Abstract
Hypophosphatemic rickets (HR) is a syndrome of hypophosphatemia and rickets that resembles vitamin D deficiency, which is caused by malfunction of renal tubules in phosphate reabsorption. Phosphate is an essential mineral, which is important for bone and tooth structure. It is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast-growth-factor 23 (FGF23). X-linked hypophosphatemia (XLH), autosomal dominant HR (ADHR), and autosomal recessive HR (ARHR) are examples of hereditary forms of HR, which are mainly caused by mutations in the phosphate regulating endopeptidase homolog, X-linked (PHEX), FGF23, and, dentin matrix protein-1 (DMP1) and ecto-nucleotide pyro phosphatase/phosphodiesterase 1 (ENPP1) genes, respectively. Mutations in these genes are believed to cause elevation of circulating FGF23 protein. Increase in FGF23 disrupts phosphate homeostasis, leading to HR. This review aims to summarize phosphate homeostasis and focuses on the genes and mutations related to XLH, ADHR, and ARHR. A compilation of XLH mutation hotspots based on the PHEX gene database and mutations found in the FGF23, DMP1, and ENPP1 genes are also made available in this review.
Acknowledgments
We would like to thank Associate Professor Dr. Cheah Yoke Kqueen for serving as a peer-reviewer for this manuscript before submission. This work is funded by the Fundamental Research Grant Scheme (Grant No. 04-02-13-1327FR) and the MyBrain fellowship by the Ministry of Education, Malaysia.
Declaration of interest: The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.
Funding: This work was supported by the Fundamental Research Grant Scheme (Grant No. 04-02-13-1327FR) funded by the Ministry of Education, Malaysia.
References
1. Wharton B, Bishop N. Rickets. Lancet 2003;362:1389–400.10.1016/S0140-6736(03)14636-3Search in Google Scholar
2. Bhadada SK, Bhansali A, Upreti V, Dutta P, Santosh R, et al. Hypophosphataemic rickets/osteomalacia: a descriptive analysis. Indian J Med Res 2010;131:399–404.Search in Google Scholar
3. Roth KS, Kemp S. Hypophosphatemic Rickets. Medscape; Dec 3, 2014. Available from: http://emedicine.medscape.com/article/922305-overview.Search in Google Scholar
4. McBride A, Edwards M, Monsell F, Gargan M. Vitamin D-resistant rickets (X-linked hypophosphataemic rickets). Curr Orthop 2007;21:396–9.10.1016/j.cuor.2007.09.004Search in Google Scholar
5. Tiosano D, Hochberg Z. Hypophosphatemia: the common denominator of all rickets. J Bone Miner Metab 2009;27:392–401.10.1007/s00774-009-0079-1Search in Google Scholar
6. Penido MGMG, Alon US. Phosphate homeostasis and its role in bone health. Pediatr Nephrol 2012;27:2039–48.10.1007/s00467-012-2175-zSearch in Google Scholar
7. Jagtap VS, Sarathi V, Lila AR, Bandgar T, Menon P, et al. Hypophosphatemic rickets. Indian J Endocrinol Metab 2012;16:177–82.10.4103/2230-8210.93733Search in Google Scholar
8. Douyere D, Joseph C, Gaucher C, Chaussain C, Courson F. Familial hypophosphatemic vitamin D-resistant rickets–prevention of spontaneous dental abscesses on primary teeth: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:525–30.10.1016/j.tripleo.2008.12.003Search in Google Scholar
9. Pettifor JM. What’s new in hypophosphataemic rickets? Eur J Pediatr 2008;167:493–9.10.1007/s00431-007-0662-1Search in Google Scholar
10. Ruppe MD, Brosnan PG, Au KS, Tran PX, Barbara W. Mutation Analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets. 2012;74:312–8.10.1111/j.1365-2265.2010.03919.xSearch in Google Scholar
11. Kang Q, Xu J, Zhang Z, He J, Lu L, et al. Three novel mutations of the PHEX gene in three Chinese families with X-linked dominant hypophosphatemic rickets. Biochem Biophys Res Commun 2012;81:415–20.10.1016/j.bbrc.2012.06.042Search in Google Scholar
12. 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;127:395–402.10.1016/S0022-3476(95)70070-6Search in Google Scholar
13. Seton M, Jüppner H. Autosomal dominant hypophosphatemic rickets in an 85 year old woman: characterization of her disease from infancy through adulthood. Bone 2013;52:640–3.10.1016/j.bone.2012.11.012Search in Google Scholar PubMed PubMed Central
14. Masi L, Carbonella Sala S, Gozzini A, Pela I, Luzi E, et al. A novel mutation of PHEX causes a dominant X-linked hypophosphatemic rickets. Bone 2007;40.10.1016/j.bone.2007.04.082Search in Google Scholar
15. Jonsson K, Zahradnik R, Larsson T, White KE, Sugimoto T, et al. Fibroblast Growth Factor 23 in Oncogenic Osteomalacia and X-Linked Hypophosphatemia. N Engl J Med 2003;348:1656–63.10.1056/NEJMoa020881Search in Google Scholar PubMed
16. Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, et al. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest 2003;112:785–94.10.1172/JCI18563Search in Google Scholar PubMed PubMed Central
17. Carpenter TO, Ellis BK, Insogna KL, Philbrick WM, Sterpka J, et al. FGF7 – an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. J Clin Endocrinol Metab 2005;90:1012–20.10.1210/jc.2004-0357Search in Google Scholar PubMed
18. Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics 2000;67:54–68.10.1006/geno.2000.6235Search in Google Scholar PubMed
19. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006;38:1310–5.10.1038/ng1905Search in Google Scholar PubMed PubMed Central
20. Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, et al. Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics 2012;13:134.10.1186/1471-2105-13-134Search in Google Scholar PubMed PubMed Central
21. Andrukhova O, Zeitz U, Goetz R, Mohammadi M, Lanske B, et al. FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1_2–SGK1 signaling pathway.pdf. Bone 2012;51:621–8.10.1016/j.bone.2012.05.015Search in Google Scholar PubMed PubMed Central
22. Prié D, Torres PU, Friedlander G. Latest findings in phosphate homeostasis. Kidney Int 2009;75:882–9.10.1038/ki.2008.643Search in Google Scholar PubMed
23. Goetz R, Nakada Y, Hu MC, Kurosu H, Wang L, et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci USA 2010;107:407–12.10.1073/pnas.0902006107Search in Google Scholar
24. Raina R, Garg G, Sethi SK, Schreiber MJ, Simon JF, et al. Phosphorus Metabolism. J Nephrol Therapeutic 2012; S3:008.10.4172/2161-0959.S3-008Search in Google Scholar
25. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006;281:6120–3.10.1074/jbc.C500457200Search in Google Scholar
26. Ben-dov IZ, Galitzer H, Lavi-moshayoff V, Goetz R, Kuro-o M, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007;117:4003–8.10.1172/JCI32409Search in Google Scholar
27. Wheeler DL, Barrett T, Benson D a, Bryant SH, Canese K, et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 2007;35(Database issue):D5–12.10.1093/nar/gkl1031Search in Google Scholar
28. Sabbagh Y, Jones AO, Tenenhouse HS. PHEXdb, a locus-specific database for mutations causing X-linked hypophosphatemia. Wiley Online Libr 2000;16:1–6.10.1002/1098-1004(200007)16:1<1::AID-HUMU1>3.0.CO;2-JSearch in Google Scholar
29. Durmaz E, Zou M, Al-Rijjal RA, Baitei EY, Hammami S, et al. Novel and de novo PHEX mutations in patients with hypophosphatemic rickets. Bone 2013;52:286–91.10.1016/j.bone.2012.10.012Search in Google Scholar
30. Nelson AE, Mason RS, Robinson BG. The PEX gene: not a simple answer for X-linked hypophosphataemic rickets and oncogenic osteomalacia. Mol Cell Endocrinol 1997;132:1–5.10.1016/S0303-7207(97)00111-1Search in Google Scholar
31. Fukumoto S, Yamashita T. FGF23 is a hormone-regulating phosphate metabolism–unique biological characteristics of FGF23. Bone 2007;40:1190–5.10.1016/j.bone.2006.12.062Search in Google Scholar
32. Rowe PSN. Regulation of bone–renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway. Crit Rev Eukaryot Gene Expr 2013;22:61–86.10.1615/CritRevEukarGeneExpr.v22.i1.50Search in Google Scholar
33. Song H-R, Park J-W, Cho D-Y, Yang JH, Yoon H-R, et al. PHEX gene mutations and genotype-phenotype analysis of Korean patients with hypophosphatemic rickets. J Korean Med Sci 2007;22:981.10.3346/jkms.2007.22.6.981Search in Google Scholar PubMed PubMed Central
34. Qiu Z, Travers R, Rauch F, Glorieux F, Scriver C, et al. Effect of gene dose and parental origin on bone histomorphometry in X-linked Hyp mice. Bone 2004;34:134–9.10.1016/j.bone.2003.09.004Search in Google Scholar PubMed
35. Francis F, Strom TM, Hennig S, Bo A, Lorenz B, et al. Genomic organization of the human PEX gene mutated in X-linked genomic organization of the human PEX gene mutated in X-linked dominant hypophosphatemic rickets. Genome Res 1997;7:573–85.10.1101/gr.7.6.573Search in Google Scholar PubMed
36. Morey M, Castro-Feijóo L, Barreiro J, Cabanas P, Pombo M, et al. Genetic diagnosis of X-linked dominant hypophosphatemic rickets in a cohort study: tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type. BMC Med Genet 2011;12:116.10.1186/1471-2350-12-116Search in Google Scholar PubMed PubMed Central
37. Reichardt B, Schrader M, Mojto J, Mehltretter G, Muller O-A, et al. The decrease in growth hormone (GH) Response after Repeated Stimulation with GH-releasing hormone os partly caused by an elevation of somatostatin tonus. J Clin Endocrinol Metab1996;81:1994–8.10.1210/jcem.81.5.8626871Search in Google Scholar PubMed
38. Sabbagh Y, Boileau G, DesGroseillers L, Tenenhouse HS. Disease-causing missense mutations in the PHEX gene interfere with membrane targeting of the recombinant protein. Hum Mol Genet 2001;10:1539–46.10.1093/hmg/10.15.1539Search in Google Scholar PubMed
39. Young L, Jernigan RL, Covell DG. A role for surface hydrophobicity in protein-protein recognition. Protein Sci 1994;3:717–29.10.1002/pro.5560030501Search in Google Scholar PubMed PubMed Central
40. Ichikawa S, Traxler E a, Estwick S a, Curry LR, Johnson ML, et al. Mutational survey of the PHEX gene in patients with X-linked hypophosphatemic rickets. Bone 2008;43:663–6.10.1016/j.bone.2008.06.002Search in Google Scholar PubMed PubMed Central
41. Holm IA, Nelson AE, Robinson BG, Mason RS, Marsh DJ, et al. Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 2001;86:3889–99.10.1210/jcem.86.8.7761Search in Google Scholar PubMed
42. Lo F-S, Kuo M-T, Wang C-J, Chang C-H, Lee Z-L, et al. Two novel PHEX mutations in Taiwanese patients with X-linked hypophosphatemic rickets. Nephron Physiol 2006;103:157–63.10.1159/000092916Search in Google Scholar PubMed
43. Quinlan C, Guegan K, Offiah A, Neill RO, Hiorns MP, et al. Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment. Pediatr Nephrol 2012;27:581–8.10.1007/s00467-011-2046-zSearch in Google Scholar PubMed
44. Živičnjak M, Schnabel D, Staude H, Even G, Marx M, et al. Three-year growth hormone treatment in short children with X-linked hypophosphatemic rickets: effects on linear growth and body disproportion. J Clin Endocrinol Metab 2011;96:E2097–105.10.1210/jc.2011-0399Search in Google Scholar PubMed
45. Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, et al. A clinical and molecular genetic study of hypophosphatemic rickets in children. Pediatr Res 2005;58:329–33.10.1203/01.PDR.0000169983.40758.7BSearch in Google Scholar PubMed
46. Sato K, Tajima T, Nakae J, Adachi M, Asakura Y, et al. Three novel PHEX gene mutations in Japanese patients with X-linked hypophosphatemic rickets. Pediatr Res 2000;48:536–40.10.1203/00006450-200010000-00019Search in Google Scholar PubMed
47. Kim J, Yang KH, Nam JS, Choi JR, Song J, et al. A novel PHEX mutation in a Korean patient with sporadic hypophosphatemic rickets. Ann Clin Lab Sci 2009;39:182–7.Search in Google Scholar
48. Yang L, Yang J, Huang X. PHEX gene mutation in a Chinese family with six cases of X linked hypophosphatemic rickets. J Pediatr Endocrinol Metab 2013;26:4–5.10.1515/jpem-2013-0101Search in Google Scholar PubMed
49. Dunstan CR, Zhou H, Seibel MJ. Fibroblast growth factor 23: a phosphatonin regulating phosphate homeostasis? Endocrinology 2004;145:3084–6.10.1210/en.2004-0354Search in Google Scholar PubMed
50. Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, et al. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab 2011;96:3541–9.10.1210/jc.2011-1239Search in Google Scholar PubMed PubMed Central
51. Gribaa M, Younes M, Bouyacoub Y, Korbaa W, Ben Charfeddine I, et al. An autosomal dominant hypophosphatemic rickets phenotype in a Tunisian family caused by a new FGF23 missense mutation. J Bone Miner Metab 2010;28:111–5.10.1007/s00774-009-0111-5Search in Google Scholar PubMed
52. Kinoshita Y, Saito T, Shimizu Y, Hori M, Taguchi M, et al. Mutational analysis of patients with FGF23-related hypophosphatemic rickets. Eur J Endocrinol 2012;167:165–72.10.1530/EJE-12-0071Search in Google Scholar PubMed
53. Farrow EG, Davis SI, Ward LM, Summers LJ, Bubbear JS, et al. Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets. Bone 2009;44:287–94.10.1016/j.bone.2008.10.040Search in Google Scholar PubMed PubMed Central
54. Turan S, Aydin C, Bereket A, Akcay T, Güran T, 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;46:402–9.10.1016/j.bone.2009.09.016Search in Google Scholar PubMed PubMed Central
55. Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet 2006;78:193–201.10.1086/499410Search in Google Scholar PubMed PubMed Central
56. Koshida R, Yamaguchi H, Yamasaki K, Tsuchimochi W, Yonekawa T, et al. A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets. J Bone Miner Metab 2010;28:585–90.10.1007/s00774-010-0169-0Search in Google Scholar PubMed
57. Saito T, Shimizu Y, Hori M, Taguchi M, Igarashi T, et al. A patient with hypophosphatemic rickets and ossification of posterior longitudinal ligament caused by a novel homozygous mutation in ENPP1 gene. Bone. Elsevier Inc. 2011;49:913–6.Search in Google Scholar
58. Mackenzie NCW, Zhu D, Milne EM, van ’t Hof R, Martin A, et al. Altered bone development and an increase in FGF-23 expression in Enpp1(-/-) mice. PLoS One 2012;7:e32177.10.1371/journal.pone.0032177Search in Google Scholar PubMed PubMed Central
59. Lorenz-Depiereux B, Schnabel D, Tiosano D, Häusler 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;86:267–72.10.1016/j.ajhg.2010.01.006Search in Google Scholar PubMed PubMed Central
60. Mäkitie O, Pereira RC, Kaitila I, Turan S, Bastepe M, et al. Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation. J Bone Miner Res 2010;25:2165–74.10.1002/jbmr.105Search in Google Scholar PubMed PubMed Central
61. Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet 2010;86:273–8.10.1016/j.ajhg.2010.01.010Search in Google Scholar PubMed PubMed Central
©2015 by De Gruyter
