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Rickets

Abstract

Rickets is a bone disease associated with abnormal serum calcium and phosphate levels. The clinical presentation is heterogeneous and depends on the age of onset and pathogenesis but includes bowing deformities of the legs, short stature and widening of joints. The disorder can be caused by nutritional deficiencies or genetic defects. Mutations in genes encoding proteins involved in vitamin D metabolism or action, fibroblast growth factor 23 (FGF23) production or degradation, renal phosphate handling or bone mineralization have been identified. The prevalence of nutritional rickets has substantially declined compared with the prevalence 200 years ago, but the condition has been re-emerging even in some well-resourced countries; prematurely born infants or breastfed infants who have dark skin types are particularly at risk. Diagnosis is usually established by medical history, physical examination, biochemical tests and radiography. Prevention is possible only for nutritional rickets and includes supplementation or food fortification with calcium and vitamin D either alone or in combination with sunlight exposure. Treatment of typical nutritional rickets includes calcium and/or vitamin D supplementation, although instances infrequently occur in which phosphate repletion may be necessary. Management of heritable types of rickets associated with defects in vitamin D metabolism or activation involves the administration of vitamin D metabolites. Oral phosphate supplementation is usually indicated for FGF23-independent phosphopenic rickets, whereas the conventional treatment of FGF23-dependent types of rickets includes a combination of phosphate and activated vitamin D; an anti-FGF23 antibody has shown promising results and is under further study.

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Figure 1: Morphology of the growth plate in rickets.
Figure 2: Histological characteristics of osteomalacia.
Figure 3: Regulation of calcium and phosphate homeostasis.
Figure 4: Regulation of renal phosphate transport and vitamin D metabolism by FGF23.
Figure 5: The pathogenesis of rickets associated with nutritional vitamin D or dietary calcium deficiency.
Figure 6: FGF23: tissue sources and mechanisms of regulation.
Figure 7: Clinical manifestations of rickets.
Figure 8: Radiographic characteristics of rickets.
Figure 9: Radiograph of metaphyseal chondrodysplasia.

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References

  1. Shore, R. M. & Chesney, R. W. Rickets: Part I. Pediatr. Radiol. 43, 140-151 (2012).

    Google Scholar 

  2. Creo, A. L., Thacher, T. D., Pettifor, J. M., Strand, M. A. & Fischer, P. R. Nutritional rickets around the world: an update. Paediatr. Int. Child Health 37, 84–98 (2016). This paper discusses the global epidemiology of rickets, including the key risk factors for rickets in different parts of the world. The key relationship between calcium deficiency and vitamin D deficiency in the aetiology of rickets and how the relative importance of these aetiologies varies by location and age are emphasized.

    Google Scholar 

  3. Chick, H. Study of rickets in Vienna 1919–1922. Med. Hist. 20, 41–51 (1976).

    Google Scholar 

  4. O’Riordan, J. L. H. & Bijvoet, O. L. M. Rickets before the discovery of vitamin D. Bonekey Rep. 3, 478 (2014).

    Google Scholar 

  5. Thacher, T. D. et al. Increasing incidence of nutritional rickets: a population-based study in Olmsted County. Minnesota. Mayo Clin. Proc. 88, 176–183 (2013). This epidemiological study demonstrates that rickets has increased in frequency over the past 35 years and that incidences are greatest in breastfed, African-American infants and low birthweight infants.

    Google Scholar 

  6. Goldacre, M., Hall, N. & Yeates, D. G. R. Hospitalisation for children with rickets in England: a historical perspective. Lancet 383, 597–598 (2014). This paper highlights the rising rate of hospital admissions for rickets in England over the past 20 years. Although global data providing a population-based rate are limited, those that are available support the contention of an increasing prevalence of rickets in a number of countries over the past few decades.

    Google Scholar 

  7. Bener, A. & Hoffmann, G. Nutritional rickets among children in a sun rich country. Int. J. Pediatr. Endocrinol. 2010, 410502 (2010).

    Google Scholar 

  8. Uush, T. Prevalence of classic signs and symptoms of rickets and vitamin D deficiency in Mongolian children and women. J. Steroid Biochem. Mol. Biol. 136, 207–210 (2013).

    Google Scholar 

  9. Holick, M. F. Resurrection of vitamin D deficiency and rickets. J. Clin. Invest. 116, 2062–2072 (2006).

    Google Scholar 

  10. Rajakumar, K., Greenspan, S. L., Thomas, S. B. & Holick, M. F. SOLAR ultraviolet radiation and vitamin D. Am. J. Public Health 97, 1746–1754 (2007).

    Google Scholar 

  11. Ward, L. M., Gaboury, I., Ladhani, M. & Zlotkin, S. Vitamin D-deficiency rickets among children in Canada. Can. Med. Assoc. J. 177, 161–166 (2007).

    Google Scholar 

  12. Wheeler, B. J., Dickson, N. P., Houghton, L. A., Ward, L. M. & Taylor, B. J. Incidence and characteristics of vitamin D deficiency rickets in New Zealand children: a New Zealand Paediatric Surveillance Unit study. Aust. N. Z. J. Public Health 39, 380–383 (2015).

    Google Scholar 

  13. Munns, C. F. et al. Incidence of vitamin D deficiency rickets among Australian children: an Australian Paediatric Surveillance Unit study. Med. J. Aust. 196, 466–468 (2012).

    Google Scholar 

  14. Beck-Nielsen, S. S., Brock-Jacobsen, B., Gram, J., Brixen, K. & Jensen, T. K. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur. J. Endocrinol. 160, 491–497 (2008).

    Google Scholar 

  15. Munns, C. F. et al. Global consensus recommendations on prevention and management of nutritional rickets. J. Clin. Endocrinol. Metab. 101, 394–415 (2016). This paper is a consensus document drawn up by experts in the field of nutritional rickets on the prevention and management of nutritional rickets globally. Particular attention is paid to making the recommendations appropriate and relevant for poorly resourced countries.

    Google Scholar 

  16. Prentice, A. Nutritional rickets around the world. J. Steroid Biochem. Mol. Biol. 136, 201–206 (2013).

    Google Scholar 

  17. viÐ Streym, S. et al. Vitamin D content in human breast milk: a 9-mo follow-up study. Am. J. Clin. Nutr. 103, 107–114 (2016).

    Google Scholar 

  18. Callaghan, A. L., Moy, R. J. D., Booth, I. W., Debelle, G. & Shaw, N. J. Incidence of symptomatic vitamin D deficiency. Arch. Dis. Child. 91, 606–607 (2005).

    Google Scholar 

  19. Abrams, S. A. Nutritional rickets: an old disease returns. Nutr. Rev. 60, 111–115 (2002).

    Google Scholar 

  20. Mitchell, S. M. et al. High frequencies of elevated alkaline phosphatase activity and rickets exist in extremely low birth weight infants despite current nutritional support. BMC Pediatr. 9, 47 (2009).

    Google Scholar 

  21. Wagner, C. L. & Greer, F. R., American Academy of Pediatrics Section on Breastfeeding & American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 122, 1142–1152 (2008).

    Google Scholar 

  22. Kooh, S. W. et al. Rickets due to calcium deficiency. N. Engl. J. Med. 297, 1264–1266 (1977).

    Google Scholar 

  23. Dagnelie, P. C. et al. High prevalence of rickets in infants on macrobiotic diets. Am. J. Clin. Nutr. 51, 202–208 (1990).

    Google Scholar 

  24. Abrams, S. A. Calcium and vitamin D requirements of enterally fed preterm infants. Pediatrics 131, e1676–e1683 (2013).

    Google Scholar 

  25. McIntosh, N., Livesey, A. & Brooke, O. G. Plasma 25-hydroxyvitamin D and rickets in infants of extremely low birthweight. Arch. Dis. Child. 57, 848–850 (1982).

    Google Scholar 

  26. Martin, J. A., Hamilton, B. E., Osterman, M. J. K., Driscoll, A. K. & Mathews, T. J. National Vital Statistics Reports, Volume 66, Number 1 (CDC, 2017).

    Google Scholar 

  27. Holm, I. A. et al. Mutational analysis and genotype–phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets. J. Clin. Endocrinol. Metab. 86, 3889–3899 (2001).

    Google Scholar 

  28. Endo, I. et al. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. Endocr. J. 62, 811–816 (2015).

    Google Scholar 

  29. Hazzazi, M., Alzeer, I., Tamimi, W., Al Atawi, M. & Al Alwan, I. Clinical presentation and etiology of osteomalacia/rickets in adolescents. Saudi J. Kidney Dis. Transplant. 24, 938–941 (2013).

    Google Scholar 

  30. Ward, K. A. et al. A randomized, controlled trial of vitamin D supplementation upon musculoskeletal health in postmenarchal females. J. Clin. Endocrinol. Metab. 95, 4643–4651 (2010).

    Google Scholar 

  31. Agarwal, A. & Gulati, D. Early adolescent nutritional rickets. J. Orthop. Surg. (Hong Kong) 17, 340–345 (2009).

    Google Scholar 

  32. Palacios, C. & Gonzalez, L. Is vitamin D deficiency a major global public health problem? J. Steroid Biochem. Mol. Biol. 144, 138–145 (2014).

    Google Scholar 

  33. Habibesadat, S., Ali, K., Shabnam, J. M. & Arash, A. Prevalence of vitamin D deficiency and its related factors in children and adolescents living in North Khorasan, Iran. J. Pediatr. Endocrinol. Metab. 27, 431–436 (2014).

    Google Scholar 

  34. Dahifar, H., Faraji, A., Ghorbani, A. & Yassobi, S. Impact of dietary and lifestyle on vitamin D in healthy student girls aged 11–15 years. J. Med. Investig. 53, 204–208 (2006).

    Google Scholar 

  35. Wakayo, T., Belachew, T., Vatanparast, H. & Whiting, S. J. Vitamin D deficiency and its predictors in a country with thirteen months of sunshine: the case of school children in central Ethiopia. PLoS ONE 10, e0120963 (2015). This study shows that almost half of adolescents aged 11–18 years living in Ethiopia had prevalent vitamin D deficiency (25(OH)D levels of <50 nmol per litre). Vitamin D deficiency was higher in urban settings, and lack of sunlight, higher body fat, availability of television or computers at home, maternal education and low socioeconomic status were key predictors.

    Google Scholar 

  36. Bikle, D. D. Vitamin D metabolism, mechanism of action, and clinical applications. Chem. Biol. 21, 319–329 (2014).

    Google Scholar 

  37. Tenenhouse, H. S. et al. Renal Na+-phosphate cotransport in murine X-linked hypophosphatemic rickets. Molecular characterization. J. Clin. Invest. 93, 671–676 (1994).

    Google Scholar 

  38. Carpenter, T. O. in www.endotext.org (eds DeGroot, L. & Singer, F.) (MDText.com, Inc., 2014).

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

    Google Scholar 

  40. Sabbagh, Y. et al. Intestinal npt2b plays a major role in phosphate absorption and homeostasis. J. Am. Soc. Nephrol. 20, 2348–2358 (2009).

    Google Scholar 

  41. Meyer, R. A., Meyer, M. H., Gray, R. W. & Bruns, M. E. Evidence that low plasma 1,25-dihydroxyvitamin D causes intestinal malabsorption of calcium and phosphate in juvenile X-linked hypophosphatemic mice. J. Bone Miner. Res. 2, 67–82 (1987).

    Google Scholar 

  42. Fukumoto, S. et al. Pathogenesis and diagnostic criteria for rickets and osteomalacia — proposal by an expert panel supported by Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society. Endocr. J. 62, 665–671 (2015).

    Google Scholar 

  43. Sabbagh, Y., Carpenter, T. O. & Demay, M. B. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc. Natl Acad. Sci. USA 102, 9637–9642 (2005).

    Google Scholar 

  44. Carmeliet, G., Dermauw, V. & Bouillon, R. Vitamin D signaling in calcium and bone homeostasis: a delicate balance. Best Pract. Res. Clin. Endocrinol. Metab. 29, 621–631 (2015).

    Google Scholar 

  45. Oramasionwu, G. E., Thacher, T. D., Pam, S. D., Pettifor, J. M. & Abrams, S. A. Adaptation of calcium absorption during treatment of nutritional rickets in Nigerian children. Br. J. Nutr. 100, 387–392 (2008).

    Google Scholar 

  46. Thacher, T. D., Obadofin, M. O., O’Brien, K. O. & Abrams, S. A. The effect of vitamin D2 and vitamin D3 on intestinal calcium absorption in Nigerian children with rickets. J. Clin. Endocrinol. Metab. 94, 3314–3321 (2009).

    Google Scholar 

  47. Aggarwal, V. et al. Role of calcium deficiency in development of nutritional rickets in Indian children: a case control study. J. Clin. Endocrinol. Metab. 97, 3461–3466 (2012).

    Google Scholar 

  48. Pettifor, J. M. Calcium and vitamin D metabolism in children in developing countries. Ann. Nutr. Metab. 64, 15–22 (2014).

    Google Scholar 

  49. Prentice, A., Ceesay, M., Nigdikar, S., Allen, S. J. & Pettifor, J. M. FGF23 is elevated in Gambian children with rickets. Bone 42, 788–797 (2008).

    Google Scholar 

  50. Braithwaite, V., Jarjou, L. M. A., Goldberg, G. R. & Prentice, A. Iron status and fibroblast growth factor-23 in Gambian children. Bone 50, 1351–1356 (2012).

    Google Scholar 

  51. Cheng, J. B., Motola, D. L., Mangelsdorf, D. J. & Russell, D. W. De-orphanization of cytochrome P450 2R1. J. Biol. Chem. 278, 38084–38093 (2003).

    Google Scholar 

  52. Zhu, J. G., Ochalek, J. T., Kaufmann, M., Jones, G. & DeLuca, H. F. CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. Proc. Natl Acad. Sci. USA 110, 15650–15655 (2013).

    Google Scholar 

  53. Cheng, J. B., Levine, M. A., Bell, N. H., Mangelsdorf, D. J. & Russell, D. W. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc. Natl Acad. Sci. USA 101, 7711–7715 (2004).

    Google Scholar 

  54. Thacher, T. D., Fischer, P. R., Singh, R. J., Roizen, J. & Levine, M. A. CYP2R1 mutations impair generation of 25-hydroxyvitamin D and cause an atypical form of vitamin D deficiency. J. Clin. Endocrinol. Metab. 100, E1005–E1013 (2015).

    Google Scholar 

  55. Al Mutair, A. N., Nasrat, G. H. & Russell, D. W. Mutation of the CYP2R1 vitamin D 25-hydroxylase in a Saudi Arabian family with severe vitamin D deficiency. J. Clin. Endocrinol. Metab. 97, E2022–E2025 (2012).

    Google Scholar 

  56. Prader, A., Illig, R. & Heierli, E. Eine besondere form des primare vitamin-D-resistenten rachitis mit hypocalcamie und autosomal-dominanten erbgang: die hereditare pseudomangelrachitis [German]. Helv. Paediatr. Acta 16, 452–468 (1961).

    Google Scholar 

  57. Scriver, C. R. Vitamin D dependency. Pediatrics 45, 361–363 (1970).

    Google Scholar 

  58. De Braekeleer, M. & Larochelle, J. Population genetics of vitamin D-dependent rickets in northeastern Quebec. Ann. Hum. Genet. 55, 283–290 (1991).

    Google Scholar 

  59. Miller, W. L. Genetic disorders of Vitamin D biosynthesis and degradation. J. Steroid Biochem. Mol. Biol. 165, 101–108 (2017).

    Google Scholar 

  60. Alzahrani, A. S. et al. A novel G102E mutation of CYP27B1 in a large family with vitamin D-dependent rickets type 1. J. Clin. Endocrinol. Metab. 95, 4176–4183 (2010).

    Google Scholar 

  61. Wang, X. Novel gene mutations in patients with 1 -hydroxylase deficiency that confer partial enzyme activity in vitro. J. Clin. Endocrinol. Metab. 87, 2424–2430 (2002).

    Google Scholar 

  62. Brooks, M. H., Stern, P. H. & Bell, N. H. Vitamin D-dependent rickets type II. N. Engl. J. Med. 302, 810 (1980).

    Google Scholar 

  63. Marx, S. J. et al. A familial syndrome of decrease in sensitivity to 1,25-dihydroxyvitamin D. J. Clin. Endocrinol. Metab. 47, 1303–1310 (1978).

    Google Scholar 

  64. Beer, S. et al. Vitamin D resistant rickets with alopecia: a form of end organ resistance to 1,25 dihydroxy vitamin D. Clin. Endocrinol. (Oxf.) 14, 395–402 (1981).

    Google Scholar 

  65. Rosen, J. F., Fleischman, A. R., Finberg, L., Hamstra, A. & DeLuca, H. F. Rickets with alopecia: an inborn error of vitamin D metabolism. J. Pediatr. 94, 729–735 (1979).

    Google Scholar 

  66. Hochberg, Z. et al. 1,25-dihydroxyvitamin D resistance, rickets, and alopecia. Am. J. Med. 77, 805–811 (1984).

    Google Scholar 

  67. Hochberg, Z. Calcitriol-resistant rickets with alopecia. Arch. Dermatol. 121, 646–647 (1985).

    Google Scholar 

  68. Marx, S. J., Bliziotes, M. M. & Nanes, M. Analysis of the relation between alopecia and resistance to 1,25-dihydroxyvitamin D. Clin. Endocrinol. (Oxf.) 25, 373–381 (1986).

    Google Scholar 

  69. Haussler, M. R. et al. The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J. Bone Miner. Res. 13, 325–349 (1998).

    Google Scholar 

  70. Bouillon, R. et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr. Rev. 29, 726–776 (2008).

    Google Scholar 

  71. Malloy, P. J., Xu, R., Peng, L., Clark, P. A. & Feldman, D. A. Novel mutation in helix 12 of the vitamin D receptor impairs coactivator interaction and causes hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. Mol. Endocrinol. 16, 2538–2546 (2002).

    Google Scholar 

  72. Malloy, P. J., Xu, R., Cattani, A., Reyes, M. L. & Feldman, D. A. Unique insertion/substitution in helix H1 of the vitamin D receptor ligand binding domain in a patient with hereditary 1,25-dihydroxyvitamin D-resistant rickets. J. Bone Miner. Res. 19, 1018–1024 (2004).

    Google Scholar 

  73. Malloy, P. J. et al. Hereditary 1,25-dihydroxyvitamin D resistant rickets due to a mutation causing multiple defects in vitamin D receptor function. Endocrinology 145, 5106–5114 (2004).

    Google Scholar 

  74. Hsieh, J.-C. et al. Analysis of hairless corepressor mutants to characterize molecular cooperation with the vitamin D receptor in promoting the mammalian hair cycle. J. Cell. Biochem. 110, 671–686 (2010).

    Google Scholar 

  75. Cianferotti, L., Cox, M., Skorija, K. & Demay, M. B. Vitamin D receptor is essential for normal keratinocyte stem cell function. Proc. Natl Acad. Sci. USA 104, 9428–9433 (2007).

    Google Scholar 

  76. Teichert, A., Elalieh, H. & Bikle, D. Disruption of the hedgehog signaling pathway contributes to the hair follicle cycling deficiency in Vdr knockout mice. J. Cell. Physiol. 225, 482–489 (2010).

    Google Scholar 

  77. Bikle, D. D. Vitamin D and the skin. J. Bone Miner. Metab. 28, 117–130 (2010).

    Google Scholar 

  78. Chen, H., Hewison, M. & Adams, J. S. Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein. J. Biol. Chem. 281, 39114–39120 (2006).

    Google Scholar 

  79. Baylink, D., Wergedal, J. & Stauffer, M. Formation, mineralization, and resorption of bone in hypophosphatemic rats. J. Clin. Invest. 50, 2519–2530 (1971).

    Google Scholar 

  80. Schanler, R. J., Abrams, S. A. & Garza, C. Bioavailability of calcium and phosphorus in human milk fortifiers and formula for very low birth weight infants. J. Pediatr. 113, 95–100 (1988).

    Google Scholar 

  81. Abrams, S. A. In utero physiology: role in nutrient delivery and fetal development for calcium, phosphorus, and vitamin D. Am. J. Clin. Nutr. 85, 604S–607S (2007).

    Google Scholar 

  82. Gonzalez Ballesteros, L. F. et al. Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children. Bone 97, 287–292 (2017).

    Google Scholar 

  83. Insogna, K. L., Bordley, D. R., Caro, J. F. & Lockwood, D. H. Osteomalacia and weakness from excessive antacid ingestion. JAMA 244, 2544–2546 (1980).

    Google Scholar 

  84. Kagitani, K. et al. Hypophosphatemic rickets accompanying congenital microvillous atrophy. J. Bone Miner. Res. 13, 1946–1952 (1998).

    Google Scholar 

  85. Bonewald, L. F. & Wacker, M. J. FGF23 production by osteocytes. Pediatr. Nephrol. 28, 563–568 (2012).

    Google Scholar 

  86. Wolf, M. & White, K. E. Coupling fibroblast growth factor 23 production and cleavage. Curr. Opin. Nephrol. Hypertens. 23, 411–419 (2014).

    Google Scholar 

  87. White, K. E. et al. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. 60, 2079–2086 (2001).

    Google Scholar 

  88. Tagliabracci, V. S. et al. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc. Natl Acad. Sci. USA 111, 5520–5525 (2014).

    Google Scholar 

  89. Rafaelsen, S. H. et al. Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J. Bone Miner. Res. 28, 1378–1385 (2013).

    Google Scholar 

  90. Takeyari, S. et al. Hypophosphatemic osteomalacia and bone sclerosis caused by a novel homozygous mutation of the FAM20C gene in an elderly man with a mild variant of Raine syndrome. Bone 67, 56–62 (2014).

    Google Scholar 

  91. 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).

    Google Scholar 

  92. Smith, R. C. et al. Circulating αKlotho influences phosphate handling by controlling FGF23 production. J. Clin. Invest. 122, 4710–4715 (2012).

    Google Scholar 

  93. Brownstein, C. A. et al. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc. Natl Acad. Sci. USA 105, 3455–3460 (2008).

    Google Scholar 

  94. Lee, J.-C. et al. Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. Mod. Pathol. 29, 1335–1346 (2016).

    Google Scholar 

  95. White, K. E. et al. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am. J. Hum. Genet. 76, 361–367 (2005).

    Google Scholar 

  96. Lim, Y. H., Ovejero, D., Derrick, K. M., Collins, M. T. & Choate, K. A. Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy. J. Am. Acad. Dermatol. 75, 420–427 (2016).

    Google Scholar 

  97. Lim, Y. H. et al. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum. Mol. Genet. 23, 397–407 (2014).

    Google Scholar 

  98. Shimizu, Y. et al. Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: another form of FGF23-related hypophosphatemia. Bone 45, 814–816 (2009).

    Google Scholar 

  99. 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).

    Google Scholar 

  100. 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).

    Google Scholar 

  101. Schlingmann, K. P. et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N. Engl. J. Med. 365, 410–421 (2011).

    Google Scholar 

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

    Google Scholar 

  103. 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).

    Google Scholar 

  104. 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).

    Google Scholar 

  105. Karim, Z. et al. NHERF1 mutations and responsiveness of renal parathyroid hormone. N. Engl. J. Med. 359, 1128–1135 (2008).

    Google Scholar 

  106. Courbebaisse, M. et al. A new human NHERF1 mutation decreases renal phosphate transporter NPT2a expression by a PTH-independent mechanism. PLoS ONE 7, e34764 (2012).

    Google Scholar 

  107. Sneddon, W. B. et al. Convergent signaling pathways regulate parathyroid hormone and fibroblast growth factor-23 action on NPT2A-mediated phosphate transport. J. Biol. Chem. 291, 18632–18642 (2016).

    Google Scholar 

  108. Bai, X. et al. Partial rescue of the Hyp phenotype by osteoblast-targeted PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) expression. Mol. Endocrinol. 16, 2913–2925 (2002).

    Google Scholar 

  109. Liu, S., Guo, R., Tu, Q. & Quarles, L. D. Overexpression of Phex in osteoblasts fails to rescue the Hyp mouse phenotype. J. Biol. Chem. 277, 3686–3697 (2001).

    Google Scholar 

  110. Boskey, A. et al. The PHEX transgene corrects mineralization defects in 9-month-old hypophosphatemic mice. Calcif. Tissue Int. 84, 126–137 (2008).

    Google Scholar 

  111. Marie, P. J., Travers, R. & Glorieux, F. H. Bone response to phosphate and vitamin D metabolites in the hypophosphatemic male mouse. Calcif. Tissue Int. 34, 158–164 (1982).

    Google Scholar 

  112. Marie, P. J. & Glorieux, F. H. Stimulation of cortical bone mineralization and remodeling by phosphate and 1,25-dihydroxyvitamin D in vitamin D-resistant rickets. Metab. Bone Dis. Relat. Res. 3, 159–164 (1981).

    Google Scholar 

  113. Kaludjerovic, J. et al. Klotho expression in long bones regulates FGF23 production during renal failure. FASEB J. 31, 2050–2064 (2017).

    Google Scholar 

  114. Murali, S. K., Andrukhova, O., Clinkenbeard, E. L., White, K. E. & Erben, R. G. Excessive osteocytic Fgf23 secretion contributes to pyrophosphate accumulation and mineralization defect in Hyp mice. PLoS Biol. 14, e1002427 (2016).

    Google Scholar 

  115. Addison, W. N., Nakano, Y., Loisel, T., Crine, P. & McKee, M. D. MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J. Bone Miner. Res. 23, 1638–1649 (2008).

    Google Scholar 

  116. Martin, A. 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 149, 1757–1772 (2008).

    Google Scholar 

  117. Thacher, T. D. in Vitamin D and Rickets Vol. 6 (ed Hochberg, Z. ) 105–125 (Karger, 2003).

    Google Scholar 

  118. Basatemur, E. & Sutcliffe, A. Incidence of hypocalcemic seizures due to vitamin D deficiency in children in the United Kingdom and Ireland. J. Clin. Endocrinol. Metab. 100, E91–E95 (2015).

    Google Scholar 

  119. Maiya, S. et al. Hypocalcaemia and vitamin D deficiency: an important, but preventable, cause of life-threatening infant heart failure. Heart 94, 581–584 (2008).

    Google Scholar 

  120. Steichen-Gersdorf, E., Lorenz-Depiereux, B., Strom, T. M. & Shaw, N. J. Early onset hearing loss in autosomal recessive hypophosphatemic rickets caused by loss of function mutation in ENPP1. J. Pediatr. Endocrinol. Metab. 28, 967–970 (2015).

    Google Scholar 

  121. Liang, G., Katz, L. D., Insogna, K. L., Carpenter, T. O. & Macica, C. M. Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice. Calcif. Tissue Int. 85, 235–246 (2009).

    Google Scholar 

  122. Nordblad, M., Graham, F., Mughal, M. Z. & Padidela, R. Rapid assessment of dietary calcium intake. Arch. Dis. Child. 101, 634–636 (2015).

    Google Scholar 

  123. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D (The National Academies Press, 2011).

  124. Holick, M. F. et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 96, 1911–1930 (2011).

    Google Scholar 

  125. Public Health England. SACN vitamin D and health report. GOV.UKhttps://www.gov.uk/government/publications/sacn-vitamin-d-and-health-report (2016).

  126. Wang, T. J. et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376, 180–188 (2010).

    Google Scholar 

  127. Walton, R. J. & Bijvoet, O. L. M. Nomogram for derivation of renal threshold phosphate concentration. Lancet 306, 309–310 (1975).

    Google Scholar 

  128. 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).

    Google Scholar 

  129. Marie, P. J. & Glorieux, F. H. Relation between hypomineralized periosteocytic lesions and bone mineralization in vitamin D-resistant rickets. Calcif. Tissue Int. 35, 443–448 (1983).

    Google Scholar 

  130. Stickler, G. B. et al. Familial bone disease resembling rickets (hereditary metaphysial dysostosis). Pediatrics 29, 996–1004 (1962).

    Google Scholar 

  131. Jüppner, H. Jansen's metaphyseal chondrodysplasia. Trends Endocrinol. Metab. 7, 157–162 (1996).

    Google Scholar 

  132. Kaur, S. & Kulkarni, K. Osteopetrorickets: a twin paradox. BMJ Case Rep. http://dx.doi.org/10.1136/bcr.06.2009.2012 (2010).

  133. Whyte, M. P. Hypophosphatasia: enzyme replacement therapy brings new opportunities and new challenges. J. Bone Miner. Res. 32, 667–675 (2017).

    Google Scholar 

  134. Whyte, M. P. et al. Asfotase alfa treatment improves survival for perinatal and infantile hypophosphatasia. J. Clin. Endocrinol. Metab. 101, 334–342 (2016).

    Google Scholar 

  135. Ekbote, V. H. et al. A pilot randomized controlled trial of oral calcium and vitamin D supplementation using fortified laddoos in underprivileged Indian toddlers. Eur. J. Clin. Nutr. 65, 440–446 (2011).

    Google Scholar 

  136. Thacher, T. D., Bommersbach, T. J., Pettifor, J. M., Isichei, C. O. & Fischer, P. R. Comparison of limestone and ground fish for treatment of nutritional rickets in children in Nigeria. J. Pediatr. 167, 148–154.e1 (2015).

    Google Scholar 

  137. Gallo, S. et al. Effect of different dosages of oral vitamin D supplementation on vitamin D status in healthy, breastfed infants. JAMA 309, 1785–1792 (2013). This paper is a randomized controlled clinical trial assessing four different doses of vitamin D given to healthy breastfed infants in the first year of life and demonstrates that 400 IU daily will achieve a 25(OH)D concentration of >50 nmol per litre.

    Google Scholar 

  138. Hatun, S., Ozkan, B. & Bereket, A. Vitamin D deficiency and prevention: Turkish experience. Acta Paediatr. 100, 1195–1199 (2011). This paper reports the impact of a nationwide vitamin D supplementation programme in reducing the incidence of nutritional rickets in a region of Turkey.

    Google Scholar 

  139. Moy, R. J., McGee, E., Debelle, G. D., Mather, I. & Shaw, N. J. Successful public health action to reduce the incidence of symptomatic vitamin D deficiency. Arch. Dis. Child. 97, 952–954 (2012).

    Google Scholar 

  140. Umaretiya, P. J. et al. Maternal preferences for vitamin D supplementation in breastfed infants. Ann. Fam. Med. 15, 68–70 (2017).

    Google Scholar 

  141. Fatani, T. et al. Differential low uptake of free vitamin D supplements in preterm infants: the Quebec experience. BMC Pediatr. 14, 291 (2014).

    Google Scholar 

  142. Huynh, J. et al. Vitamin D in newborns. A randomised controlled trial comparing daily and single oral bolus vitamin D in infants. J. Paediatr. Child Health 53, 163–169 (2017).

    Google Scholar 

  143. Hollis, B. W. et al. Maternal versus infant vitamin D supplementation during lactation: a randomized controlled trial. Pediatrics 136, 625–634 (2015).

    Google Scholar 

  144. Black, L. J., Seamans, K. M., Cashman, K. D. & Kiely, M. An updated systematic review and meta-analysis of the efficacy of vitamin D food fortification. J. Nutr. 142, 1102–1108 (2012).

    Google Scholar 

  145. Khadgawat, R. et al. Impact of vitamin D fortified milk supplementation on vitamin D status of healthy school children aged 10–14 years. Osteoporos. Int. 24, 2335–2343 (2013).

    Google Scholar 

  146. Tylavsky, F. A., Cheng, S., Lyytikäinen, A., Viljakainen, H. & Lamberg-Allardt, C. Strategies to improve vitamin D status in northern European children: exploring the merits of vitamin D fortification and supplementation. J. Nutr. 136, 1130–1134 (2006).

    Google Scholar 

  147. Allen, R. E., Dangour, A. D., Tedstone, A. E. & Chalabi, Z. Does fortification of staple foods improve vitamin D intakes and status of groups at risk of deficiency? A United Kingdom modeling study. Am. J. Clin. Nutr. 102, 338–344 (2015).

    Google Scholar 

  148. Saraff, V. & Shaw, N. Sunshine and vitamin D. Arch. Dis. Child. 101, 190–192 (2015).

    Google Scholar 

  149. Specker, B. L., Valanis, B., Hertzberg, V., Edwards, N. & Tsang, R. C. Sunshine exposure and serum 25-hydroxyvitamin D concentrations in exclusively breast-fed infants. J. Pediatr. 107, 372–376 (1985).

    Google Scholar 

  150. Meena, P. et al. Sunlight exposure and vitamin D status in breastfed infants. Indian Pediatr. 54, 105–111 (2016).

    Google Scholar 

  151. Farrar, M. D. et al. Recommended summer sunlight exposure amounts fail to produce sufficient vitamin D status in UK adults of South Asian origin. Am. J. Clin. Nutr. 94, 1219–1224 (2011).

    Google Scholar 

  152. Farrar, M. D. et al. Efficacy of a dose range of simulated sunlight exposures in raising vitamin D status in South Asian adults: implications for targeted guidance on sun exposure. Am. J. Clin. Nutr. 97, 1210–1216 (2013).

    Google Scholar 

  153. Thacher, T. D. et al. Optimal dose of calcium for treatment of nutritional rickets: a randomized controlled trial. J. Bone Miner. Res. 31, 2024–2031 (2016).

    Google Scholar 

  154. Tripkovic, L. et al. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am. J. Clin. Nutr. 95, 1357–1364 (2012).

    Google Scholar 

  155. Cesur, Y., Çaksen, H., Gündem, A., Kirimi, E. & Odabas¸, D. Comparison of low and high dose of vitamin D treatment in nutritional vitamin D deficiency rickets. J. Pediatr. Endocrinol. Metab. 16, 1105–1109 (2003).

    Google Scholar 

  156. Mittal, H. et al. 300,000 IU or 600,000 IU of oral vitamin D3 for treatment of nutritional rickets: a randomized controlled trial. Indian Pediatr. 51, 265–272 (2014).

    Google Scholar 

  157. Pearce, S. H. & Cheetham, T. D. Diagnosis and management of vitamin D deficiency. BMJ 340, b5664 (2010).

    Google Scholar 

  158. Dong, Q. & Miller, W. L. Vitamin D 25-hydroxylase deficiency. Mol. Genet. Metab. 83, 197–198 (2004).

    Google Scholar 

  159. Casella, S. J., Reiner, B. J., Chen, T. C., Holick, M. F. & Harrison, H. E. A possible genetic defect in 25-hydroxylation as a cause of rickets. J. Pediatr. 124, 929–932 (1994).

    Google Scholar 

  160. Glorieux, F. H. & Pettifor, J. M. Vitamin D/dietary calcium deficiency rickets and pseudo-vitamin D deficiency rickets. Bonekey Rep. 3, 524 (2014).

    Google Scholar 

  161. Reade, T. M. et al. Response to crystalline 1α-hydroxyvitamin D3 in vitamin D dependency. Pediatr. Res. 9, 593–599 (1975).

    Google Scholar 

  162. Delvin, E. E., Glorieux, F. H., Marie, P. J. & Pettifor, J. M. Vitamin D dependency: replacement therapy with calcitriol. J. Pediatr. 99, 26–34 (1981).

    Google Scholar 

  163. Wang, J. T. et al. Genetics of vitamin D 1α-hydroxylase deficiency in 17 families. Am. J. Hum. Genet. 63, 1694–1702 (1998).

    Google Scholar 

  164. Edouard, T. et al. Short- and long-term outcome of patients with pseudo-vitamin D deficiency rickets treated with calcitriol. J. Clin. Endocrinol. Metab. 96, 82–89 (2011). This paper details the long-term clinical and biochemical response to treatment of 1α-hydroxylase deficiency with 1,25(OH)2D.

    Google Scholar 

  165. Chaturvedi, D., Garabedian, M., Carel, J.-C. & Léger, J. Different mechanisms of intestinal calcium absorption at different life stages: therapeutic implications and long-term responses to treatment in patients with hereditary vitamin D-resistant rickets. Horm. Res. Paediatr. 78, 326–331 (2012).

    Google Scholar 

  166. Balsan, S. et al. Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D. J. Clin. Invest. 77, 1661–1667 (1986).

    Google Scholar 

  167. Hochberg, Z., Tiosano, D. & Even, L. Calcium therapy for calcitriol-resistant rickets. J. Pediatr. 121, 803–808 (1992).

    Google Scholar 

  168. Yagi, H. et al. A new point mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor in a kindred with hereditary 1,25-dihydroxyvitamin D-resistant rickets. J. Clin. Endocrinol. Metab. 76, 509–512 (1993).

    Google Scholar 

  169. Ma, N. S. et al. Hereditary vitamin D resistant rickets: identification of a novel splice site mutation in the vitamin D receptor gene and successful treatment with oral calcium therapy. Bone 45, 743–746 (2009).

    Google Scholar 

  170. Kanakamani, J., Tomar, N., Kaushal, E., Tandon, N. & Goswami, R. Presence of a deletion mutation (c.716delA) in the ligand binding domain of the vitamin D receptor in an Indian patient with vitamin D-dependent rickets type II. Calcif. Tissue Int. 86, 33–41 (2009).

    Google Scholar 

  171. Tamura, M. et al. Detection of hereditary 1,25-hydroxyvitamin D-resistant rickets caused by uniparental disomy of chromosome 12 using genome-wide single nucleotide polymorphism array. PLoS ONE 10, e0131157 (2015).

    Google Scholar 

  172. Kinoshita, Y., Ito, N., Makita, N., Nangaku, M. & Fukumoto, S. Changes in bone metabolic parameters following oral calcium supplementation in an adult patient with vitamin D-dependent rickets type 2A. Endocr. J. 64, 589–596 (2017).

    Google Scholar 

  173. Carpenter, T. O., Imel, E. A., Holm, I. A., Jan de Beur, S. M. & Insogna, K. L. A clinician's guide to X-linked hypophosphatemia. J. Bone Miner. Res. 26, 1381–1388 (2011). This paper written by adult and paediatric clinicians provides the rationale and details of current treatment approaches for XLH.

    Google Scholar 

  174. Alon, U. S. et al. Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin. J. Am. Soc. Nephrol. 3, 658–664 (2008).

    Google Scholar 

  175. Carpenter, T. O. et al. Effect of paricalcitol on circulating parathyroid hormone in X-linked hypophosphatemia: a randomized, double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 99, 3103–3111 (2014).

    Google Scholar 

  176. Sharkey, M. S., Grunseich, K. & Carpenter, T. O. Contemporary medical and surgical management of X-linked hypophosphatemic rickets. J. Am. Acad. Orthop. Surg. 23, 433–442 (2015).

    Google Scholar 

  177. Novais, E. & Stevens, P. M. Hypophosphatemic rickets. J. Pediatr. Orthop. 26, 238–244 (2006).

    Google Scholar 

  178. Chaussain-Miller, C. et al. Dental abnormalities in patients with familial hypophosphatemic vitamin D-resistant rickets: prevention by early treatment with 1-hydroxyvitamin D. J. Pediatr. 142, 324–331 (2003).

    Google Scholar 

  179. Connor, J. et al. Conventional therapy in adults with X-linked hypophosphatemia: effects on enthesopathy and dental disease. J. Clin. Endocrinol. Metab. 100, 3625–3632 (2015).

    Google Scholar 

  180. Carpenter, T. O. et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J. Clin. Invest. 124, 1587–1597 (2014).

    Google Scholar 

  181. Imel, E. A. et al. Prolonged correction of serum phosphorus in adults with X-linked hypophosphatemia using monthly doses of KRN23. J. Clin. Endocrinol. Metab. 100, 2565–2573 (2015). This paper details the long-term biochemical response to anti-FGF23 antibody therapy in XLH.

    Google Scholar 

  182. Carpenter, T. O. et al. Randomized, open-label, dose-finding, phase 2 study of KRN23, a human monoclonal anti-FGF23 antibody, in children with X-linked hypophosphatemia (XLH). Presented at Endocrine Society's 98th Annual Meeting and Expo (2016).

  183. Insogna, K. A phase 3 randomized, 24 week, double-blind, placebo-controlled study evaluating the efficacy of burosumab, an anti-FGF23 antibody, in adults with X-linked hypophosphatemia (XLH) [abstract LB-1159]. Presented at the Annual Meeting of the American Society of Bone and Mineral Research (2017).

  184. Econs, M. J. et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat. Genet. 26, 345–348 (2000).

    Google Scholar 

  185. Imel, E. A. et al. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J. Clin. Endocrinol. Metab. 96, 3541–3549 (2011).

    Google Scholar 

  186. Carpenter, T. O. Effects of KRN23, an anti-FGF23 antibody, in patients with tumor induced osteomalacia and epidermal nevus syndrome: results from an ongoing phase 2 study. Presented at the Annual Meeting of the American Society of Bone and Mineral Research (2016).

  187. Reid, I. R. et al. X-Linked hypophosphatemia. Medicine (Baltimore) 68, 336–352 (1989).

    Google Scholar 

  188. Che, H. et al. Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms. Eur. J. Endocrinol. 174, 325–333 (2016). This paper highlights the extent and predictors of impaired QOL in adults with XLH. The presence of enthesopathy was a key determinant of reduced QOL, whereas treatment with phosphate supplements and/or vitamin D was linked to a better mental health score.

    Google Scholar 

  189. Ruppe, M. D. et al. Effect of four monthly doses of a human monoclonal anti-FGF23 antibody (KRN23) on quality of life in X-linked hypophosphatemia. Bone Rep. 5, 158–162 (2016).

    Google Scholar 

  190. Mäkitie, O. et al. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J. Clin. Endocrinol. Metab. 88, 3591–3597 (2003).

    Google Scholar 

  191. Wöhrle, S. et al. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J. Bone Miner. Res. 28, 899–911 (2013).

    Google Scholar 

  192. Yuan, B. et al. Hexa-D-arginine treatment increases 7B2•PC2 activity in hyp-mouse osteoblasts and rescues the HYP phenotype. J. Bone Miner. Res. 28, 56–72 (2012).

    Google Scholar 

  193. Goetz, R. et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc. Natl Acad. Sci. USA 107, 407–412 (2010).

    Google Scholar 

  194. Miedlich, S. U., Zhu, E. D., Sabbagh, Y. & Demay, M. B. The receptor-dependent actions of 1,25-dihydroxyvitamin D are required for normal growth plate maturation in NPt2a knockout mice. Endocrinology 151, 4607–4612 (2010).

    Google Scholar 

  195. Liu, E. S. et al. c-Raf promotes angiogenesis during normal growth plate maturation. Development 143, 348–355 (2016).

    Google Scholar 

  196. Gattineni, J. et al. Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am. J. Physiol. Renal Physiol. 306, F351–F358 (2013).

    Google Scholar 

  197. Shimada, T. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J. Bone Miner. Res. 19, 429–435 (2003).

    Google Scholar 

  198. Andrukhova, O. et al. FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2–SGK1 signaling pathway. Bone 51, 621–628 (2012).

    Google Scholar 

  199. Imel, E. A., DiMeglio, L. A., Hui, S. L., Carpenter, T. O. & Econs, M. J. Treatment of X-linked hypophosphatemia with calcitriol and phosphate increases circulating fibroblast growth factor 23 concentrations. J. Clin. Endocrinol. Metab. 95, 1846–1850 (2010).

    Google Scholar 

  200. Clinkenbeard, E. L. et al. Neonatal iron deficiency causes abnormal phosphate metabolism by elevating FGF23 in normal and ADHR mice. J. Bone Miner. Res. 29, 361–369 (2014).

    Google Scholar 

  201. Schouten, B. J., Hunt, P. J., Livesey, J. H., Frampton, C. M. & Soule, S. G. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study. J. Clin. Endocrinol. Metab. 94, 2332–2337 (2009).

    Google Scholar 

  202. Wolf, M., Koch, T. A. & Bregman, D. B. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J. Bone Miner. Res. 28, 1793–1803 (2013).

    Google Scholar 

  203. Martin, A., David, V. & Quarles, L. D. Regulation and function of the FGF23/Klotho endocrine pathways. Physiol. Rev. 92, 131–155 (2012).

    Google Scholar 

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Introduction (T.O.C. and J.M.P.); Epidemiology (L.M.W. and S.A.A.); Mechanisms/pathophysiology (T.O.C., J.M.P., A.A.P. and S.A.A.); Diagnosis, screening and prevention (N.J.S.); Management (T.O.C. and J.M.P.); Quality of life (L.M.W.); Outlook (A.A.P.); Overview of Primer (T.O.C. and J.M.P.).

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Correspondence to Thomas O. Carpenter or John M. Pettifor.

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Competing interests

T.O.C. is a consultant for and is participating in clinical trials of burosumab with Ultragenyx Pharmaceutical and has served as a consultant for Alexion. A.A.P. has received honoraria from and is participating in a clinical trial of burosumab with Ultragenyx Pharmaceutical. L.M.W. has received honoraria from and is participating in a clinical trial of burosumab with Ultragenyx Pharmaceutical and has been a consultant to Alexion. J.M.P. is a consultant for Biomedical Systems Corporation. N.J.S. and S.A.A. declare no competing interests.

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Carpenter, T., Shaw, N., Portale, A. et al. Rickets. Nat Rev Dis Primers 3, 17101 (2017). https://doi.org/10.1038/nrdp.2017.101

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