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Hereditary disorders of renal phosphate wasting

Nature Reviews Nephrology volume 6, pages 657–665 (2010)Cite this article

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Abstract

Inherited diseases of renal phosphate handling lead to urinary phosphate wasting and depletion of total body phosphorus stores. Clinical sequelae of inherited disorders that are associated with increased urinary phosphate excretion are deleterious and can lead to abnormal skeletal growth and deformities. This Review describes hereditary disorders of renal phosphate wasting taking into account developments in our understanding of renal phosphate handling from the last decade. The cloning of genes involved in these disorders and further studies on their pathophysiological mechanisms have given important insights in to how phosphatonins, such as FGF-23, regulate renal phosphate reabsorption in health and disease. X-linked dominant hypophosphatemic rickets results from mutation of a metalloprotease (PHEX) that has an unidentified role in FGF-23 degradation. Mutation of an RXXR proteolytic cleavage site in FGF-23 prevents degradation and increases circulating levels of FGF-23 in autosomal dominant hypophosphatemic rickets. FGF-23 acts to remove sodium phosphate co-transporters from the luminal membrane of proximal tubular cells with resultant renal phosphate wasting. Loss of function mutations in genes encoding the transporters NaPi-IIc and NaPi-IIa also result in renal phosphate wasting and rickets.

Key Points

  • Hereditary disorders of renal phosphate wasting are rare genetic diseases

  • X-linked dominant hypophosphatemic rickets is more frequent than autosomal dominant or recessive hypophosphatemic rickets

  • Depending on the disease entity, patients with hereditary disorders of renal phosphate wasting can be symptomatic during childhood or in adulthood

  • Clinically, these disease entities often have similar presentation to nutritional rickets during childhood and to osteomalacia in adults

  • Early diagnosis and treatment could prevent growth retardation and skeletal deformities in children and decrease osteomalacia in adults

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Figure 1: Total body phosphorus homeostasis.
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References

  1. Reilly, R. F. & Perazella, M. A. Nephrology in 30 Days (McGraw-Hill Medical Pub. Division, New York, 2005).

    Google Scholar 

  2. Amanzadeh, J. & Reilly, R. F. Jr. Hypophosphatemia: an evidence-based approach to its clinical consequences and management. Nat. Clin. Pract. Nephrol. 2, 136–148 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Hilfiker, H. et al. Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc. Natl Acad. Sci. USA 95, 14564–14569 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Giral, H. et al. Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate. Am. J. Physiol. Renal Physiol. 297, F1466–F1475 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Danisi, G., Bonjour, J. P. & Straub, R. W. Regulation of Na-dependent phosphate influx across the mucosal border of duodenum by 1,25-dihydroxycholecalciferol. Pflugers Arch. 388, 227–232 (1980).

    Article  CAS  PubMed  Google Scholar 

  6. Danisi, G., Caverzasio, J., Trechsel, U., Bonjour, J. P. & Straub, R. W. Phosphate transport adaptation in rat jejunum and plasma level of 1,25-dihydroxyvitamin D3. Scand. J. Gastroenterol. 25, 210–215 (1990).

    CAS  PubMed  Google Scholar 

  7. Hildmann, B., Storelli, C., Danisi, G. & Murer, H. Regulation of Na+-Pi cotransport by 1,25-dihydroxyvitamin D3 in rabbit duodenal brush-border membrane. Am. J. Physiol. 242, G533–G539 (1982).

    CAS  PubMed  Google Scholar 

  8. Radanovic, T., Wagner, C. A., Murer, H. & Biber, J. Regulation of intestinal phosphate transport. I. Segmental expression and adaptation to low-P(i) diet of the type IIb Na(+)-P(i) cotransporter in mouse small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G496–G500 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Xu, H., Bai, L., Collins, J. F. & Ghishan, F. K. Age-dependent regulation of rat intestinal type IIb sodium-phosphate cotransporter by 1,25-(OH)2 vitamin D3 . Am. J. Physiol. Cell Physiol. 282, C487–C493 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Coe, F. L. & Favus, M. J. Disorders of Bone and Mineral Metabolism, 2nd edn (Lippincott Williams & Wilkins, Philadelphia, 2002).

    Google Scholar 

  11. Lang, F., Greger, R., Marchand, G. R. & Knox, F. G. Stationary microperfusion study of phosphate reabsorption in proximal and distal nephron segments. Pflugers Arch. 368, 45–48 (1977).

    Article  CAS  PubMed  Google Scholar 

  12. Villa-Bellosta, R. et al. The Na+-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. Am. J. Physiol. Renal Physiol. 296, F691–F699 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Segawa, H. et al. Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development. Am. J. Physiol. Renal Physiol. 297, F671–F678 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Murer, H., Forster, I. & Biber, J. The sodium phosphate cotransporter family SLC34. Pflugers Arch. 447, 763–767 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Werner, A. et al. Cloning and expression of cDNA for a Na/Pi cotransport system of kidney cortex. Proc. Natl Acad. Sci. USA 88, 9608–9612 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Busch, A. E. et al. Expression of a renal type I sodium/phosphate transporter (NaPi-1) induces a conductance in Xenopus oocytes permeable for organic and inorganic anions. Proc. Natl Acad. Sci. USA 93, 5347–5351 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Virkki, L. V., Biber, J., Murer, H. & Forster, I. C. Phosphate transporters: a tale of two solute carrier families. Am. J. Physiol. Renal Physiol. 293, F643–F654 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Reimer, R. J. & Edwards, R. H. Organic anion transport is the primary function of the SLC17/type I phosphate transporter family. Pflugers Arch. 447, 629–635 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Beck, L. et al. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc. Natl Acad. Sci. USA 95, 5372–5377 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Prie, D. et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N. Engl. J. Med. 347, 983–991 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Virkki, L. V., Forster, I. C., Hernando, N., Biber, J. & Murer, H. Functional characterization of two naturally occurring mutations in the human sodium-phosphate cotransporter type IIa. J. Bone Miner. Res. 18, 2135–2141 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Lapointe, J. Y. et al. NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak. Kidney Int. 69, 2261–2267 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Magen, D. et al. A loss-of-function mutation in NaPi-IIa and renal Fanconi's syndrome. N. Engl. J. Med. 362, 1102–1109 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Kavanaugh, M. P. et al. Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium-dependent phosphate symporters. Proc. Natl Acad. Sci. USA 91, 7071–-7075 (1994).

  25. Miller, D. G. & Miller, A. D. A family of retroviruses that utilize related phosphate transporters for cell entry. J. Virol. 68, 8270–8276 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Tenenhouse, H. S., Roy, S., Martel, J. & Gauthier, C. Differential expression, abundance, and regulation of Na+-phosphate cotransporter genes in murine kidney. Am. J. Physiol. 275, F527–F534 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Leung, J. C., Barac-Nieto, M., Hering-Smith, K. & Silverstein, D. M. Expression of the rat renal PiT-2 phosphate transporter. Horm. Metab. Res. 37, 265–269 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Nowik, M. et al. Renal phosphaturia during metabolic acidosis revisited: molecular mechanisms for decreased renal phosphate reabsorption. Pflugers Arch. 457, 539–549 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Breusegem, S. Y. et al. Differential regulation of the renal sodium-phosphate cotransporters NaPi-IIa, NaPi-IIc, and PiT-2 in dietary potassium deficiency. Am. J. Physiol. Renal Physiol. 297, F350–F361 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Villa-Bellosta, R. & Sorribas, V. Compensatory regulation of the sodium/phosphate cotransporters NaPi-IIc (SCL34A3) and Pit-2 (SLC20A2) during Pi deprivation and acidosis. Pflugers Arch. 459, 499–508 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Moe, O. W. PiT-2 coming out of the pits. Am. J. Physiol. Renal Physiol. 296, F689–F690 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Forster, I. C., Loo, D. D. & Eskandari, S. Stoichiometry and Na+ binding cooperativity of rat and flounder renal type II Na+-Pi cotransporters. Am. J. Physiol. 276, F644–F649 (1999).

    CAS  PubMed  Google Scholar 

  33. Segawa, H. et al. Growth-related renal type II Na/Pi cotransporter. J. Biol. Chem. 277, 19665–19672 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Ravera, S., Virkki, L. V., Murer, H. & Forster, I. C. Deciphering PiT transport kinetics and substrate specificity using electrophysiology and flux measurements. Am. J. Physiol. Cell Physiol. 293, C606–C620 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Berndt, T. & Kumar, R. Phosphatonins and the regulation of phosphate homeostasis. Annu. Rev. Physiol. 69, 341–359 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Miyamoto, K., Ito, M., Tatsumi, S., Kuwahata, M. & Segawa, H. New aspect of renal phosphate reabsorption: the type IIc sodium-dependent phosphate transporter. Am. J. Nephrol. 27, 503–515 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Murer, H., Hernando, N., Forster, I. & Biber, J. Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol. Rev. 80, 1373–1409 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Cai, Q. et al. Brief report: inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia. N. Engl. J. Med. 330, 1645–1649 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Econs, M. J. & Drezner, M. K. Tumor-induced osteomalacia—unveiling a new hormone. N. Engl. J. Med. 330, 1679–1681 (1994).

    Article  CAS  PubMed  Google Scholar 

  40. Weidner, N. & Santa Cruz, D. Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets. Cancer 59, 1442–1454 (1987).

    Article  CAS  PubMed  Google Scholar 

  41. ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat. Genet. 26, 345–348 (2000).

  42. Carpenter, T. O. et al. Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. J. Clin. Endocrinol. Metab. 90, 1012–1020 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Dobbie, H., Unwin, R. J., Faria, N. J. & Shirley, D. G. Matrix extracellular phosphoglycoprotein causes phosphaturia in rats by inhibiting tubular phosphate reabsorption. Nephrol. Dial. Transplant. 23, 730–733 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Berndt, T. et al. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J. Clin. Invest. 112, 785–794 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shaikh, A., Berndt, T. & Kumar, R. Regulation of phosphate homeostasis by the phosphatonins and other novel mediators. Pediatr. Nephrol. 23, 1203–1210 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Shimada, T. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J. Bone Miner. Res. 19, 429–435 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Perwad, F., Zhang, M. Y., Tenenhouse, H. S. & Portale, A. A. Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1-alpha-hydroxylase expression in vitro. Am. J. Physiol. Renal Physiol. 293, F1577–F1583 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Perwad, F. et al. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146, 5358–5364 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Antoniucci, D. M., Yamashita, T. & Portale, A. A. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J. Clin. Endocrinol. Metab. 91, 3144–3149 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Nishida, Y. et al. Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney Int. 70, 2141–2147 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Shimada, T. et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem. Biophys. Res. Commun. 314, 409–414 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Shimada, T. et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc. Natl Acad. Sci. USA 98, 6500–6505 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Farrow, E. G. & White, K. E. Recent advances in renal phosphate handling. Nat. Rev. Nephrol. 6, 207–217 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Prie, D., Urena Torres, P. & Friedlander, G. Latest findings in phosphate homeostasis. Kidney Int. 75, 882–889 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Gaasbeek, A. & Meinders, A. E. Hypophosphatemia: an update on its etiology and treatment. Am. J. Med. 118, 1094–1101 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Young, J. A., Lichtman, M. A. & Cohen, J. Reduced red cell 2,3-diphosphoglycerate and adenosine triphosphate, hypophosphatemia, and increased hemoglobin-oxygen affinity after cardiac surgery. Circulation 47, 1313–1318 (1973).

    Article  CAS  PubMed  Google Scholar 

  58. Hettleman, B. D., Sabina, R. L., Drezner, M. K., Holmes, E. W. & Swain, J. L. Defective adenosine triphosphate synthesis. An explanation for skeletal muscle dysfunction in phosphate-deficient mice. J. Clin. Invest. 72, 582–589 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. de Menezes Filho, H., de Castro, L. C. & Damiani, D. Hypophosphatemic rickets and osteomalacia. Arq. Bras. Endocrinol. Metabol. 50, 802–813 (2006).

    Article  PubMed  Google Scholar 

  60. Hypophosphatemic rickets, X-linked dominant Online Mendelian Inheritance in Man [online].

  61. Winters, R. W., Graham, J. B., Williams, T. F., McFalls, V. W. & Burnett, C. H. A genetic study of familial hypophosphatemia and vitamin D resistant rickets with a review of the literature. Medicine (Baltimore) 37, 97–142 (1958).

    Article  CAS  Google Scholar 

  62. Morgan, J. M., Hawley, W. L, Chenoweth, A. I., Retan, W. J. & Diethelm, A. G. Renal transplantation in hypophosphatemia with vitamin D-resistant rickets. Arch. Intern. Med. 134, 549–552 (1974).

    Article  CAS  PubMed  Google Scholar 

  63. Phosphate-regulating endopeptidase homolog, X-linked; PHEX Online Mendelian Inheritance in Man [online].

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

  65. Guo, R. & Quarles, L. D. Cloning and sequencing of human PEX from a bone cDNA library: evidence for its developmental stage-specific regulation in osteoblasts. J. Bone Miner. Res. 12, 1009–1017 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Holm, I. A., Huang, X. & Kunkel, L. M. Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets. Am. J. Hum. Genet. 60, 790–797 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Dixon, P. H. et al. Mutational analysis of PHEX gene in X-linked hypophosphatemia. J. Clin. Endocrinol. Metab. 83, 3615–3623 (1998).

    CAS  PubMed  Google Scholar 

  68. Filisetti, D. et al. Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues. Eur. J. Hum. Genet. 7, 615–619 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Bowe, A. E. et al. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem. Biophys. Res. Commun. 284, 977–981 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Benet-Pages, A. et al. FGF23 is processed by proprotein convertases but not by PHEX. Bone 35, 455–462 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Liu, S. et al. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J. Biol. Chem. 278, 37419–37426 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Strom, T. M. & Juppner, H. PHEX, FGF23, DMP1 and beyond. Curr. Opin. Nephrol. Hypertens. 17, 357–362 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Hypophosphatemic rickets, Autosomal dominant; ADHR Online Mendelian Inheritance in Man [online].

  74. Bianchine, J. W., Stambler, A. A. & Harrison, H. E. Familial hypophosphatemic rickets showing autosomal dominant inheritance. Birth Defects Orig. Artic. Ser. 7, 287–295 (1971).

    CAS  PubMed  Google Scholar 

  75. Riminucci, M. et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J. Clin. Invest. 112, 683–692 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mirams, M., Robinson, B. G., Mason, R. S. & Nelson, A. E. Bone as a source of FGF23: regulation by phosphate? Bone 35, 1192–1199 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Shimada, T. et al. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am. J. Physiol. Renal Physiol. 289, F1088–F1095 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Larsson, T. 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 145, 3087–3094 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Fibroblast growth factor 23; FGF23 Online Mendelian Inheritance in Man, [online].

  80. Gribaa, M. et al. An autosomal dominant hypophosphatemic rickets phenotype in a Tunisian family caused by a new FGF23 missense mutation. J. Bone Miner. Metab. 28, 111–115 (2009).

    Article  PubMed  Google Scholar 

  81. Econs, M. J. & McEnery, P. T. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J. Clin. Endocrinol. Metab. 82, 674–681 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Hypophosphatemic rickets, autosomal recessive, 1; ARHR1 Online Mendelian Inheritance in Man, [online].

  83. Feng, J. Q. et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat. Genet. 38, 1310–1315 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lorenz-Depiereux, B. et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat. Genet. 38, 1248–1250 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dentin matrix acidic phosphoprotein 1; DMP1 Online Mendelian Inheritance in Man, [online].

  86. George, A., Sabsay, B., Simonian, P. A. & Veis, A. Characterization of a novel dentin matrix acidic phosphoprotein. Implications for induction of biomineralization. J. Biol. Chem. 268, 12624–12630 (1993).

    CAS  PubMed  Google Scholar 

  87. George, A., Ramachandran, A., Albazzaz, M. & Ravindran, S. DMP1-a key regulator in mineralized matrix formation. J. Musculoskelet. Neuronal Interact. 7, 308 (2007).

    CAS  PubMed  Google Scholar 

  88. Narayanan, K. et al. Dual functional roles of dentin matrix protein 1. Implications in biomineralization and gene transcription by activation of intracellular Ca2+ store. J. Biol. Chem. 278, 17500–17508 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Levy-Litan, V. et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am. J. Hum. Genet. 86, 273–278 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rutsch, F. et al. Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification. Nat. Genet. 34, 379–381 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Hypophosphatemic rickets with hypercalciuria, hereditary; HHRH Online Mendelian Inheritance in Man, [online].

  92. Lorenz-Depiereux, B. et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am. J. Hum. Genet. 78, 193–201 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Bergwitz, C. 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. 78, 179–192 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Solute carrier family 34 (sodium/phosphate cotransporter), member 3; SLC34A3 Online Mendelian Inheritance in Man, [online].

  95. Tieder, M. et al. Hereditary hypophosphatemic rickets with hypercalciuria. N. Engl. J. Med. 312, 611–617 (1985).

    Article  CAS  PubMed  Google Scholar 

  96. Tencza, A. L. et al. Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter: presentation as hypercalciuria and nephrolithiasis. J. Clin. Endocrinol. Metab. 94, 4433–4438 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kremke, B. et al. 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 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Page, K., Bergwitz, C., Jaureguiberry, G., Harinarayan, C. V. & Insogna, K. A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3. Endocr. Pract. 14, 869–874 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Tieder, M. et al. Elevated serum 1,25-dihydroxyvitamin D concentrations in siblings with primary Fanconi's syndrome. N. Engl. J. Med. 319, 845–849 (1988).

    Article  CAS  PubMed  Google Scholar 

  100. McCune-albright syndrome; MAS Online Mendelian Inheritance in Man, [online].

  101. Weinstein, L. S. et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N. Engl. J. Med. 325, 1688–1695 (1991).

    Article  CAS  PubMed  Google Scholar 

  102. Chapurlat, R. D. & Orcel, P. Fibrous dysplasia of bone and McCune-Albright syndrome. Best Pract. Res. Clin. Rheumatol. 22, 55–69 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Yamamoto, T. et al. The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune-Albright syndrome. J. Bone Miner. Metab. 23, 231–237 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Collins, M. T. 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. 16, 806–813 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Kobayashi, K. et al. Expression of FGF23 is correlated with serum phosphate level in isolated fibrous dysplasia. Life Sci. 78, 2295–2301 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Faroqui, S., Levi, M., Soleimani, M. & Amlal, H. Estrogen downregulates the proximal tubule type IIa sodium phosphate cotransporter causing phosphate wasting and hypophosphatemia. Kidney Int. 73, 1141–1150 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ishiguro, M. et al. Thyroid hormones regulate phosphate homoeostasis through transcriptional control of the renal type IIa sodium-dependent phosphate co-transporter (Npt2a) gene. Biochem. J. 427, 161–169 (2010).

    Article  CAS  PubMed  Google Scholar 

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Laurie Barclay, Medscape, LLC, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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  1. Division of Nephrology, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Room 416, Baltimore, 21205, MD, USA

    Amir S. Alizadeh Naderi

  2. Department of Medicine 111, University of Texas Southwestern Medical Center at Dallas, VA North Texas Heath Care System, Dallas, 75390, TX, USA

    Robert F. Reilly

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Alizadeh Naderi, A., Reilly, R. Hereditary disorders of renal phosphate wasting. Nat Rev Nephrol 6, 657–665 (2010). https://doi.org/10.1038/nrneph.2010.121

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