height among small children with X-linked hypophosphatemic rickets. Pediatrics 2004; 113:e593.
  51. Saggese G, Baroncelli GI, Bertelloni S, Perri G. Long-term growth hormone treatment in children with renal hypophosphatemic rickets: effects on growth, mineral metabolism, and bone density. J Pediatr 1995; 127:395.
  52. Alon U, Chan JC. Effects of hydrochlorothiazide and amiloride in renal hypophosphatemic rickets. Pediatrics 1985; 75:754.
  53. Carpenter TO, Keller M, Schwartz D, et al. 24,25 Dihydroxyvitamin D supplementation corrects hyperparathyroidism and improves skeletal abnormalities in X-linked hypophosphatemic rickets--a clinical research center study. J Clin Endocrinol Metab 1996; 81:2381.
  54. 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.
  55. ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26:345.
  56. White KE, Carn G, Lorenz-Depiereux B, et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 2001; 60:2079.
  57. 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.
  58. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19:429.
  59. Larsson T, Marsell R, Schipani E, et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 2004; 145:3087.
  60. Wolf M, White KE. Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Curr Opin Nephrol Hypertens 2014; 23:411.
  61. Drezner MK, Whyte MP. Heritable renal phosphate wasting disorders. In: Genetics of bone biology and skeletal disease, 2nd ed, Thakker RV, Whyte MP, Eisman JA, Igarashi T (Eds), Academic Press, Amsterdam 2017.
  62. Kapelari K, Köhle J, Kotzot D, Högler W. Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets. J Clin Endocrinol Metab 2015; 100:3388.
  63. 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.
  64. Farrow EG, Davis SI, Ward LM, et al. Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets. Bone 2009; 44:287.
  65. Lorenz-Depiereux B, Bastepe M, Benet-Pagès 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.
  66. Gannagé-Yared MH, Makrythanasis P, Chouery E, et al. Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia. Bone 2014; 68:142.
  67. Mäkitie O, Pereira RC, Kaitila I, et al. Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation. J Bone Miner Res 2010; 25:2165.
  68. Turan S, Aydin C, Bereket A, et al. Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia. Bone 2010; 46:402.
  69. Rafaelsen S, Johansson S, Ræder H, Bjerknes R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol 2016; 174:125.
  70. Ichikawa S, Gerard-O'Riley RL, Acton D, et al. A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice. Endocrinology 2017; 158:470.
  71. Gambaro G, Vezzoli G, Casari G, et al. Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am J Kidney Dis 2004; 44:963.
  72. 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.
  73. 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.
  74. Dhir G, Li D, Hakonarson H, Levine MA. Late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH) due to mutation of SLC34A3/NPT2c. Bone 2017; 97:15.
  75. Tieder M, Modai D, Samuel R, et al. Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med 1985; 312:611.
  76. Tieder M, Arie R, Bab I, et al. A new kindred with hereditary hypophosphatemic rickets with hypercalciuria: implications for correct diagnosis and treatment. Nephron 1992; 62:176.
  77. Lau YK, Wasserstein A, Westby GR, et al. Proximal tubular defects in idiopathic hypercalciuria: resistance to phosphate administration. Miner Electrolyte Metab 1982; 7:237.
  78. Scheinman SJ. X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int 1998; 53:3.
  79. Lloyd SE, Pearce SH, Fisher SE, et al. A common molecular basis for three inherited kidney stone diseases. Nature 1996; 379:445.
  80. Scheinman SJ. Chapter 12: Dent's disease. In: Genetic Diseases of the Kidney, Lifton RP, Somlo S, Giebisch GH, Seldin DW (Eds), Academic Press, New York 2009.
  81. Drezner MK. Tumor-induced osteomalacia. In: Primer On the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 4th ed, Favus MJ (Ed), Lippincott Williams & Wilkins, Philadelphia 1999. p.331.
  82. Agus ZS. Oncogenic hypophosphatemic osteomalacia. Kidney Int 1983; 24:113.
  83. Salassa RM, Jowsey J, Arnaud CD. Hypophosphatemic osteomalacia associated with "nonendocrine" tumors. N Engl J Med 1970; 283:65.
  84. Ryan EA, Reiss E. Oncogenous osteomalacia. Review of the world literature of 42 cases and report of two new cases. Am J Med 1984; 77:501.
  85. Folpe AL, Fanburg-Smith JC, Billings SD, et al. 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.
  86. Reyes-Múgica M, Arnsmeier SL, Backeljauw PF, et al. Phosphaturic mesenchymal tumor-induced rickets. Pediatr Dev Pathol 2000; 3:61.
  87. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 29-2001. A 14-year-old boy with abnormal bones and a sacral mass. N Engl J Med 2001; 345:903.
  88. Shane E, Parisien M, Henderson JE, et al. Tumor-induced osteomalacia: clinical and basic studies. J Bone Miner Res 1997; 12:1502.
  89. Cai Q, Hodgson SF, Kao PC, et al. Brief report: inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia. N Engl J Med 1994; 330:1645.
  90. Wilkins GE, Granleese S, Hegele RG, et al. Oncogenic osteomalacia: evidence for a humoral phosphaturic factor. J Clin Endocrinol Metab 1995; 80:1628.
  91. 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.
  92. Feng J, Jiang Y, Wang O, et al. The diagnostic dilemma of tumor induced osteomalacia: a retrospective analysis of 144 cases. Endocr J 2017; 64:675.
  93. Jan de Beur SM, Streeten EA, Civelek AC, et al. Localisation of mesenchymal tumours by somatostatin receptor imaging. Lancet 2002; 359:761.
  94. Duet M, Kerkeni S, Sfar R, et al. Clinical impact of somatostatin receptor scintigraphy in the management of tumor-induced osteomalacia. Clin Nucl Med 2008; 33:752.
  95. Agrawal K, Bhadada S, Mittal BR, et al. Comparison of 18F-FDG and 68Ga DOTATATE PET/CT in localization of tumor causing oncogenic osteomalacia. Clin Nucl Med 2015; 40:e6.
  96. Zhang J, Zhu Z, Zhong D, et al. 68Ga DOTATATE PET/CT is an Accurate Imaging Modality in the Detection of Culprit Tumors Causing Osteomalacia. Clin Nucl Med 2015; 40:642.
  97. El-Maouche D, Sadowski SM, Papadakis GZ, et al. (68)Ga-DOTATATE for Tumor Localization in Tumor-Induced Osteomalacia. J Clin Endocrinol Metab 2016; 101:3575.
  98. Ito N, Shimizu Y, Suzuki H, et al. Clinical utility of systemic venous sampling of FGF23 for identifying tumours responsible for tumour-induced osteomalacia. J Intern Med 2010; 268:390.
  99. Chong WH, Andreopoulou P, Chen CC, et al. Tumor localization and biochemical response to cure in tumor-induced osteomalacia. J Bone Miner Res 2013; 28:1386.
  100. Kawai S, Ariyasu H, Furukawa Y, et al. Effective localization in tumor-induced osteomalacia using (68)Ga-DOTATOC-PET/CT, venous sampling and 3T-MRI. Endocrinol Diabetes Metab Case Rep 2017; 2017.
  101. Seufert J, Ebert K, Müller J, et al. Octreotide therapy for tumor-induced osteomalacia. N Engl J Med 2001; 345:1883.
  102. Paglia F, Dionisi S, Minisola S. Octreotide for tumor-induced osteomalacia. N Engl J Med 2002; 346:1748.