Skip to main content
Top
Published in: Current Osteoporosis Reports 2/2015

01-04-2015 | Rare Bone Disease (CB Langman and E Shore, Section Editors)

Hypophosphatemic Rickets: Lessons from Disrupted FGF23 Control of Phosphorus Homeostasis

Authors: Bracha K. Goldsweig, Thomas O. Carpenter

Published in: Current Osteoporosis Reports | Issue 2/2015

Login to get access

Abstract

Fibroblast growth factor-23 (FGF23) regulates phosphate reabsorption in the kidney and therefore plays an essential role in phosphate balance in humans. There is a host of defects that ultimately lead to excess FGF23 levels and thereby cause renal phosphate wasting and hypophosphatemic rickets. We describe the genetic, pathophysiologic, and clinical aspects of this group of disorders with a focus on X-linked hypophosphatemia (XLH), the best characterized of these abnormalities. We also discuss autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR) and tumor-induced osteomalacia (TIO) in addition to other rarer FGF23-mediated conditions. We contrast the FGF23-mediated disorders with FGF23-independent hypophosphatemia, specifically hypophosphatemic rickets with hypercalciuria (HHRH). Errant diagnosis of hypophosphatemic disorders is common. This review aims to enhance the recognition and appropriate diagnosis of hypophosphatemia and to guide appropriate treatment.
Literature
1.
go back to reference Winters RW, Graham JB, Williams TF, McFalls VW, Burnett CH. A genetic study of familial hypophosphatemia and vitamin D resistant rickets with a review of the literature. Medicine. 1958;37:97–142.CrossRefPubMed Winters RW, Graham JB, Williams TF, McFalls VW, Burnett CH. A genetic study of familial hypophosphatemia and vitamin D resistant rickets with a review of the literature. Medicine. 1958;37:97–142.CrossRefPubMed
2.
go back to reference The HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet. 1995;11:130–6. The HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet. 1995;11:130–6.
3.
go back to reference White KE. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26:345–8.CrossRef White KE. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26:345–8.CrossRef
4.
go back to reference Berndt T, Thomas LF, Craig TA, Sommer S, Li X, Bergstralh EJ, et al. Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption. Proc Natl Acad Sci U S A. 2007;104:11085–90.CrossRefPubMedCentralPubMed Berndt T, Thomas LF, Craig TA, Sommer S, Li X, Bergstralh EJ, et al. Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption. Proc Natl Acad Sci U S A. 2007;104:11085–90.CrossRefPubMedCentralPubMed
5.
go back to reference Lee DB, Walling MW, Brautbar N. Intestinal phosphate absorption: influence of vitamin D and non-vitamin D factors. Am J Physiol. 1986;250:G369–73.PubMed Lee DB, Walling MW, Brautbar N. Intestinal phosphate absorption: influence of vitamin D and non-vitamin D factors. Am J Physiol. 1986;250:G369–73.PubMed
6.
go back to reference Sabbagh Y, O’Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C, et al. Intestinal npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol. 2009;20:2348–58.CrossRefPubMedCentralPubMed Sabbagh Y, O’Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C, et al. Intestinal npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol. 2009;20:2348–58.CrossRefPubMedCentralPubMed
7.
go back to reference Marks J, Debnam ES, Unwin RJ. Phosphate homeostasis and the renal-gastrointestinal axis. Am J Physiol Renal Physiol. 2010;299:F285–96.CrossRefPubMed Marks J, Debnam ES, Unwin RJ. Phosphate homeostasis and the renal-gastrointestinal axis. Am J Physiol Renal Physiol. 2010;299:F285–96.CrossRefPubMed
8.
go back to reference Villa-Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, 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. 2009;296:F691–9.CrossRefPubMedCentralPubMed Villa-Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, 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. 2009;296:F691–9.CrossRefPubMedCentralPubMed
9.
go back to reference Murer H, Forster I, Hernando N, Lambert G, Traebert M, Biber J. Posttranscriptional regulation of the proximal tubule NaPi-II transporter in response to PTH and dietary P(i). Am J Physiol. 1999;277:F676–84.PubMed Murer H, Forster I, Hernando N, Lambert G, Traebert M, Biber J. Posttranscriptional regulation of the proximal tubule NaPi-II transporter in response to PTH and dietary P(i). Am J Physiol. 1999;277:F676–84.PubMed
10.
go back to reference Murer H, Forster I, Hilfiker H, Pfister M, Kaissling B, Lotscher M, et al. Cellular/molecular control of renal Na/Pi-cotransport. Kidney Int Suppl. 1998;65:S2–S10.CrossRefPubMed Murer H, Forster I, Hilfiker H, Pfister M, Kaissling B, Lotscher M, et al. Cellular/molecular control of renal Na/Pi-cotransport. Kidney Int Suppl. 1998;65:S2–S10.CrossRefPubMed
11.
go back to reference Oberbauer R, Schreiner GF, Biber J, Murer H, Meyer TW. In vivo suppression of the renal Na+/Pi cotransporter by antisense oligonucleotides. Proc Natl Acad Sci U S A. 1996;93:4903–6.CrossRefPubMedCentralPubMed Oberbauer R, Schreiner GF, Biber J, Murer H, Meyer TW. In vivo suppression of the renal Na+/Pi cotransporter by antisense oligonucleotides. Proc Natl Acad Sci U S A. 1996;93:4903–6.CrossRefPubMedCentralPubMed
12.
go back to reference Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci U S A. 1998;95:5372–7.CrossRefPubMedCentralPubMed Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci U S A. 1998;95:5372–7.CrossRefPubMedCentralPubMed
13.
go back to reference Hoag HM, Martel J, Gauthier C, Tenenhouse HS. Effects of Npt2 gene ablation and low-phosphate diet on renal Na(+)/phosphate cotransport and cotransporter gene expression. J Clin Invest. 1999;104:679–86.CrossRefPubMedCentralPubMed Hoag HM, Martel J, Gauthier C, Tenenhouse HS. Effects of Npt2 gene ablation and low-phosphate diet on renal Na(+)/phosphate cotransport and cotransporter gene expression. J Clin Invest. 1999;104:679–86.CrossRefPubMedCentralPubMed
14.
go back to reference Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, 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;78:179–92.CrossRefPubMedCentralPubMed Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, 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;78:179–92.CrossRefPubMedCentralPubMed
15.•
go back to reference Biber J, Hernando N, Forster I. Phosphate transporters and their function. Annu Rev Physiol. 2013;75:535–50. Reviews the regulation of phosphate absorption in the kidney through NaPi-IIa and NaPi-IIc cotransporters.CrossRefPubMed Biber J, Hernando N, Forster I. Phosphate transporters and their function. Annu Rev Physiol. 2013;75:535–50. Reviews the regulation of phosphate absorption in the kidney through NaPi-IIa and NaPi-IIc cotransporters.CrossRefPubMed
16.
go back to reference Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG, et al. Pex/PEX tissue distribution and evidence for a deletion in the 3′ region of the Pex gene in X-linked hypophosphatemic mice. J Clin Invest. 1997;99:1200–9.CrossRefPubMedCentralPubMed Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG, et al. Pex/PEX tissue distribution and evidence for a deletion in the 3′ region of the Pex gene in X-linked hypophosphatemic mice. J Clin Invest. 1997;99:1200–9.CrossRefPubMedCentralPubMed
17.
go back to reference Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003;348:1656–63.CrossRefPubMed Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003;348:1656–63.CrossRefPubMed
18.
go back to reference Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab. 2002;87:4957–60.CrossRefPubMed Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab. 2002;87:4957–60.CrossRefPubMed
19.
go back to reference 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;278:37419–26.CrossRefPubMed 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;278:37419–26.CrossRefPubMed
20.
go back to reference Tenenhouse HS, Beck L. Renal Na(+)-phosphate cotransporter gene expression in X-linked Hyp and Gy mice. Kidney Int. 1996;49(4):1027–32.CrossRefPubMed Tenenhouse HS, Beck L. Renal Na(+)-phosphate cotransporter gene expression in X-linked Hyp and Gy mice. Kidney Int. 1996;49(4):1027–32.CrossRefPubMed
21.
go back to reference Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, et al. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun. 2001;284:977–81.CrossRefPubMed Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, et al. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun. 2001;284:977–81.CrossRefPubMed
22.
go back to reference Perwad F, Zhang MY, Tenenhouse HS, Portale AA. 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:F1577–83.CrossRefPubMed Perwad F, Zhang MY, Tenenhouse HS, Portale AA. 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:F1577–83.CrossRefPubMed
23.
go back to reference Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19:429–35.CrossRefPubMed Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19:429–35.CrossRefPubMed
24.••
go back to reference Carpenter TO, Imel EA, Holm IA, de Beur SM J, Insogna KL. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26:1381–8. Reviews clinical and biochemical features of XLH. Discusses current treatment and monitoring recommendations for individuals with XLH.CrossRefPubMedCentralPubMed Carpenter TO, Imel EA, Holm IA, de Beur SM J, Insogna KL. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26:1381–8. Reviews clinical and biochemical features of XLH. Discusses current treatment and monitoring recommendations for individuals with XLH.CrossRefPubMedCentralPubMed
25.
go back to reference Stickler GB. Familial hypophosphatemic vitamin D resistant rickets. The neonatal period and infancy. Acta Paediatr Scand. 1969;58:213–9.CrossRefPubMed Stickler GB. Familial hypophosphatemic vitamin D resistant rickets. The neonatal period and infancy. Acta Paediatr Scand. 1969;58:213–9.CrossRefPubMed
26.
go back to reference McNair SL, Stickler GB. Growth in familial hypophosphatemic vitamin-D-resistant rickets. N Engl J Med. 1969;281:512–6.CrossRefPubMed McNair SL, Stickler GB. Growth in familial hypophosphatemic vitamin-D-resistant rickets. N Engl J Med. 1969;281:512–6.CrossRefPubMed
27.
go back to reference Frost HM. A unique histological feature of vitamin D resistant rickets observed in four cases. Acta Orthop Scand. 1963;33:220–6.CrossRefPubMed Frost HM. A unique histological feature of vitamin D resistant rickets observed in four cases. Acta Orthop Scand. 1963;33:220–6.CrossRefPubMed
28.
go back to reference Reid IR, Hardy DC, Murphy WA, Teitelbaum SL, Bergfeld MA, Whyte MP. X-linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults. Medicine. 1989;68:336–52.CrossRefPubMed Reid IR, Hardy DC, Murphy WA, Teitelbaum SL, Bergfeld MA, Whyte MP. X-linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults. Medicine. 1989;68:336–52.CrossRefPubMed
29.
go back to reference Marie PJ, Glorieux FH. Bone histomorphometry in asymptomatic adults with hereditary hypophosphatemic vitamin D-resistant osteomalacia. Metab Bone Dis Relat Res. 1982;4:249–53.CrossRefPubMed Marie PJ, Glorieux FH. Bone histomorphometry in asymptomatic adults with hereditary hypophosphatemic vitamin D-resistant osteomalacia. Metab Bone Dis Relat Res. 1982;4:249–53.CrossRefPubMed
30.
go back to reference Marie PJ, Glorieux FH. Histomorphometric study of bone remodeling in hypophosphatemic vitamin D-resistant rickets. Metab Bone Dis Relat Res. 1981;3:31–8.CrossRefPubMed Marie PJ, Glorieux FH. Histomorphometric study of bone remodeling in hypophosphatemic vitamin D-resistant rickets. Metab Bone Dis Relat Res. 1981;3:31–8.CrossRefPubMed
31.
go back to reference Abe K, Ooshima T, Lily TS, Yasufuku Y, Sobue S. Structural deformities of deciduous teeth in patients with hypophosphatemic vitamin D-resistant rickets. Oral Surg Oral Med Oral Pathol. 1988;65:191–8.CrossRefPubMed Abe K, Ooshima T, Lily TS, Yasufuku Y, Sobue S. Structural deformities of deciduous teeth in patients with hypophosphatemic vitamin D-resistant rickets. Oral Surg Oral Med Oral Pathol. 1988;65:191–8.CrossRefPubMed
32.
go back to reference Hillmann G, Geurtsen W. Pathohistology of undecalcified primary teeth in vitamin D-resistant rickets: review and report of two cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:218–24.CrossRefPubMed Hillmann G, Geurtsen W. Pathohistology of undecalcified primary teeth in vitamin D-resistant rickets: review and report of two cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:218–24.CrossRefPubMed
33.
go back to reference Seeto E, Seow WK. Scanning electron microscopic analysis of dentin in vitamin D-resistant rickets—assessment of mineralization and correlation with clinical findings. Pediatr Dent. 1991;13:43–8.PubMed Seeto E, Seow WK. Scanning electron microscopic analysis of dentin in vitamin D-resistant rickets—assessment of mineralization and correlation with clinical findings. Pediatr Dent. 1991;13:43–8.PubMed
34.
go back to reference Seow WK, Romaniuk K, Sclavos S. Micromorphologic features of dentin in vitamin D-resistant rickets: correlation with clinical grading of severity. Pediatr Dent. 1989;11:203–8.PubMed Seow WK, Romaniuk K, Sclavos S. Micromorphologic features of dentin in vitamin D-resistant rickets: correlation with clinical grading of severity. Pediatr Dent. 1989;11:203–8.PubMed
35.
go back to reference Liang G, Katz LD, Insogna KL, Carpenter TO, Macica CM. Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice. Calcif Tissue Int. 2009;85:235–46.CrossRefPubMedCentralPubMed Liang G, Katz LD, Insogna KL, Carpenter TO, Macica CM. Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice. Calcif Tissue Int. 2009;85:235–46.CrossRefPubMedCentralPubMed
36.
go back to reference Berndt M, Ehrich JH, Lazovic D, Zimmermann J, Hillmann G, Kayser C, et al. Clinical course of hypophosphatemic rickets in 23 adults. Clin Nephrol. 1996;45:33–41.PubMed Berndt M, Ehrich JH, Lazovic D, Zimmermann J, Hillmann G, Kayser C, et al. Clinical course of hypophosphatemic rickets in 23 adults. Clin Nephrol. 1996;45:33–41.PubMed
37.
go back to reference Liang G, Vanhouten J, Macica CM. An atypical degenerative osteoarthropathy in Hyp mice is characterized by a loss in the mineralized zone of articular cartilage. Calcif Tissue Int. 2011;89:151–62.CrossRefPubMed Liang G, Vanhouten J, Macica CM. An atypical degenerative osteoarthropathy in Hyp mice is characterized by a loss in the mineralized zone of articular cartilage. Calcif Tissue Int. 2011;89:151–62.CrossRefPubMed
38.
go back to reference Megerian CA, Semaan MT, Aftab S, Kisley LB, Zheng QY, Pawlowski KS, et al. A mouse model with postnatal endolymphatic hydrops and hearing loss. Hear Res. 2008;237:90–105.CrossRefPubMedCentralPubMed Megerian CA, Semaan MT, Aftab S, Kisley LB, Zheng QY, Pawlowski KS, et al. A mouse model with postnatal endolymphatic hydrops and hearing loss. Hear Res. 2008;237:90–105.CrossRefPubMedCentralPubMed
39.
go back to reference Lorenz-Depiereux B, Guido VE, Johnson KR, Zheng QY, Gagnon LH, Bauschatz JD, et al. New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice. Mamm Genome. 2004;15:151–61.CrossRefPubMedCentralPubMed Lorenz-Depiereux B, Guido VE, Johnson KR, Zheng QY, Gagnon LH, Bauschatz JD, et al. New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice. Mamm Genome. 2004;15:151–61.CrossRefPubMedCentralPubMed
40.
go back to reference Carpenter TO, Mitnick MA, Ellison A, Smith C, Insogna KL. Nocturnal hyperparathyroidism: a frequent feature of X-linked hypophosphatemia. J Clin Endocrinol Metab. 1994;78:1378–83.PubMed Carpenter TO, Mitnick MA, Ellison A, Smith C, Insogna KL. Nocturnal hyperparathyroidism: a frequent feature of X-linked hypophosphatemia. J Clin Endocrinol Metab. 1994;78:1378–83.PubMed
41.
go back to reference Makitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 2003;88:3591–7.CrossRefPubMed Makitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 2003;88:3591–7.CrossRefPubMed
42.
go back to reference Verge CF, Lam A, Simpson JM, Cowell CT, Howard NJ, Silink M. Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med. 1991;325:1843–8.CrossRefPubMed Verge CF, Lam A, Simpson JM, Cowell CT, Howard NJ, Silink M. Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med. 1991;325:1843–8.CrossRefPubMed
43.
go back to reference Sullivan W, Carpenter T, Glorieux F, Travers R, Insogna K. A prospective trial of phosphate and 1,25-dihydroxyvitamin D3 therapy in symptomatic adults with X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 1992;75:879–85.PubMed Sullivan W, Carpenter T, Glorieux F, Travers R, Insogna K. A prospective trial of phosphate and 1,25-dihydroxyvitamin D3 therapy in symptomatic adults with X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 1992;75:879–85.PubMed
44.
go back to reference Seikaly MG, Brown R, Baum M. The effect of recombinant human growth hormone in children with X-linked hypophosphatemia. Pediatrics. 1997;100:879–84.CrossRefPubMed Seikaly MG, Brown R, Baum M. The effect of recombinant human growth hormone in children with X-linked hypophosphatemia. Pediatrics. 1997;100:879–84.CrossRefPubMed
45.
go back to reference Haffner D, Wuhl E, Blum WF, Schaefer F, Mehls O. Disproportionate growth following long-term growth hormone treatment in short children with X-linked hypophosphataemia. Eur J Pediatr. 1995;154:610–3.CrossRefPubMed Haffner D, Wuhl E, Blum WF, Schaefer F, Mehls O. Disproportionate growth following long-term growth hormone treatment in short children with X-linked hypophosphataemia. Eur J Pediatr. 1995;154:610–3.CrossRefPubMed
46.
go back to reference Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S, Quarles LD. Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol. 2008;3:658–64.CrossRefPubMedCentralPubMed Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S, Quarles LD. Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol. 2008;3:658–64.CrossRefPubMedCentralPubMed
47.
go back to reference Grove-Laugesen D, Rejnmark L. Three-year successful cinacalcet treatment of secondary hyperparathyroidism in a patient with x-linked dominant hypophosphatemic rickets: a case report. Case Rep Endocrinol. 2014;2014:479641.PubMedCentralPubMed Grove-Laugesen D, Rejnmark L. Three-year successful cinacalcet treatment of secondary hyperparathyroidism in a patient with x-linked dominant hypophosphatemic rickets: a case report. Case Rep Endocrinol. 2014;2014:479641.PubMedCentralPubMed
48.••
go back to reference Carpenter TO, Olear EA, Zhang JH, Ellis BK, Simpson CA, Cheng D, et al. Effect of paricalcitol on circulating parathyroid hormone in X-linked hypophosphatemia: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2014;99:3103–11. Reports results from a clinical trial using Paricalcitol to treat secondary hyperparathyroidism in XLH.CrossRefPubMed Carpenter TO, Olear EA, Zhang JH, Ellis BK, Simpson CA, Cheng D, et al. Effect of paricalcitol on circulating parathyroid hormone in X-linked hypophosphatemia: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2014;99:3103–11. Reports results from a clinical trial using Paricalcitol to treat secondary hyperparathyroidism in XLH.CrossRefPubMed
49.
go back to reference Alon U, Chan JC. Effects of hydrochlorothiazide and amiloride in renal hypophosphatemic rickets. Pediatrics. 1985;75:754–63.PubMed Alon U, Chan JC. Effects of hydrochlorothiazide and amiloride in renal hypophosphatemic rickets. Pediatrics. 1985;75:754–63.PubMed
50.
go back to reference Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I, et al. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res. 2009;24:1879–88.CrossRefPubMed Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I, et al. Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res. 2009;24:1879–88.CrossRefPubMed
51.••
go back to reference Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014;124:1587–97. Reports results from a clinical trial using anti-FGF23 antibody to treat XLH by targeting the underlying disease-causing mechanism, FGF23 excess.CrossRefPubMedCentralPubMed Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014;124:1587–97. Reports results from a clinical trial using anti-FGF23 antibody to treat XLH by targeting the underlying disease-causing mechanism, FGF23 excess.CrossRefPubMedCentralPubMed
52.
53.
go back to reference 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;60:2079–86.CrossRefPubMed 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;60:2079–86.CrossRefPubMed
54.
go back to reference Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology. 2002;143:3179–82.CrossRefPubMed Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology. 2002;143:3179–82.CrossRefPubMed
55.
go back to reference Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res. 2007;22:520–6.CrossRefPubMed Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res. 2007;22:520–6.CrossRefPubMed
56.
go back to reference Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab. 1997;82:674–81.CrossRefPubMed Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab. 1997;82:674–81.CrossRefPubMed
57.
go back to reference Farrow EG, Yu X, Summers LJ, Davis SI, Fleet JC, Allen MR, et al. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A. 2011;108:E1146–55.CrossRefPubMedCentralPubMed Farrow EG, Yu X, Summers LJ, Davis SI, Fleet JC, Allen MR, et al. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A. 2011;108:E1146–55.CrossRefPubMedCentralPubMed
58.
go back to reference Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. 2011;96:3541–9.CrossRefPubMedCentralPubMed Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. 2011;96:3541–9.CrossRefPubMedCentralPubMed
59.
go back to reference Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006;38:1310–5.CrossRefPubMedCentralPubMed Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006;38:1310–5.CrossRefPubMedCentralPubMed
60.
go back to reference Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet. 2006;38:1248–50.CrossRefPubMed Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet. 2006;38:1248–50.CrossRefPubMed
61.
go back to reference Perry W, Stamp TC. Hereditary hypophosphataemic rickets with autosomal recessive inheritance and severe osteosclerosis. A report of two cases. J Bone Joint Surg Br. 1978;60-B:430–4.PubMed Perry W, Stamp TC. Hereditary hypophosphataemic rickets with autosomal recessive inheritance and severe osteosclerosis. A report of two cases. J Bone Joint Surg Br. 1978;60-B:430–4.PubMed
62.
go back to reference 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;86:267–72.CrossRefPubMedCentralPubMed 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;86:267–72.CrossRefPubMedCentralPubMed
63.
go back to reference Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet. 2010;86:273–8.CrossRefPubMedCentralPubMed Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet. 2010;86:273–8.CrossRefPubMedCentralPubMed
64.
go back to reference Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, et al. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet. 2003;34:379–81.CrossRefPubMed Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, et al. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet. 2003;34:379–81.CrossRefPubMed
65.
go back to reference White KE, Jonsson KB, Carn G, Hampson G, Spector TD, Mannstadt M, et al. The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. J Clin Endocrinol Metab. 2001;86:497–500.CrossRefPubMed White KE, Jonsson KB, Carn G, Hampson G, Spector TD, Mannstadt M, et al. The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. J Clin Endocrinol Metab. 2001;86:497–500.CrossRefPubMed
66.
go back to reference Weidner N. Review and update: oncogenic osteomalacia-rickets. Ultrastruct Pathol. 1991;15:317–33.CrossRefPubMed Weidner N. Review and update: oncogenic osteomalacia-rickets. Ultrastruct Pathol. 1991;15:317–33.CrossRefPubMed
67.
go back to reference Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY, 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;28:1–30.CrossRefPubMed Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY, 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;28:1–30.CrossRefPubMed
68.
69.•
go back to reference Chong WH, Molinolo AA, Chen CC, Collins MT. Tumor-induced osteomalacia. Endocr Relat Cancer. 2011;18:R53–77. A comprehensive review of clinical aspects of tumor-induced osteomalacia with attention to recent developments in diagnostics and tumor localization.CrossRefPubMedCentralPubMed Chong WH, Molinolo AA, Chen CC, Collins MT. Tumor-induced osteomalacia. Endocr Relat Cancer. 2011;18:R53–77. A comprehensive review of clinical aspects of tumor-induced osteomalacia with attention to recent developments in diagnostics and tumor localization.CrossRefPubMedCentralPubMed
70.
go back to reference Geller JL, Khosravi A, Kelly MH, Riminucci M, Adams JS, Collins MT. Cinacalcet in the management of tumor-induced osteomalacia. J Bone Miner Res. 2007;22:931–7.CrossRefPubMed Geller JL, Khosravi A, Kelly MH, Riminucci M, Adams JS, Collins MT. Cinacalcet in the management of tumor-induced osteomalacia. J Bone Miner Res. 2007;22:931–7.CrossRefPubMed
72.
go back to reference Farrow EG, Davis SI, Mooney SD, Beighton P, Mascarenhas L, Gutierrez YR, et al. Extended mutational analyses of FGFR1 in osteoglophonic dysplasia. Am J Med Genet A. 2006;140:537–9.CrossRefPubMed Farrow EG, Davis SI, Mooney SD, Beighton P, Mascarenhas L, Gutierrez YR, et al. Extended mutational analyses of FGFR1 in osteoglophonic dysplasia. Am J Med Genet A. 2006;140:537–9.CrossRefPubMed
73.
go back to reference 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;134:233–6.CrossRefPubMed 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;134:233–6.CrossRefPubMed
74.
go back to reference Sethi SK, Hari P, Bagga A. Elevated FGF-23 and parathormone in linear nevus sebaceous syndrome with resistant rickets. Pediatr Nephrol. 2010;25:1577–8.CrossRefPubMed Sethi SK, Hari P, Bagga A. Elevated FGF-23 and parathormone in linear nevus sebaceous syndrome with resistant rickets. Pediatr Nephrol. 2010;25:1577–8.CrossRefPubMed
75.
go back to reference Lim YH, Ovejero D, Sugarman JS, Deklotz CM, Maruri A, Eichenfield LF, et al. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum Mol Genet. 2014;23:397–407.CrossRefPubMedCentralPubMed Lim YH, Ovejero D, Sugarman JS, Deklotz CM, Maruri A, Eichenfield LF, et al. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum Mol Genet. 2014;23:397–407.CrossRefPubMedCentralPubMed
77.
go back to reference Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest. 2003;112:683–92.CrossRefPubMedCentralPubMed Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest. 2003;112:683–92.CrossRefPubMedCentralPubMed
78.
go back to reference Konishi K, Nakamura M, Yamakawa H, Suzuki H, Saruta T, Hanaoka H, et al. Hypophosphatemic osteomalacia in von Recklinghausen neurofibromatosis. Am J Med Sci. 1991;301:322–8.CrossRefPubMed Konishi K, Nakamura M, Yamakawa H, Suzuki H, Saruta T, Hanaoka H, et al. Hypophosphatemic osteomalacia in von Recklinghausen neurofibromatosis. Am J Med Sci. 1991;301:322–8.CrossRefPubMed
79.
go back to reference Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, et al. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci U S A. 2008;105:3455–60.CrossRefPubMedCentralPubMed Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, et al. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci U S A. 2008;105:3455–60.CrossRefPubMedCentralPubMed
80.
go back to reference Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, et al. Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res. 2013;28:1378–85.CrossRefPubMed Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, et al. Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res. 2013;28:1378–85.CrossRefPubMed
81.
go back to reference Wang X, Wang S, Li C, Gao T, Liu Y, Rangiani A, et al. Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice. PLoS Genet. 2012;8:e1002708.CrossRefPubMedCentralPubMed Wang X, Wang S, Li C, Gao T, Liu Y, Rangiani A, et al. Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice. PLoS Genet. 2012;8:e1002708.CrossRefPubMedCentralPubMed
82.
go back to reference Tieder M, Modai D, Samuel R, Arie R, Halabe A, Bab I, et al. Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med. 1985;312:611–7.CrossRefPubMed Tieder M, Modai D, Samuel R, Arie R, Halabe A, Bab I, et al. Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med. 1985;312:611–7.CrossRefPubMed
83.
go back to reference Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, 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.CrossRefPubMedCentralPubMed Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, 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.CrossRefPubMedCentralPubMed
85.
go back to reference Bokenkamp A, Bockenhauer D, Cheong HI, Hoppe B, Tasic V, Unwin R, et al. Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr. 2009;155:94–9.CrossRefPubMed Bokenkamp A, Bockenhauer D, Cheong HI, Hoppe B, Tasic V, Unwin R, et al. Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr. 2009;155:94–9.CrossRefPubMed
Metadata
Title
Hypophosphatemic Rickets: Lessons from Disrupted FGF23 Control of Phosphorus Homeostasis
Authors
Bracha K. Goldsweig
Thomas O. Carpenter
Publication date
01-04-2015
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 2/2015
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-015-0259-y

Other articles of this Issue 2/2015

Current Osteoporosis Reports 2/2015 Go to the issue

Kidney and Bone (SM Moe and IB Salusky, Section Editors)

Defective Skeletal Mineralization in Pediatric CKD

Osteoporosis and Cancer (P Clezardin and G van der Pluijm, Section Editors)

Antiresorptive Therapy in the Management of Cancer Treatment-Induced Bone Loss

Bone and Diabetes (AV Schwartz and P Vestergaard, Section Editors)

Diabetes, Diabetic Complications, and Fracture Risk

Skeletal Development (E Schanipani and E Zelzer, Section Editors)

The Immunological Contribution to Heterotopic Ossification Disorders

Osteocytes (T Bellido and J Klein-Nulend, Section Editors)

Cx43 and Mechanotransduction in Bone

Rare Bone Disease (CB Langman and E Shore, Section Editors)

Hyperphosphatemic Familial Tumoral Calcinosis: Genetic Models of Deficient FGF23 Action